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Clinical Trial Results:
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL TO EVALUATE THE EFFECT OF 300 MG OF INCLISIRAN SODIUM GIVEN AS SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) OR ASCVD-RISK EQUIVALENTS AND ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C)

Summary
EudraCT number	2017-001846-90
Trial protocol	DE HU GB CZ NL
Global end of trial date	31 Jul 2019

Results information
Results version number	v1(current)
This version publication date	16 Aug 2020
First version publication date	16 Aug 2020
Other versions

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

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Trial information

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Sponsor protocol code

MDCO-PCS-17-08

ISRCTN number

US NCT number

NCT03400800

WHO universal trial number (UTN)

Sponsor organisation name

The Medicines Company

Sponsor organisation address

8 Sylvan Way, Parsippany, United States, NJ 07054

Public contact

Global Health Science Center , The Medicines Company, +1 9732906000, medical.information@themedco.com

Scientific contact

Global Health Science Center , The Medicines Company, +1 9732906000, medical.information@themedco.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

05 Oct 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jul 2019

Global end of trial reached?

Yes

Global end of trial date

31 Jul 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to evaluate the effect of inclisiran treatment on: •LDL-C levels at Day 510 •Time adjusted percent change in LDL-C levels from baseline between Day 90 and Day 540 levels

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.

Background therapy

All subjects participating must be on and maintain maximally tolerated statin therapy and/or other LDLC lowering therapies such as ezetimibe in addition to receiving inclisiran or placebo.

Evidence for comparator

Use of placebo is consistent with other investigational lipid lowering therapy Phase III designs, including the statins and the monoclonal antibody PCSK9 inhibitors. All subjects participating must be on and maintain maximally tolerated statin therapy and/or other LDL-C lowering therapies such as ezetimibe in addition to receiving inclisiran or placebo. The use of placebo in this type of study is consistent with EU guidance on clinical investigation of medicinal products in the treatment of lipid disorders (EMA/CHMP/748108/2013, Rev. 3).

Actual start date of recruitment

01 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Ethical reason

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 717

Country: Number of subjects enrolled

United Kingdom: 462

Country: Number of subjects enrolled

Czech Republic: 21

Country: Number of subjects enrolled

Germany: 83

Country: Number of subjects enrolled

Hungary: 104

Country: Number of subjects enrolled

South Africa: 121

Country: Number of subjects enrolled

Ukraine: 109

Worldwide total number of subjects

1617

EEA total number of subjects

1387

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

733

From 65 to 84 years

884

85 years and over

Subject disposition

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Recruitment details

Not applicable

Screening details

Screening occurred prior to randomization and consisted of confirming eligibility and collecting baseline assessments. Subjects enrolled must have fasting triglyceride <4.52 mmol/L (<400 mg/dL) and serum LDL-C ≥1.8 mmol/L (≥70 mg/dL) at screening.

Number of subjects started

1617

Number of subjects completed

1617

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

As inclisiran may by visually distinguishable from placebo, blinded syrunges were provided to all study sites and used to maintain the blind.

Are arms mutually exclusive

Yes

Inclisiran

Arm description

Inclisiran sodium 300 mg

Arm type

Experimental

Investigational medicinal product name

Inclisiran

Investigational medicinal product code

ALN-60212

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Inclisiran sodium 300 milligrams (mg) was administered as a subcutaneous injection on Day 1, Day 90 then every 6 months.

Placebo

Arm description

Placebo arm

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo was administered as a subcutaneous injection on Day 1, Day 90 then every 6 months.

Number of subjects in period 1	Inclisiran	Placebo
Started	810	807
Completed	772	770
Not completed	38	37
Consent withdrawn by subject	13	17
Physician decision	1	1
Adverse Event	4	-
Death	14	15
Not specified	-	1
Lost to follow-up	6	3

Baseline characteristics

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Reporting group title

Inclisiran

Reporting group description

Inclisiran sodium 300 mg

Reporting group title

Placebo

Reporting group description

Placebo arm

Reporting group values	Inclisiran	Placebo	Total
Number of subjects	810	807	1617
Age categorical
Units: Subjects
Adults (18-64 years)	367	366	733
Adults (65 - 74 years)	354	327	681
Adults (from 75 years)	89	114	203
Gender categorical
Units: Subjects
Female	231	226	457
Male	579	581	1160

Subject analysis set title

Inclisiran

Subject analysis set type

Intention-to-treat

Subject analysis set description

Inclisiran Intention-to-treat population

Subject analysis set title

Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Intention-to-treat population

Subject analysis sets values	Inclisiran	Placebo
Number of subjects	810	807
Age categorical
Units: Subjects
Adults (18-64 years)	367	366
Adults (65 - 74 years)	354	327
Adults (from 75 years)	89	114
Age continuous
Units:
	±	±
Gender categorical
Units: Subjects
Female	231	226
Male	579	581

End points

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Reporting group title

Inclisiran

Reporting group description

Inclisiran sodium 300 mg

Reporting group title

Placebo

Reporting group description

Placebo arm

Subject analysis set title

Inclisiran

Subject analysis set type

Intention-to-treat

Subject analysis set description

Inclisiran Intention-to-treat population

Subject analysis set title

Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Placebo Intention-to-treat population

Primary: Percentage Change in LDL-C From Baseline to Day 510

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End point title

Percentage Change in LDL-C From Baseline to Day 510

End point description

End point type

Primary

End point timeframe

Baseline to Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-49.3 (-51.22 to -47.48)	4.2 (1.62 to 6.69)	-49.3 (-51.22 to -47.48)	4.2 (1.62 to 6.69)

Percentage Change in LDL-C from Baseline - Day 510

Statistical analysis description

Difference in the percentage change in LDL-C from baseline to Day 510 between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-53.5

Confidence interval

level

95%

sides

2-sided

lower limit

-56.7

upper limit

-50.3

Primary: Time-adjusted Percent Change in LDL-C Levels from Baseline After Day 90 to up Day 540

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End point title

Time-adjusted Percent Change in LDL-C Levels from Baseline After Day 90 to up Day 540

End point description

End point type

Primary

End point timeframe

Baseline, Day 90, Day 540

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-45.82 (-47.52 to -44.13)	3.35 (1.65 to 5.05)	-45.82 (-47.52 to -44.13)	3.35 (1.65 to 5.05)

Percentage Change in LDL-C from Day 90 to Day 540

Statistical analysis description

Difference in time-adjusted percentage change in LDL-C Levels From Baseline After Day 90 and up to Day 540 between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-49.17

Confidence interval

level

95%

sides

2-sided

lower limit

-51.57

upper limit

-46.77

Secondary: Absolute Change in LDL-C from Baseline to Day 510

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End point title

Absolute Change in LDL-C from Baseline to Day 510

End point description

End point type

Secondary

End point timeframe

Baseline, Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-50.91 (-53.14 to -48.67)	0.96 (-1.26 to 3.18)	-50.91 (-53.14 to -48.67)	0.96 (0.96 to 3.18)

Absolute Change in LDL-C From Baseline To Day 510

Statistical analysis description

Difference in Absolute Change in LDL-C From Baseline To Day 510 between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-51.87

Confidence interval

level

95%

sides

2-sided

lower limit

-55.01

upper limit

-48.72

Secondary: Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

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End point title

Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

End point description

End point type

Secondary

End point timeframe

Baseline, Day 90, Day 540

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-48.63 (-50.37 to -46.89)	0.31 (-1.42 to 2.04)	-48.63 (-50.37 to -46.89)	0.31 (-1.42 to 2.04)

Absolute Change in Time-adjusted Change in LDL-C

Statistical analysis description

Difference in the change in time-adjusted LDL-C after Day 90 and up to Day 540, between inclisiran and placebo groups

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-48.94

Confidence interval

level

95%

sides

2-sided

lower limit

-51.39

upper limit

-46.48

Secondary: Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

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End point title

Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

End point description

End point type

Secondary

End point timeframe

Baseline, Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: & change
least squares mean (confidence interval 95%)	-63.64 (-65.55 to -61.74)	15.62 (13.72 to 17.53)	-63.64 (-65.55 to -61.74)	15.62 (13.72 to 17.53)

Percentage change in PCSK9 from Baseline - Day 510

Statistical analysis description

Difference in percentage change in PCSK9 from baseline to Day 510, between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-79.27

Confidence interval

level

95%

sides

2-sided

lower limit

-81.97

upper limit

-76.57

Secondary: Percentange Change in Total Cholesterol From Baseline to Day 510

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End point title

Percentange Change in Total Cholesterol From Baseline to Day 510

End point description

End point type

Secondary

End point timeframe

Baseline, Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-28.00 (-29.40 to -26.60)	1.79 (0.38 to 3.21)	-28.00 (-29.40 to -26.60)	1.79 (0.38 to 3.21)

Percentage change in Total Cholesterol

Statistical analysis description

Difference in the percentage change in total cholesterol from baseline to Day 510, between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-29.79

Confidence interval

level

95%

sides

2-sided

lower limit

-31.78

upper limit

-27.81

Secondary: Percentage change in Apolipoprotein B From Baseline to Day 510

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End point title

Percentage change in Apolipoprotein B From Baseline to Day 510

End point description

End point type

Secondary

End point timeframe

Baseline, Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % Change
least squares mean (confidence interval 95%)	-38.15 (-39.76 to -36.54)	0.79 (-0.82 to 2.41)	-38.15 (-39.76 to -36.54)	0.79 (-0.82 to 2.41)

Percentage change in Apo B form Baseline - Day 510

Statistical analysis description

Difference in the percentage change in Apolipoprotein B (ApoB) from baseline to Day 510

Comparison groups

Placebo v Inclisiran

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-38.94

Confidence interval

level

95%

sides

2-sided

lower limit

-41.21

upper limit

-36.67

Secondary: Percentage Change in Non-HDL-C From Baseline to Day 510

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End point title

Percentage Change in Non-HDL-C From Baseline to Day 510

End point description

End point type

Secondary

End point timeframe

Baseline, Day 510

End point values	Inclisiran	Placebo	Inclisiran	Placebo
Number of subjects analysed	810	807	810	807
Units: % change
least squares mean (confidence interval 95%)	-41.16 (-43.09 to -39.24)	2.15 (0.22 to 4.09)	-41.16 (-43.09 to -39.24)	2.15 (0.22 to 4.09)

Percentage Change in Non-HDL-C: baseline - Day 510

Statistical analysis description

Difference in the percentage change in Non-HDL-C from baseline to Day 510, between inclisiran and placebo arms

Comparison groups

Inclisiran v Placebo

Number of subjects included in analysis

1617

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-43.32

Confidence interval

level

95%

sides

2-sided

lower limit

-46

upper limit

-40.6

Adverse events

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Timeframe for reporting adverse events

17 months

Adverse event reporting additional description

The Efficacy population was comprised of 807 (Placebo) and 810 (Inclisiran) for a total of 1617 subjects. The Safety population consisted of 804 (Placebo) and 811 (Inclisiran). Two randomized subjects (Placebo) were not dosed. One placebo subject received inclisiran at Day 450 so was reallocated to the inclisiran group for safety.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Inclisiran

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Inclisiran	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	181 / 811 (22.32%)	181 / 804 (22.51%)
number of deaths (all causes)	14	15
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma gastric
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Bladder neoplasm
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma recurrent
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carcinoid tumour of the stomach
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clear cell renal cell carcinoma
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endometrial adenocarcinoma
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal carcinoma
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular carcinoma
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Intestinal adenocarcinoma
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal cancer stage IV
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lentigo maligna
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Linitis plastica
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung carcinoma cell type unspecified recurrent
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	2 / 811 (0.25%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Metastases to liver
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Metastatic carcinoma of the bladder
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Non-Hodgkin's lymphoma
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Oral neoplasm
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral nerve sheath tumour malignant
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 811 (0.12%)	6 / 804 (0.75%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cancer metastatic
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Salivary gland cancer
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of the cervix
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheal neoplasm
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood pressure inadequately controlled
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Granulomatosis with polyangiitis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 811 (0.25%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Iliac artery embolism
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	7 / 811 (0.86%)	8 / 804 (1.00%)
occurrences causally related to treatment / all	0 / 7	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thromboangiitis obliterans
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Leg amputation
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Cardiac death
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chest pain
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 2
Exercise tolerance decreased
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	4 / 811 (0.49%)	8 / 804 (1.00%)
occurrences causally related to treatment / all	0 / 4	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Vascular stent occlusion
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular stent restenosis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Sarcoidosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic prolapse
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatomegaly
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	3 / 811 (0.37%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Choking
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	3 / 811 (0.37%)	3 / 804 (0.37%)
occurrences causally related to treatment / all	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Dyspnoea
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Emphysema
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 811 (0.25%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sleep apnoea syndrome
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device loosening
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Liver function test increased
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Acetabulum fracture
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arterial bypass occlusion
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary vascular graft occlusion
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	2 / 811 (0.25%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incision site pain
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial reocclusion
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Periprocedural myocardial infarction
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural hypotension
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 811 (0.00%)	3 / 804 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic fracture
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	14 / 811 (1.73%)	13 / 804 (1.62%)
occurrences causally related to treatment / all	0 / 14	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	5 / 811 (0.62%)	18 / 804 (2.24%)
occurrences causally related to treatment / all	0 / 5	0 / 21
deaths causally related to treatment / all	0 / 0	0 / 1
Angina unstable
subjects affected / exposed	11 / 811 (1.36%)	11 / 804 (1.37%)
occurrences causally related to treatment / all	0 / 12	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	10 / 811 (1.23%)	6 / 804 (0.75%)
occurrences causally related to treatment / all	0 / 11	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 811 (0.37%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	3 / 811 (0.37%)	6 / 804 (0.75%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure chronic
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	5 / 811 (0.62%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	8 / 811 (0.99%)	11 / 804 (1.37%)
occurrences causally related to treatment / all	0 / 8	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery insufficiency
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Left ventricular dysfunction
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Mitral valve incompetence
subjects affected / exposed	2 / 811 (0.25%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	5 / 811 (0.62%)	4 / 804 (0.50%)
occurrences causally related to treatment / all	0 / 5	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 2
Myocardial ischaemia
subjects affected / exposed	4 / 811 (0.49%)	5 / 804 (0.62%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 2
Palpitations
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paroxysmal arrhythmia
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Silent myocardial infarction
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain injury
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dementia Alzheimer's type
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial venous sinus thrombosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 811 (0.12%)	3 / 804 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Lacunar stroke
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 811 (0.37%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenopathy mediastinal
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chronic gastritis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incarcerated umbilical hernia
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 811 (0.25%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis chronic
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis necrotising
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peptic ulcer
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal prolapse
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Volvulus
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis erosive
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Biliary dilatation
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	3 / 811 (0.37%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	3 / 811 (0.37%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pyoderma gangrenosum
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	5 / 811 (0.62%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
End stage renal disease
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis membranous
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hypopituitarism
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Facet joint syndrome
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Inclusion body myositis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc space narrowing
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	3 / 811 (0.37%)	3 / 804 (0.37%)
occurrences causally related to treatment / all	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	2 / 811 (0.25%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue necrosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Undifferentiated connective tissue disease
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	2 / 811 (0.25%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chondrocalcinosis pyrophosphate
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 811 (0.25%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 811 (0.25%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest wall abscess
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Erysipelas
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder abscess
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder empyema
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	1 / 811 (0.12%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	3 / 811 (0.37%)	3 / 804 (0.37%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Neuroborreliosis
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pathogen resistance
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 811 (1.11%)	7 / 804 (0.87%)
occurrences causally related to treatment / all	0 / 9	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Pneumonia pneumococcal
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 811 (0.00%)	2 / 804 (0.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sialoadenitis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 811 (0.37%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	2 / 811 (0.25%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 811 (0.12%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 811 (0.25%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	1 / 811 (0.12%)	0 / 804 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 811 (0.00%)	1 / 804 (0.12%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Inclisiran	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	331 / 811 (40.81%)	319 / 804 (39.68%)
Vascular disorders
Hypertension
subjects affected / exposed	53 / 811 (6.54%)	54 / 804 (6.72%)
occurrences all number	60	59
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	47 / 811 (5.80%)	32 / 804 (3.98%)
occurrences all number	56	37
Infections and infestations
Nasopharyngitis
subjects affected / exposed	91 / 811 (11.22%)	90 / 804 (11.19%)
occurrences all number	105	110
Upper respiratory tract infection
subjects affected / exposed	52 / 811 (6.41%)	49 / 804 (6.09%)
occurrences all number	59	57
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	88 / 811 (10.85%)	94 / 804 (11.69%)
occurrences all number	101	100

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Were there any global substantial amendments to the protocol? Yes

18 Dec 2017

Clarifications to the protocol synopsis and main body were included in order to address comments received from the FDA. The exclusion criterion #3, site training requirements and statistics sections were revised. Changes were made to the following sections: Synopsis-Exclusion Criteria, Synopsis-Statistical Methods, Section 4.3-Exclusion Criteria, Section 10.3.2.1-Intent-to-Treat (ITT) Population, Section 10.3.2.2-Modified Intent-to-Treat (mITT) Population, Section 10.3.4-Missing Data Handling, Section 10.4.3-Efficacy Analysis, 10.4.3.1.1-Sensitivity Analysis for Primary Efficacy Endpoints and 10.4.3.2-Secondary Efficacy Endpoint. Administrative amendments were made to the protocol.

31 Jan 2019

Synopsis, Section 2.1, Section 3.3, Section 3.4, Section 7.2.1, Section 10.4.3.1 to account for refinement in the description of time adjusted analyses of LDL-C. Section 6.1. Table 2. Section 6.4, Section 6.6, Section 6.8, Section 7.1.8.8 to clarify the plan to test for ADA. Section 6.1. Table 2. Schedule of Assessments to align with Health Authority feedback for wider visit windows. Section 10.3.2.2., Section 10.4.1., Section 10.4.3 to add to account for the addition of a new analysis set (Full Analysis Set). Section 10.3.3. Analysis Windows and Baseline to clarify that analysis windows will be defined to maximize the amount of data that are included in the analysis models and that full details will be provided in the Statistical Analysis Plan. Synopsis, Section 10.3.4, Section 10.4.3.1, Section 10.4.3.1.1. Missing Data Handling to align approach to missing data handling with Health Authority feedback and that details are provided in the Statistical Analysis Plan. Section 10.4.4.2. Laboratory Tests to add analyses for clinically significant laboratory parameters.

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.

Not applicable.

http://www.ncbi.nlm.nih.gov/pubmed/32187462

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Change in LDL-C From Baseline to Day 510

Primary: Percentage Change in LDL-C From Baseline to Day 510

Primary: Time-adjusted Percent Change in LDL-C Levels from Baseline After Day 90 to up Day 540

Primary: Time-adjusted Percent Change in LDL-C Levels from Baseline After Day 90 to up Day 540

Secondary: Absolute Change in LDL-C from Baseline to Day 510

Secondary: Absolute Change in LDL-C from Baseline to Day 510

Secondary: Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

Secondary: Time-adjusted Absolute Change in LDL-C From Baseline After Day 90 and up to Day 540

Secondary: Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

Secondary: Percentage Change in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) From Baseline to Day 510

Secondary: Percentange Change in Total Cholesterol From Baseline to Day 510

Secondary: Percentange Change in Total Cholesterol From Baseline to Day 510

Secondary: Percentage change in Apolipoprotein B From Baseline to Day 510

Secondary: Percentage change in Apolipoprotein B From Baseline to Day 510

Secondary: Percentage Change in Non-HDL-C From Baseline to Day 510

Secondary: Percentage Change in Non-HDL-C From Baseline to Day 510

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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