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Clinical Trial Results:
A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease

Summary
EudraCT number	2007-005839-28
Trial protocol	SE ES HU FR AT FI NL DE
Global end of trial date	23 Nov 2017

Results information
Results version number	v2(current)
This version publication date	26 Dec 2018
First version publication date	15 Apr 2017
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

0859-019

ISRCTN number

US NCT number

NCT00685776

WHO universal trial number (UTN)

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp and Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp and Dohme Corp., ClinicalTrialsDisclosure@merck.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

01 Jul 2009

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Nov 2017

Was the trial ended prematurely?

Main objective of the trial

This study evaluated the efficacy of anacetrapib 100 mg for 24 weeks relative to placebo, on plasma concentrations of Low Density Lipoprotein Cholesterol and assessed the 76-week safety and tolerability of anacetrapib 100mg in participants with coronary heart disease (CHD)/CHD risk equivalent disease on stable dose regimen of statin with or without other lipid-modifying therapy. The 2 year extension to this study further evaluated the long-term safety profile and efficacy of anacetrapib 100 mg in CHD/CHD-risk equivalent participants who were on ongoing therapy with a statin with or without other lipid-modifying therapy.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

All participants were required to be on a stable-regimen of statin ± other lipid-modifying medication(s) for at least 6-weeks prior to enrollment.

Evidence for comparator

Actual start date of recruitment

24 Mar 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 59

Country: Number of subjects enrolled

Austria: 34

Country: Number of subjects enrolled

Canada: 62

Country: Number of subjects enrolled

Colombia: 5

Country: Number of subjects enrolled

Finland: 51

Country: Number of subjects enrolled

France: 38

Country: Number of subjects enrolled

Germany: 42

Country: Number of subjects enrolled

Hong Kong: 36

Country: Number of subjects enrolled

Hungary: 82

Country: Number of subjects enrolled

Israel: 59

Country: Number of subjects enrolled

Malaysia: 66

Country: Number of subjects enrolled

Mexico: 68

Country: Number of subjects enrolled

Netherlands: 186

Country: Number of subjects enrolled

New Zealand: 48

Country: Number of subjects enrolled

Norway: 48

Country: Number of subjects enrolled

Peru: 35

Country: Number of subjects enrolled

Russian Federation: 47

Country: Number of subjects enrolled

Spain: 93

Country: Number of subjects enrolled

Sweden: 74

Country: Number of subjects enrolled

United States: 490

Worldwide total number of subjects

1623

EEA total number of subjects

648

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)

889

From 65 to 84 years

734

85 years and over

Subject disposition

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Recruitment details

Base study consisted of a 76 week treatment period and a 12-week reversal period (no treatment). The active study was extended for 2-years which was followed by a 1 year reversal (no treatment).

Screening details

This study was enrolled participants with coronary heart disease (CHD) or CHD risk-equivalent disease that were taking a statin with or without other lipid-modifying medications. Other inclusion and exclusion criteria applied.

Period 1 title

Base Study - Treatment Phase (Part A)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Anacetrapib

Arm description

one 100-mg Anacetrapib tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Arm type

Experimental

Investigational medicinal product name

Anacetrapib

Investigational medicinal product code

Other name

MK-0859

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one 100-mg tablet once daily

Placebo

Arm description

one placebo tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one 100-mg tablet once daily

Number of subjects in period 1	Anacetrapib	Placebo
Started	811	812
Completed	548	663
Not completed	263	149
Consent withdrawn by subject	46	57
Physician decision	6	6
Adverse Event	46	48
LDL-C Stopping Criteria Met	142	1
Study Terminated by Sponsor	5	3
Lost to follow-up	3	13
Lack of efficacy	1	1
Protocol deviation	14	20

Period 2 title

Base Study - Reversal (Part B)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

Anacetrapib 100 mg - Base Study Reversal

Arm description

Completers and Non-completers who received 100 mg Anacetrapib during treatment period. Participants continue with current stable regimen of lipid-lowering therapy.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo -Base Study Reversal

Arm description

Completers and non-completers who received placebo in treatment period of base study. Participants continue with current stable regimen of lipid-lowering therapy.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	Anacetrapib 100 mg - Base Study Reversal	Placebo -Base Study Reversal
Started	548	663
Completed	655	690
Not completed	29	24
Unknown	29	24
Joined	136	51
non-completers from treatment phase	136	51

Period 3 title

2-year Extension (Part C)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Anacetrapib-Extension Study

Arm description

one 100-mg Anacetrapib tablet daily with food for 104 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Arm type

Experimental

Investigational medicinal product name

Anacetrapib

Investigational medicinal product code

Other name

MK-0859

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one 100-mg tablet once daily

Placebo-Extension Study

Arm description

one placebo tablet daily with food for 104 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

one 100-mg tablet once daily

Number of subjects in period 3	Anacetrapib-Extension Study	Placebo-Extension Study
Started	370	433
Completed	328	386
Not completed	42	47
Consent withdrawn by subject	17	18
Physician decision	2	4
Adverse event, non-fatal	18	23
Lost to follow-up	1	1
Protocol deviation	4	-
Lack of efficacy	-	1

Period 4 title

1-year Reversal (Part D)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Anacetrapib-1 year Reversal Study

Arm description

Participants who received Anacetrapib 100 mg in Extension (Part C). Participants continue with current stable regimen of lipid-lowering therapy.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Placebo-1 year Reversal Study

Arm description

Participants who received placebo in Extension (Part C). Participants continue with current stable regimen of lipid-lowering therapy.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 4	Anacetrapib-1 year Reversal Study	Placebo-1 year Reversal Study
Started	271	1
Completed	266	1
Not completed	5	0
Consent withdrawn by subject	1	-
Physician decision	1	-
Adverse event, non-fatal	1	-
Lost to follow-up	1	-
Progressive disease	1	-

Baseline characteristics

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Reporting group title

Anacetrapib

Reporting group description

one 100-mg Anacetrapib tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group title

Placebo

Reporting group description

one placebo tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group values	Anacetrapib	Placebo	Total
Number of subjects	811	812	1623
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	62.5 ( 8.7 )	62.9 ( 9 )	-
Gender Categorical
Units: Subjects
Female	182	194	376
Male	629	618	1247

End points

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Reporting group title

Anacetrapib

Reporting group description

one 100-mg Anacetrapib tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group title

Placebo

Reporting group description

one placebo tablet daily with food for 76 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group title

Anacetrapib 100 mg - Base Study Reversal

Reporting group description

Completers and Non-completers who received 100 mg Anacetrapib during treatment period. Participants continue with current stable regimen of lipid-lowering therapy.

Reporting group title

Placebo -Base Study Reversal

Reporting group description

Completers and non-completers who received placebo in treatment period of base study. Participants continue with current stable regimen of lipid-lowering therapy.

Reporting group title

Anacetrapib-Extension Study

Reporting group description

one 100-mg Anacetrapib tablet daily with food for 104 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group title

Placebo-Extension Study

Reporting group description

one placebo tablet daily with food for 104 weeks administered with participant's current stable regimen of lipid-lowering therapy.

Reporting group title

Anacetrapib-1 year Reversal Study

Reporting group description

Participants who received Anacetrapib 100 mg in Extension (Part C). Participants continue with current stable regimen of lipid-lowering therapy.

Reporting group title

Placebo-1 year Reversal Study

Reporting group description

Participants who received placebo in Extension (Part C). Participants continue with current stable regimen of lipid-lowering therapy.

Subject analysis set title

Anacetrapib 100 mg - Base Study- Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

All randomized participants who were not excluded due to failure to receive at least 1 dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment or lacked baseline data for those analyses that required baseline data.

Subject analysis set title

Placebo - Base Study - Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

All randomized participants who were not excluded due to failure to receive at least 1 dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment or lack, of baseline data for those analyses that require baseline data.

Subject analysis set title

Anacetrapib 100 mg - Base Study - Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized participants who received at least 1 dose of study treatment in Base Study and had at least 1 post-baseline measurement for parameter assessed.

Subject analysis set title

Placebo - Base Study- Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized participants who received at least 1 dose of study treatment in Base Study and has at least 1 post-baseline measurement for parameter assessed.

Subject analysis set title

Anacetrapib 100 mg - Extension Study - Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

All randomized participants who were not excluded due to failure to receive at least 1 dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment or lack of baseline data for those analyses that required baseline data.

Subject analysis set title

Placebo- Extension Study - Efficacy

Subject analysis set type

Full analysis

Subject analysis set description

All randomized participants who were not excluded due to failure to receive at least 1 dose of study treatment, lack of any post-randomization endpoint data subsequent to at least 1 dose of study treatment, or lack of baseline data for those analyses that required baseline data.

Subject analysis set title

Anacetrapib 100 mg -Extension-Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized participants who received at least 1 dose of study treatment in extension and had at least 1 post-baseline measurement for parameter assessed.

Subject analysis set title

Placebo-Extension Study-Safety

Subject analysis set type

Safety analysis

Subject analysis set description

All randomized participants who received at least 1 dose of study treatment in Extension Study and had at least 1 post-baseline measurement for parameter assessed.

Subject analysis set title

Anacetrapib-1 year Reversal Study-Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received Anacetrapib 100 mg in Extension (Part C) and had available safety data

Subject analysis set title

Placebo-1 year Reversal Study-Safety

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received placebo in Extension (Part C) and had available safety data

Primary: Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24- Base Study

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End point title

Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24- Base Study

End point description

LDL-C levels measured at baseline and after 24 weeks of treatment measured by Friedewald method

End point type

Primary

End point timeframe

Baseline and Week 24

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	682	742
Units: Percentage Change
least squares mean (confidence interval 95%)	-44.6 (-46.3 to -42.8)	-4.5 (-6.2 to -2.8)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1424

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis;

Parameter type

Difference in Least squares (LS) means

Point estimate

-40.1

Confidence interval

level

95%

sides

2-sided

lower limit

-42.4

upper limit

-37.7

Primary: Number of Participants With Hepatitis-related Adverse Events (AEs)- Base Study

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End point title

Number of Participants With Hepatitis-related Adverse Events (AEs)- Base Study ^[1]

End point description

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. Hepatitis-related AEs were identified by a collective review using the following prespecified set of preferred terms: cholestasis, hepatic necrosis, hepatocellular damage, cytolytic hepatitis, hepatitis, hepatomegaly, jaundice, hepatic failure, hepatitis cholestatic, jaundice cholestatic, hepatitis fulminant, hyperbilirubinaemia, jaundice hepatocellular, ocular icterus, yellow skin, hepatic function abnormal, acute hepatic failure, subacute hepatic failure, hepatitis acute, hepatitis toxic, hepatotoxicity, and mixed hepatocellular-cholestatic injury.

End point type

Primary

End point timeframe

up to 88 weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparisons were planned for this endpoint.

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	808	804
Units: Participants	1	1

No statistical analyses for this end point

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Treatment Phase-Base Study

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End point title

Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Treatment Phase-Base Study

End point description

Participants had alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels assessed throughout the 76 week Treatment Phase. Participants who had 2 consecutive assessments of ALT and/or AST that were 3 x ULN or greater were recorded. The ALT UNLs for males and females were 40 U/L and 33 U/L, respectively. The AST UNLs for males and females were 43 U/L and 36 U/L, respectively.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	800	796
Units: Percentage of Participants
number (not applicable)	0.1	1

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.019

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

-0.2

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN- Treatment Phase-Base Study

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End point title

Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN- Treatment Phase-Base Study

End point description

Participants had creatine phosphokinase (CK) levels assessed throughout the 76 week Treatment Phase. Participants who had any CK level that was ≥ 10 x ULN were recorded. The ULNs for males and females were 207 IU/L and 169 IU/L, respectively.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	800	796
Units: Percentage of Participants
number (not applicable)	0	0.3

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.156

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.2

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN with Muscle Symptoms- Treatment Phase-Base Study

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End point title

Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN with Muscle Symptoms- Treatment Phase-Base Study

End point description

Participants had CK levels assessed throughout the 76 week Treatment Phase. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days were recorded. The ULNs for males and females were 207 IU/L and 169 IU/L, respectively.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	800	796
Units: Percentage of Participants
number (not applicable)	0	0

Comparison Between Groups

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.999

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

0.5

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN-Treatment Phase- Base Study

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End point title

Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN-Treatment Phase- Base Study

End point description

Participants had sodium, chloride, and bicarbonate levels assessed throughout the 76 week Treatment Phase. Participants who had any sodium level that was > the ULN of 145 mEq/L had any chloride level that was > the ULN of 110 mEq/L or had any bicarbonate level that was > the ULN of 33 mEq/L were recorded

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	800	796
Units: Percentage of Participants
number (not applicable)
Sodium	13.9	12.9
Chloride	3.9	4.4
Bicarbonate	1.5	2.1

Comparison Between Groups - Sodium

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.584

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

4.3

Between Group Comparison- Chloride

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.601

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

1.5

Between Group Comparison - Bicarbonate

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.342

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

0.7

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Treatment Phase- Base Study

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End point title

Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Treatment Phase- Base Study

End point description

Participants had potassium levels assessed throughout the 76 week Treatment Phase. Participants who had any potassium level that was < the LLN of 3.5 mEq/L were recorded.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	800	796
Units: Percentage of Participants
number (not applicable)	5	4.6

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1596

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.743

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

2.5

Primary: Percentage of Participants with Myalgia- Treatment Phase- Base Study

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End point title

Percentage of Participants with Myalgia- Treatment Phase- Base Study

End point description

Adverse events were recorded throughout the 76 week Treatment Phase. The percentage of participants who experienced an AE reported with verbatim term "myalgia" were summarized.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	808	804
Units: Percentage of Participants
number (not applicable)	4	3.5

Comparison Between Groups

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.612

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

2.4

Primary: Percentage of Participants with Rhabdomyolysis- Treatment Phase- Base Study

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End point title

Percentage of Participants with Rhabdomyolysis- Treatment Phase- Base Study

End point description

Adverse events were recorded throughout the 76 week Treatment Phase. The percentage of participants who experienced an AE reported with verbatim term "rhabdomyolysis" were summarized.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	808	804
Units: Percentage of Participants
number (not applicable)	0	0

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other

P-value

> 0.999

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

0.5

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Treatment Phase- Base Study

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End point title

Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Treatment Phase- Base Study

End point description

Participants who experienced the SAEs of CV death, Non-fatal stroke, non-fatal myocardial infarction, or unstable angina during the 76 week Treatment Phase were recorded. These cardiovascular events that occurred during the Base Study were adjudicated by an expert committee external to the sponsor.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	808	804
Units: Percentage of Participants
number (not applicable)	1.6	2.6

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.161

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

0.4

Primary: Percentage of Participants with Death from Any Cause- Treatment Phase- Base Study

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End point title

Percentage of Participants with Death from Any Cause- Treatment Phase- Base Study

End point description

Participants who died from any cause during the 76 week Treatment Phase were recorded. All deaths were adjudicated by an expert committee independent of the Sponsor.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	808	804
Units: Percentage of Participants
number (not applicable)	0.7	0.9

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1612

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.774

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.8

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Extension Study

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End point title

Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Extension Study

End point description

Participants had alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels assessed throughout the 104 week Extension Study. Participants who had 2 consecutive assessments of ALT and/or AST that were 3 x ULN or greater were recorded. The ALT UNLs for males and females were 40 U/L and 33 U/L, respectively.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	433
Units: Percentage of Participants
number (not applicable)	0.3	0.9

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

0.7

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN- Extension Study

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End point title

Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN- Extension Study

End point description

Participants had creatine phosphokinase (CK) levels assessed throughout the 104 week Extension Study. Participants who had any CK level that was >=10 x ULN were recorded. The ULNs for males and females were 207 IU/L and 169 IU/L, respectively.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	433
Units: Percentage of Participants
number (not applicable)	0	0

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN with Muscle Symptoms- Extension Study

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End point title

Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN with Muscle Symptoms- Extension Study

End point description

Participants had CK levels assessed throughout the 104 week Extension Study. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days were recorded. The ULNs for males and females were 207 IU/L and 169 IU/L, respectively.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	433
Units: Percentage of Participants
number (not applicable)	0	0

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN- Extension Study

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End point title

Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN- Extension Study

End point description

Participants had sodium, chloride, and bicarbonate levels assessed throughout the 104 week Extension Study. Participants who had any sodium level that was > the ULN of 145 mEq/L had any chloride level that was > the ULN of 110 mEq/L or had any bicarbonate level that was > the ULN of 33 mEq/L were recorded

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	433
Units: Percentage of Participants
number (not applicable)
Sodium	7.1	5.3
Chloride	1.4	0.5
Bicarbonate	1.4	1.4

Between Group Comparison- Sodium

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

5.4

Between Group Comparison- Bicarbonate

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

1.9

Between Group Comparison- Chloride

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

799

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

2.7

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Extension Study

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End point title

Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Extension Study

End point description

Participants had potassium levels assessed throughout the 104 week Extension Study. Participants who had any potassium level that was < the LLN of 3.5 mEq/L were recorded.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	432
Units: Percentage of Participants
number (not applicable)	2.2	3

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.2

upper limit

1.6

Primary: Percentage of Participants with Myalgia- Extension Study

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End point title

Percentage of Participants with Myalgia- Extension Study

End point description

Adverse events were recorded throughout the 104 week Extension Study. The number of participants who experienced an AE reported with verbatim term "myalgia" were summarized.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	369	433
Units: Percentage of Participants
number (not applicable)	1.6	2.5

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

802

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.371

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

1.2

Primary: Percentage of Participants with Rhabdomyolysis- Extension Study

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End point title

Percentage of Participants with Rhabdomyolysis- Extension Study

End point description

Adverse events were recorded throughout the 104 week Extension Study. The number of participants who experienced an AE reported with verbatim term "rhabdomyolysis" were summarized.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	369	433
Units: Percentage of Participants
number (not applicable)	0	0.2

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

802

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.356

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

0.8

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Extension Study

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End point title

Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Extension Study

End point description

Participants who experienced the SAEs of cardiovascular (CV) death, Non-fatal stroke, non-fatal myocardial infarction, or unstable angina during the 104 week Extension Study were recorded. These cardiovascular events that occurred during the Base Study were adjudicated by an expert committee external to the sponsor.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	370	433
Units: Percentage of Participants
number (not applicable)	3.8	3.2

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

803

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

3.3

Primary: Percentage of Participants with Death from Any Cause- Extension Study

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End point title

Percentage of Participants with Death from Any Cause- Extension Study

End point description

Participants who died from any cause during the 104 week Extension Study were recorded. All deaths were adjudicated by an expert committee independent of the Sponsor.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	370	433
Units: Percentage of Participants
number (not applicable)	2.4	2.1

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

803

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

2.7

Primary: Percentage of Participants Who Experience at Least 1 AE- 1 year Reversal Study

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End point title

Percentage of Participants Who Experience at Least 1 AE- 1 year Reversal Study ^[2]

End point description

An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. Note: An interactive voice response system (IVRS) distribution error resulted in only 1 participant who received placebo during the 2-year extension enrolled in the 1-year reversal phase instead of the approximately 68 placebo participants that were planned. All participants who had received anacetrapib 100 mg during the 2 year extension enrolled as planned in the 1-year reversal phase. Thus no comparative analysis was performed on data from the 1-year reversal phase.

End point type

Primary

End point timeframe

up to 52 weeks

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparisons were planned for this endpoint.

End point values	Anacetrapib-1 year Reversal Study-Safety	Placebo-1 year Reversal Study-Safety
Number of subjects analysed	271	1
Units: Percentage of Participants
number (not applicable)	49.4	0.0

No statistical analyses for this end point

Primary: Percentage of Participants Who Experience at Least 1 Drug-related AE- 1 year Reversal Study

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End point title

Percentage of Participants Who Experience at Least 1 Drug-related AE- 1 year Reversal Study ^[3]

End point description

An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. Adverse events reported as at least possibly related to study drug were summarized. Note: An IVRS distribution error resulted in only 1 participant who received placebo during the 2-year extension enrolled in the 1-year reversal phase instead of the approximately 68 placebo participants that were planned. All participants who had received anacetrapib 100 mg during the 2 year extension enrolled as planned in the 1-year reversal phase. Thus no comparative analysis was performed on data from the 1-year reversal phase.

End point type

Primary

End point timeframe

up to 52 weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical comparisons were planned for this endpoint.

End point values	Anacetrapib-1 year Reversal Study-Safety	Placebo-1 year Reversal Study-Safety
Number of subjects analysed	271	1
Units: Percentage of Participants
number (not applicable)	1.5	0.0

No statistical analyses for this end point

Primary: Change From Baseline in Sodium at Week 76-Base Study

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End point title

Change From Baseline in Sodium at Week 76-Base Study

End point description

Sodium levels were assessed at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	551	662
Units: mEq/L
least squares mean (confidence interval 95%)	-1 (-1.2 to -0.8)	-1.3 (-1.5 to -1.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1213

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.019

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.5

Primary: Change From Baseline in Chloride at Week 76-Base Study

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End point title

Change From Baseline in Chloride at Week 76-Base Study

End point description

Chloride levels were assessed at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	551	662
Units: mEq/L
least squares mean (confidence interval 95%)	-1.8 (-2 to -1.5)	-1.9 (-2.1 to -1.7)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1213

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.414

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.4

Primary: Change From Baseline in Bicarbonate at Week 76-Base Study

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End point title

Change From Baseline in Bicarbonate at Week 76-Base Study

End point description

Bicarbonate levels were assessed at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	552	664
Units: mEq/L
least squares mean (confidence interval 95%)	0.2 (0 to 0.4)	0.3 (0.1 to 0.5)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.791

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.2

Primary: Change From Baseline in Potassium at Week 76-Base Study

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End point title

Change From Baseline in Potassium at Week 76-Base Study

End point description

Potassium levels were assessed at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	549	657
Units: mEq/L
least squares mean (confidence interval 95%)	-0.1 (-0.1 to -0.1)	-0.1 (-0.1 to -0.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1206

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.282

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Primary: Percentage of Participants With Elevations in Systolic Blood Pressure (SBP) ≥ 10 mm Hg-Treatment Phase- Base Study

Top of page

End point title

Percentage of Participants With Elevations in Systolic Blood Pressure (SBP) ≥ 10 mm Hg-Treatment Phase- Base Study

End point description

Participants had SBP assessed at baseline and throughout the 76 week Treatment Phase. Participants who had a SBP reading that was ≥ 10 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	801	796
Units: Percentage of Participants
number (not applicable)	62.5	64.8

Between Group comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1597

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.344

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-7

upper limit

2.4

Primary: Percentage of Participants With Elevations in SBP ≥ 15 mm Hg- Treatment Phase- Base Study

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End point title

Percentage of Participants With Elevations in SBP ≥ 15 mm Hg- Treatment Phase- Base Study

End point description

Participants had SBP assessed throughout the 76 week Treatment Phase. Participants who had a SBP reading that was ≥ 15 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	801	796
Units: Percentage of Participants
number (not applicable)	44.2	47.4

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1597

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.204

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

-3.2

Confidence interval

level

95%

sides

2-sided

lower limit

-8

upper limit

1.7

Primary: Percentage of Participants With Elevations in Diastolic Blood Pressure (DBP) ≥ 10 mm Hg-Treatment Phase- Base Study

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End point title

Percentage of Participants With Elevations in Diastolic Blood Pressure (DBP) ≥ 10 mm Hg-Treatment Phase- Base Study

End point description

Participants had DBP assessed throughout the 76 week Treatment Phase. Participants who had a DBP reading that was ≥ 10 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 76 weeks

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	801	796
Units: Percentage of Participants
number (not applicable)	40.4	39.9

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1597

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.839

Method

Miettinen and Nurminen

Parameter type

Difference in Percentages

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

5.3

Primary: Change From Baseline in SBP at Week 76-Base Study

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End point title

Change From Baseline in SBP at Week 76-Base Study

End point description

Participants had SBP measured at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	551	665
Units: mmHg
least squares mean (confidence interval 95%)	2.2 (1 to 3.3)	2.1 (1 to 3.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.896

Method

Miettinen and Nurminen

Parameter type

Difference in Least-squares Means

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

1.6

Primary: Change From Baseline in DBP at Week 76-Base Study

Top of page

End point title

Change From Baseline in DBP at Week 76-Base Study

End point description

Participants had DBP measured at baseline and after 76 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study - Safety	Placebo - Base Study- Safety
Number of subjects analysed	551	665
Units: mmHg
least squares mean (confidence interval 95%)	0.7 (0 to 1.3)	0.7 (0.1 to 1.3)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study - Safety v Placebo - Base Study- Safety

Number of subjects included in analysis

1216

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.87

Method

Miettinen and Nurminen

Parameter type

Difference in Least-squares Means

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.8

Primary: Change from Baseline in Sodium at Week 104-Extension Study

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End point title

Change from Baseline in Sodium at Week 104-Extension Study

End point description

Sodium levels were assessed at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	308	359
Units: mEq/L
least squares mean (confidence interval 95%)	-0.3 (-0.5 to -0.1)	-0.3 (-0.5 to -0.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.3

Primary: Change From Baseline in Chloride at Week 104-Extension Study

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End point title

Change From Baseline in Chloride at Week 104-Extension Study

End point description

Chloride levels were assessed at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	308	359
Units: mEq/L
least squares mean (confidence interval 95%)	-1.9 (-2.2 to -1.6)	-2.1 (-2.4 to -1.8)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

0.5

Primary: Change From Baseline in Bicarbonate at Week 104-Extension Study

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End point title

Change From Baseline in Bicarbonate at Week 104-Extension Study

End point description

Bicarbonate levels were assessed at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	308	359
Units: mEq/L
least squares mean (confidence interval 95%)	0.2 (0 to 0.5)	0.2 (0 to 0.5)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

0.4

Primary: Change From Baseline in Potassium at Week 104-Extension Study

Top of page

End point title

Change From Baseline in Potassium at Week 104-Extension Study

End point description

Potassium levels were assessed at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	308	359
Units: mEq/L
least squares mean (confidence interval 95%)	0 (-0.1 to 0)	-0.1 (-0.1 to -0.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

0.1

Primary: Percentage of Participants With Elevations in SBP ≥ 10 mmHg-Extension Study

Top of page

End point title

Percentage of Participants With Elevations in SBP ≥ 10 mmHg-Extension Study

End point description

Participants had SBP assessed at baseline and throughout the 104 week Extension Study. Participants who had a SBP reading that was ≥ 10 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	432
Units: Percentage of Participants
number (not applicable)	63.9	59.7

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

10.9

Primary: Percentage of Participants With Elevations in SBP ≥ 15mm Hg-Extension Study

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End point title

Percentage of Participants With Elevations in SBP ≥ 15mm Hg-Extension Study

End point description

Participants had SBP assessed at baseline and throughout the 104 week Extension Study. Participants who had a SBP reading that was ≥ 15 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	432
Units: Percentage of Participants
number (not applicable)	49.7	45.8

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

10.8

Primary: Percentage of Participants With Elevations in DBP ≥ 10 mm Hg-Extension Study

Top of page

End point title

Percentage of Participants With Elevations in DBP ≥ 10 mm Hg-Extension Study

End point description

Participants had DBP assessed at baseline and throughout the 104 week Extension Study. Participants who had a DBP reading that was ≥ 10 mm Hg higher than their baseline level for any assessment performed during the treatment period were recorded.

End point type

Primary

End point timeframe

up to 104 weeks

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	366	432
Units: Percentage of Participants
number (not applicable)	38	33.8

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Percentages

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

10.9

Primary: Change From Baseline in SBP at Week 104-Extension Study

Top of page

End point title

Change From Baseline in SBP at Week 104-Extension Study

End point description

Participants had SBP measured at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	313	361
Units: mmHg
least squares mean (confidence interval 95%)	2.8 (1.2 to 44)	2.1 (0.6 to 3.6)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

674

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

2.7

Primary: Change From Baseline in DBP at Week 104-Extension Study

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End point title

Change From Baseline in DBP at Week 104-Extension Study

End point description

Participants had DBP measured at baseline and after 104 weeks of treatment. The change from baseline was recorded.

End point type

Primary

End point timeframe

Baseline and Week 104

End point values	Anacetrapib 100 mg -Extension-Safety	Placebo-Extension Study-Safety
Number of subjects analysed	313	361
Units: mmHg
least squares mean (confidence interval 95%)	-0.1 (-1 to 0.9)	-0.9 (-1.8 to -0.1)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg -Extension-Safety v Placebo-Extension Study-Safety

Number of subjects included in analysis

674

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

2.1

Secondary: Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 24- Base Study

Top of page

End point title

Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 24- Base Study

End point description

HDL-C levels measured at baseline and after 24 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	685	744
Units: Percentage Change
least squares mean (confidence interval 95%)	153 (149.9 to 156.2)	14.6 (11.6 to 17.7)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1429

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

138.4

Confidence interval

level

95%

sides

2-sided

lower limit

134.2

upper limit

142.6

Secondary: Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 24- Base Study

Top of page

End point title

Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 24- Base Study

End point description

Non-HDL-C measured at baseline and after 24 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	685	744
Units: Percentage Change
least squares mean (confidence interval 95%)	-36.1 (-37.5 to -34.7)	-4.1 (-5.5 to -2.8)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1429

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

-31.9

Confidence interval

level

95%

sides

2-sided

lower limit

-33.8

upper limit

-30

Secondary: Percentage Change from Baseline in Apolipoprotein B at Week 24- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein B at Week 24- Base Study

End point description

Apolipoprotein B was measured at baseline and after 24 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	769	767
Units: Percentage Change
least squares mean (confidence interval 95%)	-19.1 (-20.4 to -17.8)	2 (0.7 to 3.3)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1536

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

-21.1

Confidence interval

level

95%

sides

2-sided

lower limit

-22.8

upper limit

-19.4

Secondary: Percentage Change from Baseline in Apolipoprotein A-1 at Week 24- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein A-1 at Week 24- Base Study

End point description

Apolipoprotein A-1 measured at baseline and after 24 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	769	767
Units: Percentage Change
least squares mean (confidence interval 95%)	47.5 (46.1 to 48.9)	2.8 (1.4 to 4.2)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1536

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

44.7

Confidence interval

level

95%

sides

2-sided

lower limit

42.8

upper limit

46.6

Secondary: Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 76- Base Study

Top of page

End point title

Percentage Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 76- Base Study

End point description

LDL-C levels measured at baseline and after 76 weeks of treatment measured by Friedewald method

End point type

Secondary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	543	665
Units: Percentage Change
least squares mean (confidence interval 95%)	-40.5 (-42.5 to -38.6)	-4.4 (-6.2 to -2.6)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1208

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis;

Parameter type

Difference in Least-squares Means

Point estimate

-36.1

Confidence interval

level

95%

sides

2-sided

lower limit

-38.7

upper limit

-33.5

Secondary: Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 76- Base Study

Top of page

End point title

Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 76- Base Study

End point description

HDL-C measured at baseline and after 76 week of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	548	666
Units: Percentage Change
least squares mean (confidence interval 95%)	151.2 (148 to 154.3)	12.2 (9.2 to 15.3)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1214

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

138.9

Confidence interval

level

95%

sides

2-sided

lower limit

134.7

upper limit

143.2

Secondary: Percentage Change from Baseline in Non-high Density Lipoprotein Cholesterol at Week 76- Base Study

Top of page

End point title

Percentage Change from Baseline in Non-high Density Lipoprotein Cholesterol at Week 76- Base Study

End point description

Non-HDL-C measured at baseline and after 76 week of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	548	666
Units: Percentage Change
least squares mean (confidence interval 95%)	-33.1 (-34.8 to -31.5)	-3.8 (-5.3 to -2.2)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1214

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

-29.3

Confidence interval

level

95%

sides

2-sided

lower limit

-31.5

upper limit

-27.1

Secondary: Percentage Change from Baseline in Apolipoprotein B at Week 76- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein B at Week 76- Base Study

End point description

Apolipoprotein B measured at baseline and after 76 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	572	670
Units: Percentage Change
least squares mean (confidence interval 95%)	-20.6 (-22.1 to -19.1)	-2.3 (-3.7 to -0.9)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1242

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

-18.3

Confidence interval

level

95%

sides

2-sided

lower limit

-20.2

upper limit

-16.4

Secondary: Percentage Change from Baseline in Apolipoprotein A-1 at Week 76- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein A-1 at Week 76- Base Study

End point description

Apolipoprotein A-1 measured at baseline and after 76 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 76

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	572	670
Units: Percentage Change
least squares mean (confidence interval 95%)	41.8 (40.4 to 43.2)	-0.5 (-1.8 to 0.9)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1242

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Constrained Longitudinal Data Analysis

Parameter type

Difference in Least-squares Means

Point estimate

42.2

Confidence interval

level

95%

sides

2-sided

lower limit

40.4

upper limit

44.1

Secondary: Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 88- Base Study

Top of page

End point title

Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 88- Base Study

End point description

LDL-C measured at baseline and at Week 88 (76 weeks treatment then 12 week reversal [no treatment])

End point type

Secondary

End point timeframe

Baseline and Week 88

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	641	681
Units: Percentage Change
least squares mean (confidence interval 95%)	-24.5 (-26.6 to -22.4)	-5.9 (-7.9 to -3.9)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1322

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

-18.6

Confidence interval

level

95%

sides

2-sided

lower limit

-21.5

upper limit

-15.7

Secondary: Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 88- Base Study

Top of page

End point title

Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 88- Base Study

End point description

HDL-C measured at baseline and at Week 88 (76 weeks treatment then 12 week reversal [no treatment])

End point type

Secondary

End point timeframe

Baseline and Week 88

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	655	685
Units: Percentage Change
least squares mean (confidence interval 95%)	87.1 (84.6 to 89.7)	14.1 (11.6 to 16.6)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1340

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

69.4

upper limit

76.6

Secondary: Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 88- Base Study

Top of page

End point title

Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 88- Base Study

End point description

Non-HDL-C measured at baseline and at Week 88 (76 weeks treatment then 12 week reversal [no treatment])

End point type

Secondary

End point timeframe

Baseline and Week 88

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	655	685
Units: Percentage Change
least squares mean (confidence interval 95%)	-21.8 (-23.6 to -20)	-4.2 (-6 to -2.5)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1340

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

-17.6

Confidence interval

level

95%

sides

2-sided

lower limit

-20

upper limit

-15.1

Secondary: Percentage Change from Baseline in Apolipoprotein B at Week 88- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein B at Week 88- Base Study

End point description

Apolipoprotein B measured at baseline and at Week 88 (76 weeks treatment then 12 week reversal [no treatment])

End point type

Secondary

End point timeframe

Baseline and Week 88

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	651	677
Units: Percentage Change
least squares mean (confidence interval 95%)	-14.9 (-16.4 to -13.4)	-4.7 (-6.2 to -3.2)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1328

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

-10.2

Confidence interval

level

95%

sides

2-sided

lower limit

-12.3

upper limit

-8.1

Secondary: Percentage Change from Baseline in Apolipoprotein A-1 at Week 88- Base Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein A-1 at Week 88- Base Study

End point description

Apolipoprotein A-1 measured at baseline and at Week 88 (76 weeks treatment then 12 week reversal [no treatment])

End point type

Secondary

End point timeframe

Baseline and Week 88

End point values	Anacetrapib 100 mg - Base Study- Efficacy	Placebo - Base Study - Efficacy
Number of subjects analysed	651	677
Units: Percentage Change
least squares mean (confidence interval 95%)	21.7 (20.6 to 22.9)	-2.8 (-3.9 to -1.6)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Base Study- Efficacy v Placebo - Base Study - Efficacy

Number of subjects included in analysis

1328

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

24.5

Confidence interval

level

95%

sides

2-sided

lower limit

22.9

upper limit

26.1

Secondary: Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 104- Extension Study

Top of page

End point title

Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 104- Extension Study

End point description

LDL-C levels measured at baseline and after 104 weeks of treatment measured by Friedewald method

End point type

Secondary

End point timeframe

Baseline and Week 104 of Extension Study

End point values	Anacetrapib 100 mg - Extension Study - Efficacy	Placebo- Extension Study - Efficacy
Number of subjects analysed	308	361
Units: Percentage Change
least squares mean (confidence interval 95%)	-45.2 (-48.2 to -42.3)	-5.4 (-8.1 to -2.6)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Extension Study - Efficacy v Placebo- Extension Study - Efficacy

Number of subjects included in analysis

669

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

-39.9

Confidence interval

level

95%

sides

2-sided

lower limit

-43.8

upper limit

-36

Secondary: Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 104- Extension Study

Top of page

End point title

Percentage Change from Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 104- Extension Study

End point description

HDL-C levels measured at baseline and after 104 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and week 104 of Extension

End point values	Anacetrapib 100 mg - Extension Study - Efficacy	Placebo- Extension Study - Efficacy
Number of subjects analysed	310	361
Units: Percentage Change
least squares mean (confidence interval 95%)	169.3 (165 to 173.7)	15.8 (11.7 to 19.8)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Extension Study - Efficacy v Placebo- Extension Study - Efficacy

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

153.5

Confidence interval

level

95%

sides

2-sided

lower limit

147.9

upper limit

159.2

Secondary: Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 104- Extension Study

Top of page

End point title

Percentage Change from Baseline in Non-High Density Lipoprotein Cholesterol at Week 104- Extension Study

End point description

Non-HDL-C levels measured at baseline and after 104 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 104 of Extension Study

End point values	Anacetrapib 100 mg - Extension Study - Efficacy	Placebo- Extension Study - Efficacy
Number of subjects analysed	310	361
Units: Percentage Change
least squares mean (confidence interval 95%)	-35.5 (-38.1 to -33)	-4.6 (-7 to -2.3)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Extension Study - Efficacy v Placebo- Extension Study - Efficacy

Number of subjects included in analysis

671

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares means

Point estimate

-30.9

Confidence interval

level

95%

sides

2-sided

lower limit

-34.2

upper limit

-27.5

Secondary: Percentage Change from Baseline in Apolipoprotein B at Week 104- Extension Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein B at Week 104- Extension Study

End point description

Apolipoprotein B levels measured at baseline and after 104 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 104 of Extension Study

End point values	Anacetrapib 100 mg - Extension Study - Efficacy	Placebo- Extension Study - Efficacy
Number of subjects analysed	310	358
Units: Percentage Change
least squares mean (confidence interval 95%)	-30.6 (-32.6 to -28.6)	-14.3 (-16.2 to -12.4)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Extension Study - Efficacy v Placebo- Extension Study - Efficacy

Number of subjects included in analysis

668

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

-16.3

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

-13.7

Secondary: Percentage Change from Baseline in Apolipoprotein A-1 at Week 104- Extension Study

Top of page

End point title

Percentage Change from Baseline in Apolipoprotein A-1 at Week 104- Extension Study

End point description

Apolipoprotein A-1 levels measured at baseline and after 104 weeks of treatment.

End point type

Secondary

End point timeframe

Baseline and Week 104 of Extension Study

End point values	Anacetrapib 100 mg - Extension Study - Efficacy	Placebo- Extension Study - Efficacy
Number of subjects analysed	310	358
Units: Percentage Change
least squares mean (confidence interval 95%)	41.8 (39.5 to 44.1)	-2.7 (-4.8 to -0.5)

Between Group Comparison

Comparison groups

Anacetrapib 100 mg - Extension Study - Efficacy v Placebo- Extension Study - Efficacy

Number of subjects included in analysis

668

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Difference in Least-squares Means

Point estimate

44.5

Confidence interval

level

95%

sides

2-sided

lower limit

41.6

upper limit

47.4

Adverse events

Top of page

Timeframe for reporting adverse events

Base Study-Treatment Phase-up to 76 weeks; Reversal Phase-up to 12 weeks; Post-study Phase- up to 24 weeks. Extension Study-up to 104 weeks. Reversal Study-up to 52 weeks

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Placebo-Treatment Phase-Base Study

Reporting group description

Participants who received at least 1 dose of placebo in Treatment Phase of Base Study and had available safety data.

Reporting group title

Placebo-Reversal Phase-Base Study

Reporting group description

Participants, who received at least 1 dose of Placebo in Treatment Phase of Base Study, started Reversal Phase of Base Study and had available safety data.

Reporting group title

Anacetrapib 100 mg-Treatment Phase-Base Study

Reporting group description

Participants who received at least 1 dose of Anacetrapib in Treatment Phase of Base Study and had available safety data.

Reporting group title

Anacetrapid 100 mg-Reversal Phase-Base Study

Reporting group description

-Participants, who received at least 1 dose of Anacetrapib in Treatment Phase of Base Study, started Reversal Phase of Base Study and had available safety data.

Reporting group title

Anacetrapib 100 mg-Post Treatment Phase-Base Study

Reporting group description

Participant enrolled in Base Study who received at least 1 dose of Anacetrapib in Treatment Phase of Base Study and had available safety data. Post Treatment period was period from end of Reversal Phase up to start of 2–year extension.

Reporting group title

Anacetrapib-2-year Extension Study

Reporting group description

Participants who were enrolled in 2-year extension, received at least 1 dose of Anacetrapib and had available safety data.

Reporting group title

Placebo-Post Treatment Phase-Base Study

Reporting group description

Participant enrolled in Base Study who received at least 1 dose of Placebo in Treatment Phase of Base Study and had available safety data. Post Treatment period was period from end of Reversal Phase up to start of 2–year extension.

Reporting group title

Placebo-2-year Extension Study

Reporting group description

Participants who were enrolled in 2-year extension, received at least 1 dose of placebo and had available safety data.

Reporting group title

Anacetrapib-1-year Reversal Study

Reporting group description

Participants who were enrolled in 1-year reversal, received at least 1 dose of Anacetrapib in the extension and had available safety data.

Reporting group title

Placebo-1-year Reversal Study

Reporting group description

Participants who were enrolled in 1-year reversal, received at least 1 dose of Placebo in the extension and had available safety data.

Serious adverse events	Placebo-Treatment Phase-Base Study	Placebo-Reversal Phase-Base Study	Anacetrapib 100 mg-Treatment Phase-Base Study	Anacetrapid 100 mg-Reversal Phase-Base Study	Anacetrapib 100 mg-Post Treatment Phase-Base Study	Anacetrapib-2-year Extension Study	Placebo-Post Treatment Phase-Base Study	Placebo-2-year Extension Study	Anacetrapib-1-year Reversal Study	Placebo-1-year Reversal Study
Total subjects affected by serious adverse events
subjects affected / exposed	118 / 804 (14.68%)	19 / 714 (2.66%)	112 / 808 (13.86%)	21 / 684 (3.07%)	34 / 808 (4.21%)	88 / 369 (23.85%)	24 / 804 (2.99%)	90 / 433 (20.79%)	35 / 271 (12.92%)	0 / 1 (0.00%)
number of deaths (all causes)	7	1	6	1	7	9	5	9	1	0
number of deaths resulting from adverse events	0	0	1	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign gastric neoplasm
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	2 / 271 (0.74%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carcinoid tumour
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal tract adenoma
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lip neoplasm malignant stage unspecified
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	3 / 433 (0.69%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic renal cell carcinoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian neoplasm
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	4 / 804 (0.50%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer stage II
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma stage III
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	2 / 369 (0.54%)	1 / 804 (0.12%)	1 / 433 (0.23%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 2	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	1 / 808 (0.12%)	1 / 684 (0.15%)	1 / 808 (0.12%)	3 / 369 (0.81%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 5	0 / 1	0 / 1	0 / 4	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic lymphocytic leukaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	3 / 808 (0.37%)	1 / 684 (0.15%)	1 / 808 (0.12%)	3 / 369 (0.81%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 5	0 / 1	0 / 1	0 / 3	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic squamous cell carcinoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Throat cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraocular melanoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma metastatic
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectosigmoid cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leiomyosarcoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer stage IV
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glioblastoma multiforme
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arterial stenosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral artery aneurysm
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral embolism
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic aneurysm rupture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest discomfort
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	3 / 808 (0.37%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	5 / 804 (0.62%)	1 / 714 (0.14%)	6 / 808 (0.74%)	1 / 684 (0.15%)	1 / 808 (0.12%)	4 / 369 (1.08%)	1 / 804 (0.12%)	9 / 433 (2.08%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 6	0 / 1	0 / 1	0 / 4	0 / 1	0 / 9	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis in device
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocution
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaphylactic shock
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostatism
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	3 / 369 (0.81%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal septum deviation
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	2 / 808 (0.25%)	1 / 369 (0.27%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis chronic
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anxiety
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid bruit
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus lesion
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin laceration
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Heat stroke
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle rupture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	6 / 804 (0.75%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	6 / 369 (1.63%)	0 / 804 (0.00%)	3 / 433 (0.69%)	3 / 271 (1.11%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 2	0 / 0	0 / 0	0 / 6	0 / 0	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	11 / 804 (1.37%)	1 / 714 (0.14%)	5 / 808 (0.62%)	2 / 684 (0.29%)	2 / 808 (0.25%)	6 / 369 (1.63%)	1 / 804 (0.12%)	5 / 433 (1.15%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 11	0 / 1	0 / 5	0 / 2	0 / 2	0 / 9	0 / 1	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	3 / 804 (0.37%)	0 / 714 (0.00%)	3 / 808 (0.37%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	3 / 433 (0.69%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve disease
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	4 / 804 (0.50%)	1 / 714 (0.14%)	5 / 808 (0.62%)	0 / 684 (0.00%)	2 / 808 (0.25%)	5 / 369 (1.36%)	2 / 804 (0.25%)	1 / 433 (0.23%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 5	0 / 0	0 / 2	0 / 6	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	1 / 808 (0.12%)	1 / 684 (0.15%)	2 / 808 (0.25%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	4 / 804 (0.50%)	0 / 714 (0.00%)	5 / 808 (0.62%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 5	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 804 (0.37%)	0 / 714 (0.00%)	4 / 808 (0.50%)	0 / 684 (0.00%)	1 / 808 (0.12%)	2 / 369 (0.54%)	0 / 804 (0.00%)	2 / 433 (0.46%)	2 / 271 (0.74%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 4	0 / 0	0 / 1	0 / 2	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	3 / 804 (0.37%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	2 / 808 (0.25%)	2 / 369 (0.54%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 4	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nodal rhythm
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Ischaemic cardiomyopathy
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain injury
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral arteriosclerosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 804 (0.50%)	0 / 714 (0.00%)	4 / 808 (0.50%)	1 / 684 (0.15%)	2 / 808 (0.25%)	2 / 369 (0.54%)	0 / 804 (0.00%)	4 / 433 (0.92%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 4	0 / 1	0 / 2	0 / 2	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple system atrophy
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peroneal nerve palsy
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Petit mal epilepsy
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post herpetic neuralgia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	3 / 804 (0.37%)	0 / 714 (0.00%)	5 / 808 (0.62%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	3 / 433 (0.69%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 8	0 / 0	0 / 0	0 / 4	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal ganglia haemorrhage
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Amyotrophic lateral sclerosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone marrow oedema
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic polyp
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 804 (0.37%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	1 / 804 (0.12%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	3 / 808 (0.37%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric vein thrombosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal perforation
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal symptom
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic gastroparesis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal vascular malformation
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia, obstructive
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia, obstructive
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder necrosis
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemobilia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytoclastic vasculitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scar pain
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stress urinary incontinence
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Carcinoid syndrome
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperparathyroidism
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Costochondritis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	2 / 808 (0.25%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	4 / 808 (0.50%)	2 / 684 (0.29%)	2 / 808 (0.25%)	2 / 369 (0.54%)	0 / 804 (0.00%)	2 / 433 (0.46%)	2 / 271 (0.74%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4	0 / 3	0 / 3	0 / 2	0 / 0	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal stiffness
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendonitis
subjects affected / exposed	0 / 804 (0.00%)	1 / 714 (0.14%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	1 / 804 (0.12%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exostosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic foot infection
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	2 / 433 (0.46%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	3 / 433 (0.69%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaria
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mastoiditis
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal abscess
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 804 (0.25%)	1 / 714 (0.14%)	3 / 808 (0.37%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	1 / 804 (0.12%)	7 / 433 (1.62%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 1	0 / 1	0 / 0	0 / 1	0 / 8	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	2 / 804 (0.25%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	2 / 808 (0.25%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vestibular neuronitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	2 / 369 (0.54%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	1 / 804 (0.12%)	2 / 433 (0.46%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon gangrene
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	1 / 808 (0.12%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	1 / 804 (0.12%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	1 / 684 (0.15%)	1 / 808 (0.12%)	0 / 369 (0.00%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	0 / 369 (0.00%)	0 / 804 (0.00%)	1 / 433 (0.23%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	0 / 271 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	2 / 369 (0.54%)	0 / 804 (0.00%)	1 / 433 (0.23%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 804 (0.00%)	0 / 714 (0.00%)	0 / 808 (0.00%)	0 / 684 (0.00%)	0 / 808 (0.00%)	1 / 369 (0.27%)	0 / 804 (0.00%)	0 / 433 (0.00%)	1 / 271 (0.37%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo-Treatment Phase-Base Study	Placebo-Reversal Phase-Base Study	Anacetrapib 100 mg-Treatment Phase-Base Study	Anacetrapid 100 mg-Reversal Phase-Base Study	Anacetrapib 100 mg-Post Treatment Phase-Base Study	Anacetrapib-2-year Extension Study	Placebo-Post Treatment Phase-Base Study	Placebo-2-year Extension Study	Anacetrapib-1-year Reversal Study	Placebo-1-year Reversal Study
Total subjects affected by non serious adverse events
subjects affected / exposed	600 / 804 (74.63%)	0 / 714 (0.00%)	573 / 808 (70.92%)	0 / 684 (0.00%)	158 / 808 (19.55%)	269 / 369 (72.90%)	169 / 804 (21.02%)	313 / 433 (72.29%)	122 / 271 (45.02%)	0 / 1 (0.00%)
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	60 / 804 (7.46%)	0 / 714 (0.00%)	47 / 808 (5.82%)	0 / 684 (0.00%)	6 / 808 (0.74%)	13 / 369 (3.52%)	3 / 804 (0.37%)	17 / 433 (3.93%)	3 / 271 (1.11%)	0 / 1 (0.00%)
occurrences all number	77	0	54	0	6	14	3	24	3	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	33 / 804 (4.10%)	0 / 714 (0.00%)	45 / 808 (5.57%)	0 / 684 (0.00%)	5 / 808 (0.62%)	14 / 369 (3.79%)	0 / 804 (0.00%)	19 / 433 (4.39%)	5 / 271 (1.85%)	0 / 1 (0.00%)
occurrences all number	36	0	48	0	5	14	0	21	5	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	37 / 804 (4.60%)	0 / 714 (0.00%)	46 / 808 (5.69%)	0 / 684 (0.00%)	4 / 808 (0.50%)	16 / 369 (4.34%)	6 / 804 (0.75%)	25 / 433 (5.77%)	3 / 271 (1.11%)	0 / 1 (0.00%)
occurrences all number	54	0	52	0	5	19	6	26	3	0
Back pain
subjects affected / exposed	36 / 804 (4.48%)	0 / 714 (0.00%)	42 / 808 (5.20%)	0 / 684 (0.00%)	1 / 808 (0.12%)	30 / 369 (8.13%)	8 / 804 (1.00%)	28 / 433 (6.47%)	3 / 271 (1.11%)	0 / 1 (0.00%)
occurrences all number	40	0	46	0	1	36	8	29	3	0
Pain in extremity
subjects affected / exposed	23 / 804 (2.86%)	0 / 714 (0.00%)	18 / 808 (2.23%)	0 / 684 (0.00%)	1 / 808 (0.12%)	21 / 369 (5.69%)	2 / 804 (0.25%)	16 / 433 (3.70%)	2 / 271 (0.74%)	0 / 1 (0.00%)
occurrences all number	23	0	20	0	1	26	2	19	2	0
Infections and infestations
Bronchitis
subjects affected / exposed	44 / 804 (5.47%)	0 / 714 (0.00%)	36 / 808 (4.46%)	0 / 684 (0.00%)	3 / 808 (0.37%)	23 / 369 (6.23%)	1 / 804 (0.12%)	11 / 433 (2.54%)	4 / 271 (1.48%)	0 / 1 (0.00%)
occurrences all number	47	0	38	0	3	25	1	13	4	0
Nasopharyngitis
subjects affected / exposed	82 / 804 (10.20%)	0 / 714 (0.00%)	87 / 808 (10.77%)	0 / 684 (0.00%)	12 / 808 (1.49%)	31 / 369 (8.40%)	6 / 804 (0.75%)	34 / 433 (7.85%)	17 / 271 (6.27%)	0 / 1 (0.00%)
occurrences all number	102	0	129	0	13	39	6	39	20	0
Upper respiratory tract infection
subjects affected / exposed	63 / 804 (7.84%)	0 / 714 (0.00%)	47 / 808 (5.82%)	0 / 684 (0.00%)	6 / 808 (0.74%)	18 / 369 (4.88%)	8 / 804 (1.00%)	32 / 433 (7.39%)	4 / 271 (1.48%)	0 / 1 (0.00%)
occurrences all number	76	0	54	0	6	28	8	43	4	0
Metabolism and nutrition disorders
Type 2 diabetes mellitus
subjects affected / exposed	25 / 804 (3.11%)	0 / 714 (0.00%)	16 / 808 (1.98%)	0 / 684 (0.00%)	4 / 808 (0.50%)	8 / 369 (2.17%)	4 / 804 (0.50%)	23 / 433 (5.31%)	2 / 271 (0.74%)	0 / 1 (0.00%)
occurrences all number	27	0	16	0	4	9	4	24	2	0

More information

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Were there any global substantial amendments to the protocol? Yes

11 Jun 2008

AM1: Primary reason for the amendment was to revise the Participant Population to include only CHD/CHD risk-equivalent participants.

20 Mar 2009

AM2: Primary reason for the amendment was to add an interim safety analysis once all participants had reached Week 54.

19 Aug 2009

AM3: The primary reason for the amendment was to add the collection of safety follow-up information (serious cardiovascular adverse events or death) for discontinued participants at their intended Week 54 visit.

22 Feb 2010

AM4: The primary reason for this amendment was to extend the 12-week reversibility phase of Base Study by up to another 12 weeks (if required) in order to allow participants completing final visit (Week 88) to continue in the study until the planned extension study was ready for implementation at the site.

17 Mar 2010

Ext 10: The primary reason for this amendment was to add a 2-year Extension Study to the Base Study in order to further evaluate the long-term safety profile (~3.5years) and efficacy of anacetrapib in CHD/CHD-risk equivalent participants who were on ongoing therapy with a statin ± other lipid-modifying therapy.

07 Mar 2011

AM11 (AM1 to Ext10): The primary reason for this amendment was to add the results from the warfarin and digoxin drug interaction studies that was recently added to the Investigator’s Brochure. As a result, digoxin or other cardiac glycosides and Coumadin (warfarin) or coumadin-like anticoagalants were no longer prohibited medications for the study. Added blood draws to estimate the time to steady state levels for anacetrapib. Also added an archive blood sample for biomarkers.

13 Jan 2012

AM12 (AM2 to Ext 10): The primary reason for this amendment was to extend the reversal period of the 2-year extension study from 12 weeks to 1-year.

24 Apr 2013

AM6: The primary reason for this amendment was to add a follow-up of 5 months up to 5 years for evaluation of pharmacokinetics and lipids for all participants who were previously treated with anacetrapib in the Base or Extension Studies (completed or discontinued). Additionally All women of child-bearing potential (WOCBP), who had previously received anacetrapib in the treatment phase would be contacted annually by the site for pregnancy and outcome. WOCBP would also receive guidance for proper use of contraception.

02 Jun 2013

AM14 (AM4 to Ext): The primary reason for this amendment was to reconcile the unblinding text such that participants can be unblinded after they complete the 2-year Extension Study on a rolling basis and then enrolled in AM6.

17 Oct 2013

AM7: The primary reason for the amendment was to add evaluations of participants to determine if anacetrapib levels were present in the adipose tissue, approximately 1 up to 5 years after the participant last took anacetrapib.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24- Base Study

Primary: Percentage Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24- Base Study

Primary: Number of Participants With Hepatitis-related Adverse Events (AEs)- Base Study

Primary: Number of Participants With Hepatitis-related Adverse Events (AEs)- Base Study

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Treatment Phase-Base Study

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Treatment Phase-Base Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN- Treatment Phase-Base Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN- Treatment Phase-Base Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN with Muscle Symptoms- Treatment Phase-Base Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10 x ULN with Muscle Symptoms- Treatment Phase-Base Study

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN-Treatment Phase- Base Study

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN-Treatment Phase- Base Study

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Treatment Phase- Base Study

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Treatment Phase- Base Study

Primary: Percentage of Participants with Myalgia- Treatment Phase- Base Study

Primary: Percentage of Participants with Myalgia- Treatment Phase- Base Study

Primary: Percentage of Participants with Rhabdomyolysis- Treatment Phase- Base Study

Primary: Percentage of Participants with Rhabdomyolysis- Treatment Phase- Base Study

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Treatment Phase- Base Study

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Treatment Phase- Base Study

Primary: Percentage of Participants with Death from Any Cause- Treatment Phase- Base Study

Primary: Percentage of Participants with Death from Any Cause- Treatment Phase- Base Study

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Extension Study

Primary: Percentage of Participants with Alanine Aminotransferase and/or Aspartate Aminotransferase Consecutive Elevations ≥ 3xULN (Upper Limit of Normal)- Extension Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN- Extension Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN- Extension Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN with Muscle Symptoms- Extension Study

Primary: Percentage of Participants with Creatine Phosphokinase Elevations ≥10xULN with Muscle Symptoms- Extension Study

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN- Extension Study

Primary: Percentage of Participants with Sodium, Chloride, or Bicarbonate Elevations >ULN- Extension Study

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Extension Study

Primary: Percentage of Participants with Potassium Levels <LLN (Lower Limit of Normal)- Extension Study

Primary: Percentage of Participants with Myalgia- Extension Study

Primary: Percentage of Participants with Myalgia- Extension Study

Primary: Percentage of Participants with Rhabdomyolysis- Extension Study

Primary: Percentage of Participants with Rhabdomyolysis- Extension Study

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Extension Study

Primary: Percentage of Participants with Prespecified Adjudicated Cardiovascular Serious Adverse Events (SAEs)- Extension Study

Primary: Percentage of Participants with Death from Any Cause- Extension Study

Primary: Percentage of Participants with Death from Any Cause- Extension Study

Primary: Percentage of Participants Who Experience at Least 1 AE- 1 year Reversal Study

Primary: Percentage of Participants Who Experience at Least 1 AE- 1 year Reversal Study

Primary: Percentage of Participants Who Experience at Least 1 Drug-related AE- 1 year Reversal Study

Primary: Percentage of Participants Who Experience at Least 1 Drug-related AE- 1 year Reversal Study

Primary: Change From Baseline in Sodium at Week 76-Base Study

Primary: Change From Baseline in Sodium at Week 76-Base Study

Primary: Change From Baseline in Chloride at Week 76-Base Study

Primary: Change From Baseline in Chloride at Week 76-Base Study

Primary: Change From Baseline in Bicarbonate at Week 76-Base Study

Primary: Change From Baseline in Bicarbonate at Week 76-Base Study

Primary: Change From Baseline in Potassium at Week 76-Base Study

Primary: Change From Baseline in Potassium at Week 76-Base Study

Primary: Percentage of Participants With Elevations in Systolic Blood Pressure (SBP) ≥ 10 mm Hg-Treatment Phase- Base Study

Primary: Percentage of Participants With Elevations in Systolic Blood Pressure (SBP) ≥ 10 mm Hg-Treatment Phase- Base Study

Primary: Percentage of Participants With Elevations in SBP ≥ 15 mm Hg- Treatment Phase- Base Study

Primary: Percentage of Participants With Elevations in SBP ≥ 15 mm Hg- Treatment Phase- Base Study

Primary: Percentage of Participants With Elevations in Diastolic Blood Pressure (DBP) ≥ 10 mm Hg-Treatment Phase- Base Study

Primary: Percentage of Participants With Elevations in Diastolic Blood Pressure (DBP) ≥ 10 mm Hg-Treatment Phase- Base Study

Primary: Change From Baseline in SBP at Week 76-Base Study

Primary: Change From Baseline in SBP at Week 76-Base Study

Primary: Change From Baseline in DBP at Week 76-Base Study

Primary: Change From Baseline in DBP at Week 76-Base Study

Primary: Change from Baseline in Sodium at Week 104-Extension Study

Primary: Change from Baseline in Sodium at Week 104-Extension Study

Primary: Change From Baseline in Chloride at Week 104-Extension Study

Primary: Change From Baseline in Chloride at Week 104-Extension Study

Primary: Change From Baseline in Bicarbonate at Week 104-Extension Study

Primary: Change From Baseline in Bicarbonate at Week 104-Extension Study

Primary: Change From Baseline in Potassium at Week 104-Extension Study

Primary: Change From Baseline in Potassium at Week 104-Extension Study

Clinical Trial Results:
A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease