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

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 will be a further period of at least 2 years during which participants will be followed-up by telephone, off treatment.

• Drug: anacetrapib
  tablet, 100mg daily
• Drug: placebo anacetrapib
  tablet, 1 tablet daily

• Experimental: anacetrapib
  Intervention: Drug: anacetrapib
• Placebo Comparator: placebo anacetrapib
  Intervention: Drug: placebo anacetrapib

• Landmesser U, von Eckardstein A, Kastelein J, Deanfield J, Lüscher TF. Increasing high-density lipoprotein cholesterol by cholesteryl ester transfer protein-inhibition: a rocky road and lessons learned? The early demise of the dal-HEART programme. Eur Heart J. 2012 Jul;33(14):1712-5. doi: 10.1093/eurheartj/ehs182. Epub 2012 Jun 13.
• Krauss RM, Wojnooski K, Orr J, Geaney JC, Pinto CA, Liu Y, Wagner JA, Luk JM, Johnson-Levonas AO, Anderson MS, Dansky HM. Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res. 2012 Mar;53(3):540-7. doi: 10.1194/jlr.M018010. Epub 2011 Dec 17.

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:

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

    4. 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.