Trial Outcomes & Findings for REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (NCT NCT01252953)

Last Updated: 2024-06-25

Results Overview

Primary assessment involves an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib versus placebo on major coronary events (defined as the occurrence of coronary death, myocardial infarction or coronary revascularization procedure) during the scheduled treatment period. Data reported is for the first major coronary event.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

30449 participants

Primary outcome timeframe

Randomized treatment phase during median follow-up period of 4.1years

Results posted on

2024-06-25

Participant Flow

Participants were randomized between August 2011 and October 2013. Follow-up continued until 31st January 2017.

Successfully screened participants were entered into a run-in period. Attendees were discouraged from continuing to randomization if it was thought unlikely they would be able to continue attending follow-up visits for at least 4-5years. During run-in participants were issued atorvastatin (1 tablet/day) and placebo anacetrapib (1 tablet/day).

Participant milestones

Participant milestones
Measure	Anacetrapib Anacetrapib: 100mg tablet daily	Placebo Anacetrapib Placebo anacetrapib: 1 tablet daily
Overall Study STARTED	15225	15224
Overall Study COMPLETED	15187	15186
Overall Study NOT COMPLETED	38	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Anacetrapib Anacetrapib: 100mg tablet daily	Placebo Anacetrapib Placebo anacetrapib: 1 tablet daily
Overall Study Withdrawal by Subject	16	17
Overall Study Lost to Follow-up	22	21

Baseline Characteristics

REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Anacetrapib n=15225 Participants Anacetrapib: 100mg tablet daily	Placebo Anacetrapib n=15224 Participants Placebo anacetrapib: 1 tablet daily	Total n=30449 Participants Total of all reporting groups
LDL Cholesterol, Continuous	61 mg/dl STANDARD_DEVIATION 15 • n=5 Participants	61 mg/dl STANDARD_DEVIATION 15 • n=7 Participants	61 mg/dl STANDARD_DEVIATION 15 • n=5 Participants
Non-HDL Cholesterol, Categorical < 85 mg/dl	5642 Participants n=5 Participants	5701 Participants n=7 Participants	11343 Participants n=5 Participants
Non-HDL Cholesterol, Categorical ≥ 85 to <101 mg/dl	4896 Participants n=5 Participants	4853 Participants n=7 Participants	9749 Participants n=5 Participants
Non-HDL Cholesterol, Categorical ≥ 101 mg/dl	4687 Participants n=5 Participants	4670 Participants n=7 Participants	9357 Participants n=5 Participants
Non-HDL Cholesterol, Continuous	92 mg/dl STANDARD_DEVIATION 19 • n=5 Participants	92 mg/dl STANDARD_DEVIATION 19 • n=7 Participants	92 mg/dl STANDARD_DEVIATION 19 • n=5 Participants
HDL Cholesterol, Categorical < 35 mg/dl	4583 Participants n=5 Participants	4590 Participants n=7 Participants	9173 Participants n=5 Participants
HDL Cholesterol, Categorical ≥ 35 to < 43 mg/dl	5438 Participants n=5 Participants	5269 Participants n=7 Participants	10707 Participants n=5 Participants
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6634 Participants n=5 Participants	6643 Participants n=7 Participants	13277 Participants n=5 Participants
Age, Categorical >=65 years	8591 Participants n=5 Participants	8581 Participants n=7 Participants	17172 Participants n=5 Participants
Age, Continuous	67 years STANDARD_DEVIATION 8 • n=5 Participants	67 years STANDARD_DEVIATION 8 • n=7 Participants	67 years STANDARD_DEVIATION 8 • n=5 Participants
Sex: Female, Male Female	2456 Participants n=5 Participants	2459 Participants n=7 Participants	4915 Participants n=5 Participants
Sex: Female, Male Male	12769 Participants n=5 Participants	12765 Participants n=7 Participants	25534 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	121 Participants n=5 Participants	114 Participants n=7 Participants	235 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2560 Participants n=5 Participants	2522 Participants n=7 Participants	5082 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	12544 Participants n=5 Participants	12588 Participants n=7 Participants	25132 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	160 Participants n=5 Participants	168 Participants n=7 Participants	328 Participants n=5 Participants
Race/Ethnicity, Customized Race · Chinese	4323 Participants n=5 Participants	4323 Participants n=7 Participants	8646 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other North East Asian	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Race/Ethnicity, Customized Race · South Asian	95 Participants n=5 Participants	97 Participants n=7 Participants	192 Participants n=5 Participants
Race/Ethnicity, Customized Race · South East Asian	11 Participants n=5 Participants	11 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	10561 Participants n=5 Participants	10558 Participants n=7 Participants	21119 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	47 Participants n=5 Participants	49 Participants n=7 Participants	96 Participants n=5 Participants
Race/Ethnicity, Customized Race · Mixed	21 Participants n=5 Participants	12 Participants n=7 Participants	33 Participants n=5 Participants
Race/Ethnicity, Customized Race · Unknown	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment United Kingdom	4204 participants n=5 Participants	4177 participants n=7 Participants	8381 participants n=5 Participants
Region of Enrollment Norway	426 participants n=5 Participants	418 participants n=7 Participants	844 participants n=5 Participants
Region of Enrollment Sweden	427 participants n=5 Participants	434 participants n=7 Participants	861 participants n=5 Participants
HDL Cholesterol, Categorical ≥ 43 mg/dl	5204 Participants n=5 Participants	5365 Participants n=7 Participants	10569 Participants n=5 Participants
HDL Cholesterol, Continuous	40 mg/dl STANDARD_DEVIATION 10 • n=5 Participants	40 mg/dl STANDARD_DEVIATION 10 • n=7 Participants	40 mg/dl STANDARD_DEVIATION 10 • n=5 Participants
Region of Enrollment Denmark	918 participants n=5 Participants	932 participants n=7 Participants	1850 participants n=5 Participants
Region of Enrollment Finland	307 participants n=5 Participants	306 participants n=7 Participants	613 participants n=5 Participants
Region of Enrollment Germany	755 participants n=5 Participants	774 participants n=7 Participants	1529 participants n=5 Participants
Region of Enrollment Italy	826 participants n=5 Participants	834 participants n=7 Participants	1660 participants n=5 Participants
Region of Enrollment United States	2687 participants n=5 Participants	2643 participants n=7 Participants	5330 participants n=5 Participants
Region of Enrollment Canada	361 participants n=5 Participants	391 participants n=7 Participants	752 participants n=5 Participants
Region of Enrollment China	4314 participants n=5 Participants	4315 participants n=7 Participants	8629 participants n=5 Participants
Previous disease Coronary heart disease	13325 Participants n=5 Participants	13354 Participants n=7 Participants	26679 Participants n=5 Participants
Previous disease Cerebrovascular disease	3385 Participants n=5 Participants	3396 Participants n=7 Participants	6781 Participants n=5 Participants
Previous disease Peripheral-artery disease	1229 Participants n=5 Participants	1206 Participants n=7 Participants	2435 Participants n=5 Participants
Previous disease Diabetes	5654 Participants n=5 Participants	5666 Participants n=7 Participants	11320 Participants n=5 Participants
Previous disease Heart failure	902 Participants n=5 Participants	869 Participants n=7 Participants	1771 Participants n=5 Participants
Region Europe	7863 Participants n=5 Participants	7875 Participants n=7 Participants	15738 Participants n=5 Participants
Region North America	3048 Participants n=5 Participants	3034 Participants n=7 Participants	6082 Participants n=5 Participants
Region China	4314 Participants n=5 Participants	4315 Participants n=7 Participants	8629 Participants n=5 Participants
Systolic Blood Pressure, Categorical <125 mmHg	5678 Participants n=5 Participants	5760 Participants n=7 Participants	11438 Participants n=5 Participants
Systolic Blood Pressure, Categorical ≥125 to <140 mmHg	4819 Participants n=5 Participants	4740 Participants n=7 Participants	9559 Participants n=5 Participants
Systolic Blood Pressure, Categorical ≥140 mmHg	4728 Participants n=5 Participants	4724 Participants n=7 Participants	9452 Participants n=5 Participants
Systolic Blood Pressure, Continuous	131.3 mmHg STANDARD_DEVIATION 18.5 • n=5 Participants	131.1 mmHg STANDARD_DEVIATION 18.5 • n=7 Participants	131.2 mmHg STANDARD_DEVIATION 18.5 • n=5 Participants
Diastolic Blood Pressure, Categorical < 75 mmHg	5656 Participants n=5 Participants	5790 Participants n=7 Participants	11446 Participants n=5 Participants
Diastolic Blood Pressure, Categorical ≥ 75 to < 85 mmHg	5408 Participants n=5 Participants	5277 Participants n=7 Participants	10685 Participants n=5 Participants
Diastolic Blood Pressure, Categorical ≥ 85 mmHg	4161 Participants n=5 Participants	4157 Participants n=7 Participants	8318 Participants n=5 Participants
Diastolic Blood Pressure, Continuous	78.1 mmHg STANDARD_DEVIATION 10.9 • n=5 Participants	78.0 mmHg STANDARD_DEVIATION 11.0 • n=7 Participants	78.1 mmHg STANDARD_DEVIATION 11.0 • n=5 Participants
Body Mass Index, Categorical <25 kg/m^2	3447 Participants n=5 Participants	3361 Participants n=7 Participants	6808 Participants n=5 Participants
Body Mass Index, Categorical ≥25 to < 30 kg/m^2	6949 Participants n=5 Participants	6995 Participants n=7 Participants	13944 Participants n=5 Participants
Body Mass Index, Categorical ≥ 30 kg/m^2	4829 Participants n=5 Participants	4868 Participants n=7 Participants	9697 Participants n=5 Participants
Body Mass Index, Continuous	28.6 kg/m^2 STANDARD_DEVIATION 5.0 • n=5 Participants	28.6 kg/m^2 STANDARD_DEVIATION 5.1 • n=7 Participants	28.6 kg/m^2 STANDARD_DEVIATION 5.1 • n=5 Participants
LDL Cholesterol, Categorical < 54 mg/dl	5023 Participants n=5 Participants	5077 Participants n=7 Participants	10100 Participants n=5 Participants
LDL Cholesterol, Categorical ≥ 54 to < 66 mg/dl	4643 Participants n=5 Participants	4705 Participants n=7 Participants	9348 Participants n=5 Participants
LDL Cholesterol, Categorical ≥ 66 mg/dl	5559 Participants n=5 Participants	5442 Participants n=7 Participants	11001 Participants n=5 Participants
Glomerular Filtration Rate, Categorical < 60 ml/min/1.73m^2	1655 Participants n=5 Participants	1698 Participants n=7 Participants	3353 Participants n=5 Participants
Glomerular Filtration Rate, Categorical ≥ 60 ml/min/1.73m^2	13570 Participants n=5 Participants	13526 Participants n=7 Participants	27096 Participants n=5 Participants
Glomerular Filtration Rate, Continuous	83 ml/min/1.73m^2 STANDARD_DEVIATION 17 • n=5 Participants	83 ml/min/1.73m^2 STANDARD_DEVIATION 17 • n=7 Participants	83 ml/min/1.73m^2 STANDARD_DEVIATION 17 • n=5 Participants

PRIMARY outcome

Timeframe: Randomized treatment phase during median follow-up period of 4.1years

Outcome measures

Outcome measures
Measure	Anacetrapib n=15225 Participants Anacetrapib: 100mg tablet daily	Placebo Anacetrapib n=15224 Participants Placebo anacetrapib: 1 tablet daily
Number of Participants With Major Coronary Event	1640 Participants	1803 Participants

SECONDARY outcome

Timeframe: Randomized treatment phase during median follow-up period of 4.1years

Major atherosclerotic events (defined as coronary death, myocardial infarction or presumed ischaemic stroke; the key secondary outcome). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period.

Outcome measures

Outcome measures
Measure	Anacetrapib n=15225 Participants Anacetrapib: 100mg tablet daily	Placebo Anacetrapib n=15224 Participants Placebo anacetrapib: 1 tablet daily
Number of Participants With Major Atherosclerotic Event	1383 Participants	1483 Participants

SECONDARY outcome

Timeframe: Randomized treatment phase during median follow-up period of 4.1years

Presumed ischaemic stroke (i.e. not known to be haemorrhagic). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period.

Outcome measures

Outcome measures
Measure	Anacetrapib n=15225 Participants Anacetrapib: 100mg tablet daily	Placebo Anacetrapib n=15224 Participants Placebo anacetrapib: 1 tablet daily
Number of Participants With Presumed Ischaemic Stroke	485 Participants	489 Participants

SECONDARY outcome

Timeframe: Randomized treatment phase during median follow-up period of 4.1years

Major vascular events (defined as coronary death, myocardial infarction, coronary revascularization or presumed ischaemic stroke). Secondary assessments involve intention-to-treat comparisons among all randomized participants of the effects of allocation to anacetrapib versus placebo during the scheduled treatment period

Outcome measures

Outcome measures
Measure	Anacetrapib n=15225 Participants Anacetrapib: 100mg tablet daily	Placebo Anacetrapib n=15224 Participants Placebo anacetrapib: 1 tablet daily
Number of Participants With Major Vascular Event	2068 Participants	2214 Participants

Adverse Events

Anacetrapib

Serious events: 8898 serious events

Other events: 2493 other events

Deaths: 1122 deaths

Placebo Anacetrapib

Serious events: 8912 serious events

Other events: 2503 other events

Deaths: 1155 deaths

Serious adverse events

Other adverse events

Additional Information

Prof Martin Landray

Nuffield Department of Population Health, University of Oxford

Phone: +44 (0)1865 743743

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Anacetrapib n=3048 participants at risk；n=15225 participants at risk anacetrapib: tablet, 100mg daily	Placebo Anacetrapib n=3034 participants at risk；n=15224 participants at risk placebo anacetrapib: tablet, 1 tablet daily
Cardiac disorders Cardiac disorders	5.5% 169/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	6.9% 208/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Eye disorders Eye disorders	7.4% 227/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	7.6% 230/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Gastrointestinal disorders Gastrointestinal disorders	19.6% 596/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	18.4% 557/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
General disorders General disorders and administration site conditions	10.5% 321/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	11.1% 338/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Infections and infestations Infections and infestations	32.0% 974/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	31.1% 943/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Injury, poisoning and procedural complications Injury, poisoning and procedural complications	15.7% 480/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	17.0% 516/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Investigations Investigations	10.7% 327/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	10.1% 307/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Metabolism and nutrition disorders Metabolism and nutrition disorders	13.3% 405/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	13.0% 393/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders	36.9% 1125/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	36.4% 1105/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Nervous system disorders Nervous system disorders	20.5% 625/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	20.5% 623/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Psychiatric disorders Psychiatric disorders	5.1% 155/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	4.6% 139/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Renal and urinary disorders Renal and urinary disorders	5.2% 160/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	5.6% 171/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders	15.2% 463/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	13.6% 412/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders	6.7% 203/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	7.0% 211/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Surgical and medical procedures Surgical and medical procedures	6.9% 211/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	6.7% 202/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).
Vascular disorders Vascular disorders	6.1% 185/3048 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).	6.2% 189/3034 • Randomized treatment phase during median follow-up period of 4.1years All participants were assessed for adverse events at 6-monthly intervals at which relevant information was recorded on the electronic case report form. In accordance with the protocol, Serious Adverse Events were recorded for all participants (30,449 subjects) and non-serious Adverse Events (presented in the 'Other Adverse Events' section) were recorded in North America only (6,082 subjects).