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

Sub-study: Does anacetrapib as a CETP inhibitor lead to mobilization of stem cells and enhance myocardial function via neoangiogenesis and tissue regeneration?

Following the main on-treatment part of the study, there was a further period of at least 2 years during which participants were followed-up by telephone, off treatment.

All participants stopped study treatment prior to February 2017 (results for the main-trial have been reported) and direct participant follow-up was completed in April 2019.

In the UK we will continue to collect information on health outcomes via central data registries and NHS sources for many years.

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).

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. alanine transaminase (ALT) >2x the upper limit of normal (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 creatine kinase (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

• Concurrent treatment with a medication that is contraindicated with anacetrapib or atorvastatin:

(i) any potent CYP3A4 inhibitor, such as:

• macrolide antibiotics (erythromycin, clarithromycin, telithromycin);
• systemic imidazole or triazole antifungals (e.g. itraconazole, posaconazole);
• protease inhibitors (e.g. atazanavir);
• 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.