DEFINE Trial
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DEFINE Trial On the Web |
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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.[1]
Timeline
Start Date
April 2008
Methods
- Phase III trial
- Prospective, randomized, multicenter, placebo-controlled double-blind clinical trial that recuited 1,623 patients.
- Run-in phase: 2 weeks
- Two arms of the study: anacetrapib 100 mg daily or placebo for 76 weeks
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
- 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.
Outcomes
- 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).
Conclusion
Anacetrapib causes a significant increase in HDL with no alteration in other biochemical levels with sustained effects. Unlike torcetrapib, anacetrapib is not associated with cardiovascular events.
References
- ↑ Cannon CP, Dansky HM, Davidson M, Gotto AM, Brinton EA, Gould AL; et al. (2009). "Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib". Am Heart J. 158 (4): 513–519.e3. doi:10.1016/j.ahj.2009.07.028. PMID 19781408.