DEFINE Trial
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Objective
The objective of this trial is to study the therapeutic and adverse effect of anacetrapib, a CETP inhibitor, alone and with statin.
Timeline
Start Date
April 2008
Methods
- Phase III trial
- Prospective, randomized, multicenter, placebo-controlled double-blind clinical trial that recuited 1,623 patients.
- Inclusion criteria: Age between 18-80 years, LDL-C < 100 mg/dL and coronary heart disease or risk equivalent , patient receiving statin therapy with or without other anti-lipidemics, HDL < 60 mg/dL, triglycerides < 400 mg/dL, abstinence or use of at least 2 effective contraceptive methods, be at least 75% compliant during run-in phase
- Exclusion criteria: NYHA class III or IV heart failure, any of the following events within 3 months: Uncontrolled arrhythmias, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, unstable angina, or stroke, LDL-C<50 mg/dL, uncontrolled hypertension defined as SBP ≥ 160 mmHg / DBP≥ 100 mmHg for non-diabetics or SBP ≥ 150 mmHg / DBP ≥ 90 mmHg for diabetics, CPK or liver function tests twice the upper normal limit, active or chronic hepatic or biliary disease, renal failure with eGFR < 30 mL/min/1.73 m2, diabetes mellitus diagnosed within 3 months or HbA1c > 8.5%, TSH below or 20% above normal limit, homozygous familial hypercholesterolemia, type I and type II hyperlipidemia , currently on warfarin, systemic corticosteroids, anabolic steroids, or any drug that potently affects CYP3A4.
- Run-in phase: 2 weeks
- Two arms of the study: anacetrapib 100 mg daily or placebo for 76 weeks
- Primary end points: Percent change in LDL after 24 weeks, adverse experiences including cardiovascular end points, other lab values, ECG changes, vital sign and physical examination assessments after 76 weeks of treatment.
- Secondary end points: Change in HDL, total cholesterol, triglyceride, CRP apo A-I, A-II, B, C-III, and E, lipoprotein(a) and ratios of total cholesterol/HDL, LDL/HDL, apo B/ apo A-I, and LDL/apo B after 24 and 76 weeks of treatment *
- Cardiovascular end points are defined as cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina.
Results
- 17.6% of patients on anacetrapib vs. only 0.1% of placebo were discontinued due to LDL < 25 mg/dL at 2 consecutive visits.
- With respect to LDL reduction and HDL elevation, anacetrapib showed significant changes: 39.8% and 138.1% change, respectively at 24 weeks. LDL was approximately halved from 81 to 45 mg/dL and HDL increased from 41 to 101 mg/dL. Change in HDL was further accentuated in patients with baseline low HDL < 40 mg/dL, with an increase of 152% in this sub-population.
- Similarly, a significant decrease in apoB, non-HDL-C, lipoprotein, and triglycerides, and an increase in ApoA-I were all seen with anacetrapib at 24 and 76 weeks.
- In the reversal phage, 1398 patients were enrolled. Significant reduction in LDL, non-HDL, apo-B and an increase in HDL and apo A-I persisted during that period for patients on anacetrapib, who continued to have trace concentrations of the medication. These alterations reached 50-60% of values observed during on-medication trial period.
- Anacetrapib had no effect on adverse events during the trial or the reversal phase, but had a significantly lower number of patients with liver function test disturbances by the end of the trial (p=0.02).
- In comparison to placebo, Post-hoc analysis revealed that patients on anacetrapib had significantly less revascularization procedures (p=0.001) and cardiovascular end points (p=0.048).