Study to Assess the Tolerability and Efficacy of Anacetrapib in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease (MK-0859-019) (DEFINE)

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

This study will evaluate the efficacy of anacetrapib (100 mg) for 24 weeks relative to placebo, on plasma concentrations of Low Density Lipoprotein Cholesterol and assess the safety and tolerability of anacetrapib (100 mg) in participants with CHD/CHD risk-equivalent disease on stable dose regimen of statin with or without other lipid-modifying therapy. The two year extension to this study will further evaluate the long-term safety profile and efficacy of anacetrapib in CHD/CHD-risk equivalent patients who are on ongoing therapy with a statin with or without other lipid-modifying therapy.

Study Overview

• Status: Completed
• Conditions: Coronary Heart Disease (CHD); CHD Risk-Equivalent Disease
• Intervention / Treatment: Drug: anacetrapib; Drug: Comparator: placebo

Detailed Description

The 76 week treatment period is followed by a 12 week reversibility phase which can be extended by up to another 12 weeks in order to allow participants who have completed their week 88 visit to continue in the study until the Extension study is ready to be implemented.

In the optional extension, participants will be assigned to the same treatment arm to which they were assigned in the base study. The total duration of the extension study will be up to 116 weeks; which will include a 2 year treatment period, followed by a 12 week reversal phase. A post-extension study follow-up phone call will be completed 12 weeks after discontinuation or completion of study treatment. Participants previously treated with anacetrapib or placebo will be invited in a 4:1 ratio in an optional extended reversal phase. The total duration of the extended reversal phase will be 1 year.

Participants previously treated with anacetrapib in the DEFINE study will be followed periodically for up to 4 years to determine plasma levels of anacetrapib. Participants will also be invited to participate in a sub-study consisting of one clinic visit to measure anacetrapib levels in the plasma and the subcutaneous adipose tissue.

ACRONYM: DEFINE= Determining the EFficacy and Tolerability of Cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib

• Study Type: Interventional
• Enrollment (Actual): 1623
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anacetrapib; Participants randomly assigned to anacetrapib in base study will continue same treatment if enrolled in study extension.	Drug: anacetrapib; Participants will receive one tablet of anacetrapib 100 mg once daily for 76 weeks.; Other Names: MK0859
Placebo Comparator: Placebo; Participants randomly assigned to placebo in base study will continue same treatment if enrolled in study extension.	Drug: Comparator: placebo; Participants will receive one placebo tablet once daily for 76 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in Low Density Lipoprotein Cholesterol	Baseline and 24 weeks
Number of participants with hepatitis-related adverse experiences	Through 88 weeks
Number of participants with Alanine Transaminase consecutive elevations greater than or equal to 3xULN (Upper Limit of Normal)	Through 88 weeks
Number of participants with Aspartate Aminotransferase consecutive elevations greater than or equal to 3xULN	Through 88 weeks
Number of participants with Creatine Phosphokinase elevations greater than or equal to 10xULN	Through 88 weeks
Number of participants with Creatine Phosphokinase elevations greater than or equal 10xULN with muscle symptoms	Through 88 weeks
Number of participants with sodium, chloride, or bicarbonate elevations greater than ULN	Through 88 weeks
Number of participants with reduction in potassium levels less than LLN (Lower Limit of Normal)	Through 88 weeks
Number of participants with myalgia	Through 88 weeks
Number of participants with rhabdomyolysis	Through 88 weeks
Number of participants with pre-specified adjudicated cardiovascular serious adverse events	Through 88 weeks
Number of participants with death from any cause	Through 88 weeks
Number of participants with significant increase in Blood Pressure	Through 88 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in High Density Lipoprotein Cholesterol	Baseline, 24 weeks, and 76 weeks
Change from baseline in non-High Density Lipoprotein Cholesterol	Baseline, 24 weeks, and 76 weeks
Change from baseline in Apolipoprotein B	Baseline, 24 weeks, and 76 weeks
Change from baseline in Apolipoprotein A-1	Baseline, 24 weeks, and 76 weeks
Change from baseline in Low Density Lipoprotein Cholesterol	Baseline, 24 weeks, and 76 weeks

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Brinton EA, Kher U, Shah S, Cannon CP, Davidson M, Gotto AM, Ashraf TB, McCrary Sisk C, Dansky H, Mitchel Y, Barter P; DEFINE Investigators. Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial. J Clin Lipidol. 2015 Jan-Feb;9(1):65-71. doi: 10.1016/j.jacl.2014.10.005. Epub 2014 Nov 4.
• Gotto AM Jr, Kher U, Chatterjee MS, Liu Y, Li XS, Vaidya S, Cannon CP, Brinton EA, Moon JE, Shah S, Dansky HM, Mitchel Y, Barter P; DEFINE Investigators. Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study. J Cardiovasc Pharmacol Ther. 2014 Nov;19(6):543-9. doi: 10.1177/1074248414529621. Epub 2014 Apr 14.
• Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P; Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010 Dec 16;363(25):2406-15. doi: 10.1056/NEJMoa1009744. Epub 2010 Nov 17.
• Cannon CP, Dansky HM, Davidson M, Gotto AM Jr, Brinton EA, Gould AL, Stepanavage M, Liu SX, Shah S, Rubino J, Gibbons P, Hermanowski-Vosatka A, Binkowitz B, Mitchel Y, Barter P; DEFINE investigators. Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J. 2009 Oct;158(4):513-519.e3. doi: 10.1016/j.ahj.2009.07.028.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2008
• Primary Completion (Actual): July 2, 2009
• Study Completion (Actual): November 23, 2017

Study Registration Dates

• First Submitted: May 23, 2008
• First Submitted That Met QC Criteria: May 27, 2008
• First Posted (Estimate): May 28, 2008

Study Record Updates

• Last Update Posted (Actual): December 11, 2017
• Last Update Submitted That Met QC Criteria: December 7, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Coronary Heart Disease (CHD); CHD/CHD risk-equivalent disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Anacetrapib
• Other Study ID Numbers: 0859-019; 2007_648 (Other Identifier: Merck Study Number)