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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 Maintenance Treatment of Anemia in Subjects with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) (PRO2TECT - CONVERSION)

Summary
EudraCT number	2015-004774-14
Trial protocol	HU DE AT CZ ES BG SK GB IT
Global end of trial date	18 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-0015

ISRCTN number

-

US NCT number

NCT02680574

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

18 Jun 2020

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study was to demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for the maintenance treatment of anemia in subjects with non-dialysis-dependent chronic kidney disease (NDD-CKD) after conversion from current erythropoiesis-stimulating agents (ESA) therapy.

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

09 Feb 2016

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: 97

Country: Number of subjects enrolled

Australia: 31

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Brazil: 86

Country: Number of subjects enrolled

Bulgaria: 96

Country: Number of subjects enrolled

Chile: 11

Country: Number of subjects enrolled

Colombia: 20

Country: Number of subjects enrolled

Czechia: 4

Country: Number of subjects enrolled

France: 22

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Hungary: 64

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

Korea, Republic of: 41

Country: Number of subjects enrolled

Malaysia: 26

Country: Number of subjects enrolled

Mexico: 119

Country: Number of subjects enrolled

Romania: 62

Country: Number of subjects enrolled

Russian Federation: 29

Country: Number of subjects enrolled

Serbia: 58

Country: Number of subjects enrolled

Slovakia: 13

Country: Number of subjects enrolled

South Africa: 34

Country: Number of subjects enrolled

Spain: 38

Country: Number of subjects enrolled

Turkey: 21

Country: Number of subjects enrolled

Ukraine: 112

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

United States: 665

Worldwide total number of subjects

1725

EEA total number of subjects

347

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)

651

From 65 to 84 years

952

85 years and over

122

Subject disposition

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Recruitment details

-

Screening details

A total of 2961 subjects were screened for entry into the study. Of these, 1725 subjects were enrolled and randomized into the study.

Period 1 title

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

AKB-6548

Other name

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

Experimental

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	862	863
Completed	704	711
Not completed	158	152
Consent withdrawn by subject	17	9
Death	137	137
Lost to follow-up	4	6

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	862	863	1725
Age categorical
Units:
Age continuous
Units: years
arithmetic mean (standard deviation)	67.3 ± 13.14	66.5 ± 13.52	-
Gender categorical
Units: subjects
Female	468	488	956
Male	394	375	769
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	32	26	58
Asian	62	55	117
Black or African American	93	131	224
Native Hawaiian or Other Pacific Islander	3	0	3
White	631	603	1234
Not Reported	15	13	28
Reported as Other	25	32	57
Multiple	1	3	4
Average hemoglobin
Units: milligrams per deciliter (mg/dL)
arithmetic mean (standard deviation)	10.423 ± 0.8871	10.390 ± 0.9430	-

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	862 ^[1]	863 ^[2]
Units: grams per deciliter (g/dL)
least squares mean (standard error)	0.41 ± 0.036	0.42 ± 0.037

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

1725

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Least squares mean difference

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.07

Variability estimate

Standard error of the mean

Dispersion value

0.042

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 Hb Value between Baseline and the Secondary Efficacy Period (Weeks 40 to 52)

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End point title

Change in Average Hb Value 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	862 ^[4]	863 ^[5]
Units: g/dL
least squares mean (standard error)	0.43 ± 0.044	0.44 ± 0.044

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

1725

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

Method

Parameter type

Least squares mean difference

Point estimate

0

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

0.09

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

Top of page

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	504 / 861 (58.54%)	488 / 862 (56.61%)
number of deaths (all causes)	139	139
number of deaths resulting from adverse events	135	137
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Plasma cell myeloma
subjects affected / exposed	3 / 861 (0.35%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Basal cell carcinoma
subjects affected / exposed	4 / 861 (0.46%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer recurrent
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cancer
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lung neoplasm malignant
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Adenocarcinoma gastric
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Bladder cancer
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bladder cancer recurrent
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Breast cancer metastatic
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cancer pain
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar tumour
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cervix carcinoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangiocarcinoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clear cell renal cell carcinoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gallbladder cancer
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastric cancer
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastric cancer stage IV
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hairy cell leukaemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lung cancer metastatic
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lung neoplasm
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Metastatic bronchial carcinoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Neoplasm malignant
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 stage I
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Oesophageal squamous cell carcinoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ovarian adenoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cancer stage II
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seborrhoeic keratosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 pharynx
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	8 / 861 (0.93%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	1 / 8	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	5 / 861 (0.58%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	1 / 6	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	4 / 861 (0.46%)	8 / 862 (0.93%)
occurrences causally related to treatment / all	0 / 4	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	4 / 861 (0.46%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	6 / 861 (0.70%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 861 (0.00%)	6 / 862 (0.70%)
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	3 / 861 (0.35%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Aortic stenosis
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery thrombosis
subjects affected / exposed	4 / 861 (0.46%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	4 / 861 (0.46%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Hypovolaemic shock
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Steal syndrome
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Accelerated hypertension
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Axillary vein thrombosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocele
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphorrhoea
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant hypertension
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subclavian vein stenosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular rupture
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular stenosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	20 / 861 (2.32%)	13 / 862 (1.51%)
occurrences causally related to treatment / all	0 / 20	0 / 13
deaths causally related to treatment / all	0 / 20	0 / 13
Multiple organ dysfunction syndrome
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 3	0 / 1
Non-cardiac chest pain
subjects affected / exposed	5 / 861 (0.58%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 861 (0.12%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	3 / 861 (0.35%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	3 / 861 (0.35%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Chest discomfort
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.12%)	0 / 862 (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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Treatment noncompliance
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney transplant rejection
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Transplant rejection
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical polyp
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Female genital tract fistula
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	14 / 861 (1.63%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	0 / 14	0 / 11
deaths causally related to treatment / all	0 / 2	0 / 2
Chronic obstructive pulmonary disease
subjects affected / exposed	10 / 861 (1.16%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 13	0 / 7
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	5 / 861 (0.58%)	11 / 862 (1.28%)
occurrences causally related to treatment / all	0 / 6	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	5 / 861 (0.58%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 5	1 / 7
deaths causally related to treatment / all	0 / 0	1 / 3
Respiratory failure
subjects affected / exposed	4 / 861 (0.46%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 4	0 / 7
deaths causally related to treatment / all	0 / 3	0 / 1
Acute pulmonary oedema
subjects affected / exposed	2 / 861 (0.23%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Pleural effusion
subjects affected / exposed	1 / 861 (0.12%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	1 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 861 (0.23%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	3 / 861 (0.35%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 3	1 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Asthma
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Emphysema
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Epistaxis
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Aspiration
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Bronchiectasis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea at rest
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax spontaneous
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
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	2 / 861 (0.23%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Delirium
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anger
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Major depression
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Panic attack
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Schizophrenia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	7 / 861 (0.81%)	8 / 862 (0.93%)
occurrences causally related to treatment / all	1 / 7	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	4 / 861 (0.46%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	1 / 4	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Blood potassium increased
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anticoagulation drug level below therapeutic
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood glucose fluctuation
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Electrocardiogram repolarisation abnormality
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prothrombin time prolonged
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	8 / 861 (0.93%)	12 / 862 (1.39%)
occurrences causally related to treatment / all	0 / 10	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	12 / 861 (1.39%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 12	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	1 / 861 (0.12%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 1	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	2 / 861 (0.23%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Tibia fracture
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula maturation failure
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haematoma
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (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 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Road traffic accident
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Animal bite
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula aneurysm
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haemorrhage
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest injury
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Complications of transplanted kidney
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device placement issue
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye contusion
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Forearm fracture
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle strain
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital haematoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt malfunction
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt occlusion
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt thrombosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site haematoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access site thrombosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound evisceration
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	29 / 861 (3.37%)	31 / 862 (3.60%)
occurrences causally related to treatment / all	0 / 39	1 / 43
deaths causally related to treatment / all	0 / 3	0 / 2
Acute myocardial infarction
subjects affected / exposed	34 / 861 (3.95%)	24 / 862 (2.78%)
occurrences causally related to treatment / all	1 / 36	1 / 26
deaths causally related to treatment / all	0 / 3	0 / 9
Cardiac failure acute
subjects affected / exposed	15 / 861 (1.74%)	16 / 862 (1.86%)
occurrences causally related to treatment / all	0 / 17	0 / 16
deaths causally related to treatment / all	0 / 2	0 / 3
Atrial fibrillation
subjects affected / exposed	16 / 861 (1.86%)	13 / 862 (1.51%)
occurrences causally related to treatment / all	0 / 20	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	10 / 861 (1.16%)	19 / 862 (2.20%)
occurrences causally related to treatment / all	0 / 12	0 / 21
deaths causally related to treatment / all	0 / 4	0 / 6
Cardiac arrest
subjects affected / exposed	9 / 861 (1.05%)	16 / 862 (1.86%)
occurrences causally related to treatment / all	0 / 9	1 / 16
deaths causally related to treatment / all	0 / 7	1 / 13
Coronary artery disease
subjects affected / exposed	7 / 861 (0.81%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	0 / 7	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure chronic
subjects affected / exposed	7 / 861 (0.81%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	1 / 12	0 / 8
deaths causally related to treatment / all	0 / 1	0 / 2
Acute left ventricular failure
subjects affected / exposed	5 / 861 (0.58%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	7 / 861 (0.81%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 6	0 / 3
Left ventricular failure
subjects affected / exposed	3 / 861 (0.35%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 4	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	3 / 861 (0.35%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial flutter
subjects affected / exposed	2 / 861 (0.23%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 4
Bradycardia
subjects affected / exposed	4 / 861 (0.46%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	2 / 861 (0.23%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 2
Cardiorenal syndrome
subjects affected / exposed	4 / 861 (0.46%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Angina pectoris
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 3	0 / 0
Myocardial ischaemia
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Atrioventricular block
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Acute coronary syndrome
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Arrhythmia
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac valve disease
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Heart valve incompetence
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Mitral valve calcification
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulseless electrical activity
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia induced cardiomyopathy
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular hypokinesia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	6 / 861 (0.70%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	0 / 6	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	5 / 861 (0.58%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	0 / 5	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebrovascular accident
subjects affected / exposed	7 / 861 (0.81%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Ischaemic stroke
subjects affected / exposed	8 / 861 (0.93%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 8	1 / 2
deaths causally related to treatment / all	0 / 4	0 / 0
Transient ischaemic attack
subjects affected / exposed	6 / 861 (0.70%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 6	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	3 / 861 (0.35%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 0
Seizure
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Dementia
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic cerebral infarction
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Migraine
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Toxic encephalopathy
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uraemic encephalopathy
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain stem stroke
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebellar infarction
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral artery thrombosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diabetic coma
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Diabetic encephalopathy
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolic cerebral infarction
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic encephalopathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemic unconsciousness
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intraventricular haemorrhage
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lacunar stroke
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental impairment
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thalamic infarction
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombotic stroke
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
VIth nerve disorder
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo CNS origin
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	16 / 861 (1.86%)	18 / 862 (2.09%)
occurrences causally related to treatment / all	1 / 19	0 / 23
deaths causally related to treatment / all	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	2 / 861 (0.23%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrogenic anaemia
subjects affected / exposed	1 / 861 (0.12%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Iron deficiency anaemia
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract diabetic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tractional retinal detachment
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	7 / 861 (0.81%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 8	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	6 / 861 (0.70%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 6	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Vomiting
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	2 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 861 (0.46%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	3 / 861 (0.35%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic gastritis
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Intestinal obstruction
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	3 / 861 (0.35%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal vascular malformation haemorrhagic
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic erosive gastritis
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Peptic ulcer
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngo-oesophageal diverticulum
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cyclic vomiting syndrome
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic gastroparesis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyschezia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral hernia incarcerated
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal angiectasia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal polyp haemorrhage
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic mass
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumatosis intestinalis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Portal hypertensive gastropathy
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	3 / 861 (0.35%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute hepatic failure
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cholecystitis
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Liver injury
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic hepatic failure
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gallbladder rupture
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Granulomatous liver disease
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis alcoholic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.12%)	0 / 862 (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	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Steatohepatitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	5 / 861 (0.58%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Decubitus ulcer
subjects affected / exposed	4 / 861 (0.46%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathic ulcer
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Capillaritis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hidradenitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pemphigoid
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pruritus
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash scarlatiniform
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	232 / 861 (26.95%)	238 / 862 (27.61%)
occurrences causally related to treatment / all	0 / 241	0 / 247
deaths causally related to treatment / all	0 / 11	0 / 10
Acute kidney injury
subjects affected / exposed	34 / 861 (3.95%)	32 / 862 (3.71%)
occurrences causally related to treatment / all	0 / 40	0 / 35
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	6 / 861 (0.70%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 0
Azotaemia
subjects affected / exposed	4 / 861 (0.46%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 2	0 / 2
Renal impairment
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	3 / 861 (0.35%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chronic kidney disease
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis haemorrhagic
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysuria
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Urinary retention
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute phosphate nephropathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis membranoproliferative
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulosclerosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive nephropathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurogenic bladder
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reflux nephropathy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal papillary necrosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal vascular thrombosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adrenal insufficiency
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	5 / 861 (0.58%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	3 / 861 (0.35%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	3 / 861 (0.35%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ankylosing spondylitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest wall haematoma
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic amyotrophy
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Groin pain
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle spasms
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myopathy endocrine
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	56 / 861 (6.50%)	49 / 862 (5.68%)
occurrences causally related to treatment / all	0 / 63	0 / 50
deaths causally related to treatment / all	0 / 2	0 / 5
Urinary tract infection
subjects affected / exposed	20 / 861 (2.32%)	20 / 862 (2.32%)
occurrences causally related to treatment / all	0 / 20	0 / 23
deaths causally related to treatment / all	0 / 0	0 / 1
Sepsis
subjects affected / exposed	17 / 861 (1.97%)	16 / 862 (1.86%)
occurrences causally related to treatment / all	0 / 20	0 / 16
deaths causally related to treatment / all	0 / 2	0 / 1
Cellulitis
subjects affected / exposed	6 / 861 (0.70%)	17 / 862 (1.97%)
occurrences causally related to treatment / all	0 / 9	0 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	10 / 861 (1.16%)	7 / 862 (0.81%)
occurrences causally related to treatment / all	0 / 10	0 / 7
deaths causally related to treatment / all	0 / 5	0 / 2
Osteomyelitis
subjects affected / exposed	5 / 861 (0.58%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	8 / 861 (0.93%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 12	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	6 / 861 (0.70%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Pyelonephritis acute
subjects affected / exposed	3 / 861 (0.35%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Pyelonephritis chronic
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	3 / 861 (0.35%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	4 / 861 (0.46%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 861 (0.23%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	3 / 861 (0.35%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 861 (0.12%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 2
Bronchitis
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	2 / 861 (0.23%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 861 (0.00%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site infection
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 861 (0.00%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (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 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 861 (0.00%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumococcal sepsis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sinusitis
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
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	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal wall abscess
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess neck
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac valve vegetation
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site cellulitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cryptosporidiosis infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis bacterial
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis klebsiella
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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 / 861 (0.00%)	1 / 862 (0.12%)
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 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterobacter infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis bacterial
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fournier's gangrene
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fungal peritonitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Furuncle
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis viral
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Helicobacter gastritis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intestinal sepsis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis bacterial
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parotid abscess
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal abscess
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia escherichia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural cellulitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proteus infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pyonephrosis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal graft infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Salmonella bacteraemia
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Scarlet fever
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Scrotal abscess
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Serratia bacteraemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tinea pedis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection pseudomonal
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral diarrhoea
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection pseudomonas
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
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	17 / 861 (1.97%)	12 / 862 (1.39%)
occurrences causally related to treatment / all	0 / 18	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 1
Dehydration
subjects affected / exposed	16 / 861 (1.86%)	10 / 862 (1.16%)
occurrences causally related to treatment / all	0 / 16	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	13 / 861 (1.51%)	9 / 862 (1.04%)
occurrences causally related to treatment / all	0 / 15	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	13 / 861 (1.51%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 14	0 / 6
deaths causally related to treatment / all	0 / 3	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	4 / 861 (0.46%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	3 / 861 (0.35%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 861 (0.23%)	6 / 862 (0.70%)
occurrences causally related to treatment / all	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	3 / 861 (0.35%)	5 / 862 (0.58%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	3 / 861 (0.35%)	4 / 862 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	4 / 861 (0.46%)	3 / 862 (0.35%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	3 / 861 (0.35%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	3 / 861 (0.35%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 861 (0.12%)	2 / 862 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gout
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	2 / 861 (0.23%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 861 (0.12%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obesity
subjects affected / exposed	2 / 861 (0.23%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acidosis
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cachexia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Decreased appetite
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypercalcaemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	1 / 861 (0.12%)	0 / 862 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 861 (0.00%)	1 / 862 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	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	482 / 861 (55.98%)	436 / 862 (50.58%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	64 / 861 (7.43%)	53 / 862 (6.15%)
occurrences all number	78	68
Vascular disorders
Hypertension
subjects affected / exposed	120 / 861 (13.94%)	123 / 862 (14.27%)
occurrences all number	157	165
Nervous system disorders
Headache
subjects affected / exposed	22 / 861 (2.56%)	45 / 862 (5.22%)
occurrences all number	24	50
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	84 / 861 (9.76%)	85 / 862 (9.86%)
occurrences all number	107	102
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	117 / 861 (13.59%)	76 / 862 (8.82%)
occurrences all number	147	93
Nausea
subjects affected / exposed	73 / 861 (8.48%)	57 / 862 (6.61%)
occurrences all number	82	68
Constipation
subjects affected / exposed	44 / 861 (5.11%)	38 / 862 (4.41%)
occurrences all number	50	40
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	42 / 861 (4.88%)	48 / 862 (5.57%)
occurrences all number	44	57
Infections and infestations
Urinary tract infection
subjects affected / exposed	93 / 861 (10.80%)	113 / 862 (13.11%)
occurrences all number	120	186
Nasopharyngitis
subjects affected / exposed	53 / 861 (6.16%)	61 / 862 (7.08%)
occurrences all number	68	79
Upper respiratory tract infection
subjects affected / exposed	55 / 861 (6.39%)	44 / 862 (5.10%)
occurrences all number	64	49
Bronchitis
subjects affected / exposed	44 / 861 (5.11%)	32 / 862 (3.71%)
occurrences all number	52	36
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	71 / 861 (8.25%)	78 / 862 (9.05%)
occurrences all number	84	94

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Were there any global substantial amendments to the protocol? Yes

17 Mar 2016

• Added Exclusion Criteria. • Clarified 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 arm and 100 subjects from the darbepoetin alfa treatment arm) 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 be 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

• Update 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 was 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. • Described and justified the sparse pharmacokinetic (PK) sampling scheme. 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 provided additional information to help characterize the population PK and PK/pharmacodynamic (PD) relationships. • Aligned adverse event reporting related to critically increased liver function test results with the United States Food and Drug Administration (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 from the current screening period of up to 4 weeks to up to 8 weeks and allowed iron, vitamin B12, and folate supplementation as needed during the screening period. • Screening period changed from up to 4 weeks to up to 8 weeks. • Allowed one retest for each laboratory parameter, within the screening period. • Clarified that subjects who received iron replacement may have retested screening hemoglobin (Hb) a minimum of 3 weeks after completion of iron replacement therapy. • Updated Inclusion and Exclusion Criteria. • Increased the 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. • Updated to reflect information from recently completed trials. • Added information regarding 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. • Modified laboratory evaluations schedule. • Clarified study analysis populations.

18 Jan 2018

• Updated with information from recently completed trials and aligned with vadadustat Investigator’s Brochure. • Updated to reflect addition of 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 clarify that all enrolled subjects in this study were to have had the opportunity to complete (at least) the Week 36 visit. • Updated to add Lack of Efficacy as a reason for discontinuation for accurate data capture. • Updated dosing guidelines and instructions. • Updated to align with published guidelines to prescribe iron supplementation and for initiation of erythropoiesis-stimulating agent (ESA) rescue. • Updated to specify a dosing compliance range of 80% to 120% which is commonly used in clinical trials with oral products. • Updated 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 the requirement for monthly monitoring of Hb drawn as part of local standard of care labs or via an unscheduled visit. • Added text defining overdose of study drugs. • Updated to require all new and recurrent malignancies (with a few exceptions) to be reported as a serious adverse events (SAEs) to standardize reporting. • Updated to reflect a change in the noninferiority margin from -0.5 to -1.0 grams per deciliter (g/dL). • Updated with enrollment projections as well as median study drug exposure times. • Updated missing data information to align with the Statistical Analysis Plan (SAP). • Updated to pre-specify key subgroups for subsequent analysis. • Clarified that adverse event (AE) summaries were to be provided for specific subgroups.

13 Sep 2018

• Revised subject number. • Clarified that all enrolled subjects were to be allowed to complete the primary efficacy period prior to global study completion (GSC). • Clarified procedures at time of GSC. • Emphasized the importance of continuing to follow subjects through GSC. • Stated that if study drug was temporarily interrupted for more than 60 days, Medical Monitor should be contacted before resuming study drug. • Updated timing of End of Trial (EOT) visit and Follow-up visit following permanent discontinuation of study medication. • 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 to reflect information for which the Sponsor and Contract Research Organization (CRO) study teams were to remain blinded. • Clarified restarting of study drug after erythropoiesis-stimulating agent (ESA) rescue and red blood cell (RBC) transfusion. • Clarified study drug dosing following ESA administration. • Provided guidance on how to manage concomitant use of statins with vadadustat. • Included timing of collection of AEs. • Detailed managing subjects that permanently stopped study drug and subjects on study drug at GSC. • Defined the end of study assessments that documented subject status. • Added guidance on managing subjects who developed malignancy while on study drug. • Indicated that Sponsor had defined events that were to be classified as serious regardless of their assessment. • Clarified AE reporting period. • Updated how Baseline was calculated for Hb. • Updated with a change in the non-inferiority 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).

18 Dec 2018

• Updated to include reference to the Pharmacy Manual which provides further details on storage and managing temperature excursions. •Provided further guidance regarding concomitant use of simvastatin drug interactions with vadadustat. • Provide guidance regarding concomitant use of breast cancer resistance protein (BCRP) substrates with vadadustat. • Updated to reflect 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

• Include a reference to Study Drug Stopping Rules for management of subjects with alanine aminotransferase (ALT) and asparate 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 ULN from conditions of temporary discontinuation, as this was a condition for permanent discontinuation. • Section 10.1.2 Serious adverse events was 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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