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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Click here to download slides for DEFINE Trial.

Official Title

A 76-Week, Worldwide, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Tolerability and Efficacy of Anacetrapib When Added to Ongoing Therapy With a Statin in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease

Objective

The objective of this trial is to study the therapeutic and adverse effect of anacetrapib, a CETP inhibitor, alone and with statin.[1]

Merck

Timeline

Timeline
Start Date May 2008
End Date July 2009
Status Active, recruiting

The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.

Study Description

Study Description
Study Type Interventional
Study Phase Phase 3
Study Design
Allocation Randomized
Endpoint Safety/Efficacy Study
Interventional Model Parallel Assignment
Masking Double Blind
Study Details
Primary Purpose Treatment
Condition Coronary Heart Disease (CHD)
CHD Risk-Equivalent Disease
Intervention Drug: anacetrapib (also known as MK0859)one tablet of 100 mg once daily for 76 weeks
Placebo: one tablet once daily for 76 weeks
Study Arms Drug: anacetrapib
Comparator: placebo
Population Size 1500

The previous information was derived from ClinicalTrials.gov on 09/20/2013 using the identification number NCT00685776.

Eligibility Criteria

Inclusion Criteria

  • Base Study:
    • Patient has Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease and is treated with a statin, with well controlled LDL-C
  • Extension Study:
    • Patient has completed the base study including the reversibility period (i.e. 12 or to up to 24 weeks)
    • Patient is on statin therapy ± lipid-modifying therapy since the end of the base study and planning to continue taking a statin throughout the study

Exclusion Criteria

  • History of heart failure, arrhythmias, heart attack, unstable angina, or stroke within 3 months prior to screening, uncontrolled blood pressure, uncontrolled *High cholesterol or liver disease.
  • History of mental instability, drug/alcohol abuse within the past 5 years
  • Pregnant or breast-feeding
  • History of cancer within the last 5 years
  • HIV positive
  • Donated blood products within 8 weeks
  • Currently participating or have participated in a study with an investigational compound within the last 30 days

Outcomes

Primary Outcomes

Reduction in LDL-C compared to placebo [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Secondary Outcomes

Increase in HDL-C, safety (adverse events, vital signs, ECG, physical exam, and laboratory tests) [ Time Frame: 76 weeks ] [ Designated as safety issue: No ]

Publications

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).[2]

After balancing proportions, the percentage of patients who discontinued the study due to 2 consecutive LDL-C levels < 25 mg/dL was 14.6% in patients receiving anacetrapib and 17.4% in patients receiving placebo.

The decrease in LDL-C levels after 24 weeks of treatment was significant in patients receiving anacetrapib compared to those on placebo. The LDL-C in the former group was reduced from 81 mg/dL to 45 mg/dL, where was it was only reduced from 82 mg/dL to 77 mg/dL in the latter (p<0.001). The percent change of LDL-C in anacetrapib group was a 39.8% reduction. Similarly, HDL-C increased 138.1%, from 41 mg/dL to 101 mg/dL in anacetrapib group, also significantly different from placebo that only raised HDL-C from 40 mg/dL to 46 mg/dL after 24 weeks (p<0.001).

There was a 44.7% increase in apo A-1 and a 21% decrease in apo B among patients receiving anacetrapib (p<0.001).

Changes associated with anacetrapib were maintained throughout 76 weeks of follow-up.

No adverse event was significantly associated with anacetrapib alone when compared to placebo. Common adverse events in both groups included: elevation in systolic and diastolic blood pressures, electrolyte disturbances, elevation in creatinine kinase, and myalgias. Significantly, there was a 0.96mmol/L decrease in serum sodium levels in patients on anacetrapib vs. a 1.2 mmol/L in patients on placebo (p=0.02). The rates of liver function tests increase to three times above upper normal limit was in fact significantly less in patients on anacetrapib (p=0.02).

Conclusion

Anacetrapib is associated with a significant increase in HDL and decrease in LDL with a tolerable side effect probile. Further clinical trials are required to prove the beneficial effects of increasing HDL levels in preventing adverse cardiovascular events in high risk patients.

References

  1. 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.
  2. Davidson M, Liu SX, Barter P, Brinton EA, Cannon CP, Gotto AM; et al. (2013). "Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib". J Lipid Res. 54 (2): 467–72. doi:10.1194/jlr.M032615. PMC 3588873. PMID 23172660.