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Clinical Trial Results:
Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy and Safety of Oral Vadadustat for the Correction of Anemia in Subjects with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) (PRO2TECT - CORRECTION)

Summary
EudraCT number	2015-004265-81
Trial protocol	HU ES BG GB IT
Global end of trial date	04 Jun 2020

Results information
Results version number	v1(current)
This version publication date	20 Jun 2021
First version publication date	20 Jun 2021
Other versions

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

AKB-6548-CI-0014

ISRCTN number

-

US NCT number

NCT02648347

WHO universal trial number (UTN)

-

Sponsor organisation name

Akebia Therapeutics, Inc.

Sponsor organisation address

245 First Street, Suite 1400, Cambridge, Massachusetts, United States, 02142

Public contact

Clinical Trial Information Desk, Akebia Therapeutics, Inc., +1 617-844-6128, trials@akebia.com

Scientific contact

Steven Burke, Chief Medical Officer, Akebia Therapeutics, Inc., +1 617-844-6128, trials@akebia.com

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

31 Jul 2020

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

04 Jun 2020

Was the trial ended prematurely?

No

Main objective of the trial

The primary objectives of this study was to demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for the correction and maintenance of hemoglobin (Hb) in subjects with anemia secondary to non-dialysis-dependent chronic kidney disease (NDD-CKD).

Protection of trial subjects

The study was conducted in full compliance with the principles of the “Declaration of Helsinki" (as amended in Tokyo, Venice, Hong Kong, and South Africa), International Council for Harmonisation (ICH) guidelines, and all of the applicable United States Code of Federal Regulations 21 (US CFR 21 CFR Part 50 and 312).

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

17 Dec 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 51

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Brazil: 120

Country: Number of subjects enrolled

Bulgaria: 83

Country: Number of subjects enrolled

Hungary: 15

Country: Number of subjects enrolled

Israel: 4

Country: Number of subjects enrolled

Italy: 16

Country: Number of subjects enrolled

Korea, Republic of: 16

Country: Number of subjects enrolled

Mexico: 91

Country: Number of subjects enrolled

Russian Federation: 17

Country: Number of subjects enrolled

South Africa: 103

Country: Number of subjects enrolled

Spain: 10

Country: Number of subjects enrolled

Ukraine: 131

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

United States: 1061

Worldwide total number of subjects

1751

EEA total number of subjects

124

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

772

From 65 to 84 years

869

85 years and over

110

Subject disposition

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Recruitment details

-

Screening details

A total of 4708 subjects were screened for entry into the study. Of these, 1751 subjects were enrolled and randomized into 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

Vadadustat

Arm description

Subjects were randomized to receive vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements every 4 weeks to maintain target Hb levels.

Arm type

Experimental

Investigational medicinal product name

Vadadustat

Investigational medicinal product code

Other name

AKB-6548

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

150 mg white to off-white, round, bi-convex film-coated tablets for oral administration with a starting dose of 300 mg/day

Darbepoetin alfa

Arm description

Subjects were randomized to darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult subjects with chronic kidney disease not on dialysis. For subjects already on darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.

Arm type

Active comparator

Investigational medicinal product name

Darbepoetin Alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Intravenous use

Dosage and administration details

pre-filled syringes as an injectable solution for intravenous (IV) administration

Investigational medicinal product name

Darbepoetin Alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

pre-filled syringes as an injectable solution for subcutaneous (SC) administration

Number of subjects in period 1	Vadadustat	Darbepoetin alfa
Started	879	872
Completed	670	675
Not completed	209	197
Consent withdrawn by subject	16	9
Death	174	167
Lost to follow-up	18	21
Missing	1	-

Baseline characteristics

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Reporting group title

Vadadustat

Reporting group description

Subjects were randomized to receive vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements every 4 weeks to maintain target Hb levels.

Reporting group title

Darbepoetin alfa

Reporting group description

Subjects were randomized to darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult subjects with chronic kidney disease not on dialysis. For subjects already on darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.

Reporting group values	Vadadustat	Darbepoetin alfa	Total
Number of subjects	879	872	1751
Age categorical
Units:
Age continuous
Units: years
arithmetic mean (standard deviation)	65.2 ( 14.27 )	64.9 ( 13.71 )	-
Gender categorical
Units: Subjects
Female	475	506	981
Male	404	366	770
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	22	23	45
Asian	48	37	85
Black or African American	188	172	360
Native Hawaiian or Other Pacific Islander	6	6	12
White	546	571	1117
Not Reported	5	6	11
Reported as Other	58	48	106
Multiple	6	9	15
Average hemoglobin
Units: grams per deciliter (g/dL)
arithmetic mean (standard deviation)	9.113 ( 0.8015 )	9.142 ( 0.7790 )	-

End points

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Reporting group title

Vadadustat

Reporting group description

Subjects were randomized to receive vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements every 4 weeks to maintain target Hb levels.

Reporting group title

Darbepoetin alfa

Reporting group description

Subjects were randomized to darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult subjects with chronic kidney disease not on dialysis. For subjects already on darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.

Primary: Change in Average Hemoglobin (Hb) between Baseline and the Primary Efficacy Period (Weeks 24 to 36)

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End point title

Change in Average Hemoglobin (Hb) between Baseline and the Primary Efficacy Period (Weeks 24 to 36)

End point description

Change from Baseline was calculated as the Primary Efficacy Period value minus the Baseline value. The Primary Efficacy Period was comprised of Weeks 24 to 36. Analysis was conducted in members of the Randomized Population, comprised of all subjects randomized. Analyses of this population were based on the randomized treatment. Analysis was conducted using an analysis of covariance (ANCOVA) model with multiple imputation for missing data with Baseline hemoglobin concentration, region, and New York Heart Association congestive heart failure (NYHA CHF) class as covariates.

End point type

Primary

End point timeframe

Baseline; Weeks 24 to 36

End point values	Vadadustat	Darbepoetin alfa
Number of subjects analysed	879 ^[1]	872 ^[2]
Units: milligrams per deciliter (mg/dL)
least squares mean (standard error)	1.43 ( 0.046 )	1.38 ( 0.047 )

Notes
[1] - Randomized Population
[2] - Randomized Population

ANCOVA with Multiple Imputation

Statistical analysis description

Treatment comparison: Vadadustat minus Darbepoetin Alfa

Comparison groups

Vadadustat v Darbepoetin alfa

Number of subjects included in analysis

1751

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Least squares mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[3] - Establishment of non-inferiority was based on a margin of -0.75 g/dL applied to the difference in mean change of hemoglobin: vadadustat minus darbepoetin alfa

Secondary: Change in Average Hemoglobin (Hb) between Baseline and the Secondary Efficacy Period (Weeks 40 to 52)

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End point title

Change in Average Hemoglobin (Hb) between Baseline and the Secondary Efficacy Period (Weeks 40 to 52)

End point description

Change from Baseline was calculated as the Secondary Efficacy Period value minus the Baseline value. The Secondary Efficacy Period was comprised of Weeks 40 to 52. Analysis was conducted using an ANCOVA model with multiple imputation for missing data with Baseline hemoglobin concentration, region, and NYHA CHF class as covariates.

End point type

Secondary

End point timeframe

Baseline; Weeks 40 to 52

End point values	Vadadustat	Darbepoetin alfa
Number of subjects analysed	879 ^[4]	872 ^[5]
Units: mg/dL
least squares mean (standard error)	1.52 ( 0.052 )	1.48 ( 0.053 )

Notes
[4] - Randomized Population
[5] - Randomized Population

ANCOVA with Multiple Imputation

Statistical analysis description

Treatment comparison: Vadadustat minus Darbepoetin Alfa

Comparison groups

Vadadustat v Darbepoetin alfa

Number of subjects included in analysis

1751

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

Least squares mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.06

upper limit

0.14

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[6] - Establishment of non-inferiority was based on a margin of -0.75 g/dL applied to the difference in mean change of hemoglobin: vadadustat minus darbepoetin alfa

Adverse events

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Timeframe for reporting adverse events

up to 168 weeks

Adverse event reporting additional description

Treatment-emergent adverse events (TEAEs), defined as adverse events (AEs) that began (or pre-existing AEs that worsened) or or after the first dose, are reported.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Vadadustat

Reporting group description

Subjects were randomized to receive vadadustat at an initial oral dose of 300 milligrams per day (mg/day). Thereafter, vadadustat was taken once daily on an outpatient basis. Up-and-down titration to 150, 300, 450, and 600 mg (available tablet strength was administered as the appropriate number of 150 mg tablets) was allowed during the study based on hemoglobin (Hb) level measurements every 4 weeks to maintain target Hb levels.

Reporting group title

Darbepoetin alfa

Reporting group description

Subjects were randomized to darbepoetin alfa at an initial dose that was based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics (SmPC) for all other investigational sites (non-US) for adult subjects with chronic kidney disease not on dialysis. For subjects already on darbepoetin alfa, the initial dosing regimen in the study was based on the prior dosing regimen.

Serious adverse events	Vadadustat	Darbepoetin alfa
Total subjects affected by serious adverse events
subjects affected / exposed	573 / 878 (65.26%)	561 / 870 (64.48%)
number of deaths (all causes)	180	168
number of deaths resulting from adverse events	177	165
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	1 / 878 (0.11%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 878 (0.11%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Adenocarcinoma of colon
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Bladder transitional cell carcinoma
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Malignant melanoma
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myelofibrosis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Adrenal neoplasm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Astrocytoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Astrocytoma, low grade
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervix carcinoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon neoplasm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric leiomyoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intraductal papillary mucinous neoplasm
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung carcinoma cell type unspecified recurrent
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Malignant pleural effusion
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Marginal zone lymphoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic bronchial carcinoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-small cell lung cancer metastatic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Oesophageal squamous cell carcinoma stage 0
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ovarian cancer metastatic
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Papillary renal cell carcinoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Plasma cell myeloma recurrent
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectosigmoid cancer stage IV
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Transitional cell carcinoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertensive urgency
subjects affected / exposed	9 / 878 (1.03%)	11 / 870 (1.26%)
occurrences causally related to treatment / all	1 / 9	1 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	6 / 878 (0.68%)	10 / 870 (1.15%)
occurrences causally related to treatment / all	0 / 8	1 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	4 / 878 (0.46%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 4	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	6 / 878 (0.68%)	7 / 870 (0.80%)
occurrences causally related to treatment / all	0 / 6	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	6 / 878 (0.68%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	1 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	2 / 878 (0.23%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	4 / 878 (0.46%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 878 (0.00%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	4 / 878 (0.46%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Peripheral ischaemia
subjects affected / exposed	3 / 878 (0.34%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Steal syndrome
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Accelerated hypertension
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic vascular disorder
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic aneurysm rupture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic rupture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Arteriosclerosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Essential hypertension
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iliac artery perforation
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Internal haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous perforation
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Arteriovenous fistula operation
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	23 / 878 (2.62%)	19 / 870 (2.18%)
occurrences causally related to treatment / all	0 / 23	2 / 19
deaths causally related to treatment / all	0 / 23	2 / 19
Asthenia
subjects affected / exposed	9 / 878 (1.03%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	6 / 878 (0.68%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	4 / 878 (0.46%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Chest pain
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related thrombosis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Systemic inflammatory response syndrome
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental death
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac death
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chest discomfort
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Complication of device insertion
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Anti-neutrophil cytoplasmic antibody positive vasculitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal transplant failure
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Social circumstances
Physical disability
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Benign prostatic hyperplasia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic ovarian cyst
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varicocele
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	15 / 878 (1.71%)	18 / 870 (2.07%)
occurrences causally related to treatment / all	0 / 27	0 / 20
deaths causally related to treatment / all	0 / 1	0 / 4
Pulmonary oedema
subjects affected / exposed	8 / 878 (0.91%)	13 / 870 (1.49%)
occurrences causally related to treatment / all	0 / 9	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 1
Chronic obstructive pulmonary disease
subjects affected / exposed	7 / 878 (0.80%)	11 / 870 (1.26%)
occurrences causally related to treatment / all	0 / 9	0 / 19
deaths causally related to treatment / all	0 / 0	0 / 2
Pleural effusion
subjects affected / exposed	6 / 878 (0.68%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 10	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	8 / 878 (0.91%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 8	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	5 / 878 (0.57%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 3	0 / 2
Respiratory failure
subjects affected / exposed	6 / 878 (0.68%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Acute pulmonary oedema
subjects affected / exposed	6 / 878 (0.68%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	2 / 878 (0.23%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiogenic pulmonary oedema
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary arterial hypertension
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Psychiatric disorders
Mental status changes
subjects affected / exposed	4 / 878 (0.46%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	1 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychotic disorder
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Device adhesion issue
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	4 / 878 (0.46%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute hepatic failure
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis toxic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic hepatitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Non-alcoholic steatohepatitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Transaminases increased
subjects affected / exposed	7 / 878 (0.80%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	5 / 8	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	3 / 878 (0.34%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	3 / 878 (0.34%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Troponin increased
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anticoagulation drug level above therapeutic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriogram carotid abnormal
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatine increased
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood glucose decreased
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood pressure increased
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerular filtration rate decreased
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heart rate irregular
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme abnormal
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary arterial pressure increased
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	12 / 878 (1.37%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 13	0 / 10
deaths causally related to treatment / all	0 / 1	0 / 0
Hip fracture
subjects affected / exposed	5 / 878 (0.57%)	7 / 870 (0.80%)
occurrences causally related to treatment / all	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	2 / 878 (0.23%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	3 / 878 (0.34%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	3 / 878 (0.34%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	2 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 878 (0.11%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	2 / 878 (0.23%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Thoracic vertebral fracture
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 878 (0.00%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula aneurysm
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fractured sacrum
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iatrogenic injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Keratorhexis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lisfranc fracture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic bone injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal dialysis complication
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postpericardiotomy syndrome
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural dizziness
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural nausea
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary contusion
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin injury
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Urinary tract stoma complication
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access malfunction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site pseudoaneurysm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvovaginal injury
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Gastrointestinal arteriovenous malformation
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous malformation
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	40 / 878 (4.56%)	39 / 870 (4.48%)
occurrences causally related to treatment / all	1 / 50	0 / 48
deaths causally related to treatment / all	0 / 2	0 / 4
Acute myocardial infarction
subjects affected / exposed	32 / 878 (3.64%)	27 / 870 (3.10%)
occurrences causally related to treatment / all	0 / 34	1 / 30
deaths causally related to treatment / all	0 / 2	0 / 3
Cardiac failure acute
subjects affected / exposed	21 / 878 (2.39%)	24 / 870 (2.76%)
occurrences causally related to treatment / all	0 / 25	1 / 28
deaths causally related to treatment / all	0 / 3	0 / 3
Cardiac arrest
subjects affected / exposed	23 / 878 (2.62%)	16 / 870 (1.84%)
occurrences causally related to treatment / all	1 / 23	1 / 16
deaths causally related to treatment / all	1 / 21	0 / 11
Cardiac failure
subjects affected / exposed	15 / 878 (1.71%)	12 / 870 (1.38%)
occurrences causally related to treatment / all	0 / 17	0 / 19
deaths causally related to treatment / all	0 / 4	0 / 1
Coronary artery disease
subjects affected / exposed	12 / 878 (1.37%)	12 / 870 (1.38%)
occurrences causally related to treatment / all	0 / 16	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	9 / 878 (1.03%)	12 / 870 (1.38%)
occurrences causally related to treatment / all	0 / 9	0 / 14
deaths causally related to treatment / all	0 / 7	0 / 10
Atrial fibrillation
subjects affected / exposed	11 / 878 (1.25%)	8 / 870 (0.92%)
occurrences causally related to treatment / all	0 / 14	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Acute left ventricular failure
subjects affected / exposed	8 / 878 (0.91%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	5 / 878 (0.57%)	8 / 870 (0.92%)
occurrences causally related to treatment / all	0 / 5	1 / 8
deaths causally related to treatment / all	0 / 3	1 / 4
Angina unstable
subjects affected / exposed	3 / 878 (0.34%)	8 / 870 (0.92%)
occurrences causally related to treatment / all	0 / 3	2 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	3 / 878 (0.34%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 2
Cardiogenic shock
subjects affected / exposed	6 / 878 (0.68%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 5	0 / 0
Angina pectoris
subjects affected / exposed	5 / 878 (0.57%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 878 (0.11%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Atrioventricular block complete
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 878 (0.00%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Arteriosclerosis coronary artery
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Atrial thrombosis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Ventricular tachycardia
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adams-Stokes syndrome
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial tachycardia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bundle branch block
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac valve disease
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiomegaly
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Chronic left ventricular failure
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery thrombosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Diastolic dysfunction
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular dysfunction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis uraemic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Right ventricular dysfunction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systolic dysfunction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	9 / 878 (1.03%)	12 / 870 (1.38%)
occurrences causally related to treatment / all	0 / 10	0 / 13
deaths causally related to treatment / all	0 / 2	0 / 1
Metabolic encephalopathy
subjects affected / exposed	9 / 878 (1.03%)	10 / 870 (1.15%)
occurrences causally related to treatment / all	0 / 10	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	7 / 878 (0.80%)	7 / 870 (0.80%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	5 / 878 (0.57%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Uraemic encephalopathy
subjects affected / exposed	7 / 878 (0.80%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 5	0 / 1
Transient ischaemic attack
subjects affected / exposed	6 / 878 (0.68%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	3 / 878 (0.34%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Brain injury
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Cerebral infarction
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Encephalopathy
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 878 (0.00%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Seizure
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid arteriosclerosis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular disorder
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dysarthria
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tremor
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ataxia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Autonomic neuropathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Basal ganglia infarction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain stem haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Brain stem stroke
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar stroke
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral arteriosclerosis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral small vessel ischaemic disease
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coma
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Focal dyscognitive seizures
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic encephalopathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoglycaemic seizure
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemic seizure
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Migraine
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myoclonus
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VIth nerve paralysis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular dementia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	18 / 878 (2.05%)	24 / 870 (2.76%)
occurrences causally related to treatment / all	1 / 22	0 / 25
deaths causally related to treatment / all	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	12 / 878 (1.37%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 13	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Nephrogenic anaemia
subjects affected / exposed	5 / 878 (0.57%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukaemoid reaction
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy mediastinal
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombotic thrombocytopenic purpura
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal vein thrombosis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vitreous haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blindness
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic retinopathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uveitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vision blurred
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	10 / 878 (1.14%)	10 / 870 (1.15%)
occurrences causally related to treatment / all	0 / 16	0 / 11
deaths causally related to treatment / all	0 / 1	0 / 0
Diarrhoea
subjects affected / exposed	9 / 878 (1.03%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	1 / 9	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	3 / 878 (0.34%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	4 / 878 (0.46%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	4 / 878 (0.46%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Pancreatitis acute
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Uraemic gastropathy
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Mallory-Weiss syndrome
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic gastroparesis
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peptic ulcer haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cyclic vomiting syndrome
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dieulafoy's vascular malformation
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Diverticulum intestinal
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric antral vascular ectasia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric varices haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal ulcer haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoperitoneum
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal infarction
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intussusception
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mesenteric artery thrombosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Odynophagia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic necrosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reflux gastritis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	5 / 878 (0.57%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatitis allergic
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dermal cyst
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic wound
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ingrowing nail
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
End stage renal disease
subjects affected / exposed	292 / 878 (33.26%)	292 / 870 (33.56%)
occurrences causally related to treatment / all	1 / 299	0 / 299
deaths causally related to treatment / all	0 / 19	0 / 30
Acute kidney injury
subjects affected / exposed	42 / 878 (4.78%)	40 / 870 (4.60%)
occurrences causally related to treatment / all	0 / 52	0 / 43
deaths causally related to treatment / all	0 / 2	0 / 3
Chronic kidney disease
subjects affected / exposed	15 / 878 (1.71%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 15	0 / 9
deaths causally related to treatment / all	0 / 3	0 / 4
Diabetic nephropathy
subjects affected / exposed	8 / 878 (0.91%)	12 / 870 (1.38%)
occurrences causally related to treatment / all	0 / 8	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 1
Azotaemia
subjects affected / exposed	8 / 878 (0.91%)	9 / 870 (1.03%)
occurrences causally related to treatment / all	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 3	0 / 1
Renal failure
subjects affected / exposed	9 / 878 (1.03%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 9	0 / 1
deaths causally related to treatment / all	0 / 6	0 / 1
Glomerulonephritis
subjects affected / exposed	2 / 878 (0.23%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive nephropathy
subjects affected / exposed	2 / 878 (0.23%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Renal tubular necrosis
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Hydronephrosis
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis chronic
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder outlet obstruction
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder perforation
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis rapidly progressive
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydroureter
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
IgA nephropathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lupus nephritis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephritic syndrome
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive nephropathy
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post infection glomerulonephritis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Proteinuria
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal mass
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal tubular acidosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Goitre
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inappropriate antidiuretic hormone secretion
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	4 / 878 (0.46%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	2 / 878 (0.23%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Pain in extremity
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathic arthropathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	60 / 878 (6.83%)	49 / 870 (5.63%)
occurrences causally related to treatment / all	0 / 73	0 / 60
deaths causally related to treatment / all	0 / 5	0 / 3
Sepsis
subjects affected / exposed	28 / 878 (3.19%)	19 / 870 (2.18%)
occurrences causally related to treatment / all	0 / 31	0 / 20
deaths causally related to treatment / all	0 / 5	0 / 3
Urinary tract infection
subjects affected / exposed	19 / 878 (2.16%)	13 / 870 (1.49%)
occurrences causally related to treatment / all	0 / 25	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	16 / 878 (1.82%)	13 / 870 (1.49%)
occurrences causally related to treatment / all	0 / 19	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 1
Septic shock
subjects affected / exposed	12 / 878 (1.37%)	11 / 870 (1.26%)
occurrences causally related to treatment / all	0 / 14	0 / 11
deaths causally related to treatment / all	0 / 6	0 / 5
Peritonitis
subjects affected / exposed	9 / 878 (1.03%)	8 / 870 (0.92%)
occurrences causally related to treatment / all	0 / 9	0 / 10
deaths causally related to treatment / all	0 / 2	0 / 2
Gastroenteritis
subjects affected / exposed	9 / 878 (1.03%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 11	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	6 / 878 (0.68%)	8 / 870 (0.92%)
occurrences causally related to treatment / all	0 / 8	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	7 / 878 (0.80%)	7 / 870 (0.80%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Gangrene
subjects affected / exposed	7 / 878 (0.80%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 7	0 / 6
deaths causally related to treatment / all	0 / 2	0 / 0
Influenza
subjects affected / exposed	6 / 878 (0.68%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	7 / 878 (0.80%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 9	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	5 / 878 (0.57%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 1
Bronchitis
subjects affected / exposed	3 / 878 (0.34%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	2 / 878 (0.23%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 878 (0.23%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Device related infection
subjects affected / exposed	5 / 878 (0.57%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 878 (0.11%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	5 / 878 (0.57%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	3 / 878 (0.34%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	4 / 878 (0.46%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	2 / 878 (0.23%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Clostridium difficile infection
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	2 / 878 (0.23%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site infection
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis gangrenous
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis klebsiella
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Device related sepsis
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Gas gangrene
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection staphylococcal
subjects affected / exposed	0 / 878 (0.00%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection staphylococcal
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound sepsis
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal wall abscess
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute hepatitis C
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous graft site infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter bacteraemia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis staphylococcal
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic hepatitis B
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ear infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Emphysematous cystitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis brain stem
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis viral
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis bacterial
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis staphylococcal
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endophthalmitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Furuncle
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis clostridial
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune reconstitution inflammatory syndrome associated tuberculosis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected fistula
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site joint infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising fasciitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising soft tissue infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media acute
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Overgrowth bacterial
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parotitis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia cryptococcal
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic abscess
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal bacteraemia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salmonellosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Scrotal abscess
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal abscess
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma site cellulitis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urogenital infection bacterial
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral sepsis
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound abscess
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	34 / 878 (3.87%)	22 / 870 (2.53%)
occurrences causally related to treatment / all	1 / 42	0 / 36
deaths causally related to treatment / all	0 / 1	0 / 0
Hyperkalaemia
subjects affected / exposed	20 / 878 (2.28%)	26 / 870 (2.99%)
occurrences causally related to treatment / all	0 / 26	0 / 29
deaths causally related to treatment / all	0 / 0	0 / 1
Hypoglycaemia
subjects affected / exposed	18 / 878 (2.05%)	20 / 870 (2.30%)
occurrences causally related to treatment / all	0 / 23	0 / 21
deaths causally related to treatment / all	0 / 1	0 / 0
Dehydration
subjects affected / exposed	4 / 878 (0.46%)	11 / 870 (1.26%)
occurrences causally related to treatment / all	0 / 4	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	9 / 878 (1.03%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 11	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	6 / 878 (0.68%)	5 / 870 (0.57%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Hyponatraemia
subjects affected / exposed	4 / 878 (0.46%)	6 / 870 (0.69%)
occurrences causally related to treatment / all	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	7 / 878 (0.80%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	5 / 878 (0.57%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	4 / 878 (0.46%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	5 / 878 (0.57%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 878 (0.11%)	4 / 870 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	3 / 878 (0.34%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 878 (0.11%)	3 / 870 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Calciphylaxis
subjects affected / exposed	1 / 878 (0.11%)	2 / 870 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Diabetic metabolic decompensation
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	3 / 878 (0.34%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	2 / 878 (0.23%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Malnutrition
subjects affected / exposed	1 / 878 (0.11%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acidosis
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperosmolar state
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoosmolar state
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 878 (0.00%)	1 / 870 (0.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vitamin B1 deficiency
subjects affected / exposed	1 / 878 (0.11%)	0 / 870 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0

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

Non-serious adverse events	Vadadustat	Darbepoetin alfa
Total subjects affected by non serious adverse events
subjects affected / exposed	561 / 878 (63.90%)	565 / 870 (64.94%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	74 / 878 (8.43%)	80 / 870 (9.20%)
occurrences all number	90	112
Vascular disorders
Hypertension
subjects affected / exposed	151 / 878 (17.20%)	186 / 870 (21.38%)
occurrences all number	186	237
Hypotension
subjects affected / exposed	49 / 878 (5.58%)	49 / 870 (5.63%)
occurrences all number	61	58
Nervous system disorders
Headache
subjects affected / exposed	46 / 878 (5.24%)	42 / 870 (4.83%)
occurrences all number	52	47
Dizziness
subjects affected / exposed	45 / 878 (5.13%)	34 / 870 (3.91%)
occurrences all number	47	36
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	110 / 878 (12.53%)	89 / 870 (10.23%)
occurrences all number	126	98
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	114 / 878 (12.98%)	85 / 870 (9.77%)
occurrences all number	141	108
Nausea
subjects affected / exposed	87 / 878 (9.91%)	71 / 870 (8.16%)
occurrences all number	100	88
Constipation
subjects affected / exposed	74 / 878 (8.43%)	72 / 870 (8.28%)
occurrences all number	80	80
Vomiting
subjects affected / exposed	60 / 878 (6.83%)	52 / 870 (5.98%)
occurrences all number	67	67
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	47 / 878 (5.35%)	58 / 870 (6.67%)
occurrences all number	51	62
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	55 / 878 (6.26%)	45 / 870 (5.17%)
occurrences all number	61	46
Arthralgia
subjects affected / exposed	45 / 878 (5.13%)	47 / 870 (5.40%)
occurrences all number	49	50
Infections and infestations
Urinary tract infection
subjects affected / exposed	98 / 878 (11.16%)	94 / 870 (10.80%)
occurrences all number	136	127
Upper respiratory tract infection
subjects affected / exposed	50 / 878 (5.69%)	70 / 870 (8.05%)
occurrences all number	61	93
Nasopharyngitis
subjects affected / exposed	50 / 878 (5.69%)	48 / 870 (5.52%)
occurrences all number	57	60
Bronchitis
subjects affected / exposed	28 / 878 (3.19%)	46 / 870 (5.29%)
occurrences all number	31	47
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	93 / 878 (10.59%)	121 / 870 (13.91%)
occurrences all number	110	136
Hyperphosphataemia
subjects affected / exposed	64 / 878 (7.29%)	63 / 870 (7.24%)
occurrences all number	66	65
Metabolic acidosis
subjects affected / exposed	63 / 878 (7.18%)	48 / 870 (5.52%)
occurrences all number	72	50
Fluid overload
subjects affected / exposed	45 / 878 (5.13%)	55 / 870 (6.32%)
occurrences all number	53	69
Hypoglycaemia
subjects affected / exposed	46 / 878 (5.24%)	52 / 870 (5.98%)
occurrences all number	65	63

More information

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Were there any global substantial amendments to the protocol? Yes

17 Mar 2016

• Added Exclusion Criterion: “Hypersensitivity to darbepoetin or vadadustat, or to any of their excipients.” • Added that the adrenal function assessment (adrenocorticotropic hormone [ACTH] stimulation test) was to be conducted in a subset of 200 subjects in the European Union (100 subjects from the vadadustat treatment group and 100 subjects from the darbepoetin alfa treatment group) across the 2 non-dialysis-dependent chronic kidney disease (NDD-CKD) studies, AKB 6548-CI-0014 and AKB 6548-CI-0015. • Defined that the study completion date (end of trial) was to take place when 631 major adverse cardiovascular events (MACE) events had accrued over the 2 NDD-CKD studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015). • Clarified that the double-barrier method should have been practiced starting at Screening Visit 1, throughout the study, and for 30 days after the last dose of study drug. • Added that “In case of substantial protocol amendment, the sponsor will obtain approval from responsible Regulatory Authorities before implementation.”

18 Apr 2016

• Updated Exclusion Criteria. • Added hospitalization for heart failure (HF) as an adjudicated safety endpoint in addition to MACE and thromboembolic events. • Clarified that the darbepoetin alfa dosing adjustment guidelines were based on the approved local product label for adult subjects with CKD not on dialysis. • Allowed subjects who transitioned to hemodialysis or peritoneal dialysis during the study to continue to receive study drug (vadadustat or darbepoetin alfa). This is supported by acceptable safety data from a recently-completed Phase 2 trial of vadadustat in subjects with DD-CKD. • Introduced a binary causality system (i.e., “related” or “unrelated”) for clinical trial investigators to assign causality of adverse events to study drugs in accordance with recommendations from the Council for International Organizations of Medical Sciences (CIOMS) VI Working Group. • Following discussions with the United States Food and Drug Administration (US FDA), it was requested that the sparse pharmacokinetic (PK) sampling scheme be described and justified. The results of PK simulations indicated that collection of a sample between 0.25 to 1 hour after administration of the first dose along with sparse samples collected during Weeks 4, 12, 28, and 52 would provide additional information to help characterize the population PK and PK/pharmacodynamic (PD) relationships. • Adverse event reporting related to critically increased liver function test results was aligned with the US FDA Drug-Induced Liver Injury (DILI) guidelines to provide instructions to study sites regarding reporting for improved consistency and case quality. • Added visit windows to provide flexibility to the subjects and the study sites during scheduling of study visits. • Clarified definitions for renal events to improve understanding and site compliance.

08 Jun 2017

• Updated the study design. • Updated Exclusion Criteria. • Increased number of total sites in efforts to increase enrollment. • Updated vadadustat dosing and dose adjustment guidelines to clarify that subjects receiving 1 tablet of dosing prior to interruption were to resume treatment with 1 tablet after interruption. • Clarified that intravenous (IV) iron may have been given to subjects who were intolerant or not responding well to oral iron. • Updated Summary of Clinical Experiences section to reflect information from recently completed trials. • Added details on Executive Steering Committee. • To clarify darbepoetin alfa administration and accountability, the following details were added: o Darbepoetin alfa was changed to be administered per the label. o Darbepoetin alfa was changed to allow doses to be self-administered or administered by health care professional at the clinics, site facility, or at subject’s home according to the investigator’s determination and local practice. o Added additional information on return of darbepoetin alfa for drug accountability and compliance assessment. • Revised Laboratory Evaluations section with details on sample collection. • Provided clarity regarding the study analysis populations.

18 Jan 2018

• Updated to reflect information from recently completed trials and for alignment with vadadustat Investigator’s Brochure. • Added several key secondary, other secondary efficacy endpoints and safety endpoints to align with the Statistical Analysis Plan (SAP). • Section 7.4.1 Retesting was updated for simplification. • Updated to add Lack of Efficacy as a reason for permanent discontinuation of study drug or study participation for accurate data capture. • Revised to clarify that all enrolled subjects in this study were to have completed (at least) the Week 36 visit. • Revised Dosing and Dose Adjustment Guidelines section to guide Investigators. • Updated to align with published guidelines to prescribe iron supplementation and for initiation of ESA rescue. • Updated Dosing Compliance section to specify a range of 80% to 120%. • Updated Prior and Concomitant Therapy section was to include text clarifying that if the duration of the screening period was less than 30 days, all medications taken within 30 days prior to first dose of study drug were to be recorded. • Added Year 2-4 Monthly Hb monitoring section. • Updated Serious Adverse Events section to require all new and recurrent malignancies to be reported as a Serious Adverse Events (SAEs) to standardize reporting. • Updated Special Situations section to add text defining overdose of study drugs. • Updated Sample Size for Primary Efficacy Endpoint section to reflect a change in the non-inferiority margin from -0.5 grams per deciliter (g/dL) to -1.0 g/dL. • Updated Sample Size for the Primary Safety Endpoint section with enrollment projections as well as median study drug exposure times. • Updated Missing Data section to align with SAP. • Updated Subgroups section to pre-specify key subgroups for subsequent analysis. • Updated Analysis of Adverse Events section.

13 Sep 2018

• Updated with revised subject number. • Clarified that all enrolled subjects were allowed to complete the primary efficacy period prior to global study completion (GSC). • Clarified procedures at time of GSC. • Emphasized importance of continuing to follow subjects through GSC. • Updated details related to drug interruption. • Updated timing of End of Trial (EOT) visit and Follow-up visit. • Updated with all options to be considered by the Investigator before a subject withdrew consent. • Included all options available to the Investigator to follow subjects that permanently discontinued study drug. • Detailed steps to support sites in efforts to identify subjects lost to follow-up. • Updated with information for which the Sponsor/Clinical Research Organization will remain blinded. • Clarified restart of study drug after erythropoiesis-stimulating agent (ESA) rescue/red blood cell transfusion. • Provided clarity on study drug dosing after ESA administration. • Added guidance on managing concomitant use of statins with vadadustat. • Updated collection time for AEs. • Added details on managing subjects that permanently stopped study drug and managing subjects on study drug at GSC. • Defined the end of study assessments that documented subject status at GSC or at the time of subject withdrawal or when subject was deemed lost to follow-up or upon death. • Added guidance on managing subjects who developed malignancy while on study drug. • Indicated that Sponsor had defined events that were classified as serious regardless of their assessment. • Clarified AE reporting period. • Updated to reflect how Baseline was calculated for Hb. • Updated noninferiority margin. • Updated definition for primary safety endpoint and how non-inferiority was established between treatment groups. • Defined full analysis population. • Updated with use of analysis of covariance (ANCOVA) with multiple imputation, stratified by the randomization strata and using Baseline Hb as the covariate.

18 Dec 2018

• Updated to include reference to the Pharmacy Manual which provides further details on storage and managing temperature excursions. • Updated to provide further guidance regarding concomitant use of simvastatin drug interactions with vadadustat. • Provided guidance regarding concomitant use of breast cancer resistance protein (BCRP) substrates with vadadustat. • Updated with recent results of investigative toxicology studies. • Liver function tests were increased in Year 2, 3, and 4 to include Week 64, 88, 116, 140, 168, and 192.

26 Feb 2019

• Updated to include a reference to Study Drug Stopping Rules for management of subjects with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) abnormalities. • Include the table of liver function test results that would require permanent discontinuation of vadadustat. • Updated to exclude subjects with elevations in ALT or AST >3 times the upper limit of normal (ULN) with an elevation of total serum bilirubin >2 times the ULN from conditions of temporary discontinuation, as this is now a condition for permanent discontinuation. • Updated to include information defining designated medical events.

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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