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)

• ClinicalTrials.gov Identifier: NCT00685776
• Recruitment Status: Completed
• First Posted: May 28, 2008
• Last Update Posted: December 11, 2017
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: May 23, 2008
• First Posted Date: May 28, 2008
• Last Update Posted Date: December 11, 2017
• Actual Study Start Date: March 24, 2008
• Actual Primary Completion Date: July 2, 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2010)

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

• Original Primary Outcome Measures (submitted: May 27, 2008): Reduction in LDL-C compared to placebo [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: March 10, 2010)

• Change from baseline in High Density Lipoprotein Cholesterol [ Time Frame: Baseline, 24 weeks, and 76 weeks ]
• Change from baseline in non-High Density Lipoprotein Cholesterol [ Time Frame: Baseline, 24 weeks, and 76 weeks ]
• Change from baseline in Apolipoprotein B [ Time Frame: Baseline, 24 weeks, and 76 weeks ]
• Change from baseline in Apolipoprotein A-1 [ Time Frame: Baseline, 24 weeks, and 76 weeks ]
• Change from baseline in Low Density Lipoprotein Cholesterol [ Time Frame: Baseline, 24 weeks, and 76 weeks ]

• Original Secondary Outcome Measures (submitted: May 27, 2008): Increase in HDL-C, safety (adverse events, vital signs, ECG, physical exam, and laboratory tests) [ Time Frame: 76 weeks ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Assess the Tolerability and Efficacy of Anacetrapib in Patients With Coronary Heart Disease (CHD) or CHD Risk-Equivalent Disease (MK-0859-019)
• 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
• Brief Summary: 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.

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Coronary Heart Disease (CHD)
• CHD Risk-Equivalent Disease

Intervention

• Drug: anacetrapib
  Participants will receive one tablet of anacetrapib 100 mg once daily for 76 weeks.
  Other Name: MK0859
• Drug: Comparator: placebo
  Participants will receive one placebo tablet once daily for 76 weeks.

Study Arms

• Experimental: Anacetrapib
  Participants randomly assigned to anacetrapib in base study will continue same treatment if enrolled in study extension.
  Intervention: Drug: anacetrapib
• Placebo Comparator: Placebo
  Participants randomly assigned to placebo in base study will continue same treatment if enrolled in study extension.
  Intervention: Drug: Comparator: placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 7, 2017): 1623
• Original Estimated Enrollment (submitted: May 27, 2008): 1500
• Actual Study Completion Date: November 23, 2017
• Actual Primary Completion Date: July 2, 2009 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Austria, Canada, Colombia, Finland, France, Germany, Hong Kong, Hungary, Israel, Malaysia, Mexico, Netherlands, New Zealand, Norway, Russian Federation, Spain, Sweden, United States

Administrative Information

• NCT Number: NCT00685776
• Other Study ID Numbers: 0859-019; 2007_648 ( Other Identifier: Merck Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Executive Vice President, Clinical and Quantitative Sciences, Merck & Co., Inc.
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Monitor; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: December 2017