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Clinical Trial Results:
A multicenter, randomized, double-blind, active controlled study to evaluate the effects of LCZ696 compared to valsartan on cognitive function in patients with chronic heart failure and preserved ejection fraction

Summary
EudraCT number	2016-001254-17
Trial protocol	GB LT DE ES BG NL PL BE HR IT
Global end of trial date	16 May 2022

Results information
Results version number	v1(current)
This version publication date	18 May 2023
First version publication date	18 May 2023
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CLCZ696B2320

ISRCTN number

-

US NCT number

NCT02884206

WHO universal trial number (UTN)

-

Sponsor organisation name

: Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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

16 May 2022

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

16 May 2022

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study was to evaluate the effects of LCZ696 compared to valsartan on cognitive function over 3 years in patients with heart failure and preserved ejection fraction (HFpEF) as assessed by the CogState cognitive assessment battery (Global Cognitive Composite Score (GCCS)).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

23 Nov 2016

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 25

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Bulgaria: 17

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

Croatia: 7

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Germany: 71

Country: Number of subjects enrolled

United Kingdom: 27

Country: Number of subjects enrolled

Italy: 39

Country: Number of subjects enrolled

Korea, Republic of: 10

Country: Number of subjects enrolled

Lithuania: 6

Country: Number of subjects enrolled

Netherlands: 17

Country: Number of subjects enrolled

Poland: 68

Country: Number of subjects enrolled

Russian Federation: 39

Country: Number of subjects enrolled

Spain: 23

Country: Number of subjects enrolled

Switzerland: 12

Country: Number of subjects enrolled

Taiwan: 9

Country: Number of subjects enrolled

Turkey: 7

Country: Number of subjects enrolled

United States: 197

Worldwide total number of subjects

592

EEA total number of subjects

252

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)

86

From 65 to 84 years

482

85 years and over

24

Subject disposition

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Recruitment details

-

Screening details

1200 patients were screened, of which 494 patients discontinued prior to completing the screening epoch. All 706 patients who completed the screening epoch were included in the Enrolled set. A total of 659 patients completed the valsartan run-in epoch and entered the LCZ696 run-in epoch. Overall, 592 patients completed the treatment run-in epoch.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

LCZ696 200 mg bid

Arm description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.

Arm type

Experimental

Investigational medicinal product name

Sacubitril/valsartan

Investigational medicinal product code

LCZ696

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

LCZ696 200 mg bid

Valsartan 160 mg bid

Arm description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

Arm type

Active comparator

Investigational medicinal product name

Valsartan

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Valsartan 160 mg bid

Number of subjects in period 1	LCZ696 200 mg bid	Valsartan 160 mg bid
Started	295	297
Safety set	295	297
PET substudy set	244 ^[1]	247
Completed	251	237
Not completed	44	60
Adverse event, serious fatal	28	39
Physician decision	2	-
Adverse event, non-fatal	-	3
Non-compliance with study treatment	-	1
Patient/guardian decision	10	13
Lost to follow-up	4	4

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Subset of the SAF patients who participated in the PET substudy and had non-missing baseline assessment.

Baseline characteristics

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Reporting group title

LCZ696 200 mg bid

Reporting group description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.

Reporting group title

Valsartan 160 mg bid

Reporting group description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

Reporting group values	LCZ696 200 mg bid	Valsartan 160 mg bid	Total
Number of subjects	295	297	592
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	41	45	86
From 65-84 years	243	239	482
85 years and over	11	13	24
Age Continuous
Units: years
arithmetic mean (standard deviation)	72.27 ± 6.749	72.61 ± 7.043	-
Sex: Female, Male
Units: participants
Female	134	143	277
Male	161	154	315
Race/Ethnicity, Customized
Units: Subjects
Caucasian	273	271	544
Asian	11	12	23
Black	6	9	15
Native American	2	0	2
Unknown	1	2	3
Other	2	3	5

End points

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Reporting group title

LCZ696 200 mg bid

Reporting group description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years.

Reporting group title

Valsartan 160 mg bid

Reporting group description

Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years.

Primary: Change from baseline in the CogState Global Cognitive Composite Score (GCCS)

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End point title

Change from baseline in the CogState Global Cognitive Composite Score (GCCS)

End point description

The CogState cognitive battery was composed of 7 tests, which were administered electronically by the patients at scheduled visits. For each test, a standardized z-score was calculated. The GCCS was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function. CogState GCCS changes from baseline (randomization) were analyzed using a repeated measures ANCOVA in which treatment, age stratification factor, Mini mental state examination stratification factor, education level, Apolipoprotein E ε4 allele status, cerebrovascular disease burden at screening, visit and treatment-by-visit interaction are included as fixed-effect factor, and baseline (randomization) GCCS and visit-by- baseline GCCS as covariates with a common unstructured covariance matrix among visits between treatment groups. The analysis was based on a direct likelihood method with an assumption of Missing at random.

End point type

Primary

End point timeframe

Baseline, month 36

End point values	LCZ696 200 mg bid	Valsartan 160 mg bid
Number of subjects analysed	195	183
Units: Global Cognitive Composite Score
least squares mean (standard error)	-0.0902 ± 0.0372	-0.0722 ± 0.0383

LCZ696 vs. Valsartan

Statistical analysis description

Repeated measure ANCOVA

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

378

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[1]

P-value

= 0.7363

Method

ANCOVA

Parameter type

LSM

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.123

upper limit

0.087

Notes
[1] - To demonstrate non-inferiority that LCZ696 does not lead to a relevant decrease in cognition compared to valsartan at year 3, the lower bound of 95% CI does not include the pre-specified non-inferiority (NI) boundary (Cohen’s D) of -0.3. An effect size of 0.3 in Cohen’s D is generally considered as small.

Secondary: Change from baseline in cortical composite standardized uptake value ratio (SUVr)

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End point title

Change from baseline in cortical composite standardized uptake value ratio (SUVr)

End point description

The effects of LCZ696 compared to valsartan on Aβ deposition in the brain over 3 years were evaluated in a subset of patients using amyloid positron emission tomography (PET) imaging by assessing the change from baseline in cortical composite SUVr. PET imaging was performed at selected PET-capable centers on all eligible patients participating in the substudy. Sites with patients performing the PET scan were a subset of the overall patient population and overall sites for the study. Change from baseline to 3 years was analyzed based on an ANCOVA model with treatment, age, MMSE, amyloid status (+ve/−ve) stratification factors, region, APOE4 status and cerebrovascular disease burden as fixed effects, with baseline SUVr and treatment-by-baseline SUVr interaction as covariates for each of these imputed datasets. Results were obtained by applying Rubin’s rules on the estimates from the imputed datasets.

End point type

Secondary

End point timeframe

Baseline, month 36

End point values	LCZ696 200 mg bid	Valsartan 160 mg bid
Number of subjects analysed	147	134
Units: value ratio (SUVr)
least squares mean (standard error)
Global cortical composite	0.0273 ± 0.0114	0.0564 ± 0.0101
Cingulum posterior composite	0.0416 ± 0.0113	0.0876 ± 0.0109
Frontal lobe composite	0.0218 ± 0.0117	0.0434 ± 0.0104
Parietal lobe composite	0.0231 ± 0.0119	0.0532 ± 0.0104
Temporal lobe composite	0.0249 ± 0.0110	0.0418 ± 0.0097
White matter composite	0.0061 ± 0.0094	-0.0072 ± 0.0083

LCZ696 vs. Valsartan

Statistical analysis description

Multiple Imputation ANCOVA in Global cortical composite

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

281

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

= 0.0579

Method

ANCOVA

Parameter type

Least Squares Mean

Point estimate

-0.0292

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0593

upper limit

0.001

Notes
[2] - To show that the point estimate of SUVr difference in mean change over 3 years is in favor of LCZ696 and the non-inferiority is demonstrated, with the upper bound of the 95% CI excluding the NI boundary of 0.01.

Secondary: Change from baseline in individual cognitive domains

Top of page

End point title

Change from baseline in individual cognitive domains

End point description

The effects of LCZ696 compared to valsartan on the individual cognitive domains (memory, executive function, and attention) over 3 years were evaluated by assessing the individual components of the CogState cognitive battery. Composite scores for the 3 individual cognitive domains were generated by combining the standardized z-scores of selected tests from the CogState cognitive battery. Each composite score was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function.

End point type

Secondary

End point timeframe

Baseline, month 36

End point values	LCZ696 200 mg bid	Valsartan 160 mg bid
Number of subjects analysed	197	185
Units: Z-scores
least squares mean (standard error)
Memory domain (n= 197, 185)	-0.0573 ± 0.0477	-0.0580 ± 0.0490
Executive function domain (n= 196, 184)	-0.0375 ± 0.0480	-0.0702 ± 0.0493
Attention domain (n= 197, 184)	-0.1836 ± 0.0614	-0.0794 ± 0.0634

LCZ696 vs. Valsartan for memory domain

Statistical analysis description

Repeated measure ANCOVA for memory domain

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9916

Method

ANCOVA

Parameter type

Least Squares Mean

Point estimate

0.0007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1339

upper limit

0.1353

LCZ696 vs. Valsartan for attention domain

Statistical analysis description

Repeated measure ANCOVA for attention domain

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2403

Method

ANCOVA

Parameter type

Least Squares Mean

Point estimate

-0.1042

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2783

upper limit

0.07

LCZ696 vs. Valsartan for executive function domain

Statistical analysis description

Repeated measure ANCOVA for executive function domain

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

382

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6348

Method

ANCOVA

Parameter type

Least Squares Mean

Point estimate

0.0327

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1024

upper limit

0.1677

Secondary: Change from baseline in the summary score of the instrumental activities of daily living (IADL)

Top of page

End point title

Change from baseline in the summary score of the instrumental activities of daily living (IADL)

End point description

The effects of LCZ696 compared to valsartan on the changes in IADL over 3 years were evaluated by as assessing the Functional activities questionnaire (FAQ) summary scores. The FAQ is a 30-point questionnaire that is made up of 10 questions that reflect a patient’s ability to perform activities of daily living and to function independently. A score of 0 represents no impairment and a score of 30 represents severe impairment.

End point type

Secondary

End point timeframe

Baseline, month 36

End point values	LCZ696 200 mg bid	Valsartan 160 mg bid
Number of subjects analysed	197	186
Units: FAQ scores
least squares mean (standard error)	0.5983 ± 0.2064	0.7089 ± 0.2115

LCZ696 vs. Valsartan

Statistical analysis description

Repeated measure ANCOVA

Comparison groups

LCZ696 200 mg bid v Valsartan 160 mg bid

Number of subjects included in analysis

383

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7081

Method

ANCOVA

Parameter type

Least Squares Mean

Point estimate

-0.1105

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6906

upper limit

0.4696

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 37 months.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

LCZ696

Reporting group description

LCZ696

Reporting group title

Total

Reporting group description

Total

Reporting group title

Valsartan

Reporting group description

Valsartan

Serious adverse events	LCZ696	Total	Valsartan
Total subjects affected by serious adverse events
subjects affected / exposed	145 / 295 (49.15%)	306 / 592 (51.69%)	161 / 297 (54.21%)
number of deaths (all causes)	28	67	39
number of deaths resulting from adverse events	0	1	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 295 (0.34%)	7 / 592 (1.18%)	6 / 297 (2.02%)
occurrences causally related to treatment / all	0 / 1	0 / 8	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign hepatobiliary neoplasm
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer recurrent
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Carcinoid tumour in the large intestine
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colorectal adenoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive breast carcinoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial stromal sarcoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Follicular lymphoma
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic neoplasm
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Lung neoplasm malignant
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Metastases to liver
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocytic leukaemia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	2 / 295 (0.68%)	4 / 592 (0.68%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cancer
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neoplasm prostate
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Refractory cytopenia with unilineage dysplasia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsil cancer
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Aneurysm
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Deep vein thrombosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 295 (0.00%)	5 / 592 (0.84%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	3 / 295 (1.02%)	8 / 592 (1.35%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	1 / 3	4 / 9	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	1 / 295 (0.34%)	4 / 592 (0.68%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Vasculitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian artery stenosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac death
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Asthenia
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	5 / 295 (1.69%)	8 / 592 (1.35%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 5	0 / 8	0 / 3
deaths causally related to treatment / all	0 / 5	0 / 8	0 / 3
Impaired healing
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	8 / 295 (2.71%)	10 / 592 (1.69%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 8	0 / 10	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Vascular stent stenosis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Testicular pain
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Testicular swelling
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	5 / 295 (1.69%)	10 / 592 (1.69%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 5	0 / 11	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Cough
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Central sleep apnoea syndrome
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	9 / 295 (3.05%)	13 / 592 (2.20%)	4 / 297 (1.35%)
occurrences causally related to treatment / all	0 / 14	0 / 19	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Haemoptysis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 295 (0.34%)	4 / 592 (0.68%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	3 / 295 (1.02%)	10 / 592 (1.69%)	7 / 297 (2.36%)
occurrences causally related to treatment / all	0 / 3	0 / 12	0 / 9
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Dyspnoea exertional
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiccups
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	3 / 295 (1.02%)	4 / 592 (0.68%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 5	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Hypercapnia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrothorax
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Pulmonary alveolar haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 295 (0.34%)	4 / 592 (0.68%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2
Pulmonary toxicity
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 295 (0.34%)	5 / 592 (0.84%)	4 / 297 (1.35%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Sleep apnoea syndrome
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angiocardiogram
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheterisation cardiac abnormal
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronavirus test positive
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral test positive
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 295 (0.00%)	3 / 592 (0.51%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procalcitonin increased
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight increased
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 295 (0.68%)	9 / 592 (1.52%)	7 / 297 (2.36%)
occurrences causally related to treatment / all	0 / 2	1 / 9	1 / 7
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1
Craniocerebral injury
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain contusion
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epicondylitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria traumatic
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fractured sacrum
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	2 / 295 (0.68%)	7 / 592 (1.18%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural complication
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural pulmonary embolism
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Humerus fracture
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Acute myocardial infarction
subjects affected / exposed	8 / 295 (2.71%)	20 / 592 (3.38%)	12 / 297 (4.04%)
occurrences causally related to treatment / all	0 / 8	0 / 21	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 3
Acute left ventricular failure
subjects affected / exposed	3 / 295 (1.02%)	4 / 592 (0.68%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Acute right ventricular failure
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 295 (0.00%)	3 / 592 (0.51%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Aortic valve stenosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Angina unstable
subjects affected / exposed	3 / 295 (1.02%)	8 / 592 (1.35%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 3	1 / 8	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 295 (0.68%)	5 / 592 (0.84%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 2	0 / 7	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	14 / 295 (4.75%)	25 / 592 (4.22%)	11 / 297 (3.70%)
occurrences causally related to treatment / all	1 / 15	1 / 28	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular dissociation
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	4 / 295 (1.36%)	7 / 592 (1.18%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 5	0 / 9	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	5 / 295 (1.69%)	10 / 592 (1.69%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 7	0 / 14	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	15 / 295 (5.08%)	30 / 592 (5.07%)	15 / 297 (5.05%)
occurrences causally related to treatment / all	1 / 18	2 / 38	1 / 20
deaths causally related to treatment / all	0 / 3	0 / 6	0 / 3
Cardiac arrest
subjects affected / exposed	0 / 295 (0.00%)	6 / 592 (1.01%)	6 / 297 (2.02%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 3
Cardiac amyloidosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Bradycardia
subjects affected / exposed	0 / 295 (0.00%)	3 / 592 (0.51%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	8 / 295 (2.71%)	16 / 592 (2.70%)	8 / 297 (2.69%)
occurrences causally related to treatment / all	0 / 10	0 / 20	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2
Cardiac valve disease
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 2
Cardiogenic shock
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cardiovascular insufficiency
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Chronic left ventricular failure
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	7 / 295 (2.37%)	10 / 592 (1.69%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 7	0 / 10	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 295 (1.02%)	10 / 592 (1.69%)	7 / 297 (2.36%)
occurrences causally related to treatment / all	0 / 3	0 / 10	0 / 7
deaths causally related to treatment / all	0 / 2	0 / 7	0 / 5
Myocardial ischaemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinus node dysfunction
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Ventricular extrasystoles
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain stem infarction
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Bell's palsy
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic neuropathy
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 295 (1.36%)	7 / 592 (1.18%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 5	0 / 8	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cerebellar stroke
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cerebral haematoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebellar haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Headache
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 295 (0.34%)	4 / 592 (0.68%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Lacunar stroke
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	3 / 295 (1.02%)	4 / 592 (0.68%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	6 / 295 (2.03%)	11 / 592 (1.86%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	2 / 9	4 / 15	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 295 (0.34%)	3 / 592 (0.51%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 295 (1.02%)	9 / 592 (1.52%)	6 / 297 (2.02%)
occurrences causally related to treatment / all	0 / 4	0 / 11	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombasthenia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombotic thrombocytopenic purpura
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chondrodermatitis nodularis chronica helicis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Diabetic retinopathy
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	2 / 295 (0.68%)	4 / 592 (0.68%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal degeneration
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular degeneration
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epiretinal membrane
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 295 (1.02%)	3 / 592 (0.51%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Faeces discoloured
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal ulcer haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 295 (1.02%)	6 / 592 (1.01%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 3	0 / 14	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Gastritis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal mass
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mesenteric arterial occlusion
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Intestinal haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngo-oesophageal diverticulum
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac cirrhosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	4 / 295 (1.36%)	4 / 592 (0.68%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Cholestasis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic mass
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eczema
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	6 / 295 (2.03%)	12 / 592 (2.03%)	6 / 297 (2.02%)
occurrences causally related to treatment / all	1 / 6	2 / 12	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Bladder mass
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	2 / 295 (0.68%)	4 / 592 (0.68%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	1 / 2	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis interstitial
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder tamponade
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract disorder
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 295 (0.00%)	3 / 592 (0.51%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 0	2 / 3	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	0 / 295 (0.00%)	3 / 592 (0.51%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoroacetabular impingement
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Loose body in joint
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	6 / 295 (2.03%)	10 / 592 (1.69%)	4 / 297 (1.35%)
occurrences causally related to treatment / all	0 / 7	0 / 11	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plantar fasciitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatic disorder
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal disorder
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebral foraminal stenosis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	3 / 295 (1.02%)	4 / 592 (0.68%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	2 / 295 (0.68%)	5 / 592 (0.84%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 2
COVID-19 pneumonia
subjects affected / exposed	4 / 295 (1.36%)	8 / 592 (1.35%)	4 / 297 (1.35%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Candida infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis bacterial
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 295 (0.00%)	2 / 592 (0.34%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carbuncle
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	10 / 295 (3.39%)	19 / 592 (3.21%)	9 / 297 (3.03%)
occurrences causally related to treatment / all	0 / 14	0 / 23	0 / 9
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphangitis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nosocomial infection
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	5 / 295 (1.69%)	10 / 592 (1.69%)	5 / 297 (1.68%)
occurrences causally related to treatment / all	0 / 5	0 / 10	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Pneumonia aspiration
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Septic shock
subjects affected / exposed	2 / 295 (0.68%)	4 / 592 (0.68%)	2 / 297 (0.67%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 1
Post procedural infection
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	6 / 295 (2.03%)	7 / 592 (1.18%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 8	0 / 9	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	4 / 295 (1.36%)	5 / 592 (0.84%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 4	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 295 (0.68%)	3 / 592 (0.51%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	2 / 295 (0.68%)	5 / 592 (0.84%)	3 / 297 (1.01%)
occurrences causally related to treatment / all	2 / 2	5 / 5	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 295 (0.34%)	2 / 592 (0.34%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	2 / 295 (0.68%)	2 / 592 (0.34%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	1 / 295 (0.34%)	1 / 592 (0.17%)	0 / 297 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 295 (0.00%)	1 / 592 (0.17%)	1 / 297 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	LCZ696	Total	Valsartan
Total subjects affected by non serious adverse events
subjects affected / exposed	238 / 295 (80.68%)	483 / 592 (81.59%)	245 / 297 (82.49%)
Vascular disorders
Hypertension
subjects affected / exposed	21 / 295 (7.12%)	52 / 592 (8.78%)	31 / 297 (10.44%)
occurrences all number	22	58	36
Hypotension
subjects affected / exposed	68 / 295 (23.05%)	125 / 592 (21.11%)	57 / 297 (19.19%)
occurrences all number	99	167	68
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	9 / 295 (3.05%)	22 / 592 (3.72%)	13 / 297 (4.38%)
occurrences all number	10	23	13
Fatigue
subjects affected / exposed	16 / 295 (5.42%)	39 / 592 (6.59%)	23 / 297 (7.74%)
occurrences all number	18	44	26
Asthenia
subjects affected / exposed	7 / 295 (2.37%)	20 / 592 (3.38%)	13 / 297 (4.38%)
occurrences all number	10	25	15
Oedema peripheral
subjects affected / exposed	24 / 295 (8.14%)	49 / 592 (8.28%)	25 / 297 (8.42%)
occurrences all number	32	59	27
Pyrexia
subjects affected / exposed	4 / 295 (1.36%)	10 / 592 (1.69%)	6 / 297 (2.02%)
occurrences all number	4	10	6
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	6 / 295 (2.03%)	9 / 592 (1.52%)	3 / 297 (1.01%)
occurrences all number	6	9	3
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	10 / 295 (3.39%)	20 / 592 (3.38%)	10 / 297 (3.37%)
occurrences all number	18	30	12
Epistaxis
subjects affected / exposed	6 / 295 (2.03%)	12 / 592 (2.03%)	6 / 297 (2.02%)
occurrences all number	8	21	13
Dyspnoea
subjects affected / exposed	21 / 295 (7.12%)	55 / 592 (9.29%)	34 / 297 (11.45%)
occurrences all number	28	71	43
Cough
subjects affected / exposed	17 / 295 (5.76%)	29 / 592 (4.90%)	12 / 297 (4.04%)
occurrences all number	20	33	13
Psychiatric disorders
Depression
subjects affected / exposed	13 / 295 (4.41%)	25 / 592 (4.22%)	12 / 297 (4.04%)
occurrences all number	14	29	15
Insomnia
subjects affected / exposed	4 / 295 (1.36%)	12 / 592 (2.03%)	8 / 297 (2.69%)
occurrences all number	4	12	8
Investigations
Blood creatinine increased
subjects affected / exposed	9 / 295 (3.05%)	16 / 592 (2.70%)	7 / 297 (2.36%)
occurrences all number	10	18	8
Blood pressure increased
subjects affected / exposed	4 / 295 (1.36%)	16 / 592 (2.70%)	12 / 297 (4.04%)
occurrences all number	6	20	14
Glomerular filtration rate decreased
subjects affected / exposed	15 / 295 (5.08%)	31 / 592 (5.24%)	16 / 297 (5.39%)
occurrences all number	16	32	16
SARS-CoV-2 test positive
subjects affected / exposed	2 / 295 (0.68%)	9 / 592 (1.52%)	7 / 297 (2.36%)
occurrences all number	2	9	7
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	6 / 295 (2.03%)	15 / 592 (2.53%)	9 / 297 (3.03%)
occurrences all number	7	20	13
Fall
subjects affected / exposed	19 / 295 (6.44%)	34 / 592 (5.74%)	15 / 297 (5.05%)
occurrences all number	23	49	26
Ligament sprain
subjects affected / exposed	7 / 295 (2.37%)	10 / 592 (1.69%)	3 / 297 (1.01%)
occurrences all number	7	10	3
Skin laceration
subjects affected / exposed	6 / 295 (2.03%)	13 / 592 (2.20%)	7 / 297 (2.36%)
occurrences all number	10	17	7
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	17 / 295 (5.76%)	39 / 592 (6.59%)	22 / 297 (7.41%)
occurrences all number	19	44	25
Angina pectoris
subjects affected / exposed	16 / 295 (5.42%)	28 / 592 (4.73%)	12 / 297 (4.04%)
occurrences all number	17	31	14
Cardiac failure
subjects affected / exposed	14 / 295 (4.75%)	39 / 592 (6.59%)	25 / 297 (8.42%)
occurrences all number	16	43	27
Cardiac failure chronic
subjects affected / exposed	3 / 295 (1.02%)	13 / 592 (2.20%)	10 / 297 (3.37%)
occurrences all number	3	15	12
Palpitations
subjects affected / exposed	18 / 295 (6.10%)	24 / 592 (4.05%)	6 / 297 (2.02%)
occurrences all number	20	26	6
Bradycardia
subjects affected / exposed	7 / 295 (2.37%)	12 / 592 (2.03%)	5 / 297 (1.68%)
occurrences all number	7	12	5
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 295 (0.34%)	8 / 592 (1.35%)	7 / 297 (2.36%)
occurrences all number	1	9	8
Dizziness
subjects affected / exposed	28 / 295 (9.49%)	59 / 592 (9.97%)	31 / 297 (10.44%)
occurrences all number	33	68	35
Headache
subjects affected / exposed	11 / 295 (3.73%)	18 / 592 (3.04%)	7 / 297 (2.36%)
occurrences all number	11	18	7
Syncope
subjects affected / exposed	7 / 295 (2.37%)	11 / 592 (1.86%)	4 / 297 (1.35%)
occurrences all number	7	12	5
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	6 / 295 (2.03%)	7 / 592 (1.18%)	1 / 297 (0.34%)
occurrences all number	6	7	1
Anaemia
subjects affected / exposed	24 / 295 (8.14%)	45 / 592 (7.60%)	21 / 297 (7.07%)
occurrences all number	25	49	24
Eye disorders
Cataract
subjects affected / exposed	6 / 295 (2.03%)	14 / 592 (2.36%)	8 / 297 (2.69%)
occurrences all number	6	15	9
Gastrointestinal disorders
Constipation
subjects affected / exposed	6 / 295 (2.03%)	18 / 592 (3.04%)	12 / 297 (4.04%)
occurrences all number	6	18	12
Large intestine polyp
subjects affected / exposed	4 / 295 (1.36%)	10 / 592 (1.69%)	6 / 297 (2.02%)
occurrences all number	4	10	6
Gastrooesophageal reflux disease
subjects affected / exposed	6 / 295 (2.03%)	12 / 592 (2.03%)	6 / 297 (2.02%)
occurrences all number	6	12	6
Dyspepsia
subjects affected / exposed	3 / 295 (1.02%)	9 / 592 (1.52%)	6 / 297 (2.02%)
occurrences all number	3	9	6
Diarrhoea
subjects affected / exposed	13 / 295 (4.41%)	32 / 592 (5.41%)	19 / 297 (6.40%)
occurrences all number	13	34	21
Nausea
subjects affected / exposed	10 / 295 (3.39%)	18 / 592 (3.04%)	8 / 297 (2.69%)
occurrences all number	12	22	10
Vomiting
subjects affected / exposed	4 / 295 (1.36%)	11 / 592 (1.86%)	7 / 297 (2.36%)
occurrences all number	5	13	8
Skin and subcutaneous tissue disorders
Skin lesion
subjects affected / exposed	1 / 295 (0.34%)	7 / 592 (1.18%)	6 / 297 (2.02%)
occurrences all number	1	7	6
Rash
subjects affected / exposed	3 / 295 (1.02%)	12 / 592 (2.03%)	9 / 297 (3.03%)
occurrences all number	3	13	10
Pruritus
subjects affected / exposed	8 / 295 (2.71%)	14 / 592 (2.36%)	6 / 297 (2.02%)
occurrences all number	10	17	7
Renal and urinary disorders
Renal impairment
subjects affected / exposed	26 / 295 (8.81%)	57 / 592 (9.63%)	31 / 297 (10.44%)
occurrences all number	34	72	38
Renal failure
subjects affected / exposed	5 / 295 (1.69%)	12 / 592 (2.03%)	7 / 297 (2.36%)
occurrences all number	5	13	8
Haematuria
subjects affected / exposed	10 / 295 (3.39%)	18 / 592 (3.04%)	8 / 297 (2.69%)
occurrences all number	12	20	8
Chronic kidney disease
subjects affected / exposed	5 / 295 (1.69%)	13 / 592 (2.20%)	8 / 297 (2.69%)
occurrences all number	5	13	8
Acute kidney injury
subjects affected / exposed	14 / 295 (4.75%)	27 / 592 (4.56%)	13 / 297 (4.38%)
occurrences all number	15	29	14
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	12 / 295 (4.07%)	23 / 592 (3.89%)	11 / 297 (3.70%)
occurrences all number	13	27	14
Osteoarthritis
subjects affected / exposed	10 / 295 (3.39%)	19 / 592 (3.21%)	9 / 297 (3.03%)
occurrences all number	12	22	10
Myalgia
subjects affected / exposed	7 / 295 (2.37%)	14 / 592 (2.36%)	7 / 297 (2.36%)
occurrences all number	7	16	9
Muscle spasms
subjects affected / exposed	6 / 295 (2.03%)	15 / 592 (2.53%)	9 / 297 (3.03%)
occurrences all number	6	18	12
Joint swelling
subjects affected / exposed	5 / 295 (1.69%)	11 / 592 (1.86%)	6 / 297 (2.02%)
occurrences all number	5	11	6
Back pain
subjects affected / exposed	22 / 295 (7.46%)	50 / 592 (8.45%)	28 / 297 (9.43%)
occurrences all number	23	54	31
Arthralgia
subjects affected / exposed	25 / 295 (8.47%)	57 / 592 (9.63%)	32 / 297 (10.77%)
occurrences all number	30	67	37
Infections and infestations
Bronchitis
subjects affected / exposed	18 / 295 (6.10%)	31 / 592 (5.24%)	13 / 297 (4.38%)
occurrences all number	28	42	14
COVID-19
subjects affected / exposed	12 / 295 (4.07%)	17 / 592 (2.87%)	5 / 297 (1.68%)
occurrences all number	12	17	5
Pneumonia
subjects affected / exposed	8 / 295 (2.71%)	19 / 592 (3.21%)	11 / 297 (3.70%)
occurrences all number	9	21	12
Nasopharyngitis
subjects affected / exposed	26 / 295 (8.81%)	51 / 592 (8.61%)	25 / 297 (8.42%)
occurrences all number	40	70	30
Lower respiratory tract infection
subjects affected / exposed	6 / 295 (2.03%)	12 / 592 (2.03%)	6 / 297 (2.02%)
occurrences all number	16	28	12
Herpes zoster
subjects affected / exposed	6 / 295 (2.03%)	8 / 592 (1.35%)	2 / 297 (0.67%)
occurrences all number	7	9	2
Cystitis
subjects affected / exposed	6 / 295 (2.03%)	10 / 592 (1.69%)	4 / 297 (1.35%)
occurrences all number	9	14	5
Cellulitis
subjects affected / exposed	8 / 295 (2.71%)	17 / 592 (2.87%)	9 / 297 (3.03%)
occurrences all number	9	19	10
Sinusitis
subjects affected / exposed	9 / 295 (3.05%)	18 / 592 (3.04%)	9 / 297 (3.03%)
occurrences all number	10	20	10
Upper respiratory tract infection
subjects affected / exposed	13 / 295 (4.41%)	19 / 592 (3.21%)	6 / 297 (2.02%)
occurrences all number	13	20	7
Urinary tract infection
subjects affected / exposed	26 / 295 (8.81%)	47 / 592 (7.94%)	21 / 297 (7.07%)
occurrences all number	30	56	26
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	7 / 295 (2.37%)	11 / 592 (1.86%)	4 / 297 (1.35%)
occurrences all number	7	11	4
Iron deficiency
subjects affected / exposed	4 / 295 (1.36%)	10 / 592 (1.69%)	6 / 297 (2.02%)
occurrences all number	4	10	6
Hyponatraemia
subjects affected / exposed	6 / 295 (2.03%)	15 / 592 (2.53%)	9 / 297 (3.03%)
occurrences all number	9	18	9
Hypokalaemia
subjects affected / exposed	14 / 295 (4.75%)	19 / 592 (3.21%)	5 / 297 (1.68%)
occurrences all number	16	21	5
Vitamin D deficiency
subjects affected / exposed	7 / 295 (2.37%)	13 / 592 (2.20%)	6 / 297 (2.02%)
occurrences all number	7	13	6
Gout
subjects affected / exposed	9 / 295 (3.05%)	21 / 592 (3.55%)	12 / 297 (4.04%)
occurrences all number	12	27	15
Diabetes mellitus
subjects affected / exposed	7 / 295 (2.37%)	15 / 592 (2.53%)	8 / 297 (2.69%)
occurrences all number	7	16	9
Vitamin B12 deficiency
subjects affected / exposed	6 / 295 (2.03%)	9 / 592 (1.52%)	3 / 297 (1.01%)
occurrences all number	6	9	3
Hyperkalaemia
subjects affected / exposed	31 / 295 (10.51%)	72 / 592 (12.16%)	41 / 297 (13.80%)
occurrences all number	49	115	66

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Were there any global substantial amendments to the protocol? Yes

01 Jun 2017

The key purpose of this amendment was to revise some of the study inclusion and exclusion criteria to remove unnecessary restrictions and to ensure the study population reflected the HFpEF population in the community. Although CLCZ696B2320 study was designed as an independent study to evaluate cognitive function and cerebral amyloid accretion in HFpEF patients, most of the inclusion and exclusion criteria were derived from the PARAGON-HF trial (an event-driven trial) as they were thought not to impact the objectives of the CLCZ696B2320 study. The initial screen failure rate was considerably higher than originally anticipated and many of the failures were because patients did not meet the MRI cerebrovascular criteria, which were intended to exclude patients with significant cerebrovascular pathology in whom the rate of change in cognitive function over time may differ from that in patients without significant background vascular disease. Based on CLCZ696B2320 study screening experience as well as available literature, the prevalence of cerebrovascular disease appeared to be significantly higher than originally anticipated and the existing exclusion criteria appeared to limit the population to the extent that the study cohort might not truly reflect the heart failure patient population seen in the community. Therefore, the following changes to the inclusion/exclusion criteria were made: Removed the requirement to meet MRI criteria for cerebrovascular and white matter lesions. Clinically significant cerebral pathology that may impact cognition remained as an exclusion criterion. Removed the existing exclusion criterion to allow participation of patients with a history of cardiomyopathies with an ejection fraction of >40% because exclusion of these patients was not relevant to the study objectives and these patients may benefit from treatment with LCZ696.

18 Aug 2017

The purpose of this amendment was to correct a typographical error.

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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