REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification. A Large-scale, Randomized Placebo-controlled Trial of the Clinical Effects of Anacetrapib Among People With Established Vascular Disease
Phase: PHASE3
Conditions: Atherosclerotic Cardiovascular Disease
Sponsor: University of Oxford

 
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CTSUREVEAL1 [V2.0_2016-01-11] 
 
 
 
 
ISRCTN48678192, NCT01252953 
HPS 3 / TIMI 55: REVEAL (Randomized EValuation of the 
Effects of Anacetrapib through Lipid-modification): 
A large-scale, randomized placebo-controlled trial of the 
clinical effects of anacetrapib among people with established 
vascular disease 
 
Does inhibition of cholesteryl ester transfer protein (CETP) with 
anacetrapib prevent vascular events in high-risk patients who are 
receiving intensive LDL cholesterol lowering treatment? 
 
Large-scale randomized trials have shown that lowering LDL cholesterol by about 1 mmol/L for 4-5 
years reduces the risks of coronary events and of strokes by about one fifth. Furthermore, recent 
trials assessing more intensive versus standard statin regimens have demonstrated additional 
benefit with more intensive lowering of LDL cholesterol. Nevertheless, among individuals with a 
history of vascular disease or diabetes, cardiovascular risk remains elevated even after several 
years of intensive LDL-lowering treatment. For example, in 2 recent trials, over 10% of coronary 
heart disease (CHD) patients still suffered a major cardiovascular event during 4-5 years of 
intensive statin therapy. 
 
Observational studies indicate that lower concentrations of HDL cholesterol and of apolipoprotein 
(apo) A1 are associated with an elevated risk of CHD events. Cholesteryl ester transfer protein 
(CETP) facilitates the exchange of cholesteryl esters for triglycerides between HDL particles and 
apo B containing particles. CETP inhibition leads to increases in HDL cholesterol and apo A1 
concentrations, and reductions in LDL cholesterol, apo B and triglyceride concentrations. However, 
the only reported outcome trial of a CETP inhibitor – torcetrapib – was stopped early: an 
unexpected excess risk of cardiovascular events and deaths was observed. It is unclear whether 
this was due to off-target increases in systemic blood pressure and plasma aldosterone levels 
induced by torcetrapib, or if it was attributable to some other effect of the drug or CETP inhibition. 
 
When used either as monotherapy or in combination with a statin, the CETP inhibitor anacetrapib 
increases HDL cholesterol and apo A1 concentrations by about 140% and 45% respectively, and 
reduces LDL cholesterol and apo B concentrations by about 30-40%. Anacetrapib has been well 
tolerated in early phase studies and, importantly, has no effects on blood pressure or aldosterone 
levels. The lipid changes that are produced by anacetrapib might well reduce the risk of vascular 
events substantially, but there is a clear need for large-scale randomized evidence to assess any 
benefits and hazards reliably. 
 
A streamlined international trial 
 
The present study will compare anacetrapib 100 mg once daily versus matching placebo in around 
30,000 participants with pre-existing atherosclerotic vascular disease who are also receiving 
effective LDL-lowering therapy using atorvastatin. Follow-up for about 4 years will allow reliable 
assessments of any beneficial or adverse effects of anacetrapib on mortality and major morbidity. 
This important international study will be coordinated by the Central Coordinating Office at the 
University of Oxford (which will act as the trial Sponsor), with Regional Coordinating Centres 
responsible for the conduct of the trial in about 400 hospitals worldwide. The study design is 
streamlined: extra work for collaborating doctors and hospitals has been kept to a minimum, and 
only essential data will be collected directly using bespoke user-friendly computer-based systems. 
 
 
Central Coordinating Office, Clinical Trial Service Unit, 
Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK 
Tel: +44(0)1865 743882, fax: +44 (0)1865 743988 

 
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CTSUREVEAL1 [V2.0_2016-01-11] 
 
 
 
 
ISRCTN48678192, NCT01252953 
Version History 
 
Version 
Date 
Summary 
1.0 
15 October 2010 
First released version. 
1.1 
25 May 2012 
Minor changes and updates to Steering Committee 
membership. 
2.0 
11 January 2016 
The Steering Committee (which remains blind to analyses 
of the study results by treatment allocation) has agreed the 
following changes to the protocol: 
 
1. Cancel any formal interim review of efficacy by the 
Data Monitoring Committee prior to 3 years’ median 
follow-up. (The interim review of efficacy originally 
scheduled to take place at 2.5 years after median 
randomization, was cancelled and has been removed 
from the protocol; section 2.5.2.2). 
 
2. Revise the secondary assessments (section 2.3.1.2) to: 
(i) Major atherosclerotic events (defined as coronary 
death, myocardial infarction or presumed ischaemic 
stroke; the key secondary outcome); 
(ii) Presumed ischaemic stroke; and 
(iii) Major vascular events (defined as coronary death, 
myocardial infarction, coronary revascularization or 
presumed ischaemic stroke); 
 
3. Make minor changes to the tertiary assessments 
(section 2.3.1.4) 
 
Power calculations for the new secondary endpoints have 
been added, based on the number of participants who 
have been randomized and the blinded event rates 
observed to date (section 2.4.3). 
 
A brief summary of relevant information that has emerged 
since the study background and rationale (section 1.1) 
were written has been added (section 1.2). 
 
A small number of administrative changes and 
clarifications have also been made.  
 
 
 

 
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CTSUREVEAL1 [V2.0_2016-01-11] 
 
 
 
 
ISRCTN48678192, NCT01252953 
Table of contents 
1 BACKGROUND AND RATIONALE ............................................................................................................... 5 
1.1 DOES INHIBITION OF CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) PREVENT MAJOR VASCULAR 
EVENTS IN PATIENTS WITH VASCULAR DISEASE? .......................................................................................... 5 
1.1.1 
Substantial residual cardiovascular risk even with intensive LDL-lowering  treatment .................................. 5 
1.1.2 
Higher blood concentrations of HDL cholesterol and of apolipoprotein A1 are  associated with 
lower cardiovascular risk throughout the usual range ................................................................................... 5 
1.1.3 
The clinical effects of currently available treatments for raising HDL  cholesterol remain uncertain.............. 6 
1.1.4 
Inhibition of cholesteryl ester transfer protein as a possible therapeutic target ............................................. 6 
1.1.5 
Clinical safety and effectiveness of CETP inhibition is currently uncertain .................................................... 7 
1.1.6 
Rationale for intensive background LDL cholesterol-lowering ....................................................................... 8 
1.2 BRIEF SUMMARY OF NEW INFORMATION SINCE PROTOCOL VERSION 1 ........................................................ 9 
2 PLAN OF INVESTIGATION .......................................................................................................................... 10 
2.1 STUDY AIMS ............................................................................................................................................ 10 
2.2 TREATMENT COMPARISONS ..................................................................................................................... 10 
2.2.1 
Run-in period prior to randomization ........................................................................................................... 10 
2.2.2 
Randomization to anacetrapib versus placebo ............................................................................................ 10 
2.3 DATA ANALYSIS PLAN .............................................................................................................................. 11 
2.3.1 
Main and subsidiary analyses ..................................................................................................................... 11 
2.3.1.1 Primary assessment ................................................................................................................................ 11 
2.3.1.2 Secondary assessments ......................................................................................................................... 11 
2.3.1.3 Additional assessments requested by regulatory agencies ..................................................................... 11 
2.3.1.4 Tertiary assessments .............................................................................................................................. 11 
2.3.1.5 Additional safety assessments ................................................................................................................ 12 
2.3.1.6 Analyses of biochemical efficacy............................................................................................................. 13 
2.3.1.7 Exploratory assessments ........................................................................................................................ 13 
2.3.1.8 Health economic assessments................................................................................................................ 13 
2.3.2 
Statistical analysis ....................................................................................................................................... 13 
2.4 SAMPLE SIZE AND PREDICTED NUMBER OF EVENTS .................................................................................... 14 
2.4.1 
Initial assumptions (prior to study start) ....................................................................................................... 14 
2.4.2 
Statistical power (prior to study start) .......................................................................................................... 15 
2.4.3 
Revised statistical power (protocol version 2.0) .......................................................................................... 16 
2.4.4 
Planned study duration ................................................................................................................................ 17 
2.5 DATA AND SAFETY MONITORING .............................................................................................................. 17 
2.5.1 
Recording and reporting of adverse events ................................................................................................. 17 
2.5.1.1 Definition of Serious Adverse Events (SAE) ........................................................................................... 17 
2.5.1.2 Reporting of Serious Adverse Events and other relevant events ............................................................ 17 
2.5.1.3 Reporting of Suspected Serious Adverse Reactions (SSARs) ................................................................ 18 
2.5.2 
Interim analyses: role of the Data Monitoring Committee ............................................................................ 18 
2.5.2.1 Frequency of reviews .............................................................................................................................. 18 
2.5.2.2 Early stopping for benefit ........................................................................................................................ 19 
2.5.2.3 Early stopping for safety .......................................................................................................................... 19 
2.6 CENTRAL AND REGIONAL COORDINATION OF LOCAL CLINICAL CENTRES .................................................... 20 
2.6.1 
Training and monitoring ............................................................................................................................... 20 
2.6.2 
Supply of study materials ............................................................................................................................ 20 
2.6.3 
Data management ....................................................................................................................................... 20 
2.6.4 
Biological sample assay, transport and storage .......................................................................................... 21 
2.6.4.1 Local analysis of eligibility and safety bloods .......................................................................................... 21 
2.6.4.2 Central assessment of samples collected at the randomization visit and during follow-up ..................... 21 
2.6.4.3 Consent approval for unspecified analyses on blood and urine samples ................................................ 21 
2.6.5 
Administrative details .................................................................................................................................. 22 
2.6.5.1 Source documents and archiving ............................................................................................................ 22 
2.6.5.2 Sponsor and funding ............................................................................................................................... 22 
2.6.5.3 Indemnity ................................................................................................................................................ 22 
2.6.5.4 End of trial ............................................................................................................................................... 22 
2.6.5.5 Publications, reports and substudies ....................................................................................................... 22 
3 SUMMARY OF PRACTICAL PROCEDURES ............................................................................................. 23 
3.1 ELIGIBILITY FOR THE STUDY .................................................................................................................... 24 
3.1.1 
Inclusion criteria .......................................................................................................................................... 24 
3.1.2 
Exclusion criteria ......................................................................................................................................... 24 
3.2 SCREENING VISIT AND PRE-RANDOMIZATION RUN-IN ................................................................................. 25 
3.2.1 
Assessment of relevant medical history and eligibility ................................................................................. 25 
3.2.2 
Invitation to participate and standardization of LDL-lowering therapy ......................................................... 25 
3.2.3 
Review of eligibility and LDL cholesterol control by each individual’s own  doctor ...................................... 26 

 
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ISRCTN48678192, NCT01252953 
3.3 RANDOMIZATION VISIT (0 MONTHS) .......................................................................................................... 26 
3.3.1 
Final check of eligibility and compliance before randomization ................................................................... 26 
3.3.2 
Collection of blood and urine samples ......................................................................................................... 27 
3.3.3 
Random allocation of study treatment ......................................................................................................... 27 
3.4 FOLLOW-UP VISITS (2 AND 6 MONTHS AND THEN 6-MONTHLY) .................................................................... 27 
3.4.1 
Recording adverse events and compliance ................................................................................................. 27 
3.4.2 
Collection of blood and urine samples ......................................................................................................... 28 
3.4.3 
Issuing study treatment and arranging further appointments....................................................................... 28 
3.4.4 
Follow-up for randomized participants not attending study clinics ............................................................... 28 
3.4.5 
Follow-up of randomized participants via electronic healthcare systems and  other methods 
during and after the scheduled follow-up period .......................................................................................... 28 
3.5 EARLY RECALL VISITS AND MODIFYING STUDY TREATMENT ...................................................................... 29 
3.5.1 
Monitoring significant biochemical or other problems .................................................................................. 29 
3.5.1.1 Monitoring elevated liver transaminases ................................................................................................. 29 
3.5.1.2 Monitoring elevated creatine kinase ........................................................................................................ 30 
3.5.2 
Modifying study treatment ........................................................................................................................... 30 
3.5.2.1 Discontinuation of anacetrapib (or placebo) and LDL-lowering therapy .................................................. 30 
3.5.2.2 Requirement for changes to LDL-lowering treatment .............................................................................. 31 
3.5.2.3 Additional monitoring for participants receiving oral anticoagulants ........................................................ 31 
3.5.3 
Unblinding of study treatment ...................................................................................................................... 31 
3.5.4 
Withdrawal of consent ................................................................................................................................. 32 
3.6 CONFIRMATION AND VERIFICATION OF STUDY OUTCOMES ......................................................................... 32 
4 REFERENCES .............................................................................................................................................. 33 
5 APPENDICES ............................................................................................................................................... 36 
5.1 APPENDIX 1: ORGANISATIONAL STRUCTURE AND RESPONSIBILITIES .......................................................... 36 
5.2 APPENDIX 2: VISIT SCHEDULE AND PROCEDURES ...................................................................................... 39 
5.2.1 
Clinic procedures ......................................................................................................................................... 39 
5.2.2 
Central laboratory procedures ..................................................................................................................... 40 
5.3 APPENDIX 3: STUDY INVESTIGATORS ........................................................................................................ 41 

 
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CTSUREVEAL1 [V2.0_2016-01-11] 
 
 
 
 
ISRCTN48678192, NCT01252953 
1 
BACKGROUND AND RATIONALE 
1.1 DOES INHIBITION OF CHOLESTERYL ESTER TRANSFER PROTEIN (CETP) PREVENT 
MAJOR VASCULAR EVENTS IN PATIENTS WITH VASCULAR DISEASE? 
1.1.1 Substantial residual cardiovascular risk even with intensive LDL-lowering 
 treatment 
Large-scale randomized trials have shown that lowering LDL cholesterol concentration by 
about 1 mmol/L for 4-5 years reduces the risks of coronary events (including myocardial 
infarction [MI], coronary death and revascularization procedures) and of strokes by about 
one fifth.1 Furthermore, recent trials have demonstrated that more intensive lowering of 
LDL cholesterol produces additional reductions in the risk of such events.2 Nevertheless, 
among individuals with vascular disease or diabetes, cardiovascular risk remains elevated 
even after some years of intensive LDL-lowering treatment. For example, in two recent 
trials, over 10% of patients with coronary heart disease (CHD) suffered a major 
cardiovascular event during 4-5 years of intensive statin therapy.3, 4 
 
1.1.2 Higher blood concentrations of HDL cholesterol and of apolipoprotein A1 are 
 associated with lower cardiovascular risk throughout the usual range  
HDL cholesterol is inversely associated with CHD risk.5-7 In the Prospective Studies 
Collaborative (PSC) meta-analysis of 60 observational studies involving 3000 deaths from 
CHD among 154,000 people, both higher HDL cholesterol and lower non-HDL cholesterol 
levels were associated with lower CHD risk, and these effects were approximately 
independent in multiplicative terms (Figure 1).8 Each 0.33 mmol/L (13 mg/dL) higher HDL 
cholesterol was associated with about one-third lower risk of CHD death. 
 
 
Figure 1. (a) Inverse association between HDL cholesterol and subsequent risk of CHD 
death at both higher (≥5 mmol/L; 200 mg/dL) and lower levels of non-HDL cholesterol; and 
(b) Positive association between non-HDL cholesterol and subsequent risk of CHD death 
at both higher (≥1.25 mmol/L; 50 mg/dL) and lower levels of HDL cholesterol.8 
 

 
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ISRCTN48678192, NCT01252953 
HDL particles vary considerably in size and cholesterol content, and may also vary in their 
biological activity. Small HDL particles, which are more numerous, typically carry only 1-2 
molecules of apo A1 and a few dozen cholesterol molecules, while large ones typically 
carry 3-4 molecules of apo A1 and over 100 cholesterol molecules. Analyses from the ISIS 
case-control study9 (which involved 3500 MI patients and 9800 controls) found that apo A1 
and apo B were both strongly predictive of MI risk, as would be anticipated from the 
associations of HDL and non-HDL cholesterol (Figure 1). In the Emerging Risk Factors 
Collaborative (ERFC) meta-analysis of prospective studies, 1 standard deviation (SD) 
higher apo A1 (29 mg/dL) or HDL-cholesterol (0.38 mmol/L; 15 mg/dL) was associated 
with between one-fifth and one-quarter lower risk of CHD.10 
 
The association between stroke risk and HDL cholesterol or apo A1 is much less clear. 
Neither the PSC (1000 stroke deaths among 154,000 individuals)8 nor the Asia Pacific 
Studies Collaboration (850 fatal or non-fatal strokes among 80,000 individuals)11 found any 
significant association between HDL cholesterol and stroke risk. In the ERFC meta-
analysis, the hazard ratio for stroke (after adjustment for potential confounding factors) 
was 0.96 (95% CI 0.90-1.02) per 1 SD higher HDL cholesterol and 0.97 (95% CI 0.88-
1.08) per 1 SD higher apo A1.10 There are limited data on the associations between lipid 
fractions or apolipoprotein concentrations and the risks of particular stroke subtypes. In the 
AMORIS cohort (6000 fatal or non-fatal strokes among 149,000 individuals), both HDL 
cholesterol and apo A1 were inversely associated with the risk of ischaemic, but not 
haemorrhagic, stroke.12 
 
1.1.3 The clinical effects of currently available treatments for raising HDL 
 cholesterol remain uncertain 
Randomized trial evidence for beneficial effects from raising HDL cholesterol is limited. 
Most previous trials have been performed using fibrates, which raise HDL cholesterol only 
modestly (5-10%), and those studies have produced mixed results.13-17 When used with a 
statin, niacin 2g daily increases HDL cholesterol by about 20% and apolipoprotein A1 by 
about 7%, and reduces LDL cholesterol by about 18%.18 In the Coronary Drug Project 
(which was initiated in the 1960s, before the advent of statins), niacin resulted in a 
significant reduction of about one-fifth in non-fatal MI or coronary death during the 5-8 year 
scheduled treatment period.19 However, widespread use of this agent has been limited by 
poor tolerability (mainly due to flushing produced by cutaneous vasodilatation), and it is not 
known whether any benefits are additional to those of statin therapy. The combination of 
extended release niacin with laropiprant (a selective prostaglandin D receptor antagonist 
that reduces niacin-induced flushing) is being investigated in the ongoing HPS2-THRIVE 
trial among 25,000 patients with pre-existing atherosclerotic disease, all of whom are 
receiving simvastatin 40 mg daily plus (if required for adequate control of LDL cholesterol) 
ezetimibe 10 mg daily.20 
 
1.1.4 Inhibition of cholesteryl ester transfer protein as a possible therapeutic target 
Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates the exchange 
of cholesteryl esters and triglycerides between HDL particles and the atherogenic 
apolipoprotein B-containing particles. Human genetic mutations currently known to be 
associated with reduced CETP activity produce mild elevations in HDL cholesterol and apo 
A1 (about 3-5% per allele), have negligible effects on LDL cholesterol and apo B 
concentrations, and are associated with a small reduction in cardiovascular risk (about 5% 
per allele).21 Pharmacological inhibition of CETP produces more marked increases in HDL 
cholesterol and apo A1, along with reductions in LDL cholesterol and apo B. The 

 
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ISRCTN48678192, NCT01252953 
magnitude of these effects varies significantly between the three CETP inhibitors that have 
been developed (Table 1). 
 
Table 1. Changes* in blood lipid and lipoprotein concentrations with CETP inhibitors 
 
 
Torcetrapib 
Dalcetrapib 
Anacetrapib22 
 
60 mg daily23 
600 mg daily24 
40 mg daily 
150 mg daily 
Total cholesterol 
   4% 
n/a 
   1% 
   3% 
LDL cholesterol 
-24% 
  -4% 
-27% 
-40% 
Triglycerides 
  -9% 
  -3% 
-11% 
-11% 
Apolipoprotein B 
-12% 
n/a 
-20% 
-29% 
HDL cholesterol 
 61% 
 25% 
 86% 
139% 
Apolipoprotein A1 
 25% 
 10% 
 32% 
 47% 
* Negative values indicate reductions; n/a = not available 
 
1.1.5 Clinical safety and effectiveness of CETP inhibition is currently uncertain 
Torcetrapib was the first CETP inhibitor to be studied in a large-scale outcome trial. The 
ILLUMINATE trial randomized 15,000 participants at high cardiovascular risk to receive 
torcetrapib 60 mg daily versus placebo in addition to background LDL-lowering therapy 
with atorvastatin aiming to achieve LDL cholesterol <100 mg/dL.23 Acting on the advice of 
the Data Monitoring Committee, the trial was stopped prematurely because of an excess 
of deaths among those allocated torcetrapib (93 [1.2%] vs. 59 [0.8%]; HR 1.58, 95% CI 
1.14-2.19; p=0.006). The mortality result could not be clearly attributed to any particular 
cause of death, but there was a very definite increase in cardiovascular events (464 [6.2%] 
vs. 373 [5.0%]; HR 1.25; 95% CI 1.09-1.44; p=0.001). Imaging trials of torcetrapib provided 
no clear evidence of any effects (adverse or beneficial) on arterial wall markers of 
atherosclerosis.25-27 Torcetrapib was found to increase systolic blood pressure by about 5 
mmHg, as well as producing increases in blood sodium, bicarbonate and aldosterone 
concentrations. It seems likely that these off-target effects may have contributed to the 
observed hazard, but it remains unclear whether that is the entire explanation, or whether 
CETP inhibition itself played a role. 
 
Dalcetrapib has more modest effects on HDL cholesterol than torcetrapib or anacetrapib 
(Table 1). The Dal-Outcomes study aims to assess the effect of dalcetrapib on the risk of 
major vascular events among about 15,000 patients with recent acute coronary syndrome. 
Recruitment started in 2008 and results are anticipated in 2013.28 
 
Anacetrapib is an orally-active CETP inhibitor which has been well tolerated in early phase 
studies and, importantly, has no discernible effect on resting or ambulatory blood pressure 
or on plasma aldosterone concentrations.22, 29, 30 It has a greater impact on the lipid and 
lipoprotein profile than either torcetrapib or dalcetrapib, producing increases in HDL 
cholesterol and apo A1 concentrations of about 140% and 45%, respectively, and lowering 
LDL cholesterol and apo B by about 30-40% at a dose of 150 mg daily (Table 1). It is now 
being developed at a dose of 100 mg daily,30 which has similar effects on the lipid profile to 
those seen with 150 mg daily. The present study aims to compare anacetrapib 100 mg 
once daily versus placebo for about 4 years among at least 30,000 patients with pre-
existing atherosclerotic vascular disease who are also receiving effective LDL-lowering 
therapy using atorvastatin. This will allow reliable assessment not only of the impact of 
anacetrapib on the risk of major vascular events but also of its safety. 
 

 
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ISRCTN48678192, NCT01252953 
1.1.6 Rationale for intensive background LDL cholesterol-lowering 
There is now reliable evidence that intensive LDL-lowering treatment with a higher dose of 
a statin reduces the risk of vascular events more than does a standard statin dose, with no 
evidence of any threshold below which further LDL-lowering is hazardous.2 For example, 
in the recent Cholesterol Treatment Trialists’ (CTT) meta-analysis, there was no excess of 
non-vascular death or of cancer among patients in whom LDL cholesterol was lowered 
from about 1.5 to 1.1 mmol/L (58 to 43 mg/dL), while the proportional reduction in major 
vascular events was consistent with the effect seen among those with higher baseline LDL 
cholesterol levels.31 In the present trial, all individuals will receive an atorvastatin regimen 
intended to reduce their LDL cholesterol below 2 mmol/L (77 mg/dL). For individuals 
recruited in North East Asia (e.g. China or Japan), an atorvastatin dose of either 10 mg or 
20 mg daily will be used depending on the individual’s screening total cholesterol level and 
current LDL-lowering treatment. For those in all other countries, a similar algorithm will be 
employed to determine the atorvastatin dose of 20 mg or 80 mg daily. In all countries, total 
cholesterol will be checked after a minimum of 8 weeks of pre-randomization atorvastatin 
treatment. Individuals will be excluded (prior to randomization) if their total cholesterol is 
above 4 mmol/L (155 mg/dL), which is approximately equivalent to LDL cholesterol above 
2.5 mmol/L (97 mg/dL). Estimates based on the lipid profiles of similar patient populations 
in the HPS2-THRIVE study indicate that, after 8 weeks of these atorvastatin regimens, 
fewer than 10% of screened individuals would have LDL cholesterol above 2.5 mmol/L (97 
mg/dL) and would be excluded from this study. Among eligible individuals subsequently 
randomized to placebo in the present trial, the mean LDL cholesterol should be about 1.7 
mmol/L (67 mg/dL). Allocation to anacetrapib 100 mg daily should lower LDL cholesterol 
by about a further 40% to around 1.0 mmol/L (40 mg/dL), but only about 1% of those 
participants would be expected to achieve LDL cholesterol levels below 0.5 mmol/L (19 
mg/dL), even if they are fully compliant with all of the study treatments (Figure 2). 
 
 
Figure 2. Anticipated LDL cholesterol concentrations among randomized trial participants  
(Individuals with LDL cholesterol above 2.5 mmol/L on the study atorvastatin regimens 
would be excluded. Full compliance with all of the study treatments has been assumed) 
 
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
<0.25
>=0.25<0.5
>=0.5<0.75
>=0.75<1.00
>=1.00<1.24
>=1.25<1.50
>=1.50<1.75
>=1.75<2.00
>=2.00<2.25
>=2.25<2.50
>=2.50<2.75
>=2.75<3.00
>=3.00<3.25
>=3.25<3.50
>=3.50
LDL-cholesterol (mmol/L)
Frequency
Active
Placebo
Mean LDL-cholesterol
1.04 vs. 1.73 mmol/L
(40 vs. 67 mg/dL)

 
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ISRCTN48678192, NCT01252953 
1.2 BRIEF SUMMARY OF NEW INFORMATION SINCE PROTOCOL VERSION 1 
The following new information has emerged since the background and rationale for the 
trial were originally written for protocol version 1.0: 
 The results of HPS2-THRIVE have been published: Among participants with 
atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to 
statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of 
major vascular events, but did increase the risk of serious adverse events related to 
gastrointestinal and musculoskeletal systems, skin, diabetes, infection and bleeding.32 
 The Dal-OUTCOMES trial was stopped prematurely in May 2012 due to a lack of 
clinically meaningful efficacy: Dalcetrapib increased HDL-cholesterol by about 30% 
(with no effect on LDL-cholesterol) but did not alter the risk of the primary outcome 
(hazard ratio 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) or have a 
significant effect on any component of the primary outcome. There were no significant 
safety concerns.33 
 The DEFINE study showed that, after treatment with anacetrapib, the Friedewald 
formula and two direct methods (Roche and Genzyme) for assessing LDL cholesterol 
gave lower values than those measured by a Beta Quantification (BQ) method.34 
Hence the LDL-lowering effect of anacetrapib may be of the order of 20-30% rather 
than the 40% previously reported. 
 Extended follow-up of a subset of DEFINE participants showed that anacetrapib has a 
long terminal half-life. Low levels of anacetrapib (7-8% of apparent steady-state on-
treatment trough exposures, and 1-2% of apparent steady state peak concentrations) 
were detected in the blood 2.5-4 years after cessation of therapy.35 
 The results of the IMPROVE-IT trial were announced in November 2014 and 
subsequently published in June 2015.36 Among 18,000 patients with acute coronary 
syndrome, the addition of ezetimibe 10mg to simvastatin 40 mg daily reduced the risk 
of the composite primary outcome of cardiovascular death, myocardial infarction, 
hospital admission for unstable angina, coronary revascularization (≥30 days after 
randomization) or stroke (HR 0.94, 95% CI 0.89-0.99; p=0.016). Among the tertiary 
analyses, there was a significant reduction in ischemic stroke (HR 0.79; 95% CI 0.67-
0.94; p=0.008) but not in coronary revascularization (HR 0.96; 95% CI 0.90-1.02). 
 The ACCELERATE trial, a 12000 person phase III cardiovascular outcome trial of 
evacetrapib versus placebo, was stopped early due to insufficient efficacy in October 
2015. There is reported to be no safety signal.37, 38 Full presentation of the study results 
is awaited. 
Each of these new pieces of information has been considered by the Trial Steering 
Committee as they became available. Blind to analyses of the study results by treatment 
allocation (section 2.4.4), the Trial Steering Committee has agreed to a number of 
changes to the secondary assessments as described in this version 2.0 of the protocol. 
 
 

 
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ISRCTN48678192, NCT01252953 
2 
PLAN OF INVESTIGATION 
 
2.1 STUDY AIMS 
 
The study will randomize at least 30,000 participants aged 50 years or older with pre-
existing atherosclerotic vascular disease between anacetrapib 100 mg daily and matching 
placebo for a median of about 4 years. The primary aim is to assess the effect of 
anacetrapib on the composite outcome of Major Coronary Event (MCE), defined as 
coronary death, myocardial infarction or coronary revascularization (see Section 2.3.1.1). 
The key secondary aim is to assess the effect of anacetrapib on coronary death, 
myocardial infarction or presumed ischaemic stroke (see Section 2.3.1.2). Other 
secondary, tertiary and exploratory assessments (including analyses of safety and 
biochemical efficacy) are described in Sections 2.3.1.2 to 2.3.1.7) 
 
2.2 TREATMENT COMPARISONS 
2.2.1 Run-in period prior to randomization 
At the initial Screening visit, eligible individuals (see Section 3.1) will be issued with a 12-
week supply of Run-in medication consisting of: 
 
 placebo anacetrapib; and 
 active atorvastatin (see Section 3.2.2 for dose). 
 
One tablet of each treatment is to be taken daily with a meal for 8-12 weeks (see 
Figure 3). 
 
Randomization 
Visit
Atorvastatin
Anacetrapib 100 mg
+
Atorvastatin
Matching placebo
+
Atorvastatin
Screening
Visit
Run-in
8-12 weeks
Follow-up visits at 2 & 6 months,
then 6-monthly for a median of 4 years
 
 
Figure 3. Outline of randomization and follow-up schedule 
 
2.2.2 Randomization to anacetrapib versus placebo 
Eligible and consenting individuals will be allocated anacetrapib or placebo using a 
minimized randomization program that helps maximize balance between the treatment 
groups with respect to prognostically important variables (including age, gender, history of 
prior disease, smoking status, dry chemistry total cholesterol, blood pressure, ethnic origin, 
prior statin use, and study LDL-lowering regimen).39 The algorithm includes a stochastic 
element (treatment is assigned to the arm determined by the minimization algorithm with a 
probability of 0.9). 
 

 
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Randomized participants will be issued with a supply of study treatment consisting of: 
 
 anacetrapib 100 mg or matching placebo; and 
 active atorvastatin (at the same dose issued at the Screening visit). 
 
One tablet of each treatment is to be taken daily with a meal. 
 
2.3 DATA ANALYSIS PLAN 
2.3.1 Main and subsidiary analyses 
2.3.1.1 
Primary assessment 
Primary assessment will involve 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. 
 
2.3.1.2 
Secondary assessments 
Secondary assessments will involve intention-to-treat comparisons among all randomized 
participants of the effects of allocation to anacetrapib versus placebo during the scheduled 
treatment period on:  
 
(i) Major atherosclerotic events (defined as coronary death, myocardial infarction or 
presumed ischaemic stroke; the key secondary outcome); 
 
(ii) Presumed ischaemic stroke (i.e. not known to be haemorrhagic); and 
 
(iii) Major vascular events (defined as coronary death, myocardial infarction, coronary 
revascularization or presumed ischaemic stroke). 
 
In addition, each of the individual components of the primary outcome (i.e. coronary death; 
myocardial infarction; and coronary revascularization) will be tested separately. 
 
2.3.1.3 
Additional assessments requested by regulatory agencies 
These assessments (which have been specifically requested prior to the start of the study 
by regulatory agencies) will involve intention-to-treat comparisons among all randomized 
participants of the effects of allocation to anacetrapib versus placebo during the scheduled 
treatment period on:  
 
(i) Cardiovascular death or myocardial infarction; and 
 
(ii) Cardiovascular death, myocardial infarction or stroke. 
 
2.3.1.4 
Tertiary assessments 
Tertiary assessments will involve intention-to-treat analyses among all randomized 
participants of the effects of allocation to anacetrapib versus placebo during the scheduled 
treatment period on: 
 
(i) 
Coronary death or myocardial infarction, and, separately myocardial infarction alone; 
 
(ii) Mortality from all causes combined and, separately, within particular categories of 
causes, including cardiovascular (e.g. coronary [including sudden cardiac death]; 

 
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ISRCTN48678192, NCT01252953 
other cardiac; stroke; other vascular) and non-vascular (e.g. cancer; infection, 
respiratory, hepatic; other medical, and non-medical) causes; 
 
(iii) Confirmed ischaemic stroke, confirmed haemorrhagic stroke, and stroke of 
unknown/unconfirmed aetiology, considered separately and combined; 
 
(iv) Major coronary events, major atherosclerotic events, and major vascular events in 
various subdivisions: 
(a) occurring more than one year after randomization; 
(b) prior disease type (i.e. coronary heart disease; cerebrovascular disease; 
peripheral arterial disease; diabetes) and timing (i.e. most recent qualifying 
vascular event within 12 months of randomization); 
(c) three similar-sized groups based on lipid and apolipoprotein measurements 
(including HDL and LDL cholesterol) from the Randomization visit; 
(d) various categories of participant (e.g. according to age, sex, region, blood 
pressure, kidney function, alcohol intake, cigarette smoking, body mass index, 
waist:hip ratio, history of heart failure, atorvastatin dose) based on their 
Randomization visit values; 
(e) presence and absence of other treatments used at the Randomization visit (e.g. 
angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, aspirin 
or other antiplatelet drugs, diuretics, calcium-channel blockers, beta-blockers); 
 
(v) Urgent and non-urgent coronary revascularization, considered separately and 
combined; 
 
(vi) Non-coronary revascularizations, including percutaneous interventions (with or without 
stenting), surgical revascularization procedures (e.g. grafting, endarterectomy), and 
amputation for presumed vascular disease; 
 
(vii) Hospitalization for heart failure; 
 
(viii) Development of diabetes mellitus; 
 
(ix) Combination of first and subsequent occurrences of the primary outcome; 
 
(x) Cancer at all sites (fatal or non-fatal), and site-specific cancers considered separately 
(excluding any known to pre-date randomization and non-melanoma skin cancers); 
and 
 
(xi) Serious adverse events (overall and by subtype) due to infection and, separately, due 
to respiratory disease. 
 
2.3.1.5 
Additional safety assessments 
Additional safety assessments will include intention-to-treat analyses among all 
randomized participants of the effects of allocation to anacetrapib versus placebo during 
the scheduled treatment period on: 
 systolic and diastolic blood pressure 
 muscle-related outcomes: 
o creatine kinase [CK] >5x and ≤10x laboratory upper limit of normal [ULN] plus 
ALT >1.5x ULN 
o CK >10x and ≤40x ULN overall and, separately, with muscle symptoms 

 
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o CK >40x ULN overall and, separately, with evidence of end-organ damage such 
as doubling of serum creatinine (i.e. rhabdomyolysis) 
 liver-related outcomes: 
o ALT >3x ULN plus bilirubin >2x ULN, with CK ≤5x ULN 
o ALT >3x ULN on 2 occasions within about one week, with CK ≤5x ULN 
o liver injury of unknown cause 
 renal function 
o changes in estimated glomerular filtration rate 
o development of microalbuminuria and macroalbuminuria 
 discontinuation of study treatment overall and by various causes 
 
2.3.1.6 
Analyses of biochemical efficacy 
Biochemical efficacy of anacetrapib 100 mg daily will be assessed in non-fasting 
specimens taken from all participants at the randomization visit, at the 2 month follow-up 
visit, at a follow-up visit when median follow-up is about 2 years, and at the final study visit. 
In addition, samples will be taken annually in 5% of participants. The following biochemical 
efficacy outcomes will be measured on all samples:  
 total cholesterol 
 HDL cholesterol 
 LDL cholesterol 
 non-HDL cholesterol 
 triglycerides 
 apolipoprotein A1 
 apolipoprotein B 
In addition, lipoprotein (a) will be measured in all participants at randomization and at 
about 2 years after the median participant is randomized, and in at least 5% of participants 
annually. 
 
The effect of anacetrapib on other aspects of lipid and lipoprotein profile (such as 
lipoprotein particle size) may also be examined. Exploratory analyses will be conducted 
among particular categories of participant. 
 
2.3.1.7 
Exploratory assessments 
Exploratory assessments will be made of other possible beneficial or adverse effects of 
anacetrapib during the scheduled treatment period and in more prolonged follow-up 
thereafter. In particular, wherever possible, effects on vascular events, cancer, deaths and 
other serious adverse events will be assessed during at least the first few years following 
the end of the scheduled treatment period. In interpreting the results of the many 
exploratory analyses that will be performed, allowance will be made for multiple hypothesis 
testing, their exploratory (and, perhaps, data-dependent) nature, and for evidence from 
other studies. Analyses of fatal events will be interpreted in the light of the observed 
effects on relevant non-fatal events.40 
 
2.3.1.8 
Health economic assessments 
The study results will be used to conduct appropriate health economic assessments 
regarding the use of anacetrapib among patients at risk of vascular events. 
 
2.3.2 Statistical analysis 
All participants randomized to anacetrapib will be compared with all participants 
randomized to placebo, regardless of whether a participant received all, some or none of 
their allocated treatment (i.e. intention-to-treat [ITT] analyses). A participant may contribute 

 
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ISRCTN48678192, NCT01252953 
to more than one assessment if they have events of more than one type (e.g. non-fatal 
ischaemic stroke followed by coronary death). For the time-to-event analyses, survival 
analytic methods will be used to evaluate the time to the first event during the entire study 
period. For each outcome, log-rank method will be used to estimate the average event rate 
ratio comparing all those allocated active anacetrapib with all those allocated placebo.40 
Estimates of the event rate ratio will be shown with 95% confidence intervals, and Kaplan-
Meier estimates for the time to each of the primary and secondary outcomes will also be 
plotted (with their associated log-rank p-values). In all analyses, two-sided p-values (2P) 
<0.05 will be considered statistically significant (after any adjustment). 
 
The primary outcome will be assessed without adjustment for multiplicity. If a significant 
difference is demonstrated, then the key secondary outcome (i.e. major atherosclerotic 
events) and each of the components of the primary outcome (coronary death, myocardial 
infarction, and coronary revascularization) will be tested without adjustment. If a significant 
difference is demonstrated in the key secondary outcome, then presumed ischaemic 
stroke will be assessed. The remaining secondary outcome of major vascular events and 
the two additional composite outcomes requested by regulatory agencies (see Section 
2.3.1.3) will be assessed without adjustment for multiplicity. 
 
If there is directional consistency in the effect of the treatment on the primary outcome and 
on presumed ischaemic stroke, emphasis will be placed on the subgroup analyses for the 
secondary outcome of major vascular event (which incorporates both outcomes). Tests for 
heterogeneity of the proportional effect observed in subgroups will be used (with allowance 
for multiple comparisons) to determine whether the proportional effects in specific 
subcategories are clearly different from the overall effect.40, 41 If, however, patient 
categories can be arranged in some meaningful order (e.g. age at randomization: <60, 
≥60<70, ≥70) then assessment of any trend will be made. For subgroups based on 
continuous variables (e.g. blood pressure), approximate tertiles will be used, using natural 
breaks to define categories (e.g. systolic blood pressure <140 mmHg rather than <138.7 
mmHg). Based on the observed differences in cholesterol during follow-up between all 
those allocated active anacetrapib and all those allocated placebo (i.e. irrespective of 
compliance), cholesterol-weighted analyses will be used to estimate the effects of actual 
compliance with anacetrapib on the primary and secondary outcomes overall and in 
different circumstances.42 For each of the events listed as additional safety outcomes 
(section 2.3.1.5), the number of randomized participants with at least 1 event will be 
compared using standard tests for differences in proportions. For continuous variables, 
such as blood pressure (section 2.3.1.5) and analyses of biochemical efficacy (section 
2.3.1.6), differences in means between the randomized groups will be assessed. 
 
2.4 SAMPLE SIZE AND PREDICTED NUMBER OF EVENTS 
2.4.1 Initial assumptions (prior to study start) 
Anticipated rate of major coronary events: Blinded data from the ongoing HPS2-
THRIVE trial20 indicate that the rate of non-fatal MI or coronary death is about 0.9% per 
annum (pa) in both China and in Western Europe (Scandinavia and United Kingdom). 
When coronary revascularization procedures are added, event rates are approximately 
twice as large: 1.8% pa in China and 1.7% pa in Western Europe. 
 
Anticipated effects of anacetrapib 100 mg daily on lipids: Data from HPS2-THRIVE 
have been used to model the effects on lipids of adding anacetrapib 100 mg daily to the 
background atorvastatin therapy. Full compliance with anacetrapib 100 mg daily would be 
expected to increase HDL cholesterol by 1.3 mmol/L (50 mg/dL) from 1.0 mmol/L to 2.3 

 
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ISRCTN48678192, NCT01252953 
mmol/L (39 mg/dL to 89 mg/dL) and to decrease LDL cholesterol by 0.7 mmol/L (27 
mg/dL) from 1.7 mmol/L to 1.0 mmol/L (67 mg/dL to 40 mg/dL: see Figure 2). In estimating 
the likely effects on clinical outcomes, it is assumed that only about three-quarters of the 
participants will be taking their allocated study treatment at the midpoint of study follow-up. 
 
Anticipated effects of anacetrapib 100 mg daily on major coronary events: There is 
good evidence from randomized trials that, for every 1 mmol/L (39 mg/dL) reduction in LDL 
cholesterol achieved with a statin, the risk of major coronary events is reduced by about 
one-quarter.1, 31 Anacetrapib reduces LDL cholesterol by a different mechanism to that of 
statins. But, if the relationship between LDL cholesterol reduction and risk reduction is 
similar, the anticipated 0.5 mmol/L reduction in LDL cholesterol (assuming three-quarters 
compliance at the study midpoint) would be expected to translate into a 10-15% relative 
reduction in major coronary events. There are insufficient data from randomized trials to 
make reliable estimates of the effects of increasing HDL cholesterol on the risks of such 
events. In the ERFC meta-analysis of prospective observational studies, 0.8 mmol/L (30 
mg/dL) higher HDL cholesterol was associated with about two-fifths lower risk of non-fatal 
MI or coronary death.10 If, as with LDL cholesterol, only about half of the effect associated 
epidemiologically emerges within about 4-5 years of raising HDL cholesterol, then the 
anticipated 1 mmol/L increase (assuming three-quarters compliance) would be expected to 
translate into a 20-25% relative reduction in major coronary events. 
 
2.4.2 Statistical power (prior to study start) 
Based on a major coronary event rate of 1.8% pa and median follow-up of 4 years, a trial 
of 30,000 participants would have 88% power at 2P<0.01 to detect a 15% relative risk 
reduction (see Table 2). Moreover, if the relative risk reduction was larger than 15% then 
the study might well produce compelling results earlier than anticipated, and might provide 
reliable information in important subgroups and for other major outcomes. For example, 
with 30,000 participants and an event rate of 0.9% pa, there would be 83% power at 
2P<0.01 to detect a 20% relative reduction in the key secondary outcome of coronary 
death or myocardial infarction. Follow-up of 4 years in such a large trial would provide 
reliable information on the safety of anacetrapib. 
 
 
 

 
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Table 2. Statistical power to detect 15% reduction in the primary outcome of major 
coronary events (coronary death, MI or coronary revascularization) and 20% reductions in 
the original secondary outcomes among 30,000 participants with median follow-up of 
4 years 
 
Event rate 
(pa) 
Proportional 
reduction 
Placebo 
15000 
Active 
15000 
Power 
(2P<0.01) 
Power 
(2P<0.05) 
Coronary death, MI or coronary revascularization 
1.80% 
15% 
1080 
(7.20%) 
918 
(6.12%) 
88% 
96% 
Coronary death or MI 
 
 
 
0.90% 
20% 
540 
(3.60%) 
432 
(2.88%) 
83% 
94% 
Coronary revascularization 
 
 
 
1.20% 
20% 
720 
(4.80%) 
576 
(3.84%) 
94% 
98% 
Presumed ischaemic stroke 
 
 
 
1.00% 
20% 
600 
(4.00%) 
480 
(3.20%) 
87% 
96% 
Cardiovascular death 
 
 
 
 
0.75% 
20% 
450 
(3.00%) 
360 
(2.40%) 
74% 
89% 
 
2.4.3 Revised statistical power (protocol version 2.0) 
Based on an observed blinded major coronary event rate of 2.7% pa and median follow-up 
of 4 years, a trial of 30,449 participants (i.e. the number randomized) would have 98% 
power at 2P<0.01 to detect a 15% relative risk reduction (see Table 3). 
 
Table 3. Statistical power to detect 15% reductions in the primary outcome of major 
coronary events (coronary death, MI or coronary revascularization) and in the revised 
secondary assessments among 30,449 participants with median follow-up of 4 years 
 
Event rate 
(pa) 
Proportional 
reduction 
Placebo 
15224 
Active 
15225 
Power 
(2P<0.01) 
Power 
(2P<0.05) 
Coronary death, MI or coronary revascularization 
 
 
 
2.7% 
15% 
1644 
(10.8%) 
1398 
(9.2%) 
98% 
>99% 
Coronary death, MI or presumed ischaemic stroke 
2.2% 
15% 
1340 
(8.8%) 
1139 
(7.5%) 
95% 
99% 
Presumed ischaemic stroke 
0.8% 
15% 
487 
(3.2%) 
414 
(2.7%) 
46% 
70% 
Coronary death, MI, presumed ischaemic stroke or coronary revascularization 
3.4% 
15% 
2070 
(13.6%) 
1760 
(11.6%) 
>99% 
>99% 
 

 
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ISRCTN48678192, NCT01252953 
2.4.4 Planned study duration 
Follow-up of all randomized participants is planned to continue for a median of at least 4 
years, and until at least 1900 participants have had an unrefuted major coronary event 
(primary endpoint) plus at least 950 participants have had a coronary death or myocardial 
infarction. During the study, an independent Lipid Monitoring Committee will review 
unblinded tabulations of the achieved blood lipids (but not results for individuals) and will 
inform the Steering Committee if, in their view, the achieved lipid differences vary 
materially from those anticipated in the protocol (see section 2.4.1). The Steering 
Committee may use this information, together with blinded tabulations of the overall event 
rates (i.e. not split by allocated anacetrapib or placebo treatment), to determine whether 
modifications to the protocol (such as the numbers of participants recruited or the duration 
of follow-up) are required for the reliable assessment of the effects of anacetrapib. 
Wherever possible and subject to funding, extended follow-up of all surviving randomized 
participants will continue for several years beyond the final study visit in order to provide 
valuable information on the longer-term safety and efficacy of the study treatment (see 
section 3.4.5.). 
 
 
2.5 DATA AND SAFETY MONITORING 
2.5.1 Recording and reporting of adverse events 
2.5.1.1 
Definition of Serious Adverse Events (SAE) 
Serious adverse events are defined as those adverse events that: 
 
 result in death; 
 are life-threatening; 
 require in-patient hospitalization or prolongation of existing hospitalization; 
 result in persistent or significant disability or incapacity; 
 result in congenital anomaly or birth defect;  
 are cancer; or 
 are important medical events in the opinion of the responsible investigator (i.e. not 
life-threatening or resulting in hospitalization, but may jeopardise the participant or 
require intervention to prevent one or other of the outcomes listed above); 
 
Pregnancies and overdoses of study medication are also to be recorded as serious 
adverse events. Overdose is defined as any occasion in which an investigator learns that a 
participant has taken more than 6 times the specified dose of study medication. 
 
2.5.1.2 
Reporting of Serious Adverse Events and other relevant events 
All SAEs reported by participants at each follow-up visit will be recorded directly on the 
study computer-based data entry system (see Section 2.6.3), regardless of whether the 
participant continues to take study treatment or not. Clinic staff are to record whether any 
SAE is thought likely to be due to study treatment (see Section 2.5.1.3). Participants will 
also be asked specifically whether they have had any unexplained muscle pain or muscle 
weakness to determine whether additional measures are required to detect and manage 
statin-related myopathy (see Sections 3.4.2 and 3.5.1.2). Other adverse events not 
considered serious (as defined above) will only be recorded if they lead to discontinuation 
of study treatment or are believed to be due to study treatment. SAEs that are potential 
primary or secondary study endpoints, or important safety endpoints will undergo central 
review, verification and coding as described in Section 3.6. In addition, blood pressure and 
blood tests for assessment of safety are to be recorded at each visit (see Section 2.6.4.1). 

 
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Line-listings of all reported SAEs (blind to treatment allocation) will be provided on a bi-
weekly basis to Merck Sharp & Dohme Corp. (from here on referred to as "Merck") for 
regulatory purposes. 
 
2.5.1.3 
Reporting of Suspected Serious Adverse Reactions (SSARs) 
As recommended by regulatory authorities,43 a Suspected Serious Adverse Reaction 
(SSAR) should be considered an unanticipated problem requiring expedited reporting only 
if it is either an event that is uncommon and strongly associated with drug exposure (such 
as angioedema, agranulocytosis, hepatic injury, or Stevens-Johnson syndrome), or an 
event that is not commonly associated with drug exposure, but uncommon in the study 
population (e.g. tendon rupture, progressive multifocal leukoencephalopathy).  
 
Any SAE that is considered, with a reasonable probability, to be due to study treatment is, 
potentially, a SSAR. In making this assessment, there should be consideration, based on 
the available information, of the probability of an alternative cause, the timing of the 
reaction with respect to study treatment, the response to withdrawal of the study treatment, 
and (where appropriate) the response to subsequent re-challenge. Reports of all such 
events are to be forwarded immediately to a clinician at the Regional Coordinating Centre 
(RCC) or Central Coordinating Office (CCO). This clinician will obtain standard information, 
including participant study number, identity of reporting person, description of event, and 
reason for attribution to study treatment. All such reports will then be forwarded urgently to 
the Clinical Coordinators (or their delegated deputies) at the CCO, who will review the 
evidence for seriousness and relatedness, seek any additional information required 
(including relevant information relating to medical history and treatment both prior to and 
following randomization), and assess expectedness. Each such SSAR will generally be 
classified as “expected” and not subject to expedited reporting if the Clinical Coordinators 
(or their deputies) consider it either (i) to be a study endpoint (listed in sections 2.3.1.1 to 
2.3.1.4),43, 44 or (ii) to have been reported previously as being associated with either 
anacetrapib (based on the latest version of the Investigator’s brochure and emerging data 
from this and other ongoing studies) or atorvastatin (based on the latest version of the 
clinical data sheet). Any SSARs that are considered to be “unexpected” (Suspected 
Unexpected Serious Adverse Reactions [SUSARS]) and are believed to be related to 
randomized treatment (rather than atorvastatin) will be unblinded. All SUSARs that are 
believed to be related to atorvastatin or to active anacetrapib will be reported immediately 
to Merck for regulatory authority submission, to the Chairman of the Data Monitoring 
Committee and, as required, to other relevant parties (including appropriate ethics 
committees and Institutional Review Boards [IRBs]). In addition, all expected SSARs will 
be reported in an expedited fashion, blinded to Merck and unblinded to the Chairman of 
the Data Monitoring Committee. 
 
2.5.2 Interim analyses: role of the Data Monitoring Committee 
2.5.2.1 
Frequency of reviews 
During the study, interim analyses of all SAEs and other study outcomes (both overall and 
in key subgroups, including by region and by baseline lipid levels) will be supplied in strict 
confidence to the independent Data Monitoring Committee (DMC). The DMC will request 
such analyses at a frequency relevant to the stage of the study (typically at 6-12 monthly 
intervals, with a Chairman’s review every 3-6 months) or in response to emerging data 
from other trials. Unless advised by the DMC in response to clear evidence of benefit or 
hazard, the Steering Committee, collaborators, participants, representatives of Merck, and 
all study staff (except those who provide the confidential analyses to the DMC) will remain 
blind to the interim results on mortality and major morbidity until the end of the study. 

 
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2.5.2.2 
Early stopping for benefit 
In the light of these interim analyses and any other information considered relevant, the 
DMC will advise the Steering Committee if, in their view, the randomized comparisons in 
the study have provided both (i) “proof beyond reasonable doubt” that prolonged use of 
anacetrapib reduces the primary outcome (major coronary events), plus the key secondary 
outcome (coronary death or myocardial infarction), plus cardiovascular mortality, with a 
consistent effect on all-cause mortality; and (ii) evidence that might reasonably be 
expected to influence materially patient management by many clinicians who are already 
aware of the results of other relevant trials. Any recommendation to stop the trial early for 
benefit should be based primarily on adjudicated events, with a sensitivity analysis 
showing a similar trend when all events (adjudicated and non-adjudicated) are included. In 
general, at least 75% of relevant events should have been adjudicated prior to any review 
that might lead to early stopping for benefit. Appropriate criteria of proof beyond 
reasonable doubt cannot be specified precisely, but in general to justify halting, or 
modifying, the study prematurely for benefit then it is expected that the guidelines set out 
in Table 4 would be fulfilled. This approach, which will be applied at each review of the 
emerging data, has the practical advantage that the exact number of interim analyses is of 
little importance.40 For example, if allowance was made for interim assessments of the 
primary outcome only, then it can be shown that adjustment of a two-sided P value of 0.05 
might yield a value of 0.049. But, since early stopping also requires consistency of the 
effect on the primary outcome across key subgroups plus highly significant effects on other 
vascular outcomes plus directional consistency for total mortality, the required adjustment 
would be even smaller. Consequently, a final two-sided P value of 0.05 will be considered 
significant. 
 
 
Table 4. Guidelines for early stopping for efficacy 
 
Median follow-up 
Outcome 
Stopping criteria 
 
≥3.0 years 
Primary outcome 
≥3 SD (with consistent results 
in key subgroups) 
 
Coronary death or MI 
≥2.6 SD overall plus ≥2.0 SD 
for at least one component 
 
Cardiovascular mortality 
≥2.0 SD 
 
Total mortality 
Directionally consistent effect 
SD = standard deviations 
 
2.5.2.3 
Early stopping for safety 
The DMC would also be expected to advise the Steering Committee if clear evidence 
emerged of an adverse effect on all-cause mortality or on cardiovascular mortality (at least 
2 standard deviations) or if, in the view of the DMC, there was other compelling evidence 
of hazard that seemed likely to outweigh any potential benefit.  
 
 

 
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2.6 CENTRAL AND REGIONAL COORDINATION OF LOCAL CLINICAL CENTRES 
 
The Study will be coordinated by the Central Coordinating Office (CCO), based at the 
Clinical Trial Service Unit (CTSU) of Oxford University, working with Regional Coordinating 
Centres (RCCs) which will be responsible for selection of Local Clinical Centres (LCCs) 
within their region and for the administrative support and monitoring of those LCCs. At 
each LCC, a lead investigator and research coordinator (usually a qualified nurse, but in 
some cases may be medically qualified or have other relevant qualifications and 
experience) will be responsible for identification, recruitment, and follow-up (see Appendix 
1: Organisational Structure and Responsibilities). It is intended that at least 30,000 
participants will be randomized at about 400 LCCs worldwide. 
 
2.6.1 Training and monitoring 
The study will be conducted in accordance with the principles of International Conference 
on Harmonisation Guidelines for Good Clinical Research Practice (ICH-GCP) and relevant 
local, national and international regulations (including the EU Clinical Trial Directive and 
the US Code of Federal Regulations Chapter 21). Prior to initiation of the study at any 
LCC, the RCC will confirm that the LCC has adequate facilities and resources to carry out 
the study (and, if considered necessary, a site visit will be undertaken). LCC lead 
investigators and study clinic staff will be provided with materials detailing relevant study 
procedures for LCCs, and clinic staff will be trained in study methods (including use of the 
bespoke computer-based study management systems; see Section 2.6.3). 
 
 
During the study, the relevant RCC and/or the CCO will arrange monitoring visits to study 
centres as considered appropriate based on perceived training needs and the results of 
central statistical monitoring of study data. The purpose of such visits will be to ensure that 
the study is conducted according to the protocol, particularly by helping LCC staff to 
resolve any local problems with the study and by providing additional, focussed training. 
Particular attention will be given to the effectiveness of strategies to recruit appropriate 
participants, the completeness of follow-up, the maintenance of participant compliance 
with the study treatments, and the reporting of study outcomes and collection of relevant 
supporting documentation. A report of each visit will be prepared by the study monitor and 
provided to LCC, RCC and CCO staff. 
 
2.6.2 Supply of study materials 
Study treatments will be manufactured, packaged, labelled and delivered to each LCC or 
RCC by Merck under the direction of the CCO. An inventory of study drug supplies will be 
maintained on the study computer system and monitored at the CCO. LCC lead 
investigators will be responsible for making appropriate arrangements for the storage and 
issuing of study treatments, and for the disposal of unused study drug in accordance with 
study Standard Operating Procedures (SOPs). 
 
2.6.3 Data management 
All data in the study will be processed electronically using a set of custom-written 
applications. The LCC clinic staff will use a bespoke laptop-based application for 
performing LCC tasks (including: entering participant data at study visits; minimized 
randomization and issue of appropriate study treatment; and local trial administration), with 

 
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frequent synchronization of data to central databases. RCC and CCO staff will use a suite 
of administration applications to manage centres and study participants, including clinical 
supervision (review of SAEs and safety blood results), management of follow-up and 
compliance, tracking of samples for central analysis, collection of supporting 
documentation for relevant events, and endpoint adjudication. Data transfers will be 
cryptographically secured, and all data will be stored securely. All data accesses will 
require a unique username and password, and any changes to data will require the user to 
enter their username and password as an electronic signature. Staff will have access 
restricted to only the functionality and data that are appropriate to their role in the study. 
 
2.6.4 Biological sample assay, transport and storage 
2.6.4.1 
Local analysis of eligibility and safety bloods 
Dry chemistry analysers will be used in all LCC study clinics for eligibility checks at the 
Screening visit (ALT, CK and creatinine) and Randomization visit (ALT and CK); for 
baseline measures of total cholesterol (at Screening and Randomization Visits); and for 
safety analyses during follow-up (ALT at each visit, with other liver function tests and CK 
as required). 
 
2.6.4.2 
Central assessment of samples collected at the randomization visit and during 
follow-up 
Samples of blood and urine are to be collected from all randomized participants at the 
Randomization visit for central analysis and storage, including subsequent DNA extraction 
(subject to relevant consent, see Section 2.6.4.3). Further samples are to be collected 
from all participants at the 2 month visit, at around 2 years after the median participant is 
randomized and at the final study visit. In addition, samples of blood are to be collected 
annually from 5% of participants (starting 1 year after the first participant is randomized) 
(see Appendix 2: Visit schedule and procedures). RCCs will supply LCC clinic staff with 
vacuum tubes to collect these blood samples, which are to be kept cool before 
centrifugation, separation into bar-coded cryovials, and storage at below -18°C within a 
day of the clinic visit. Samples are to be transferred to below -40°C within 4 weeks. At 
appropriate intervals, all samples will be collected from the LCCs (by the RCC or CCO) 
and transferred to a central laboratory for analysis (see section 5.2.2), and for long-term 
storage in liquid nitrogen vapour or in electric freezers (remnant blood for DNA extraction 
only). 
 
2.6.4.3 
Consent approval for unspecified analyses on blood and urine samples 
Sample tubes will be labelled with a unique Sample ID which will be linked to the 
participant and the study visit using the study data entry system (i.e. samples will be 
pseudonymised). Outside the study clinic, staff involved in the transport, storage and 
analysis of these samples will have no means of linking tubes to an identifiable participant. 
Consent for protocol-specified analyses (including assays of lipid and lipoprotein profile) 
will be included in the main consent form. In addition, all participants will be asked if they 
would provide Supplementary Consent to allow samples of plasma, serum and urine that 
have been collected to be retained and used for unspecified analyses in the future. 
Similarly, Supplementary Consent will be sought to permit genetic material in the blood 
samples to be analysed. In all cases, participants will be free to opt in or out of any part of 
the Supplementary Consent without affecting their eligibility for the trial. 
 

 
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2.6.5 Administrative details 
2.6.5.1 
Source documents and archiving 
Source documents for the study constitute the clinic visit records (including blood and 
urine assay results) held in the study main data store, the additional information obtained 
on reported serious adverse events that are relevant to the outcome measures (see 
Section 3.6), death certificates, and drug supply records. These will be retained for at least 
15 years from the completion of the study. Merck and regulatory agencies will have the 
right to commission a confidential audit of such records in the CCO, RCCs, and LCCs 
provided this does not result in unblinding while the study is in progress. 
 
2.6.5.2 
Sponsor and funding 
This study has been designed by the independent investigators at the Clinical Trial Service 
Unit (CTSU) at Oxford University in collaboration with the TIMI Study Group based at 
Brigham Women’s Hospital, Harvard Medical School, Boston, and with Merck. The 
University of Oxford will act as the trial Sponsor worldwide. The data will be collected, 
analysed and published independently of the source of funding. Merck is providing funding 
for the design and overall conduct of the study. 
 
2.6.5.3 
Indemnity 
Merck will, at all times, indemnify the study investigators and study staff from claims that 
may be made against them for any injury sustained by a study participant as a 
consequence of participation in the study in accordance with this protocol. The indemnity 
will be outlined in detail in the agreements between the CCO, RCCs and LCCs (and, if 
required, in a letter from Merck). 
 
2.6.5.4 
End of trial 
The end of the main phase of the trial is defined as the date of the last visit of the last 
participant. It is planned that wherever possible, and subject to funding, follow-up of all 
participants will continue for at least 2 years after the date of the last visit of the last 
participant (see Section 3.4.5). 
 
2.6.5.5 
Publications, reports and substudies 
The independent Steering Committee will be responsible for drafting the main reports from 
the study and for review of any other reports. Draft copies of any manuscripts will be 
provided to lead investigators at each LCC, and all other collaborators (including Merck) 
for review prior to publication. Papers will be written in the name of the Collaborative 
Group, with individual investigators named personally at the end of the report (or, to 
comply with journal requirements, in web-based material posted with the report). 
 
Proposals for substudies on participants randomized into the study must be approved by 
the Steering Committee before they begin. In considering such proposals, the Steering 
Committee will need to be satisfied that the proposed substudy is of a high quality, and 
that it will not compromise the main study in any way (for example by reducing the 
recruitment rate or compliance with study treatment). 
 

 
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3 
SUMMARY OF PRACTICAL PROCEDURES 
 
 
PRE-SCREENING PHASE 
 
 
 Identify potentially eligible individuals (age ≥50 years with vascular disease) 
 Invite to attend Screening clinic appointment in local study clinic 
 
SCREENING VISIT (-2 to 3 MONTHS) AND PRE-RANDOMIZATION RUN-IN PHASE 
 
 
 
 
 
 
 
 Medical history, relevant current treatment and other eligibility factors recorded 
 Blood pressure recorded 
 Written informed consent sought from eligible and willing individuals 
 Blood sample taken for dry chemistry assays (total cholesterol, ALT, CK, and creatinine) 
 Consenting participants asked to stop non-study statin or ezetimibe 
 Active atorvastatin plus placebo anacetrapib issued 
 Randomization visit appointment scheduled for about 10 weeks later 
 Individual’s doctor (and/or investigator) informed about entry into run-in phase 
 
RANDOMIZATION VISIT (0 MONTHS) 
 
 
 
 
 
 
 
 
 
 
 
 All serious adverse events during Run-in and non-study treatments recorded 
 Final check of compliance, eligibility and consent 
 Assessment of quality of life, including EQ5D questionnaire 
 Blood pressure, height, weight, and hip, waist and neck circumference recorded 
 Blood sample taken for dry chemistry assays (ALT, CK, and total cholesterol) and for 
central analyses and frozen storage 
 Urine collected for albumin:creatinine ratio and storage 
 Randomization via study clinic computer: allocated anacetrapib 100 mg daily or placebo 
 Treatment pack issued: atorvastatin plus randomized treatment  
 First follow-up visit appointment scheduled for 2 months’ time  
 Participant’s doctor informed of participant’s randomization 
 
FOLLOW-UP VISITS AT 2 and 6 MONTHS, THEN 6-MONTHLY 
 
 
 
 
 
 
 Serious adverse events, compliance, and changes to non-study medication recorded 
 Non-serious adverse events attributed to study treatment recorded 
 Reasons for stopping study treatments recorded 
 Blood pressure recorded 
 Blood sample taken for dry chemistry safety assays, and for central analysis and storage 
for future assays (in all participants at the 2 month visit, at 2 years after median 
participant randomized, and at the final visit, and in 5% of participants annually) 
 Urine collected for albumin:creatinine ratio and storage (final visit only) 
 Follow-up treatment pack issued: atorvastatin plus randomized treatment 
 Next Follow-up visit scheduled for 6 months and then 6 monthly 
 Assessment of cognitive function and quality of life (including EQ5D questionnaire) at 
final visit only 
 
MONITORING OF SAFETY AND EFFICACY 
 
 
 
 
 Central monitoring of blood results and adverse events (with Early Recall visits to monitor 
any problems) 
 Further details on relevant outcomes sought from participant’s doctor and other sources 
(e.g. registries and electronic healthcare records) 
 Relevant events confirmed centrally blind to treatment allocation  

 
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3.1 ELIGIBILITY FOR THE STUDY 
 
Patients are eligible for randomization if: 
 
(i) at least one of the inclusion criteria is satisfied; and 
 
(ii) none of the exclusion criteria applies; and  
 
(iii) their own doctor does not consider there to be 
(a) a definite indication for a CETP inhibitor*; or 
(b) a definite contraindication to either anacetrapib or atorvastatin 
 
3.1.1 Inclusion criteria 
Patients must be aged at least 50 at the time of initial invitation, and at least one of the 
following inclusion criteria must be satisfied: 
 
 History of MI; or 
 Cerebrovascular atherosclerotic disease (i.e. history of presumed ischaemic stroke 
or carotid revascularization); or 
 Peripheral arterial disease (i.e. history of non-coronary revascularization, including 
aortic aneurysm repair or graft); or 
 Diabetes mellitus with other evidence of symptomatic coronary heart disease (i.e. 
treatment or hospitalization for angina, or a history of coronary revascularization or 
acute coronary syndrome).  
 
3.1.2 Exclusion criteria 
None of the following must be satisfied: 
 
 Acute MI, acute coronary syndrome or stroke within 4 weeks prior to Screening Visit 
or during Run-in (but such individuals may be entered later, if appropriate); 
 Planned coronary revascularization procedure within the next 6 months (such 
individuals may be entered later, if appropriate); 
 Definite history of chronic liver disease, or abnormal liver function (i.e. ALT 
>2x ULN). Note: Individuals with a history of acute hepatitis are eligible provided 
this ALT limit is not exceeded; 
 Severe renal insufficiency (i.e. creatinine >200 µmol/L [2.3 mg/dL], dialysis or 
functioning renal transplant); 
 Evidence 
of 
active 
inflammatory 
muscle 
disease 
(e.g. 
dermatomyositis, 
polymyositis), or CK >3x ULN; 
 Previous significant adverse reaction to a statin or anacetrapib; 
 Current treatment with any of the following lipid-lowering treatments: 
(i) a regimen considered to produce substantially greater LDL cholesterol 
reduction than atorvastatin 80 mg daily for individuals in non-Asian countries or 
20 mg daily for those in North East Asia; or 
(ii) fibric acid derivative (“fibrate”, including gemfibrozil); or 
(iii) niacin (nicotinic acid) at doses above 100 mg daily 
                                            
* It is not anticipated that any CETP inhibitor will be licensed and available for routine use during the recruitment phase of this trial. 

 
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ISRCTN48678192, NCT01252953 
 Concurrent treatment with a medication that is contraindicated with anacetrapib or 
atorvastatin: 
(i) any potent CYP3A4 inhibitor, such as: 
(a) macrolide antibiotics (erythromycin, clarithromycin, telithromycin); 
(b) systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole); 
(c) protease inhibitors (e.g. atazanavir); 
(d) nefazodone 
(ii) ciclosporin 
(iii) daptomycin 
(iv) systemic use of fusidic acid 
Note: Individuals who are taking such drugs temporarily may be re-screened when 
they discontinue them, if considered appropriate; 
 Known to be poorly compliant with clinic visits or prescribed medication; 
 Medical history that might limit the individual’s ability to take trial treatments for the 
duration of the study (e.g. severe respiratory disease; history of cancer or evidence 
of spread within last 5 years, other than non-melanoma skin cancer; or recent 
history of alcohol or substance misuse); 
 Women of child-bearing potential (unless using adequate contraception); 
 Current participation in a clinical trial with an unlicensed drug or device. 
 
Individuals will also be excluded at the Screening visit if it is considered unlikely that they 
will achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the highest atorvastatin dose  
available in their region (atorvastatin 80 mg daily in non-Asian countries or 20 mg daily in 
North East Asia). 
 
In addition, individuals will be excluded at the Randomization visit if any of the following 
are true: 
 Total cholesterol above 4 mmol/L [155 mg/dL] 
 Non-compliant with run-in treatment (<90% scheduled run-in medication taken) 
 Individual is no longer willing to be randomized into the 4-5 year trial 
 The individual’s doctor is of the view that their patient should not be randomized 
(see Section 3.2.3) 
 
 
3.2 SCREENING VISIT AND PRE-RANDOMIZATION RUN-IN 
3.2.1 Assessment of relevant medical history and eligibility 
Potentially eligible individuals will be given information about the study and invited to 
attend a Screening Visit. At that visit, relevant medical history and other factors pertinent to 
eligibility will be recorded directly onto the Screening Visit Form on the study IT system. 
The LCC clinic staff will check inclusion and exclusion criteria (with the assistance of the 
study IT system), record relevant current medication and measure blood pressure. 
 
3.2.2 Invitation to participate and standardization of LDL-lowering therapy 
Individuals who appear to be eligible will have the study explained to them by the clinic 
staff, using the Participant Information Leaflet and Consent Form as a basis for discussion. 
Each individual will have an opportunity to initiate discussion, and have time to think about 
their participation in the study, perhaps after discussing it with their family, primary care 
physician, or a local physician. (Eligible individuals who choose to do this will be asked to 
attend a repeat Screening visit within a few weeks.) Attendees will be discouraged from 

 
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participating if it is thought unlikely that they would be willing and able to continue 
attending Follow-up visits for at least 4-5 years. 
 
Potentially eligible individuals who agree to take part will be asked to provide written 
informed consent to take part in the study. In addition, individuals will be asked to indicate 
on the consent form which, if any, of the samples of plasma, serum, cells or urine may be 
stored long-term for future unspecified research analyses. A blood sample will be taken for 
immediate dry chemistry analysis of total cholesterol, ALT, CK and creatinine. These 
results will be recorded onto the study clinic IT system, which will provide an assessment 
of eligibility (see Section 3.1) and guidance on the atorvastatin dose to be used for that 
particular individual. In North East Asia (e.g. China or Japan), atorvastatin will be used at a 
dose of either 10 mg or 20 mg daily, while elsewhere, the dose will be 20 mg or 80 mg 
daily. All participants are to receive a dose that is at least as effective as their current LDL-
lowering treatment. In all countries, a higher dose is to be used in those individuals who – 
based on their screening total cholesterol and pre-trial lipid-lowering therapy – do not 
appear likely to achieve total cholesterol <3.5 mmol/L (135 mg/dL) on the lower 
atorvastatin doses. The LCC clinic staff will issue 12 weeks’ supply of the appropriate 
study medication, as follows: 
 
 Active atorvastatin one tablet daily (dose determined as above) 
 Placebo anacetrapib one tablet daily 
 
Other lipid-modifying treatment (including statin, ezetimibe or resins) will be stopped. For 
individuals on oral anticoagulants, the managing doctor will be advised to check their 
international normalised ratio (INR) about one week after starting the Run-in treatment. An 
appointment will be made for the Randomization visit in 8-12 weeks.  
 
3.2.3 Review of eligibility and LDL cholesterol control by each individual’s own 
 doctor 
The pre-randomization Run-in phase is intended to help identify and exclude before 
randomization those individuals who would be unlikely to comply with long-term study 
treatment and follow-up. During run-in, each individual’s responsible doctor (e.g. primary 
care physician or hospital specialist) will be given a description of their patient’s medical 
history, previous lipid-modifying treatment and Screening Visit total cholesterol result, and 
advised of the atorvastatin dose that would be provided during the trial. The doctor would 
be asked to indicate whether, in their view, these blood results (or any other factor) make 
their patient unsuitable for entry into the randomized phase of the study.  
 
 
3.3 RANDOMIZATION VISIT (0 MONTHS) 
3.3.1 Final check of eligibility and compliance before randomization 
Individuals who attend their Randomization Clinic appointment will be asked if they have 
experienced MI, arterial revascularization (coronary or non-coronary), stroke, other SAE or 
any other significant problems during the Run-in period, and whether any arterial 
revascularization procedure is currently planned for them. Any SAE considered to be due 
to study treatment (i.e. possible SAR) is to be discussed immediately with a RCC/CCO 
clinician for expedited reporting (see Section 2.5.1.3). Details of all non-study treatments 
will be sought, compliance with Run-in treatment checked (at least 90% of scheduled 
study treatment should have been taken), and consent information checked. Information 
about smoking history and alcohol intake will be sought and an assessment of quality of 

 
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ISRCTN48678192, NCT01252953 
life is to be made (including the EQ5D questionnaire). Blood pressure, height, weight, and 
hip, waist and neck circumference will be measured. Details will be recorded directly onto 
the Randomization Form on the clinic IT system (which is designed to obtain complete 
information and to prompt appropriate actions). 
 
3.3.2 Collection of blood and urine samples 
Eligible individuals will be asked if they are still willing to take study treatment for at least 4-
5 years. If so, they will have a blood sample taken for immediate dry chemistry 
measurement of total cholesterol, ALT and CK in the clinic. In order to remain eligible, total 
cholesterol must be ≤4 mmol/L (155 mg/dL), ALT must be ≤2x ULN, and CK must be 
≤3x ULN. (If an individual is excluded because of abnormal ALT or CK, their usual doctor 
will be informed so that further investigation can be arranged.) Blood and urine samples 
will be processed in preparation for subsequent transportation to the central laboratory 
(see Section 2.6.4). 
 
3.3.3 Random allocation of study treatment 
Eligible and consenting individuals will be allocated anacetrapib or placebo using a 
minimized randomization program on the clinic IT system (see Section 2.2.2).39 
Participants will be allocated a numbered treatment pack containing a 7-month supply of 
the following treatments: 
 
 One tablet daily of active anacetrapib 100 mg or matching placebo 
 One tablet daily of active atorvastatin (at a dose to match that used during run-in) 
 
The numbered treatment packs will be issued to the participant by the LCC clinic staff or 
their local hospital pharmacy. An appointment for the first post-randomization Follow-up 
Visit will then be allocated by the study staff, with guidance from the clinic IT system. The 
participant’s doctor(s) will be notified that the participant has been randomized. 
 
 
3.4 FOLLOW-UP VISITS (2 AND 6 MONTHS AND THEN 6-MONTHLY) 
 
3.4.1 Recording adverse events and compliance 
Following randomization, all participants are scheduled to attend Follow-up visits at 2 and 
6 months, and then 6-monthly until the end of the study (see Section 2.4.3). At each visit, 
details of all hospital admissions, other SAEs, unexplained muscle pain or weakness, and 
non-serious adverse events attributed to study treatment will be sought. †  Any SAE 
considered to be due to study treatment (i.e. possible SAR) is to be discussed immediately 
with a RCC/CCO clinician for expedited reporting (see Section 2.5.1.3). Changes to non-
study treatment will be sought, and compliance with study treatment reviewed. For 
participants who discontinue study treatment, the reasons for doing so will be sought. 
Blood pressure will be measured at each visit (and, at the final visit, hip, waist and neck 
circumference and weight will be measured). At the final visit, cognitive function and 
quality of life (including EQ5D questionnaire) are to be assessed. Details are to be 
recorded directly onto the Follow-up Form on the clinic IT system.  
 
                                            
† In North America, all non-serious adverse events will be recorded (including those not attributed to study treatment). 

 
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3.4.2 Collection of blood and urine samples 
At each Follow-up visit, a non-fasting blood sample will be taken for immediate dry 
chemistry analysis of ALT. If ALT>2x ULN with symptoms that suggest possible hepatitis 
(e.g. loss of appetite, nausea, jaundice, lethargy or malaise), or if ALT>3x ULN even in the 
absence of such symptoms, then dry chemistry analysis of alkaline phosphatase and 
bilirubin are to be performed and an Early Recall visit may need to be arranged (see 
Section 3.5.1.1). If ALT>1.5x either ULN or the Randomization visit result, or if the 
participant has new or unexplained muscle symptoms (i.e. muscle pain or weakness) then 
CK is also to be measured. If CK>5x ULN then creatinine is to be measured. If CK>3x 
ULN, an Early Recall visit may need to be arranged (see Section 3.5.1.1). For all 
participants at the 2 month visit, at a follow-up visit about 2 years after the median 
participant is randomized, and at the final visit, and for 5% of participants annually, 
additional non-fasting blood samples are to be taken for central laboratory assays and 
storage (see Section 2.6.4.2). A urine sample is to be taken for central analysis and 
storage at the final follow-up visit only. 
 
3.4.3 Issuing study treatment and arranging further appointments 
Provided continuing study treatment remains appropriate, participants will be given a 
further 7-month supply of their randomly allocated study treatment (anacetrapib 100 mg or 
placebo) and study atorvastatin, and any previously allocated treatment will be retrieved 
(except at the 2-month visit). An appointment will then be made for their next scheduled 
Follow-up visit. 
 
3.4.4 Follow-up for randomized participants not attending study clinics 
Follow-up information is to be collected from all study participants, irrespective of whether 
they continue to take study treatment, usually at routine Follow-up clinic visits. If, however, 
a participant becomes unwilling or unable to attend then LCC clinic staff will telephone the 
participant (or, where appropriate, their relative or carer) at the time of each of their 
scheduled Follow-up appointments and complete the necessary Follow-up form on the 
clinic IT system. If this is not possible, then RCC staff will attempt to check a participant’s 
progress by direct correspondence with the participant’s own doctors, or by reviewing 
available information on routine healthcare systems and registries (see Section 3.4.5). If 
safety monitoring of blood is no longer possible (e.g. because the participant no longer 
attends clinic visits and no other means of measuring safety bloods can be arranged), then 
the participant will be asked to discontinue all study treatment and advised to see their 
own doctor so that the alternative LDL-lowering therapy can be considered. 
 
3.4.5 Follow-up of randomized participants via electronic healthcare systems and 
 other methods during and after the scheduled follow-up period 
Additional information about major clinical outcomes (including, but not limited to, those 
reported by participants themselves) will be sought from available electronic healthcare 
systems and routine data sources (for example, in the UK, NHS Connecting for Health, the 
Medical Research Information Service, and registries for specific diseases, devices or 
procedures). Such information will be used to clarify and enhance information recorded 
during clinic visits. Wherever possible, extended follow-up of all surviving randomized 
participants will continue for several years beyond the final study visit in order to provide 
valuable information on the longer-term safety and efficacy of the study treatment. This 
can be particularly informative for assessing effects on outcomes (e.g. cancers, 
neurodegenerative and cognitive disorders) that may only become evident many years 

 
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after initiation of treatment, and for deriving appropriate cost-effectiveness analyses. Such 
strategies have been used in a number of previous trials, including the ALERT,45 HPS46 
and WOSCOPS47 statin trials. As well as seeking long-term follow-up information via 
routine data sources, participant questionnaires may be administered by telephone, by 
mail or by electronic means (e.g. SMS text messaging or web-based survey tools). 
 
 
3.5 EARLY RECALL VISITS AND MODIFYING STUDY TREATMENT 
3.5.1 Monitoring significant biochemical or other problems 
An Early Recall Visit may be arranged for any participant who requires review outside their 
planned visit schedule. Examples of circumstances where this may be necessary include 
the assessment of abnormal values in safety bloods from routine Follow-up visits, and 
review of symptoms believed by the participant to be related to study treatment. As at 
routine study visits, the results of blood tests performed at Early Recall visits will be 
entered by LCC staff into the clinic IT system (which is designed to prompt appropriate 
actions) and these results will be monitored centrally by clinical staff at the CCO and RCCs 
in accordance with the study SOPs. For all participants randomized in Asia, an Early 
Recall will be conducted at 4 months to allow an additional check of biochemical safety. 
 
3.5.1.1 
Monitoring elevated liver transaminases 
CCO clinicians will be responsible for reviewing elevated liver transaminase results, and 
for advising on the need for (and timing of) Early Recall visits and whether study treatment 
should be stopped or restarted. In so doing, CCO clinicians will collaborate with the local 
investigator, as necessary, and will be guided by the principles described below (but the 
clinical picture in some cases may necessitate a more cautious approach, e.g. more 
frequent study visits or a lower threshold for stopping study treatment). 
 
If ALT>2x ULN with symptoms that suggest possible hepatitis (e.g. loss of appetite, 
nausea, jaundice, lethargy or malaise), or if ALT>3x ULN even in the absence of such 
symptoms, then treatment may continue but an Early Recall visit should be conducted in 
about 1 week. If ALT>2x and ≤3x ULN and there are no hepatitis symptoms, then 
treatment may continue and an Early Recall visit should be conducted in about 3 weeks. 
 
At the next appointment for such individuals, ALT is to be reassessed and subsequent 
actions are to be guided by the following: (i) if ALT>2x ULN with symptoms that suggest 
possible hepatitis, or ALT>3x ULN even in the absence of such symptoms, then study 
treatment is to be stopped and an Early Recall visit conducted in about 6 weeks; (ii) 
otherwise, if ALT>2x ULN, then study treatment may continue and an Early Recall visit 
conducted in about 6 weeks; (iii) if ALT≤2x ULN then study treatment may continue and 
the participant may return to scheduled follow-up. 
 
If at any time ALT>10x ULN or ALT>3x ULN with bilirubin>2x ULN then all study treatment 
(anacetrapib or placebo plus atorvastatin) is to be stopped and an Early Recall visit 
conducted in about 1 week. 
 
For participants who stop study treatment with ALT>3x ULN, alternative causes of liver 
dysfunction should be investigated (e.g. careful history of alcohol, non-study medications, 
travel and diet, hepatobiliary ultrasound, and viral and autoimmune serology). Restarting 
study treatment should only be considered in such participants if a plausible alternative 
explanation has been identified. The decision to restart study treatment should be based 
on the clinical presentation, including the evolving pattern of liver function tests, the 

 
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presence or absence of symptoms, and findings from other investigations. The CCO 
clinician will determine whether both study treatments (anacetrapib or placebo plus 
atorvastatin) are to be restarted simultaneously or sequentially. If any study treatment is 
restarted, there should be 2 further Early Recall visits at 4-weekly intervals. If ALT does 
not remain ≤2x ULN, then the study treatment is to be stopped permanently. 
 
When study treatment is stopped, appropriate advice is to be provided to the participant’s 
managing doctor. If a participant develops a raised ALT after stopping all study treatment, 
they would not need to be managed according to the above study visit scheme. 
 
3.5.1.2 
Monitoring elevated creatine kinase 
Participants with CK>10x ULN plus unexplained muscle pain or weakness are considered 
to have myopathy (by definition) and should be instructed to stop all study medication (i.e. 
anacetrapib or placebo plus atorvastatin) permanently. Serum creatinine should also be 
recorded. 
 
Otherwise, if CK>3x “reference” level (defined as the lower of (i) laboratory ULN and (ii) 
result at the Randomization visit) study treatment should be continued and an Early Recall 
visit conducted in about 1 week. At the next visit, CK, ALT and (if CK>10x ULN) creatinine 
should be recorded. If CK>5x reference with unexplained muscle symptoms or CK>10x 
reference without such symptoms, then all study medication is to be stopped permanently. 
Otherwise, if CK >3x reference, a CCO clinician should determine whether study treatment 
may continue and the timing of future study visits. This decision will be informed by the 
clinical presentation, including the evolving pattern of CK and ALT, the presence or 
absence of muscle symptoms, and findings from other investigations. 
 
For participants on study treatment, if CK≤3x reference then the participant may return to 
routine follow up. If study treatment is restarted following a previous finding of CK>3x 
reference, then further Early Recall visits will be arranged to monitor CK. 
 
Following any decision to stop study treatment permanently, CK is to be checked at 
approximately 3-weekly visits (weekly if CK>10x reference) until CK≤3x reference (or it is 
clear that CK is stable and the risk of myopathy is low). When study treatment is stopped, 
appropriate advice will be provided to the participant’s managing doctor. 
 
3.5.2 Modifying study treatment 
3.5.2.1 
Discontinuation of anacetrapib (or placebo) and LDL-lowering therapy 
If adverse events occur that are believed to be due to anacetrapib and/or atorvastatin, or if 
a significant elevation of liver transaminase or CK develops (see Section 3.5.1), any or all 
of the study treatments may be permanently or temporarily discontinued. The following 
events are also sufficient reason to discontinue the study anacetrapib or placebo and/or 
atorvastatin: 
 
 SAE considered likely to be due to one or more of the study treatments (see 
Section 2.5.1.3);  
 Current use of treatments that are contraindicated with atorvastatin (which still 
allows the allocated study anacetrapib or placebo to be continued);  
 Clear indication or contraindication for anacetrapib (including current use of a non-
study treatment that is contraindicated with anacetrapib);  
 At the request of the participant or their doctors (for whatever reason) or any other 
situation where continuing study treatment is not considered to be in the 

 
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ISRCTN48678192, NCT01252953 
participant’s best interests by their own doctors or the Study clinical team (including 
child-bearing potential unless using adequate contraception). 
 
If a participant is receiving a contraindicated treatment for a limited period (e.g. a short 
course of erythromycin or systemic imidazole/triazole antifungal agent), they should stop 
the relevant study treatment temporarily and restart once the contraindicated treatment 
has been stopped. CCO clinicians will be available to provide advice on such cases. 
 
Whenever possible, the clinic IT system will prompt LCC Clinic staff to consider whether 
there are specific reasons for modifying either the randomly-allocated anacetrapib or 
placebo and/or the study atorvastatin. Participants who have only study atorvastatin 
stopped may take non-study statin or other lipid-lowering medication (but not a CETP 
inhibitor) at the discretion of the local investigator and their managing doctor. CCO 
clinicians will provide advice if required. 
 
3.5.2.2 
Requirement for changes to LDL-lowering treatment 
Randomized participants who are receiving study atorvastatin and who, in the opinion of 
their managing doctors, require more or less intensive LDL-lowering therapy may have the 
dose of study atorvastatin increased (to a maximum of 20 mg daily in Far East, 80 mg 
daily elsewhere) or reduced. Furthermore, any randomized participant may stop the study 
atorvastatin and take an LDL-lowering regimen prescribed by their managing doctors. In 
both circumstances, the randomly-allocated anacetrapib or placebo should generally be 
continued. 
 
3.5.2.3 
Additional monitoring for participants receiving oral anticoagulants 
Anticoagulant control with warfarin (or similar drugs) may be disturbed when atorvastatin is 
started or stopped. For participants who are taking warfarin (or similar drugs), the study IT 
system will automatically prompt the LCC doctor/nurse to remind the participant of the 
need for additional monitoring of anticoagulant control if study atorvastatin is altered. 
 
3.5.3 Unblinding of study treatment 
There are 2 main situations in which unblinding of the treatment allocation (anacetrapib or 
placebo) for an individual participant may be warranted: 
 
 When knowledge of the treatment allocation could materially influence the 
immediate medical management (e.g. after overdose); and 
 When a Clinical Coordinator (or their deputy) reviews a report of a SSAR (see 
Section 2.5.1.3). 
 
Urgent unblinding is available on a 24-hour basis via the Clinical Trial Service Unit (CTSU) 
telephone service. Requests for unblinding will be reviewed urgently, and authorized, by 
the CCO on-call clinician. 
 
 

 
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3.5.4 Withdrawal of consent 
Participants may decide that they no longer wish to take one or more of the study 
treatments or are no longer willing to attend study visits. These decisions are not 
considered to be withdrawals of consent, and appropriate procedures for dealing with them 
are described elsewhere in this protocol (e.g. for discontinuation of study treatment see 
Section 3.5.2.1; for alternative methods of follow-up see Section 3.4.4). However, 
participants are free to withdraw consent for some or all aspects of the study at any time. 
In order to ensure that relevant safeguards are put in place to maintain the individual’s 
safety (e.g. if an important safety issue comes to light that might affect a participant who 
has previously withdrawn from the study) and to prevent a breach of the individual’s 
decision to withdraw (e.g. to prevent re-invitation of an individual who had previously 
withdrawn consent), the decision to withdraw should be put in writing and a copy of this 
should be maintained at the LCC (with key data items being recorded on the study IT 
system). This written information should specify which aspect(s) of the study consent is 
being withdrawn: for example, direct contact from study staff; collection of information from 
a relative or friend; collection of information from non-study doctors or routine data 
sources; or the storage and analysis of samples for protocol-specified future unspecified 
assays. (In accordance with FDA guidance, data that have already been collected and 
incorporated into the study database, including the results of laboratory assays, will 
continue to be processed.) 
 
 
3.6 CONFIRMATION AND VERIFICATION OF STUDY OUTCOMES 
 
The RCCs will seek additional information only about reports of SAEs that might be 
importantly relevant to assessment of the efficacy or safety of the study treatment. In 
general, this will be limited to events initially reported as MI, angina, stroke, coronary or 
non-coronary revascularization procedure, cancer (excluding non-melanoma skin cancer), 
myopathy, rhabdomyolysis, non-viral hepatitis, and all deaths. Other events may be added 
to this list if the Steering Committee consider that this is appropriate in order to ensure a 
reliable assessment of the clinical effects (particularly safety) of anacetrapib. Relevant 
information may come from the records held at the LCCs and other hospitals, from 
participant’s own doctors, from electronic sources and registries (see Section 3.4.5). In 
some cases (e.g. cancer, blood dyscrasia) it may be necessary to obtain information that 
pre-dates randomization into the study. The RCC will be responsible for the provisional 
confirmation of these events, with clinicians based at or overseen by the CCO providing 
the final adjudication. All review, processing and adjudication of SAEs will be conducted in 
accordance with the study SOPs and will be blinded to study treatment allocation 
(anacetrapib or placebo). 
 

 
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4 
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Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular 
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LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, et al. Intensive Lipid Lowering 
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Parish S, Peto R, Palmer A, Clarke R, Lewington S, Offer A, et al. The joint effects of apolipoprotein 
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Holme I, Aastveit AH, Hammar N, Jungner I, Walldius G. Relationships between lipoprotein 
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Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the 
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Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary 
artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102(1): 21-7. 

 
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16. 
Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: 
randomised controlled trial. BMJ. 2002; 325(7373): 1139. 
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The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 
9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 366(9500): 
1849-61. 
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Maccubbin D, Bays HE, Olsson AG, Elinoff V, Elis A, Mitchel Y, et al. Lipid-modifying efficacy and 
tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed 
dyslipidaemia. Int J Clin Pract. 2008; 62(12): 1959-70. 
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Clofibrate and niacin in coronary heart disease. JAMA. 1975; 231(4): 360-81. 
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HPS2-THRIVE: Treatment of High density lipoprotein to Reduce the Incidence of Vascular Events.   
[cited March 14 2013]; Available from: http://www.thrivestudy.org/ 
21. 
Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart RP, et al. Association of 
cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. 
JAMA. 2008; 299(23): 2777-88. 
22. 
Bloomfield D, Carlson GL, Sapre A, Tribble D, McKenney JM, Littlejohn TW, 3rd, et al. Efficacy and 
safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with 
atorvastatin in dyslipidemic patients. Am Heart J. 2009; 157(2): 352-60 e2. 
23. 
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. Effects of torcetrapib 
in patients at high risk for coronary events. N Engl J Med. 2007; 357(21): 2109-22. 
24. 
Stein EA, Stroes ES, Steiner G, Buckley BM, Capponi AM, Burgess T, et al. Safety and tolerability of 
dalcetrapib. Am J Cardiol. 2009; 104(1): 82-91. 
25. 
Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, et al. Effect of 
torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med. 2007; 356(16): 1620-
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26. 
Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, et al. Torcetrapib and carotid 
intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. 
Lancet. 2007; 370(9582): 153-60. 
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Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al. Effect of torcetrapib on 
the progression of coronary atherosclerosis. N Engl J Med. 2007; 356(13): 1304-16. 
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Dal-OUTCOMES 
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[cited 
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30 
2009]; 
Available 
from: 
http://clinicaltrials.gov/show/NCT00658515 
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Krishna R, Anderson MS, Bergman AJ, Jin B, Fallon M, Cote J, et al. Effect of the cholesteryl ester 
transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory 
blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. 
Lancet. 2007; 370(9603): 1907-14. 
30. 
Cannon CP, Dansky HM, Davidson M, Gotto AM, Jr., Brinton EA, Gould AL, et al. Design of the 
DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J. 
2009; 158(4): 513-9 e3. 
31. 
Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of more intensive lowering of LDL 
cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 
376(9753): 1670-81. 
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Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, et al. Effects of extended-release 
niacin with laropiprant in high-risk patients. N Eng J Med. 2014; 371(3): 203-12. 
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Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of dalcetrapib in 
patients with a recent acute coronary syndrome. N Engl J Med. 2012; 367(22): 2089-99. 

 
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34. 
Davidson M, Liu SX, Barter P, Brinton EA, Cannon CP, Gotto AM, Jr., et al. Measurement of LDL-C 
after treatment with the CETP inhibitor anacetrapib. Journal of lipid research. 2013; 54(2): 467-72. 
35. 
Gotto AM, Jr., Cannon CP, Li XS, Vaidya S, Kher U, Brinton EA, et al. Evaluation of lipids, drug 
concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer 
protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol. 2014; 
113(1): 76-83. 
36. 
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to 
Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015; 372(25): 2387-97. 
37. 
ACCELERATE trial press release. 
 2015 
 
[cited 
Dec 17th 
2015]; Available from: 
https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130 
38. 
Nicholls SJ, Lincoff AM, Barter PJ, Brewer HB, Fox KAA, Gibson CM, et al. Assessment of the 
clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for 
vascular outcomes: Rationale and design of the ACCELERATE trial. Am Heart J. 2015; 170(6): 1061-9. 
39. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics. 1975; 31(1): 103-15. 
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Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J 
Cancer. 1977; 35(1): 1-39. 
41. 
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J 
Cancer. 1976; 34(6): 585-612. 
42. 
Cuzick J, Edwards R, Segnan N. Adjusting for non-compliance and contamination in randomized 
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U.S. Department of Health and Human Services Food and Drug Administration. Guidance for 
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Eurpoean Commision Enterpise and industry directorate - General. ENTR/CT 3, Revision 2: Detailed 
guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials 
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45. 
Holdaas H, Fellstrom B, Cole E, Nyberg G, Olsson AG, Pedersen TR, et al. Long-term cardiac 
outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study. Am J Transplant. 
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46. 
Bulbulia R, Bowman L, Wallendszus K, Parish S, Armitage J, Collins R. MRC/BHF Heart Protection 
Study (HPS): Mortality, Cancer Incidence and Major Vascular Events During 4 Years Post-trial Follow-up of 
HPS. Journal of the American College of Cardiology. 2007; 49(9 Supp 1): 393A. 
47. 
Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. Long-term follow-up of the 
West of Scotland Coronary Prevention Study. N Engl J Med. 2007; 357(15): 1477-86. 
 

 
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5 
APPENDICES 
 
5.1 APPENDIX 1: ORGANISATIONAL STRUCTURE AND RESPONSIBILITIES 
 
Principal Investigators 
The Principal Investigators have overall responsibility for: 
 
 Design and conduct of the Study  
 Preparation of the Protocol and subsequent revisions 
 Managing the CCO  
 Development of SOPs and computer systems 
 
 
Steering Committee 
The Steering Committee is responsible for: 
 
 Agreement of the final Protocol 
 Agreeing the Data Analysis Plans  
 Reviewing progress of the study and, if necessary, agreeing changes to the 
Protocol 
 Reviewing new studies that may be of relevance 
 Review and approval of study reports and sub-study proposals  
 
 
Data Monitoring Committee 
The independent Data Monitoring Committee is responsible for: 
 
 Reviewing unblinded interim data according to the schedule outlined in the Protocol 
 Advising the Steering Committee if, in their view, the randomized data provide 
evidence that may warrant early termination for either efficacy or safety (see 
Section 2.5.2). 
 
 
Lipid Monitoring Committee 
The independent Lipid Monitoring Committee is responsible for: 
 
 Reviewing unblinded interim data on blood lipid results 
 Advising the Steering Committee if, in their view, the randomized lipid changes are 
significantly less than anticipated and merit a change to the study design and 
execution (e.g. modifications to duration of follow-up; see Section 2.4). 
 
 
Central Coordinating Office 
The CCO is responsible for the overall coordination of the Study, including: 
 
 Study planning and organisation of Steering Committee meetings 
 Agreement of each regional recruitment plan (including countries, number of LCCs, 
number of participants, and timelines) 
 Contractual issues with RCCs and budget administration 
 Ensuring necessary regulatory approvals  

 
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 Assistance with Ethics Committee applications 
 Design, implementation and maintenance of IT systems for the study (including 
CCO/RCC IT system for administration and clinic IT system for direct data entry) 
 Provision of laptops and other study materials to RCCs and LCCs, and provision of 
IT support to RCCs 
 Monitoring of drug supply in liaison with Merck (who will be responsible for drug 
distribution to each LCC) 
 Central laboratory assay and long-term storage of blood and urine samples 
 Auditing and monitoring of overall progress of the study 
 Clinical safety monitoring, including reporting of SSARS to the Chairman of the 
Data Monitoring Committee and to Merck (see Section 2.5.1.3)  
 Responding to technical, medical and administrative queries from the RCCs 
 Management of endpoint adjudication 
 Liaison with the Data Monitoring Committee and Merck, and (where appropriate) 
with regulatory authorities and other outside agencies 
 
 
Regional Coordinating Centres 
Each RCC is responsible, under the direction of its Regional Coordinator, for: 
 
 Liaison with regulatory authorities as appropriate 
 Identification of potential LCCs and agreement of their recruitment plans (including 
number of participants and timelines) 
 Contractual issues with LCCs and regional budget administration 
 Obtaining any central Ethics Committee approval (where appropriate) and assisting 
LCCs with local Ethics Committee applications  
 Training of LCC clinic staff and assistants 
 Assisting LCC’s with the identification of suitable individuals  
 Distribution of study laptop computers and other study materials to LCCs 
 Responding to technical, medical and administrative queries from the LCCs 
 Monitoring LCCs through site visits (by the study monitors) and by responding to 
regular or occasional reports on regional progress prepared by the CCO 
 Ensuring appropriate follow-up of abnormal safety blood results  
 Ensuring appropriate confirmation of reported events in line with study SOPs 
(including collection and initial processing of relevant documentation) 
 Collection and short-term storage of blood and urine samples from LCCs, and 
subsequent transport of them to the CCO  
 Organisation of meetings of collaborators within the region 
 
 
Local Clinical Centres 
The LCC lead investigator and LCC clinic staff are responsible for: 
 
 Obtaining Local Ethics Committee approval (aided by the RCC) 
 Obtaining local management approval where necessary 
 Provision of adequate clinic space and access to appropriate systems for the 
identification of potentially eligible individuals 
 Conducting clinic procedures; managing and distributing study drugs (in 
conjunction, if required, with the hospital pharmacy), and maintaining the laptop 
computer and other study equipment in accordance with the Protocol and SOPs 

 
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 Ensuring adequate local laboratory facilities for safety monitoring and, if necessary, 
processing and temporarily storing samples for central analysis 
 Dealing with routine enquiries from participants and their families in collaboration 
with the RCC 
 Obtaining appropriate information when requested to confirm potential primary and 
secondary study endpoints  

 
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5.2 APPENDIX 2: VISIT SCHEDULE AND PROCEDURES 
5.2.1 Clinic procedures 
 
Task
Activity
Registration (*)
Screening
Randomization
- 12 to -8 weeks
0 months
2 months
6 months
6 monthly visits
Final visit
Demographics
Contact details
X
 
 
 
 
 
 
Medical history & eligibility assessment
Medical history (incl. inclusion criteria)
X
X
Exclusion criteria (incl. relevant non-study medication)
X
X
Other information (smoking, alcohol)
X
Use of non-study medication
 
X
X
X
X
X
Consent
Obtain consent
X
Confirm consent
X
Safety & outcomes reporting
Serious adverse events (incl. serious adverse reactions [SARs])
X
X
X
X
X
Non-serious adverse reactions (NSARs)**
X
X
X
X
X
Compliance
X
X
X
X
X
Reasons for stopping study treatment (incl. SAEs, NSARs, and other reasons)
X
X
X
X
X
Remote follow-up using routine data sources and/or participant surveys
(X)***
(X)***
(X)***
(X)***
Quality of life (including EQ5D)
X
X
Cognitive function
X
Physical measurements
Blood pressure
X
X
X
X
X
X
Height
X
Weight, hip, waist & neck circumference
X
X
Laboratory assessments
Creatinine****
X
ALT, CK****
X
X
Total cholesterol****
X
X
Safety bloods (ALT, with other LFTs & CK [as indicated by ALT & clinical history])****
X
X
X
X
Samples for central analyses and storage*****
X
X
(X)*****
(X)*****
X
Randomization & study treatment handling
Issue atorvastatin (105 day supply)
X
Issue placebo anacetrapib (84 day supply)
X
Randomize eligible & willing participants
X
Issue atorvastatin (210 day supply)
X
X
X
Issue randomized treatment (anacetrapib 100 mg or placebo; 210 day supply)
X
X
X
Retrieve unused treatment
X
X
X
X
Appointment management & advice
Create appointment
X
X
X
X
X
Provide advice
X
X
X
X
X
X
In-trial follow-up
 
* Registration activities may occur before or during the screening visit and are to be checked at each visit. 
** In North America, all non-serious adverse events will be recorded (including those not attributed to study treatment). 
*** Remote follow-up may be used for some participants who are unwilling or unable to attend study visits, and for all surviving participants for several years 
**** Measured using desktop analyser in the clinic 
***** For details of sample collection and storage see section 5.2.2. 

 
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5.2.2 Central laboratory procedures 
 
Sample Collection 
 
 
Randomization 
visit 
2 month 
visit 
Annual 
sample 1* 
Annual 
sample 2* 
Annual 
sample 3** 
Annual 
sample 4* 
Final visit 
Pre-specified analysis 
Lipid and lipoprotein profile*** 
All 
All 
5% 
5% 
All 
5% 
All 
 
Lipoprotein (a) 
All 
 
5% 
5% 
All 
5% 
>5% 
  
HbA1c 
All 
 
 
 
 
 
All 
  
Creatinine 
All 
 
 
 
 
 
All 
  
Albuminuria**** 
All 
 
 
 
 
 
All 
Long-term storage 
Genetic material 
All 
 
 
 
 
 
  
 
Plasma 
All 
All 
5% 
5% 
All 
5% 
All 
  
Serum 
All 
All 
5% 
5% 
All 
5% 
All 
  
Urine 
All 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
* Annual samples to be collected from 5% randomized participants annually  
** Annual sample 3 to be collected from 100% randomized participants when median follow-up is ~2 years 
*** Total, LDL and HDL cholesterol, triglycerides, apolipoproteins A1 and B 
 
 
**** Urinary albumin:creatinine ratio 
 
 
 
 

 
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5.3 APPENDIX 3: STUDY INVESTIGATORS 
 
STEERING COMMITTEE 
(Major organisational and policy decisions; blinded to treatment allocation) 
 
Chair 
Rory Collins 
Deputy Chair 
Eugene Braunwald 
Principal investigators 
& Clinical Coordinators 
Martin Landray 
Louise Bowman 
 
Regional representatives 
China: Lixin Jiang 
 
North America: Christopher Cannon, Stephen Wiviott 
 
United Kingdom: Jane Armitage, Richard Haynes 
 
Italy: Aldo Maggioni 
 
Germany: Georg Ertl, Christiane Angermann 
 
Scandinavia: Terje Pedersen 
Japan: Shinya Goto, Tamio Teramoto 
Health economists 
Alastair Gray, Boby Mihaylova 
Statistician 
Jemma Hopewell 
Other members 
Colin Baigent, Philip Barter, Yiping Chen, Zhengming Chen, 
Jonathan Tobert, Peter Sleight 
Merck representatives (non-voting) 
Robert Blaustein, Paul DeLucca, Yale Mitchel  
Gerard van Leijenhorst 
 
LIPID MONITORING COMMITTEE 
(Assessment of unblinded effects on lipid profile) 
 
Chair 
Chris Granger 
Members 
Helen Colhoun 
 
Statistical programmer providing unblinded analyses: Karl Wallendszus 
 
DATA MONITORING COMMITTEE 
(Interim analyses and response to specific concerns) 
 
Chair 
Peter Sandercock 
Members 
David DeMets, John Kjekshus  
Andrew Tonkin; James Neuberger 
Statistician (non-voting) 
Jonathan Emberson 
 
NATIONAL COORDINATORS 
(Coordination, legal and regulatory issues in each country) 
 
Canada 
Jacques Genest 
China 
Lixin Jiang 
Denmark 
Kenneth Egstrup 
Finland 
Antero Kesäniemi 
Germany 
Christoph Wanner 
Italy 
Aldo Maggioni 
Japan 
Shinya Goto, Tamio Teramoto 
Norway 
Ottar Nygård 
Sweden 
Lena Jonasson 
UK 
Louise Bowman 
USA 
Christopher Cannon 
 
Central Coordinating Office 
Clinical Trial Service Unit (CTSU), Richard Doll Building, 
Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, UK 
Tel: +44(0)1865 743882, fax: +44 (0)1865 743988 
Email: ccoreveal@ctsu.ox.ac.uk