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.

# Sponsor
Merck

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

# Study Description
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
- 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
- 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  

## Secondary Outcomes
Increase in HDL-C, safety (adverse events, vital signs, ECG, physical exam,  and laboratory tests)  

# 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).
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.