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Clinical Trial Results:
A phase 3 randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven study in non-dialysis subjects with anemia associated with chronic kidney disease to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa

Summary
EudraCT number	2016-000542-65
Trial protocol	HU BE GB DK AT CZ DE PT SE ES NL BG GR FR PL IT
Global end of trial date	19 Apr 2021

Results information
Results version number	v2(current)
This version publication date	28 Apr 2022
First version publication date	08 Mar 2022
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

200808

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS

Public contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

02 Aug 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

19 Apr 2021

Was the trial ended prematurely?

Main objective of the trial

• To compare daprodustat to darbepoetin alfa for cardiovascular (CV) safety (non-inferiority) • To compare daprodustat to darbepoetin alfa for hemoglobin (Hgb) efficacy (non-inferiority)

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hong Kong: 29

Country: Number of subjects enrolled

India: 144

Country: Number of subjects enrolled

Korea, Republic of: 323

Country: Number of subjects enrolled

Malaysia: 71

Country: Number of subjects enrolled

Philippines: 79

Country: Number of subjects enrolled

Singapore: 18

Country: Number of subjects enrolled

Taiwan: 120

Country: Number of subjects enrolled

Thailand: 64

Country: Number of subjects enrolled

Viet Nam: 140

Country: Number of subjects enrolled

Bulgaria: 128

Country: Number of subjects enrolled

Czechia: 40

Country: Number of subjects enrolled

Estonia: 5

Country: Number of subjects enrolled

Hungary: 90

Country: Number of subjects enrolled

Poland: 51

Country: Number of subjects enrolled

Romania: 49

Country: Number of subjects enrolled

Russian Federation: 82

Country: Number of subjects enrolled

South Africa: 25

Country: Number of subjects enrolled

Turkey: 19

Country: Number of subjects enrolled

Ukraine: 198

Country: Number of subjects enrolled

Australia: 72

Country: Number of subjects enrolled

Belgium: 43

Country: Number of subjects enrolled

Canada: 29

Country: Number of subjects enrolled

Denmark: 15

Country: Number of subjects enrolled

France: 42

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Greece: 143

Country: Number of subjects enrolled

Israel: 37

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Netherlands: 6

Country: Number of subjects enrolled

New Zealand: 34

Country: Number of subjects enrolled

Portugal: 41

Country: Number of subjects enrolled

Spain: 56

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

United Kingdom: 67

Country: Number of subjects enrolled

Argentina: 146

Country: Number of subjects enrolled

Brazil: 128

Country: Number of subjects enrolled

Colombia: 37

Country: Number of subjects enrolled

Mexico: 279

Country: Number of subjects enrolled

United States: 981

Worldwide total number of subjects

3872

EEA total number of subjects

750

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1678

From 65 to 84 years

1971

85 years and over

223

Subject disposition

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Recruitment details

This was a multicenter study conducted across 39 countries. Participants were randomized to receive either daprodustat or darbepoetin alfa.

Screening details

A total of 3872 participants were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Daprodustat

Arm description

Participants received placebo tablets orally once daily in run-in period from Week-4 up to randomization (Day 1) and subsequently received treatment with daprodustat film-coated tablets at dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily up to 51.1 month. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).

Arm type

Experimental

Investigational medicinal product name

Daprodustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Daprodustat was given orally once daily at dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg).

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo was administered orally, one tablet daily.

Darbepoetin alfa

Arm description

Participants received placebo tablets orally once daily in run-in period from Week-4 up to randomization (Day 1) and subsequently received treatment with darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection at 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 100, 150, 200, 300 and 400 microgram (mcg) up to 51.1 month. Darbepoetin alfa IV injection was administered to participants undergoing hemodialysis. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo was administered orally, one tablet daily.

Investigational medicinal product name

Darbepoetin alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection, Solution for injection in pre-filled syringe

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Darbepoetin alfa was administered subcutaneously (SC) or as intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 100, 150, 200, 300 and 400 microgram (mcg).

Number of subjects in period 1	Daprodustat	Darbepoetin alfa
Started	1937	1935
Completed	1873	1870
Not completed	64	65
Consent withdrawn by subject	32	23
Unknown	1	-
Investigator Site Closed	6	13
Lost to follow-up	25	29

Baseline characteristics

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Reporting group title

Daprodustat

Reporting group description

Reporting group title

Darbepoetin alfa

Reporting group description

Reporting group values	Daprodustat	Darbepoetin alfa	Total
Number of subjects	1937	1935	3872
Age categorical
Units: Participants
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	836	842	1678
From 65-84 years	994	977	1971
85 years and over	107	116	223
Age Continuous
Units: Years
arithmetic mean (standard deviation)	64.8 ( 14.03 )	64.9 ( 13.83 )	-
Sex: Female, Male
Units: Participants
Female	1102	1071	2173
Male	835	864	1699
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaskan Native	88	100	188
Asian - Central/South Asian Heritage	58	71	129
Asian - East Asian Heritage	245	232	477
Asian - Japanese Heritage	5	3	8
Asian - South East Asian Heritage	216	229	445
Black or African American	183	185	368
Native Hawaiian or Other Pacific Islander	7	7	14
White - Arabic/North African Heritage	19	18	37
White - White/Caucasian/European Heritage	1079	1037	2116
Mixed Asian Race	1	2	3
Mixed Race	36	51	87

End points

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Reporting group title

Daprodustat

Reporting group description

Reporting group title

Darbepoetin alfa

Reporting group description

Primary: Time to first occurrence of adjudicated major adverse cardiovascular event (MACE) during cardiovascular (CV) events follow-up time period (non-inferiority analysis)

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End point title

Time to first occurrence of adjudicated major adverse cardiovascular event (MACE) during cardiovascular (CV) events follow-up time period (non-inferiority analysis)

End point description

Time to MACE defined as time to first occurrence of Clinical Events Committee(CEC)adjudicated MACE (composite of all-cause mortality,non-fatal myocardial infarction[MI],non-fatal stroke)was analyzed using Cox proportional hazards regression model with treatment group,current erythropoiesis-stimulating agents(ESA)use at randomization and region as covariates.Time to first occurrence was computed as (event date minus randomization date)+1.Incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% confidence interval(CI). First event person years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without event)/365.25,based on CV follow-up time period.All Randomized (Intent-to-treat[ITT]) Population comprised of all randomized participants. Participants were analyzed according to treatment to which they were randomized.

End point type

Primary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[1]	1935 ^[2]
Units: Events per 100 person years
number (confidence interval 95%)	10.86 (9.80 to 12.02)	10.63 (9.58 to 11.77)

Notes
[1] - All Randomized (ITT) Population.
[2] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.19

Notes
[3] - Non-inferiority was achieved if the upper limit of the two-sided 95% CI for the hazard ratio was below the pre-specified non-inferiority margin of 1.25.

Primary: Mean Change from Baseline in Hgb levels over the Evaluation Period (Week 28 to Week 52)

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End point title

Mean Change from Baseline in Hgb levels over the Evaluation Period (Week 28 to Week 52)

End point description

Blood samples were collected from participants for Hgb measurements. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb values were imputed using pre-specified multiple imputation methods. Change from Baseline was defined as post-Baseline value minus (-) Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using the Analysis of covariance (ANCOVA) model with terms for treatment, Baseline Hgb, current ESA use and region.

End point type

Primary

End point timeframe

Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[4]	1935 ^[5]
Units: Grams per deciliter
least squares mean (standard error)	0.74 ( 0.019 )	0.66 ( 0.019 )

Notes
[4] - All Randomized (ITT) Population.
[5] - All Randomized (ITT) Population.

Statistical analysis

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

Least square (LS) mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.03

upper limit

0.13

Notes
[6] - Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than -0.75 g/dL.

Secondary: Time to first occurrence of adjudicated MACE during CV events follow-up time period (Superiority analysis)

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End point title

Time to first occurrence of adjudicated MACE during CV events follow-up time period (Superiority analysis)

End point description

Time to MACE defined as the time to first occurrence of CEC adjudicated MACE was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariate. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[7]	1935 ^[8]
Units: Events per 100 person years
number (confidence interval 95%)	10.86 (9.80 to 12.02)	10.63 (9.58 to 11.77)

Notes
[7] - All Randomized (ITT) Population.
[8] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.670884 ^[9]

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.19

Notes
[9] - The p-value was compared against 0.008333 based on the Holm-Bonferonni adjustment.

Secondary: Time to first occurrence of adjudicated MACE or thromboembolic event during CV events follow-up time period

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End point title

Time to first occurrence of adjudicated MACE or thromboembolic event during CV events follow-up time period

End point description

Time to first occurrence of adjudicated MACE or thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) was analyzed using a Cox proportional hazards regression model with with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[10]	1935 ^[11]
Units: Events per 100 person years
number (confidence interval 95%)	12.34 (11.19 to 13.57)	11.77 (10.65 to 12.98)

Notes
[10] - All Randomized (ITT) Population.
[11] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.800813 ^[12]

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.22

Notes
[12] - The p-value was compared against 0.012500 based on the Holm-Bonferonni adjustment.

Secondary: Time to first occurrence of adjudicated MACE or hospitalization for heart failure during CV events follow-up time period

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End point title

Time to first occurrence of adjudicated MACE or hospitalization for heart failure during CV events follow-up time period

End point description

Time to first occurrence of adjudicated MACE or hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[13]	1935 ^[14]
Units: Events per 100 person years
number (confidence interval 95%)	13.16 (11.97 to 14.44)	12.22 (11.08 to 13.46)

Notes
[13] - All Randomized (ITT) Population.
[14] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.886195 ^[15]

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.24

Notes
[15] - The p-value was compared against 0.025000 based on the Holm-Bonferonni adjustment.

Secondary: Time to First Occurrence of chronic kidney disease (CKD) Progression during CV events follow-up time period

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End point title

Time to First Occurrence of chronic kidney disease (CKD) Progression during CV events follow-up time period

End point description

Progression of CKD defined as:40% decline in eGFR from Baseline or ESRD as defined by either initiating chronic dialysis for >=90 days or not initiating chronic dialysis when dialysis is indicated or kidney transplantation.Time to first occurrence of CKD progression was analyzed using Fine and Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates.Time to first occurrence was computed as(event date minus randomization date) +1.Incidence rate per 100 person years calculated as(100*number of participants with at least 1 event)/first event person-years).First event person years=(cumulative total time to first event for participants who have event+cumulative total of censored time for participants without event)/365.25,based on CV follow-up time period.Only those participants with data available at indicated time points were analyzed.This analysis population was restricted to those with a Baseline eGFR >=15mL/min.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1220 ^[16]	1265 ^[17]
Units: Events per 100 person years
number (confidence interval 95%)	17.55 (15.74 to 19.51)	17.76 (15.97 to 19.70)

Notes
[16] - All Randomized (ITT) Population.
[17] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Subdistribution hazard ratio was estimated using Fine and Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2485

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.36947

Method

Wald test

Parameter type

Subdistribution hazard ratio

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.13

Secondary: Time to First occurrence of Adjudicated All-Cause Mortality during Vital Status for follow-up time period

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End point title

Time to First occurrence of Adjudicated All-Cause Mortality during Vital Status for follow-up time period

End point description

Time to first occurrence of adjudicated all-cause mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the vital status follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for vital status follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[18]	1935 ^[19]
Units: Events per 100 person years
number (confidence interval 95%)	8.35 (7.43 to 9.35)	8.27 (7.35 to 9.26)

Notes
[18] - All Randomized (ITT) Population.
[19] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6197

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

1.2

Secondary: Time to First occurrence of Adjudicated CV Mortality during CV events follow-up time period

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End point title

Time to First occurrence of Adjudicated CV Mortality during CV events follow-up time period

End point description

Time to first occurrence of adjudicated CV mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[20]	1935 ^[21]
Units: Events per 100 person years
number (confidence interval 95%)	3.02 (2.48 to 3.65)	2.55 (2.06 to 3.13)

Notes
[20] - All Randomized (ITT) Population.
[21] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8976

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.58

Secondary: Time to First occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) during CV events follow-up time period

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End point title

Time to First occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) during CV events follow-up time period

End point description

Time to first occurrence of adjudicated MI (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[22]	1935 ^[23]
Units: Events per 100 person years
number (confidence interval 95%)	2.94 (2.40 to 3.56)	2.76 (2.24 to 3.36)

Notes
[22] - All Randomized (ITT) Population.
[23] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6581

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.4

Secondary: Time to First occurrence of Adjudicated Stroke (Fatal and Non-Fatal) during CV events follow-up time period

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End point title

Time to First occurrence of Adjudicated Stroke (Fatal and Non-Fatal) during CV events follow-up time period

End point description

Time to first occurrence of adjudicated stroke (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[24]	1935 ^[25]
Units: Events per 100 person years
number (confidence interval 95%)	1.26 (0.92 to 1.69)	0.95 (0.66 to 1.33)

Notes
[24] - All Randomized (ITT) Population.
[25] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.894

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

2.07

Secondary: Number of Participants with Adjudicated MACE or Hospitalization for Heart Failure (Recurrent events analysis)

Top of page

End point title

Number of Participants with Adjudicated MACE or Hospitalization for Heart Failure (Recurrent events analysis)

End point description

Number of participants with adjudicated MACE or hospitalization for heart failure (recurrent events analysis) is presented, categorized by number of occurrences of adjudicated MACE or hospitalization for heart failure per participant.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[26]	1935 ^[27]
Units: Participants
Occurrences per participant: 0	1493	1518
Occurrences per participant: 1	318	317
Occurrences per participant: 2	76	64
Occurrences per participant: 3	26	22
Occurrences per participant: 4	14	9
Occurrences per participant: 5	5	3
Occurrences per participant: 6	1	0
Occurrences per participant: 7	4	1
Occurrences per participant: 8	0	1

Notes
[26] - All Randomized (ITT) Population.
[27] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Overall HR is presented using Model 1. Model 1 assumed a common treatment effect, regardless of number of events experienced. HR was estimated using a Prentice, Williams and Peterson(PWP) model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9422

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.23

Statistical analysis 2

Statistical analysis description

First Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. Hazard Ratio (HR) was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8862

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.24

Statistical analysis 3

Statistical analysis description

Second Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6789

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

1.39

Statistical analysis 4

Statistical analysis description

Third Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9016

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

2.19

Statistical analysis 5

Statistical analysis description

First Event Hazard ratio is presented using Model 3. Model 3 assumed treatment effect for first event differs from a common effect for subsequent events. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8862

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.24

Statistical analysis 6

Statistical analysis description

Subsequent Event Hazard ratio is presented using Model 3. Model 3 assumed treatment effect for first event differs from a common effect for subsequent events. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8989

Method

Chi-squared

Parameter type

Hazard ratio (HR)

Point estimate

1.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.46

Secondary: Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI during CV events follow-up time period

End point description

Time to first occurrence of adjudicated CV mortality or non-fatal MI was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[28]	1935 ^[29]
Units: Events per 100 person years
number (confidence interval 95%)	5.36 (4.62 to 6.18)	4.98 (4.27 to 5.77)

Notes
[28] - All Randomized (ITT) Population.
[29] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7673

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.33

Secondary: Time to First Occurrence of All-Cause Hospitalization during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of All-Cause Hospitalization during CV events follow-up time period

End point description

All-cause hospitalization events were hospital admissions recorded on the hospitalization electronic case report form (eCRF) form with a hospitalization duration >=24 hours. Time to first occurrence of all-cause hospitalization was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[30]	1935 ^[31]
Units: Events per 100 person years
number (confidence interval 95%)	41.13 (38.59 to 43.80)	38.99 (36.54 to 41.56)

Notes
[30] - All Randomized (ITT) Population.
[31] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8601

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

1.15

Secondary: Time to First Occurrence of All-Cause Hospital Re-admission within 30 Days during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of All-Cause Hospital Re-admission within 30 Days during CV events follow-up time period

End point description

All-cause hospital re-admissions within 30days are defined as hospital admissions recorded on hospitalization electronic case record form with hospitalization duration of >=24 hours and admission date within 30days following previous discharge date of all-cause hospitalization event, where previous hospitalization was >=24hours.Time to first occurrence of all-cause hospital re-admission within 30days was analyzed using Cox proportional hazards regression model with treatment group, current ESA use at randomization and region as covariates.Time to the first occurrence was computed as(event date - randomization date)+1. Incidence rate per 100 person years calculated as(100*number of participants with at least 1event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[32]	1935 ^[33]
Units: Events per 100 person years
number (confidence interval 95%)	7.78 (6.87 to 8.79)	7.55 (6.65 to 8.55)

Notes
[32] - All Randomized (ITT) Population.
[33] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6207

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.22

Secondary: Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic events during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic events during CV events follow-up time period

End point description

Time to first occurrence of adjudicated MACE or hospitalization for heart failure or thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[34]	1935 ^[35]
Units: Events per 100 person years
number (confidence interval 95%)	14.60 (13.33 to 15.96)	13.32 (12.11 to 14.61)

Notes
[34] - All Randomized (ITT) Population.
[35] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9393

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.26

Secondary: Time to First Occurrence of Adjudicated Hospitalization for Heart Failure during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Adjudicated Hospitalization for Heart Failure during CV events follow-up time period

End point description

Time to first occurrence of adjudicated hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[36]	1935 ^[37]
Units: Events per 100 person years
number (confidence interval 95%)	4.05 (3.41 to 4.78)	3.30 (2.73 to 3.96)

Notes
[36] - All Randomized (ITT) Population.
[37] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9412

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.22

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.56

Secondary: Time to First Occurrence of Adjudicated Thromboembolic Events during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Adjudicated Thromboembolic Events during CV events follow-up time period

End point description

Time to first occurrence of adjudicated thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[38]	1935 ^[39]
Units: Events per 100 person years
number (confidence interval 95%)	1.81 (1.39 to 2.31)	1.43 (1.07 to 1.89)

Notes
[38] - All Randomized (ITT) Population.
[39] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, current ESA use at randomization, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8994

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.84

Secondary: Time to First Occurrence of Confirmed 40% Decline in eGFR during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Confirmed 40% Decline in eGFR during CV events follow-up time period

End point description

Time to first occurrence of confirmed 40% decline in eGFR was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates. Time to the first occurrence was computed as (event date minus randomization date)+1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1220 ^[40]	1265 ^[41]
Units: Events per 100 person years
number (confidence interval 95%)	8.21 (7.04 to 9.52)	8.90 (7.69 to 10.24)

Notes
[40] - All Randomized (ITT) Population.
[41] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Subdistribution hazard ratio was estimated using Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2485

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2073

Method

Wald test

Parameter type

Subdistribution hazard ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.13

Secondary: Time to First Occurrence of Chronic Dialysis during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Chronic Dialysis during CV events follow-up time period

End point description

Time to first occurrence of chronic dialysis was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates. Chronic dialysis is defined by either initiating dialysis for >=90 days or not initiating chronic dialysis when dialysis is indicated. Time to the first occurrence was computed as (event date minus randomization date)+1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1220 ^[42]	1265 ^[43]
Units: Events per 100 person years
number (confidence interval 95%)	12.20 (10.74 to 13.81)	12.06 (10.63 to 13.62)

Notes
[42] - All Randomized (ITT) Population.
[43] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Subdistribution hazard ratio was estimated using Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2485

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5068

Method

Wald test

Parameter type

Subdistribution hazard ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.19

Secondary: Time to First Occurrence of Kidney Transplant during CV events follow-up time period

Top of page

End point title

Time to First Occurrence of Kidney Transplant during CV events follow-up time period

End point description

Time to first occurrence of kidney transplant were analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates. Time to the first occurrence was computed as (event date minus randomization date)+1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Up to 4.3 person-years for CV follow-up time period

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1220 ^[44]	1265 ^[45]
Units: Events per 100 person years
number (confidence interval 95%)	1.00 (0.63 to 1.50)	1.14 (0.75 to 1.66)

Notes
[44] - All Randomized (ITT) Population.
[45] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Subdistribution hazard ratio was estimated using Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use, and region as covariates.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2485

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3285

Method

Wald test

Parameter type

Subdistribution hazard ratio

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

1.54

Secondary: Change From Baseline in Post-randomization Hgb levels at Week 52

Top of page

End point title

Change From Baseline in Post-randomization Hgb levels at Week 52

End point description

Blood samples were collected from participants for Hgb measurements. Change from Baseline was defined as post-randomization value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using mixed model repeated measures (MMRM) model fitted from Baseline up to Week 52, excluding values collected during the stabilization period, with factors for treatment, time, current ESA use, region, Baseline Hgb and Baseline Hgb by time and treatment by time interactions. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1557 ^[46]	1556 ^[47]
Units: Grams per deciliter
least squares mean (standard error)	0.76 ( 0.029 )	0.73 ( 0.029 )

Notes
[46] - All Randomized (ITT) Population.
[47] - All Randomized (ITT) Population.

Statistical analysis

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3113

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[48]

Method

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.11

Notes
[48] - Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than the pre-specified non-inferiority margin of -0.75 g/dL.

Secondary: Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

Top of page

End point title

Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

End point description

Mean Hgb during the evaluation period was defined as the mean of all evaluable Hgb values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled Hgb values that were taken during this time period. Hgb responders were defined as participants with a mean Hgb during the evaluation period that falls within the Hgb analysis range of 10-11.5 g/dL. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Week 28 to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1491 ^[49]	1520 ^[50]
Units: Participants	1167	1063

Notes
[49] - All Randomized (ITT) Population.
[50] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Cochran-Mantel-Haenszel (CMH) test adjusted for current ESA use and region was used to compare the number of responders between the treatment groups.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3011

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rate

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

5.2

upper limit

11.4

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

Top of page

End point title

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

End point description

Percentage of days for which a participant's Hgb was within the analysis range of 10-11.5 g/dL (both inclusive) during the evaluation period (Week 28 to Week 52), including any unscheduled evaluable Hgb values that were taken during this time period was calculated. Percentage of time in the analysis range during evaluation period is calculated as time in range during the evaluation period / [Earlier of (Date of the last evaluable Hgb value, Week 52 visit date) – Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 inclusive, Week 28 visit date)]. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Week 28 to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1461 ^[51]	1483 ^[52]
Units: Percentage of days
median (full range (min-max))	70.5 (0.0 to 100.0)	63.2 (0.0 to 100.0)

Notes
[51] - All Randomized (ITT) Population.
[52] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hodges-Lehmann estimate of the treatment difference (daprodustat-darbepoetin alfa) and associated two-sided asymptotic 95% CI is presented.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2944

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[53]

Method

Parameter type

Mean difference (final values)

Point estimate

4.57

Confidence interval

level

95%

sides

2-sided

lower limit

2.04

upper limit

7.11

Notes
[53] - Non-inferiority was to be established if the lower limit of the two-sided 95% confidence interval for the treatment difference was greater than non-inferiority margin of -15%.

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority analysis

Top of page

End point title

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority analysis

End point description

End point type

Secondary

End point timeframe

Week 28 to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1461 ^[54]	1483 ^[55]
Units: Percentage of days
median (full range (min-max))	70.5 (0.0 to 100.0)	63.2 (0.0 to 100.0)

Notes
[54] - All Randomized (ITT) Population.
[55] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Mann-Whitney estimate (Probability) of the treatment effect has been presented.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2944

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

van Elteren test

Parameter type

Probability

Point estimate

0.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.53

upper limit

0.57

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Non-inferiority analysis

Top of page

End point title

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Non-inferiority analysis

End point description

Percentage of days for which a participant's Hgb was within the analysis range of 10-11.5 g/dL (both inclusive) during the maintenance period (Week 28 to end of study), including any unscheduled evaluable Hgb values that were taken during this time period was calculated. Percentage of time in the analysis range during maintenance period is calculated as time in range during the maintenance period / [Earlier of (Date of the last evaluable Hgb value, End of study date)– Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit date)]. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Week 28 to end of study (4.3 person-years for follow-up time period)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1469 ^[56]	1489 ^[57]
Units: Percentage of days
median (full range (min-max))	66.1 (0.0 to 100.0)	62.1 (0.0 to 100.0)

Notes
[56] - All Randomized (ITT) Population.
[57] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hodges-Lehmann estimate of the treatment difference (daprodustat-darbepoetin alfa) and associated two-sided asymptotic 95% CI is presented.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2958

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[58]

Method

Parameter type

Median difference (final values)

Point estimate

3.94

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

5.91

Notes
[58] - Non-inferiority was to be established if the lower limit of the two-sided 95% confidence interval for the treatment difference was greater than non-inferiority margin of -15%.

Secondary: Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Superiority analysis

Top of page

End point title

Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Superiority analysis

End point description

End point type

Secondary

End point timeframe

Week 28 to end of study (4.3 person-years for follow-up time period)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1469 ^[59]	1489 ^[60]
Units: Percentage of days
median (full range (min-max))	66.1 (0.0 to 100.0)	62.1 (0.0 to 100.0)

Notes
[59] - All Randomized (ITT) Population.
[60] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Mann-Whitney estimate (Probability) of the treatment effect has been presented.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2958

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

van Elteren test

Parameter type

Probability

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

0.56

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

Top of page

End point title

Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

End point description

SBP, DBP and MAP were measured in a seated position after at least a 5-minutes of rest. MAP is the average (BP) in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using MMRM model with treatment group + time + current ESA use at randomization + region + Baseline value + Baseline value*time + treatment group*time, using an unstructured covariance matrix. Data for post-dialysis BP measurements have been presented. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Week -4) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1913 ^[61]	1884 ^[62]
Units: Millimeter of mercury
least squares mean (standard error)
SBP, n=1913, 1884	-0.62 ( 0.488 )	-1.17 ( 0.479 )
DBP, n=1912, 1884	0.06 ( 0.267 )	-0.59 ( 0.262 )
MAP, n=1912, 1884	-0.17 ( 0.300 )	-0.77 ( 0.294 )

Notes
[61] - All Randomized (ITT) Population.
[62] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

The difference in change from Baseline in SBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3797

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7916

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-0.79

upper limit

1.9

Statistical analysis 3

Statistical analysis description

The difference in change from Baseline in MAP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3797

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9241

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

1.43

Statistical analysis 2

Statistical analysis description

The difference in change from Baseline in DBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3797

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9581

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

1.38

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

Top of page

End point title

Change from Baseline in SBP, DBP, MAP at End of Treatment

End point description

SBP, DBP and MAP were measured in a seated position after at least a 5-minutes of rest. MAP is an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value. Data for post-dialysis BP measurements have been presented. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Week -4) and 51.1 months

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1919 ^[63]	1884 ^[64]
Units: Millimeter of mercury
least squares mean (standard error)
SBP, n=1919, 1884	-1.19 ( 0.395 )	-1.10 ( 0.398 )
DBP, n=1918, 1884	-0.26 ( 0.229 )	-0.38 ( 0.231 )
MAP, n=1918, 1884	-0.57 ( 0.248 )	-0.62 ( 0.251 )

Notes
[63] - All Randomized (ITT) Population.
[64] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

For SBP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3803

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.442

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-1.18

upper limit

1.02

Statistical analysis 2

Statistical analysis description

For DBP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3803

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6369

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.52

upper limit

0.75

Statistical analysis 3

Statistical analysis description

For MAP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3803

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.549

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.65

upper limit

0.74

Secondary: Blood Pressure (BP) Exacerbation Event Rate per 100 Participant Years

Top of page

End point title

Blood Pressure (BP) Exacerbation Event Rate per 100 Participant Years

End point description

BP exacerbation event (based on post-dialysis) was defined as: SBP >= 25 millimeter of mercury (mmHg) increased from Baseline or SBP >=180 mmHg; DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the negative binomial model with treatment, current ESA use at randomization and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Day 1 to end of treatment (51.1 months)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1919 ^[65]	1884 ^[66]
Units: Events per 100 participant years
number (confidence interval 95%)	138.50 (128.58 to 149.18)	157.35 (146.30 to 169.23)

Notes
[65] - All Randomized (ITT) Population.
[66] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Ratio of model estimated exacerbation rates and CIs were estimated using a negative binomial model with treatment, current ESA use at randomization, and region as covariates and logarithm of time on treatment as an offset variable for the treatment group comparison.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3803

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0074

Method

Negative binomial model

Parameter type

Ratio of exacerbation rate

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

0.98

Secondary: Number of Participants with at Least one BP Exacerbation Event During Study

Top of page

End point title

Number of Participants with at Least one BP Exacerbation Event During Study

End point description

BP exacerbation was defined as: SBP >= 25 mmHg increased from Baseline or SBP >=180 mmHg; DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. Number of participants with at least one BP exacerbation event is presented. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Day 1 to end of treatment (51.1 months)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1919 ^[67]	1884 ^[68]
Units: Participants	939	1012

Notes
[67] - All Randomized (ITT) Population.
[68] - All Randomized (ITT) Population.

No statistical analyses for this end point

Secondary: Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

Top of page

End point title

Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

End point description

Percentage of participants permanently stopping randomized treatment due to meeting rescue criteria has been presented.

End point type

Secondary

End point timeframe

Day 1 to 51.1 months

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1937 ^[69]	1935 ^[70]
Units: Percentage of participants
number (not applicable)	2.0	3.3

Notes
[69] - All Randomized (ITT) Population.
[70] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model adjusted for treatment group, current ESA use and region.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3872

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0113

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

0.63

Confidence interval

level

95%

sides

2-sided

lower limit

0.42

upper limit

0.94

Secondary: Change from Baseline in On-treatment Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

End point description

SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0(poorer health) to 100(better health). The PCS is an average score derived from 4 domains (physical functioning, role-physical, bodily pain and general health) representing overall physical health. PCS ranges from 0 to 100; higher score represents better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1238 ^[71]	1227 ^[72]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=1238,1187	0.42 ( 0.169 )	0.78 ( 0.172 )
Week 12, n=1237,1227	0.60 ( 0.171 )	0.71 ( 0.172 )
Week 28, n=968,956	0.16 ( 0.197 )	0.04 ( 0.198 )
Week 52, n=804,780	-0.32 ( 0.218 )	-0.12 ( 0.221 )

Notes
[71] - All Randomized (ITT) Population.
[72] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time,current ESA use at randomization, region,Baseline value and Baseline value by time and treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.932

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.83

upper limit

0.11

Statistical analysis 2

Statistical analysis description

Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented,with factors for treatment, time,current ESA use at randomization, region, Baseline value and Baseline value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6761

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.11

Confidence interval

level

95%

sides

2-sided

lower limit

-0.59

upper limit

0.36

Statistical analysis 3

Statistical analysis description

Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented,with factors for treatment, time,current ESA use at randomization, region, Baseline value and Baseline value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3335

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

0.67

Statistical analysis 4

Statistical analysis description

Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented,with factors for treatment, time,current ESA use at randomization, region, Baseline value and Baseline value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7423

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.81

upper limit

0.41

Secondary: Change from Baseline in On-treatment Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). MCS is an average score derived from 4 domains (vitality, social functioning, role-emotional and mental health) representing overall mental health. MCS ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1238 ^[73]	1227 ^[74]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=1238,1187	0.08 ( 0.217 )	0.37 ( 0.221 )
Week 12, n=1237,1227	0.02 ( 0.223 )	0.18 ( 0.224 )
Week 28, n=968,956	-0.35 ( 0.244 )	-0.02 ( 0.245 )
Week 52, n=804,780	-0.71 ( 0.290 )	-0.35 ( 0.294 )

Notes
[73] - All Randomized (ITT) Population.
[74] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented,with factors for treatment, time,current ESA use at randomization, region, Baseline value and Baseline value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8268

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.29

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.32

Statistical analysis 2

Statistical analysis description

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6851

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

0.47

Statistical analysis 3

Statistical analysis description

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8316

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-1.01

upper limit

0.35

Statistical analysis 4

Statistical analysis description

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8032

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-1.16

upper limit

0.46

Secondary: Change from Baseline in On-treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: bodily pain (b pain), general health (GH), mental health (MH), role-emotional (RE) (role limitations caused by emotional problems), role-physical (RP) (role limitations caused by physical problems), social functioning (SF), physical functioning and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline (BL) was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1238 ^[75]	1227 ^[76]
Units: Scores on a scale
least squares mean (standard error)
Bodily pain: Week 8, n=1238,1187	0.11 ( 0.221 )	0.45 ( 0.225 )
Bodily pain: Week 12, n=1237,1227	0.35 ( 0.223 )	0.50 ( 0.224 )
Bodily pain: Week 28, n=968,956	-0.48 ( 0.261 )	0.02 ( 0.263 )
Bodily pain: Week 52, n=804,780	-0.34 ( 0.283 )	0.13 ( 0.288 )
General health: Week 8, n=1238,1187	0.36 ( 0.171 )	0.43 ( 0.174 )
General health: Week 12, n=1237,1227	0.28 ( 0.174 )	0.48 ( 0.175 )
General health: Week 28, n=968,956	0.14 ( 0.200 )	0.04 ( 0.201 )
General health: Week 52, n=804,780	-0.27 ( 0.220 )	-0.19 ( 0.224 )
Mental health: Week 8, n=1238,1187	-0.19 ( 0.204 )	0.12 ( 0.208 )
Mental health: Week 12, n=1237,1227	-0.07 ( 0.210 )	-0.09 ( 0.211 )
Mental health: Week 28, n=968,956	-0.67 ( 0.231 )	-0.37 ( 0.232 )
Mental health: Week 52, n=804,780	-0.85 ( 0.271 )	-0.61 ( 0.275 )
Role-emotional: Week 8, n=1238,1187	0.45 ( 0.253 )	0.54 ( 0.258 )
Role-emotional: Week 12, n=1237,1227	0.17 ( 0.258 )	0.43 ( 0.259 )
Role-emotional: Week 28, n=968,956	-0.30 ( 0.290 )	0.07 ( 0.292 )
Role-emotional: Week 52, n=804,780	-0.90 ( 0.339 )	-0.38 ( 0.344 )
Role-physical: Week 8, n=1238,1187	0.33 ( 0.202 )	0.83 ( 0.205 )
Role-physical: Week 12, n=1237,1227	0.40 ( 0.203 )	0.73 ( 0.204 )
Role-physical: Week 28, n=968,956	0.06 ( 0.230 )	0.00 ( 0.232 )
Role-physical: Week 52, n=804,780	-0.63 ( 0.259 )	-0.44 ( 0.263 )
Social functioning: Week 8, n=1238,1187	0.19 ( 0.224 )	0.82 ( 0.228 )
Social functioning: Week 12, n=1237,1227	0.21 ( 0.224 )	0.53 ( 0.225 )
Social functioning: Week 28, n=968,956	0.04 ( 0.247 )	0.17 ( 0.249 )
Social functioning: Week 52, n=804,780	-0.58 ( 0.282 )	-0.20 ( 0.286 )

Notes
[75] - All Randomized (ITT) Population.
[76] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

B pain,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8562

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.34

Confidence interval

level

95%

sides

2-sided

lower limit

-0.95

upper limit

0.28

Statistical analysis 2

Statistical analysis description

B pain,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6849

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.77

upper limit

0.47

Statistical analysis 3

Statistical analysis description

B pain,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9074

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.22

upper limit

0.24

Statistical analysis 4

Statistical analysis description

B pain,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8765

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-1.26

upper limit

0.32

Statistical analysis 5

Statistical analysis description

GH,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6252

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.4

Statistical analysis 6

Statistical analysis description

GH,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7852

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

0.29

Statistical analysis 7

Statistical analysis description

GH,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3614

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.46

upper limit

0.66

Statistical analysis 8

Statistical analysis description

GH,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5991

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.54

Statistical analysis 9

Statistical analysis description

MH,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8526

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.27

Statistical analysis 10

Statistical analysis description

MH,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4673

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.56

upper limit

0.61

Statistical analysis 11

Statistical analysis description

MH,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8262

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.95

upper limit

0.33

Statistical analysis 12

Statistical analysis description

MH,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.738

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.51

Statistical analysis 13

Statistical analysis description

RE,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5997

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.62

Statistical analysis 14

Statistical analysis description

RE,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7649

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-0.98

upper limit

0.45

Statistical analysis 15

Statistical analysis description

RE,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8175

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-1.18

upper limit

0.43

Statistical analysis 16

Statistical analysis description

RE,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8591

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.47

upper limit

0.43

Statistical analysis 17

Statistical analysis description

RP,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9588

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.06

upper limit

0.06

Statistical analysis 18

Statistical analysis description

RP,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8761

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.23

Statistical analysis 19

Statistical analysis description

RP,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4293

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.58

upper limit

0.7

Statistical analysis 20

Statistical analysis description

RP,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6983

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.92

upper limit

0.53

Statistical analysis 21

Statistical analysis description

SF,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9743

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-1.25

upper limit

Statistical analysis 22

Statistical analysis description

SF,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time,current ESA use at randomization, region,BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8405

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.94

upper limit

0.31

Statistical analysis 23

Statistical analysis description

SF,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6459

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.82

upper limit

0.56

Statistical analysis 24

Statistical analysis description

SF,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8272

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-1.17

upper limit

0.41

Secondary: Change from Baseline in On-treatment Vitality scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Vitality scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Vitality score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1238 ^[77]	1227 ^[78]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=1238,1187	0.35 ( 0.192 )	0.90 ( 0.195 )
Week 12, n=1237,1227	0.62 ( 0.200 )	0.74 ( 0.201 )
Week 28, n=968,956	0.22 ( 0.222 )	0.32 ( 0.223 )
Week 52, n=804,780	-0.14 ( 0.250 )	0.35 ( 0.253 )

Notes
[77] - All Randomized (ITT) Population.
[78] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Week 8: Model was fitted from Baseline up to Week 52 and model adjusted Week 8 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9786

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.56

Confidence interval

level

95%

sides

2-sided

lower limit

-1.09

upper limit

-0.02

Statistical analysis 2

Statistical analysis description

Week 12: Model was fitted from Baseline up to Week 52 and model adjusted Week 12 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6642

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

0.44

Statistical analysis 3

Statistical analysis description

Week 28: Model was fitted from Baseline up to Week 52 and model adjusted Week 28 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6261

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

0.52

Statistical analysis 4

Statistical analysis description

Week 52: Model was fitted from Baseline up to Week 52 and model adjusted Week 52 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9161

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.19

upper limit

0.21

Secondary: Change from Baseline in On-treatment Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Physical functioning score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1238 ^[79]	1227 ^[80]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=1238,1187	0.51 ( 0.200 )	0.83 ( 0.203 )
Week 12, n=1237,1227	0.65 ( 0.195 )	0.52 ( 0.196 )
Week 28, n=968,956	0.05 ( 0.224 )	-0.10 ( 0.225 )
Week 52, n=804,780	-0.69 ( 0.262 )	-0.37 ( 0.266 )

Notes
[79] - All Randomized (ITT) Population.
[80] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Week 8: Model was fitted from Baseline up to Week 52 and model adjusted Week 8 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8703

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.88

upper limit

0.24

Statistical analysis 2

Statistical analysis description

Week 12: Model was fitted from Baseline up to Week 52 and model adjusted Week 12 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3167

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.41

upper limit

0.67

Statistical analysis 3

Statistical analysis description

Week 28: Model was fitted from Baseline up to Week 52 and model adjusted Week 28 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3155

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.47

upper limit

0.78

Statistical analysis 4

Statistical analysis description

Week 52: Model was fitted from Baseline up to Week 52 and model adjusted Week 52 data has been presented,with factors for treatment, time,current ESA use at randomization, region, BL value and BL value by time & treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2465

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8069

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-1.06

upper limit

0.41

Secondary: Change from Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

Top of page

End point title

Change from Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

End point description

EQ-5D-5L is self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Each of these 5 figure health states were converted to a single index score by applying country-specific value set formula that attaches weights to dimensions and levels. Range for EQ-5D-5L index score is -0.594 (worst health) to 1 (full health state). Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	443 ^[81]	399 ^[82]
Units: Scores on a scale
least squares mean (standard error)	-0.0253 ( 0.00842 )	-0.0018 ( 0.00883 )

Notes
[81] - All Randomized (ITT) Population.
[82] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

842

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9724

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.0234

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0474

upper limit

0.0005

Secondary: Change from Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52

Top of page

End point title

Change from Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52

End point description

The EQ VAS records the respondent’s self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst imaginable health and 100 represents the best imaginable health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	443 ^[83]	399 ^[84]
Units: Scores on a scale
least squares mean (standard error)	-0.7 ( 0.78 )	-1.4 ( 0.82 )

Notes
[83] - All Randomized (ITT) Population.
[84] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

842

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2687

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

2.9

Secondary: Change from Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52

End point description

CKD-AQ is 21-item PRO measure assessing symptoms and symptom impact in participants with anemia associated with CKD. It had 3domains:1.Tired/Low Energy(LE)/Weak scale consisting of 10items;2.Chest Pain(CP)/Shortness of Breath(SOB) scale consisting of 4items;3.Cognitive(Cog) scale consisting of 3 items.4 CKD-AQ single items are:SOB,no activity; severity-short breath(S-SB), resting; difficulty standing (diff. std.)for long time(LT) and difficulty sleeping (diff sleep).Single-item were recorded based on a 0-100 scoring with 0=worst possible;100=best possible score. 3 domains scores were calculated as average of items in each domain;ranged from 0-100 where 0=worst possible;100=best possible score.Change from Baseline was calculated as on-treatment visit value-Baseline value.Baseline was defined as latest non-missing pre-dose assessment on or before randomization date.Only those participants with data available at indicated time points were analyzed(represented by n=X in category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1) and Weeks 8, 12, 28, 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1341 ^[85]	1360 ^[86]
Units: Scores on a scale
least squares mean (standard error)
Tired/Low energy/Weak domain: Week 8,n=1340,1294	1.72 ( 0.424 )	2.94 ( 0.429 )
Tired/Low energy/Weak domain: Week 12,n=1341,1360	2.11 ( 0.437 )	3.08 ( 0.434 )
Tired/Low energy/Weak domain: Week 28,n=1053,1047	1.27 ( 0.495 )	1.87 ( 0.496 )
Tired/Low energy/Weak domain: Week 52,n=870,865	0.20 ( 0.554 )	1.77 ( 0.556 )
Chest pain/SOB domain: Week 8,n=1340,1294	0.63 ( 0.358 )	1.83 ( 0.363 )
Chest pain/ SOB domain: Week 12,n=1341,1360	0.88 ( 0.370 )	1.53 ( 0.368 )
Chest pain/ SOB domain: Week 28,n=1053,1047	0.01 ( 0.424 )	0.53 ( 0.425 )
Chest pain/ SOB domain: Week 52,n=870,865	-0.71 ( 0.471 )	0.47 ( 0.473 )
Cognitive domain: Week 8,n=1340,1294	0.13 ( 0.413 )	0.89 ( 0.419 )
Cognitive domain: Week 12,n=1341,1360	-0.17 ( 0.414 )	1.01 ( 0.412 )
Cognitive domain: Week 28,n=1053,1047	-0.40 ( 0.468 )	0.37 ( 0.469 )
Cognitive domain: Week 52,n=870,865	-2.00 ( 0.526 )	-0.35 ( 0.527 )
SOB, no activity: Week 8,n=1340,1294	-0.1 ( 0.42 )	1.0 ( 0.42 )
SOB, no activity: Week 12,n=1341,1360	0.1 ( 0.43 )	0.4 ( 0.42 )
SOB, no activity: Week 28,n=1053,1047	-1.1 ( 0.50 )	-0.2 ( 0.50 )
SOB, no activity: Week 52,n=870,865	-1.7 ( 0.57 )	-1.6 ( 0.57 )
Severity-short breath, Resting: Week 8,n=1340,1294	-0.3 ( 0.40 )	0.8 ( 0.40 )
Severity-short breath, Resting:Week 12,n=1341,1360	-0.3 ( 0.42 )	0.0 ( 0.42 )
Severity-short breath, Resting:Week 28,n=1053,1047	-1.1 ( 0.48 )	-0.7 ( 0.48 )
Severity-short breath, Resting:Week 52,n=870,865	-2.0 ( 0.53 )	-0.5 ( 0.53 )
Diff std for long time: Week 8,n=1340,1294	1.0 ( 0.62 )	2.5 ( 0.63 )
Diff std for long time: Week 12,n=1341,1360	0.7 ( 0.63 )	1.6 ( 0.62 )
Diff std for long time: Week 28,n=1053,1047	0.4 ( 0.71 )	1.7 ( 0.71 )
Diff std for long time: Week 52,n=870,865	-2.1 ( 0.76 )	1.2 ( 0.76 )
Difficulty sleeping: Week 8,n=1340,1294	1.6 ( 0.60 )	1.1 ( 0.61 )
Difficulty sleeping: Week 12,n=1341,1360	0.5 ( 0.60 )	2.0 ( 0.59 )
Difficulty sleeping: Week 28,n=1053,1047	-0.7 ( 0.69 )	-0.3 ( 0.70 )
Difficulty sleeping: Week 52,n=870,865	-2.6 ( 0.78 )	-0.3 ( 0.78 )

Notes
[85] - All Randomized (ITT) Population.
[86] - All Randomized (ITT) Population.

Statistical analysis 2

Statistical analysis description

Tired/LE/Weak domain,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.943

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.97

Confidence interval

level

95%

sides

2-sided

lower limit

-2.18

upper limit

0.23

Statistical analysis 1

Statistical analysis description

Tired/LE/Weak domain,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.978

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.22

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

-0.03

Statistical analysis 4

Statistical analysis description

Tired/LE/Weak domain,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.977

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.57

Confidence interval

level

95%

sides

2-sided

lower limit

-3.11

upper limit

-0.03

Statistical analysis 3

Statistical analysis description

Tired/LE/Weak domain,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8042

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.98

upper limit

0.77

Statistical analysis 6

Statistical analysis description

CP/SOB,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8939

Method

LS mean difference

Parameter type

LS mean difference

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.67

upper limit

0.37

Statistical analysis 5

Statistical analysis description

CP/SOB,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9905

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

-0.2

Statistical analysis 8

Statistical analysis description

CP/SOB,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9615

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-2.49

upper limit

0.13

Statistical analysis 7

Statistical analysis description

CP/SOB,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.807

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

0.66

Statistical analysis 9

Statistical analysis description

Cog domain,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9015

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.76

Confidence interval

level

95%

sides

2-sided

lower limit

-1.91

upper limit

0.39

Statistical analysis 10

Statistical analysis description

Cog domain,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9781

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-2.32

upper limit

-0.03

Statistical analysis 12

Statistical analysis description

Cog domain,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9864

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.65

Confidence interval

level

95%

sides

2-sided

lower limit

-3.11

upper limit

-0.19

Statistical analysis 11

Statistical analysis description

Cog domain,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8778

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.77

Confidence interval

level

95%

sides

2-sided

lower limit

-2.07

upper limit

0.53

Statistical analysis 13

Statistical analysis description

SOB, no activity,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9725

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

Statistical analysis 14

Statistical analysis description

SOB, no activity,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7188

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

0.8

Statistical analysis 15

Statistical analysis description

SOB, no activity,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8903

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

0.5

Statistical analysis 16

Statistical analysis description

SOB, no activity,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5011

Method

MMRM

Parameter type

LS mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

1.6

Statistical analysis 17

Statistical analysis description

S-SB,Resting, Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9716

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

Statistical analysis 18

Statistical analysis description

S-SB,Resting, Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6908

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

0.9

Statistical analysis 19

Statistical analysis description

S-SB,Resting, Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7462

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

0.9

Statistical analysis 20

Statistical analysis description

S-SB,Resting, Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.977

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.9

upper limit

Statistical analysis 22

Statistical analysis description

Diff std for LT, Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.833

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

0.9

Statistical analysis 21

Statistical analysis description

Diff std for LT, Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9471

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

0.3

Statistical analysis 24

Statistical analysis description

Diff std for LT, Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9986

Method

MMRM

Parameter type

LS mean difference

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

-1.1

Statistical analysis 23

Statistical analysis description

Diff std for LT, Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8918

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

0.7

Statistical analysis 25

Statistical analysis description

Diff sleep, Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3035

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

2.1

Statistical analysis 26

Statistical analysis description

Diff sleep, Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9563

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

0.2

Statistical analysis 27

Statistical analysis description

Diff sleep, Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6548

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2.3

upper limit

1.5

Statistical analysis 28

Statistical analysis description

Diff sleep, Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, current ESA use, region, BL value and BL value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2701

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9832

Method

MMRM

Parameter type

LS mean difference

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

-0.2

Secondary: Change from Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52

End point description

The PGI-S is a 1-item questionnaire designed to assess participant’s impression of disease severity on a 5-point disease severity scale (0=absent, 1=mild, 2=moderate, 3=severe, or 4=very severe). A higher score indicated more disease severity. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1341 ^[87]	1362 ^[88]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=1341,1295	0.00 ( 0.022 )	-0.02 ( 0.022 )
Week 12, n=1341,1362	0.03 ( 0.022 )	-0.02 ( 0.022 )
Week 28, n=1054,1051	0.05 ( 0.025 )	0.09 ( 0.025 )
Week 52, n=871,865	0.11 ( 0.028 )	0.06 ( 0.029 )

Notes
[87] - All Randomized (ITT) Population.
[88] - All Randomized (ITT) Population.

Statistical analysis 1

Statistical analysis description

Week 8: Model was fitted from Baseline up to Week52 and model adjusted Week 8 data has been presented, with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2703

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6917

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.05

upper limit

0.08

Statistical analysis 2

Statistical analysis description

Week 12: Model was fitted from Baseline up to Week52 and model adjusted Week 12 data has been presented, with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2703

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.951

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.01

upper limit

0.11

Statistical analysis 3

Statistical analysis description

Week 28: Model was fitted from Baseline up to Week52 and model adjusted Week 28 data has been presented, with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2703

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1136

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.03

Statistical analysis 4

Statistical analysis description

Week 52: Model was fitted from Baseline up to Week52 and model adjusted Week 52 data has been presented, with factors for treatment, time, current ESA use, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

2703

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8859

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.03

upper limit

0.13

Secondary: Change from Baseline in Post-randomization estimated Glomerular Filtration Rate (eGFR) at Week 52

Top of page

End point title

Change from Baseline in Post-randomization estimated Glomerular Filtration Rate (eGFR) at Week 52

End point description

Blood samples were collected to analyze estimated glomerular filtration rate. Change from Baseline was calculated as post-Baseline visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Pre-dose on Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	1869 ^[89]	1868 ^[90]
Units: mL per minute per 1.73 square meter
least squares mean (standard error)	-2.88 ( 0.193 )	-2.67 ( 0.193 )

Notes
[89] - All Randomized (ITT) Population.
[90] - All Randomized (ITT) Population.

Statistical analysis

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, current ESA use at randomization, region, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

3737

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7716

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

0.33

Adverse events

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Timeframe for reporting adverse events

Week -4 to randomization(Day1) in Run-in period and from Day1 to 4.3 person-years for CV follow-up time period.2 participants in All Randomized(ITT)Population did not receive treatment and were excluded from Safety Population.

Adverse event reporting additional description

All-cause mortality/Placebo run-in used All Randomized(ITT)Population consisting of all randomized participants/analyzed based on treatment to which were randomized.TESAEs/non-serious TEAEs during treatment period used SafetyPopulation,included all randomized participants who received at least1 dose of treatment,analyzed based on treatment received

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Daprodustat

Reporting group description

Participants received treatment with daprodustat film-coated tablets at dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily from randomization (Day 1) up to 51.1 month. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).

Reporting group title

Darbepoetin alfa

Reporting group description

Participants received treatment with darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection at 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 100, 150, 200, 300 and 400 microgram (mcg) from randomization (Day 1) up to 51.1 month. Darbepoetin alfa IV injection was administered to participants undergoing hemodialysis. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).

Reporting group title

Run-in Period: Placebo

Reporting group description

Participants received placebo tablets orally once daily in run-in period from Week-4 up to randomization (Day 1).

Serious adverse events	Daprodustat	Darbepoetin alfa	Run-in Period: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	850 / 1937 (43.88%)	703 / 1933 (36.37%)	63 / 3872 (1.63%)
number of deaths (all causes)	301	298	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	5 / 1937 (0.26%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	5 / 1937 (0.26%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	1 / 1937 (0.05%)	4 / 1933 (0.21%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pancreatic carcinoma
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign neoplasm of bladder
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer recurrent
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chondrosarcoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Colon adenoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial cancer stage 0
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematological malignancy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hodgkin's disease
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lip and/or oral cavity cancer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma stage I
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm of unknown primary site
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Meningioma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Monoclonal gammopathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myeloproliferative neoplasm
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic neoplasm
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer recurrent
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Refractory anaemia with an excess of blasts
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer recurrent
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal neoplasm
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the vulva
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thyroid adenoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric cancer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	15 / 1937 (0.77%)	11 / 1933 (0.57%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 16	1 / 14	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	8 / 1937 (0.41%)	8 / 1933 (0.41%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 10	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	7 / 1937 (0.36%)	9 / 1933 (0.47%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	10 / 1937 (0.52%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	6 / 1937 (0.31%)	8 / 1933 (0.41%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 8	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	4 / 1937 (0.21%)	8 / 1933 (0.41%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	5 / 1937 (0.26%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	5 / 1937 (0.26%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dialysis hypotension
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Accelerated hypertension
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic intramural haematoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Arteriovenous fistula
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic vascular disorder
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Giant cell arteritis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Internal haemorrhage
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	13 / 1937 (0.67%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 13	1 / 4	0 / 0
deaths causally related to treatment / all	1 / 13	1 / 4	0 / 0
Non-cardiac chest pain
subjects affected / exposed	9 / 1937 (0.46%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	7 / 1937 (0.36%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 6	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	4 / 1937 (0.21%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	4 / 1937 (0.21%)	2 / 1933 (0.10%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	1 / 5	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	2 / 1937 (0.10%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 1937 (0.10%)	4 / 1933 (0.21%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Cardiac death
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Catheter site extravasation
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site inflammation
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site pain
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Discomfort
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gait inability
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrobiosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic mass
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Vascular device occlusion
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal transplant failure
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaphylactic reaction
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Kidney transplant rejection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Social circumstances
Immobile
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast mass
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heavy menstrual bleeding
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intermenstrual bleeding
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Scrotal swelling
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	11 / 1937 (0.57%)	11 / 1933 (0.57%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 11	0 / 13	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	13 / 1937 (0.67%)	7 / 1933 (0.36%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 14	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	9 / 1937 (0.46%)	11 / 1933 (0.57%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 12	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	4 / 1937 (0.21%)	12 / 1933 (0.62%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 14	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Pulmonary oedema
subjects affected / exposed	5 / 1937 (0.26%)	7 / 1933 (0.36%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	6 / 1937 (0.31%)	5 / 1933 (0.26%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 8	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Respiratory failure
subjects affected / exposed	7 / 1937 (0.36%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	6 / 1937 (0.31%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 6	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	5 / 1937 (0.26%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Apnoea
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic respiratory disease
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Painful respiration
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngeal haemorrhage
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertensive crisis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory alkalosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 1937 (0.00%)	4 / 1933 (0.21%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	3 / 1937 (0.15%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Insomnia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	9 / 1937 (0.46%)	9 / 1933 (0.47%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 12	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 60
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis in device
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device failure
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lead dislodgement
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute hepatic failure
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cryptogenic cirrhosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Haemobilia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cytolysis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic mass
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-alcoholic steatohepatitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anticoagulation drug level above therapeutic
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acid base balance abnormal
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coagulation test abnormal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QRS complex prolonged
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram T wave inversion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic enzymes increased
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus test positive
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	8 / 1937 (0.41%)	12 / 1933 (0.62%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 8	0 / 12	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	9 / 1937 (0.46%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	5 / 1937 (0.26%)	9 / 1933 (0.47%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	4 / 1937 (0.21%)	6 / 1933 (0.31%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	5 / 1937 (0.26%)	5 / 1933 (0.26%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 1937 (0.05%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	6 / 1937 (0.31%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	5 / 1937 (0.26%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Peritoneal dialysis complication
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 1937 (0.00%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 1937 (0.00%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemodialysis complication
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular access malfunction
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular graft thrombosis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular pseudoaneurysm ruptured
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acetabulum fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula maturation failure
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula occlusion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site haematoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site pseudoaneurysm
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous graft thrombosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Complications of transplanted kidney
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis radiation
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heart injury
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Nasal injury
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nerve root injury lumbar
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural inflammation
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative ileus
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural vomiting
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention postoperative
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular access complication
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular access site thrombosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular graft complication
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular graft occlusion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cystic kidney disease
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syringomyelia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	37 / 1937 (1.91%)	26 / 1933 (1.35%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	2 / 40	0 / 28	0 / 1
deaths causally related to treatment / all	0 / 4	0 / 3	0 / 0
Cardiac failure congestive
subjects affected / exposed	29 / 1937 (1.50%)	20 / 1933 (1.03%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	1 / 43	0 / 23	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	28 / 1937 (1.45%)	14 / 1933 (0.72%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	1 / 35	0 / 17	0 / 2
deaths causally related to treatment / all	0 / 4	0 / 1	0 / 0
Angina unstable
subjects affected / exposed	13 / 1937 (0.67%)	15 / 1933 (0.78%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 15	0 / 17	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	10 / 1937 (0.52%)	11 / 1933 (0.57%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 12	0 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Angina pectoris
subjects affected / exposed	10 / 1937 (0.52%)	9 / 1933 (0.47%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	11 / 1937 (0.57%)	8 / 1933 (0.41%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 12	0 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	14 / 1937 (0.72%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	2 / 14	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 9	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	10 / 1937 (0.52%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 5	0 / 4	0 / 0
Cardiac failure acute
subjects affected / exposed	9 / 1937 (0.46%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 12	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Acute left ventricular failure
subjects affected / exposed	12 / 1937 (0.62%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 14	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	6 / 1937 (0.31%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	7 / 1937 (0.36%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 7	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	6 / 1937 (0.31%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	3 / 1937 (0.15%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sinus bradycardia
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardiorenal syndrome
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis uraemic
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diastolic dysfunction
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic left ventricular failure
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve prolapse
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nodal arrhythmia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular extrasystoles
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bifascicular block
subjects affected / exposed	0 / 1937 (0.00%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	13 / 1937 (0.67%)	8 / 1933 (0.41%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 13	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	6 / 1937 (0.31%)	9 / 1933 (0.47%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	6 / 1937 (0.31%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	7 / 1937 (0.36%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	7 / 1937 (0.36%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Seizure
subjects affected / exposed	4 / 1937 (0.21%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 1937 (0.00%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uraemic encephalopathy
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar stroke
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Dementia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness postural
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemic coma
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intercostal neuralgia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial haematoma
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Balance disorder
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basilar artery occlusion
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain stem haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Brain stem infarction
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidotic hyperglycaemic coma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dystonic tremor
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gliosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IIIrd nerve paresis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbosacral radiculopathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myasthenia gravis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Putamen haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo CNS origin
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	33 / 1937 (1.70%)	31 / 1933 (1.60%)	3 / 3872 (0.08%)
occurrences causally related to treatment / all	2 / 34	0 / 34	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	5 / 1937 (0.26%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	2 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrogenic anaemia
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Evans syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-immune heparin associated thrombocytopenia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sideroblastic anaemia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vestibular disorder
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Vitreous haemorrhage
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angle closure glaucoma
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eyelid ptosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal haemorrhage
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhegmatogenous retinal detachment
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulcerative keratitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vitreoretinal traction syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	12 / 1937 (0.62%)	7 / 1933 (0.36%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 13	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	12 / 1937 (0.62%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 12	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	6 / 1937 (0.31%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	4 / 1937 (0.21%)	5 / 1933 (0.26%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	3 / 1937 (0.15%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	6 / 1937 (0.31%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	2 / 1937 (0.10%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	6 / 1937 (0.31%)	1 / 1933 (0.05%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 8	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	2 / 1937 (0.10%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Abdominal pain
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 1937 (0.21%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 1937 (0.10%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	0 / 1937 (0.00%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic gastroparesis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal vascular malformation haemorrhagic
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incarcerated umbilical hernia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Melaena
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uraemic gastropathy
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute abdomen
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic gastropathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenitis haemorrhagic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mechanical ileus
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mesenteric vascular insufficiency
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic disorder
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peptic ulcer
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	7 / 1937 (0.36%)	5 / 1933 (0.26%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 8	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Skin ulcer
subjects affected / exposed	1 / 1937 (0.05%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic skin ulcer
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pruritus
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Actinic keratosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angioedema
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cutaneous calcification
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Diabetic ulcer
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erythrodermic psoriasis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peau d'orange
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin necrosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stevens-Johnson syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxic skin eruption
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	86 / 1937 (4.44%)	49 / 1933 (2.53%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 90	0 / 52	0 / 1
deaths causally related to treatment / all	0 / 6	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	70 / 1937 (3.61%)	47 / 1933 (2.43%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 76	0 / 53	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	54 / 1937 (2.79%)	35 / 1933 (1.81%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 56	0 / 35	0 / 1
deaths causally related to treatment / all	0 / 7	0 / 2	0 / 0
End stage renal disease
subjects affected / exposed	48 / 1937 (2.48%)	36 / 1933 (1.86%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 50	0 / 37	0 / 0
deaths causally related to treatment / all	0 / 4	0 / 1	0 / 0
Renal impairment
subjects affected / exposed	20 / 1937 (1.03%)	11 / 1933 (0.57%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 21	0 / 11	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	15 / 1937 (0.77%)	11 / 1933 (0.57%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 16	0 / 11	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 1	0 / 0
Nephropathy
subjects affected / exposed	6 / 1937 (0.31%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	2 / 1937 (0.10%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	3 / 1937 (0.15%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst haemorrhage
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anuria
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic end stage renal disease
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glomerulonephritis chronic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glomerulonephritis membranous
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IgA nephropathy
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intercapillary glomerulosclerosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lupus nephritis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive nephropathy
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery occlusion
subjects affected / exposed	0 / 1937 (0.00%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 1937 (0.00%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 1937 (0.00%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism secondary
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperparathyroidism
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperprolactinaemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parathyroid hyperplasia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	3 / 1937 (0.15%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	2 / 1937 (0.10%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	4 / 1937 (0.21%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	3 / 1937 (0.15%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mobility decreased
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gouty tophus
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle spasms
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle twitching
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteolysis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoporotic fracture
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sacroiliitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sarcopenia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	78 / 1937 (4.03%)	75 / 1933 (3.88%)	3 / 3872 (0.08%)
occurrences causally related to treatment / all	0 / 90	0 / 81	0 / 3
deaths causally related to treatment / all	0 / 10	0 / 4	0 / 0
COVID-19
subjects affected / exposed	39 / 1937 (2.01%)	33 / 1933 (1.71%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 39	0 / 33	0 / 1
deaths causally related to treatment / all	0 / 10	0 / 4	0 / 0
Urinary tract infection
subjects affected / exposed	33 / 1937 (1.70%)	36 / 1933 (1.86%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 34	0 / 38	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	19 / 1937 (0.98%)	14 / 1933 (0.72%)	3 / 3872 (0.08%)
occurrences causally related to treatment / all	0 / 22	0 / 15	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	14 / 1937 (0.72%)	19 / 1933 (0.98%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 15	0 / 19	0 / 0
deaths causally related to treatment / all	1 / 5	0 / 1	0 / 0
Peritonitis
subjects affected / exposed	21 / 1937 (1.08%)	10 / 1933 (0.52%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 28	0 / 15	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	7 / 1937 (0.36%)	10 / 1933 (0.52%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	7 / 1937 (0.36%)	10 / 1933 (0.52%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 11	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Osteomyelitis
subjects affected / exposed	7 / 1937 (0.36%)	8 / 1933 (0.41%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	5 / 1937 (0.26%)	10 / 1933 (0.52%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	7 / 1937 (0.36%)	7 / 1933 (0.36%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	8 / 1937 (0.41%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	7 / 1937 (0.36%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 3	0 / 0
Device related sepsis
subjects affected / exposed	7 / 1937 (0.36%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 8	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	7 / 1937 (0.36%)	5 / 1933 (0.26%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 7	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	4 / 1937 (0.21%)	7 / 1933 (0.36%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	3 / 1937 (0.15%)	7 / 1933 (0.36%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	4 / 1937 (0.21%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suspected COVID-19
subjects affected / exposed	2 / 1937 (0.10%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Pyelonephritis acute
subjects affected / exposed	4 / 1937 (0.21%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 1937 (0.05%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	5 / 1937 (0.26%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	2 / 1937 (0.10%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	2 / 1937 (0.10%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	1 / 1937 (0.05%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site infection
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	3 / 1937 (0.15%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute hepatitis B
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	3 / 1937 (0.15%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endophthalmitis
subjects affected / exposed	3 / 1937 (0.15%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	3 / 1937 (0.15%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 1937 (0.00%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related bacteraemia
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterobacter sepsis
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fungal peritonitis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 1937 (0.00%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendiceal abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous graft site infection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis staphylococcal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium bacteraemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis klebsiella
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Dengue haemorrhagic fever
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis intestinal haemorrhagic
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis intestinal perforated
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eczema infected
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Emphysematous pyelonephritis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterococcal sepsis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis Escherichia coli
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis bacillus
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cyst infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes ophthalmic
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incision site abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected fistula
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective tenosynovitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Listeria sepsis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parotitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia adenoviral
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia escherichia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonas bronchitis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomonas infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst infection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal graft infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic arthritis staphylococcal
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Serratia sepsis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinusitis fungal
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sphingomonas paucimobilis infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tuberculosis
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteritis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection staphylococcal
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular access site infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular graft infection
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fungal infection
subjects affected / exposed	0 / 1937 (0.00%)	0 / 1933 (0.00%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	26 / 1937 (1.34%)	25 / 1933 (1.29%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 26	0 / 26	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Fluid overload
subjects affected / exposed	25 / 1937 (1.29%)	23 / 1933 (1.19%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 27	0 / 24	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	16 / 1937 (0.83%)	13 / 1933 (0.67%)	2 / 3872 (0.05%)
occurrences causally related to treatment / all	0 / 20	0 / 16	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	10 / 1937 (0.52%)	16 / 1933 (0.83%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 12	0 / 20	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	7 / 1937 (0.36%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	7 / 1937 (0.36%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 9	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	3 / 1937 (0.15%)	5 / 1933 (0.26%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	3 / 1937 (0.15%)	4 / 1933 (0.21%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	4 / 1937 (0.21%)	3 / 1933 (0.16%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 1937 (0.05%)	6 / 1933 (0.31%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	4 / 1937 (0.21%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	4 / 1937 (0.21%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 1937 (0.05%)	3 / 1933 (0.16%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	2 / 1937 (0.10%)	2 / 1933 (0.10%)	1 / 3872 (0.03%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	3 / 1937 (0.15%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	2 / 1937 (0.10%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iron deficiency
subjects affected / exposed	1 / 1937 (0.05%)	2 / 1933 (0.10%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	2 / 1937 (0.10%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 1937 (0.05%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abnormal loss of weight
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acidosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperammonaemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperinsulinaemic hypoglycaemia
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemic syndrome
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic syndrome
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudohyponatraemia
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Refeeding syndrome
subjects affected / exposed	0 / 1937 (0.00%)	1 / 1933 (0.05%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Starvation ketoacidosis
subjects affected / exposed	1 / 1937 (0.05%)	0 / 1933 (0.00%)	0 / 3872 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Daprodustat	Darbepoetin alfa	Run-in Period: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	851 / 1937 (43.93%)	825 / 1933 (42.68%)	0 / 3872 (0.00%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	104 / 1937 (5.37%)	88 / 1933 (4.55%)	0 / 3872 (0.00%)
occurrences all number	128	119	0
Vascular disorders
Hypertension
subjects affected / exposed	247 / 1937 (12.75%)	264 / 1933 (13.66%)	0 / 3872 (0.00%)
occurrences all number	317	339	0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	198 / 1937 (10.22%)	162 / 1933 (8.38%)	0 / 3872 (0.00%)
occurrences all number	239	199	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	149 / 1937 (7.69%)	139 / 1933 (7.19%)	0 / 3872 (0.00%)
occurrences all number	181	172	0
Constipation
subjects affected / exposed	127 / 1937 (6.56%)	88 / 1933 (4.55%)	0 / 3872 (0.00%)
occurrences all number	150	96	0
Nausea
subjects affected / exposed	103 / 1937 (5.32%)	84 / 1933 (4.35%)	0 / 3872 (0.00%)
occurrences all number	120	101	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	82 / 1937 (4.23%)	105 / 1933 (5.43%)	0 / 3872 (0.00%)
occurrences all number	95	110	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	164 / 1937 (8.47%)	153 / 1933 (7.92%)	0 / 3872 (0.00%)
occurrences all number	245	199	0
Nasopharyngitis
subjects affected / exposed	118 / 1937 (6.09%)	133 / 1933 (6.88%)	0 / 3872 (0.00%)
occurrences all number	163	180	0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	128 / 1937 (6.61%)	122 / 1933 (6.31%)	0 / 3872 (0.00%)
occurrences all number	148	141	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Sep 2016

Amendment 1 (Austria, Belgium, Czech Republic, Denmark, Estonia, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and the United Kingdom): Clarified end of the study timing; removed requirement to reduce ESA dose if Week -8 Hgb is >11.5 g/dL; further iron management guidance; new exploratory objective for delayed graft function after deceased donor kidney transplantation

12 Oct 2016

Amendment 2 (Key changes): Applied changes from Amendment 1; added new timepoints at Week -4 and Week 2 for collection of iron therapy and at Week 52 for Kt/Vurea; changes to ambulatory blood pressure monitoring (ABPM) assessments; clarification for those randomized to rhEPO who transition from HD to PD will change from epoetin alfa to darbepoetin alfa; added country-specific requirements for France and Czech Republic

08 Feb 2017

Amendment 2/France-01: Added France only requirements for additional ultrasound added to end of study and for participants who transition to dialysis to permanently discontinue randomized treatment.

05 Oct 2017

Amendment 3 (Key changes): Added retest for Hgb and TSAT for entry; broadened exclusion to include participation in interventional study with investigational agent or device; added provisions for use of local standard of care; revised statistical section to change from two-sided testing at the 5% level to one-sided testing at the 2.5% level; correct the comparator for the Null and Alternative hypotheses; changed significance levels to p-values; added description of the adjustments to statistical model; updated hyporesponder analyses; added text regarding the interim analysis process; added exploratory endpoints around Hgb variability, iron parameters, transfusions and dose adjustment scheme; added provision for possible change to Dose Adjustment Algorithm based review of blinded instream aggregate Hgb data; updated Risk Assessment to align with Investigator’s Brochure, version 8; simplified ABPM sub-study

09 Oct 2017

Amendment 3/France-01: Apply changes from global amendment 3

16 Aug 2019

Amendment 4: Added retest values for Hgb entry at Day 1, an additional retest opportunity for TSAT for eligibility at W-8, and revised the definition of current uncontrolled hypertension; added autosomal dominant polycystic kidney disease (ADPKD) risk information and requirements for patients with ADPKD; added new adverse event of special interest of worsening of hypertension; added secondary objective/endpoint to assess renal progression via change in eGFR; updated Risk Assessment to align with Investigator’s Brochure, version 10; stated recruitment in the ABPM sub-study is closed; PK sub-study entry criteria to exclude patients transitioning or already transitioned to dialysis

16 Aug 2019

Amendment 4/France-01: Apply changes from global amendment 4 plus update France administrative considerations

30 Jul 2020

Amendment 5: Revised MACE NI margin and target MACE as a result of the NI margin change; updated analysis of the Hgb co-primary endpoint and multiplicity adjustment strategy from Hommel to Holm-Bonferroni based on FDA feedback; updated pregnancy reporting timelines to align with revised Sponsor timings

30 Jul 2020

Amendment No. 05/FRA-01: Apply changes from global amendment 4

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A phase 3 randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven study in non-dialysis subjects with anemia associated with chronic kidney disease to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to first occurrence of adjudicated major adverse cardiovascular event (MACE) during cardiovascular (CV) events follow-up time period (non-inferiority analysis)

Primary: Time to first occurrence of adjudicated major adverse cardiovascular event (MACE) during cardiovascular (CV) events follow-up time period (non-inferiority analysis)

Primary: Mean Change from Baseline in Hgb levels over the Evaluation Period (Week 28 to Week 52)

Primary: Mean Change from Baseline in Hgb levels over the Evaluation Period (Week 28 to Week 52)

Secondary: Time to first occurrence of adjudicated MACE during CV events follow-up time period (Superiority analysis)

Secondary: Time to first occurrence of adjudicated MACE during CV events follow-up time period (Superiority analysis)

Secondary: Time to first occurrence of adjudicated MACE or thromboembolic event during CV events follow-up time period

Secondary: Time to first occurrence of adjudicated MACE or thromboembolic event during CV events follow-up time period

Secondary: Time to first occurrence of adjudicated MACE or hospitalization for heart failure during CV events follow-up time period

Secondary: Time to first occurrence of adjudicated MACE or hospitalization for heart failure during CV events follow-up time period

Secondary: Time to First Occurrence of chronic kidney disease (CKD) Progression during CV events follow-up time period

Secondary: Time to First Occurrence of chronic kidney disease (CKD) Progression during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated All-Cause Mortality during Vital Status for follow-up time period

Secondary: Time to First occurrence of Adjudicated All-Cause Mortality during Vital Status for follow-up time period

Secondary: Time to First occurrence of Adjudicated CV Mortality during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated CV Mortality during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated Stroke (Fatal and Non-Fatal) during CV events follow-up time period

Secondary: Time to First occurrence of Adjudicated Stroke (Fatal and Non-Fatal) during CV events follow-up time period

Secondary: Number of Participants with Adjudicated MACE or Hospitalization for Heart Failure (Recurrent events analysis)

Secondary: Number of Participants with Adjudicated MACE or Hospitalization for Heart Failure (Recurrent events analysis)

Secondary: Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI during CV events follow-up time period

Secondary: Time to First Occurrence of All-Cause Hospitalization during CV events follow-up time period

Secondary: Time to First Occurrence of All-Cause Hospitalization during CV events follow-up time period

Secondary: Time to First Occurrence of All-Cause Hospital Re-admission within 30 Days during CV events follow-up time period

Secondary: Time to First Occurrence of All-Cause Hospital Re-admission within 30 Days during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic events during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic events during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated Hospitalization for Heart Failure during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated Hospitalization for Heart Failure during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated Thromboembolic Events during CV events follow-up time period

Secondary: Time to First Occurrence of Adjudicated Thromboembolic Events during CV events follow-up time period

Secondary: Time to First Occurrence of Confirmed 40% Decline in eGFR during CV events follow-up time period

Secondary: Time to First Occurrence of Confirmed 40% Decline in eGFR during CV events follow-up time period

Secondary: Time to First Occurrence of Chronic Dialysis during CV events follow-up time period

Secondary: Time to First Occurrence of Chronic Dialysis during CV events follow-up time period

Secondary: Time to First Occurrence of Kidney Transplant during CV events follow-up time period

Secondary: Time to First Occurrence of Kidney Transplant during CV events follow-up time period

Secondary: Change From Baseline in Post-randomization Hgb levels at Week 52

Secondary: Change From Baseline in Post-randomization Hgb levels at Week 52

Secondary: Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

Secondary: Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority analysis

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority analysis

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Non-inferiority analysis

Secondary: Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Non-inferiority analysis

Secondary: Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Superiority analysis

Secondary: Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of study): Superiority analysis

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

Secondary: Blood Pressure (BP) Exacerbation Event Rate per 100 Participant Years

Secondary: Blood Pressure (BP) Exacerbation Event Rate per 100 Participant Years

Secondary: Number of Participants with at Least one BP Exacerbation Event During Study

Secondary: Number of Participants with at Least one BP Exacerbation Event During Study

Secondary: Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

Secondary: Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

Secondary: Change from Baseline in On-treatment Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment Vitality scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in On-treatment Vitality scores using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Clinical Trial Results:
A phase 3 randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven study in non-dialysis subjects with anemia associated with chronic kidney disease to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa