A Study to Evaluate the Efficacy and Safety of Enlicitide (MK-0616, Oral PCSK9 Inhibitor) Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia (MK-0616-018/CORALreef AddOn)

A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of MK-0616 Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia

The main purpose of this study is to assess whether enlicitide is superior to ezetimibe or bempedoic acid or ezetimibe + bempedoic acid in reducing low-density lipoprotein cholesterol (LDL-C) in participants with hypercholesterolemia, and to evaluate its safety and tolerability. The primary study hypotheses are enlicitide is superior to ezetimibe, bempedoic acid, and ezetimibe + bempedoic acid on mean percent change from baseline in LDL-C at week 8.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Enlicitide; Other: Placebo for Ezetimibe; Other: Placebo for Bempedoic Acid; Drug: Ezetimibe; Other: Placebo for Enlicitide; Drug: Bempedoic Acid

• Study Type: Interventional
• Enrollment (Actual): 301
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Mar del Plata, Buenos Aires, Argentina, B7600FZO
      • Instituto de Investigaciones Clínicas Mar del Plata ( Site 1002)
  • Buenos Aires F.D.
    • Buenos Aires, Buenos Aires F.D., Argentina, C1061AAS
      • CIPREC-CIPREC Sede Arenales ( Site 1000)
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, S2000DEJ
      • Fundacion Estudios Clinicos ( Site 1001)
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V7M 2H4
      • The Medical Arts Health Research Group ( Site 1606)
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Cambridge Cardiac Care Centre ( Site 1603)
    • North York, Ontario, Canada, M6B 3H7
      • North York Diagnostic and Cardiac Centre ( Site 1605)
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Institut de Cardiologie de Montreal ( Site 1604)
    • Trois-Rivières, Quebec, Canada, G9A 4P3
      • Diex Recherche Trois-Rivieres ( Site 1602)
• France
  • Paris, France, 75018
    • Hôpital Bichat - Claude-Bernard ( Site 0504)
  • Herault
    • Montpellier, Herault, France, 34090
      • Hôpital Arnaud de Villeneuve - CHU Montpellier ( Site 0505)
  • Loire-Atlantique
    • Nantes, Loire-Atlantique, France, 44093
      • Hôpital Nord Guillaume-et-René-Laennec / CHU de Nantes-CIC Endocrinology-Diabetology-Nutrition ( Sit
  • Rhone
    • Bron, Rhone, France, 69677
      • Hospices Civils de Lyon - Hopital Louis Pradel ( Site 0501)
• Israel
  • Beer Yaakov, Israel, 70300
    • Yitzhak Shamir Medical Center. ( Site 0702)
  • Beersheba, Israel, 8489507
    • Assuta Beersheba MC ( Site 0704)
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus ( Site 0700)
  • Kfar Saba, Israel, 4428164
    • Meir Medical Center. ( Site 0703)
• Spain
  • Barcelona, Spain, 08025
    • EAP Sardenya ( Site 0800)
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron ( Site 0803)
  • Andalusia
    • Málaga, Andalusia, Spain, 29010
      • Hospital Universitario Virgen de la Victoria-UGC Endocrinologia y nutricion ( Site 0801)
  • Gerona
    • Figueres, Gerona, Spain, 17600
      • Hospital de Figueres ( Site 0804)
  • La Coruna
    • A Coruña, La Coruna, Spain, 15006
      • Hospital San Rafael de Coruna ( Site 0805)
• Taiwan
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital-Internal Medicine ( Site 0403)
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital ( Site 0400)
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital-Department of Medicine ( Site 0402)
  • Taoyuan District, Taiwan, 33305
    • Chang Gung Medical Foundation-Linkou Branch ( Site 0404)
• United Kingdom
  • England
    • London, England, United Kingdom, EC1M 6BQ
      • Barts Health NHS Trust-William Harvey Clinical Research Centre ( Site 0901)
    • London, England, United Kingdom, NW3 2QG
      • Royal Free Hospital ( Site 0900)
  • London, City of
    • London, London, City of, United Kingdom, NW1 2PG
      • National Institute for Health Research UCLH Clinical Research Facility ( Site 0908)
• United States
  • California
    • Lincoln, California, United States, 95648
      • Clinical Trials Research ( Site 1509)
  • Illinois
    • Flossmoor, Illinois, United States, 60422
      • Healthcare Research Network - Chicago ( Site 1507)
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • L-MARC Research Center ( Site 1501)
  • Maryland
    • Rockville, Maryland, United States, 20854
      • Velocity Clinical Research Rockville ( Site 1503)
  • Mississippi
    • Gulfport, Mississippi, United States, 39503
      • Velocity Clinical Research, Gulfport ( Site 1505)
  • South Carolina
    • Fort Mill, South Carolina, United States, 29707
      • Piedmont Research Partners ( Site 1506)
  • Washington
    • Renton, Washington, United States, 98057
      • Rainier Clinical Research Center ( Site 1502)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has either a) history of a major atherosclerotic cardiovascular disease (ASCVD) event or b) if no history of a major ASCVD event, has intermediate to high risk for development of a first major ASCVD event
• Has fasted lipid values (evaluated by the central laboratory) at Visit 1 (Screening) as follows: a) history of a major ASCVD event with LDL-C ≥55 mg/dL (≥1.42 mmol/L) OR b) No history of a major ASCVD event with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (≥1.81 mmol/L)
• Is treated with a low, moderate, or high intensity statin (±non-statin lipid lowering therapy [LLT])
• Is on a stable dose of all background LLTs with no planned medication or dose changes during the study
• Is an individual of any sex/gender, from 18 years of age inclusive, at the time of providing the informed consent

Exclusion Criteria:

• Has a history of homozygous familial hypercholesterolemia (FH) based on genetic or clinical criteria, compound heterozygous familial hypercholesterolemia (HeFH), or double HeFH
• Has New York Heart Association class IV heart failure, or last known left ventricular ejection fraction ≤25% by any imaging method, or had a heart failure hospitalization within 3 months before Visit 1 (Screening)
• Participants with a history of tendon disorder or tendon rupture
• Participants with a history of gout
• Is undergoing or previously underwent an LDL-C apheresis program within 3 months before Visit 1 (Screening) or plans to initiate an LDL-C apheresis program
• Was previously treated/is being treated with certain other cholesterol lowering medications, including ezetimibe, bempedoic acid, or protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors without adequate washout

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enlicitide; Participants receive enlicitide 20mg, ezetimibe-matching placebo, and bempedoic acid-matching placebo once daily (QD) orally up to approximately 56 days.	Drug: Enlicitide; Oral tablet; Other Names: MK-0616; Enlicitide Decanoate; Other: Placebo for Ezetimibe; ezetimibe-matching placebo oral tablet; Other: Placebo for Bempedoic Acid; bempedoic acid-matching placebo oral capsule
Active Comparator: Ezetimibe; Participants receive ezetimibe 10mg, enlicitide-matching placebo, and bempedoic acid-matching placebo QD orally up to approximately 56 days.	Other: Placebo for Bempedoic Acid; bempedoic acid-matching placebo oral capsule; Drug: Ezetimibe; Oral tablet; Other: Placebo for Enlicitide; enlicitide-matching placebo oral tablet
Active Comparator: Bempedoic Acid; Participants receive bempedoic acid 180mg, ezetimibe-matching placebo, and enlicitide-matching placebo QD orally up to approximately 56 days.	Other: Placebo for Ezetimibe; ezetimibe-matching placebo oral tablet; Other: Placebo for Enlicitide; enlicitide-matching placebo oral tablet; Drug: Bempedoic Acid; Oral capsule
Active Comparator: Ezetimibe + Bempedoic Acid; Participants receive ezetimibe 10 mg, bempedoic acid 180mg, enlicitide-matching placebo orally QD for approximately 56 days.	Drug: Ezetimibe; Oral tablet; Other: Placebo for Enlicitide; enlicitide-matching placebo oral tablet; Drug: Bempedoic Acid; Oral capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Day 56	Blood samples were collected at baseline and after 56 days of treatment to assess mean percentage change in LDL-C. The mean percent change from baseline in LDL-C at Day-56 is reported.	Baseline and Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change From Baseline in Apolipoprotein B (ApoB) at Day 56	Blood samples were collected at baseline and on day 56 of treatment to assess mean percent change in ApoB. The mean percent change from baseline in ApoB at Day 56 is reported.	Baseline and Day 56
Mean Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Day 56	Blood samples were collected at baseline and on day 56 of treatment to assess mean percent change in non-HDL-C. The mean percent change from baseline in non-HDL-C at 56 days is reported.	Baseline and Day 56
Median Percent Change From Baseline in Lipoprotein(a) Levels (Lp[a])	Blood samples were collected at baseline and on day 56 of treatment to assess median percent change in Lp(a) levels. The median percent change from baseline at Day 56 is reported.	Baseline and Day 56
Percentage of Participants Who at Day 56 Have an LDL-C <70 mg/dL and ≥50% Reduction From Baseline	Blood samples were collected at baseline and after 56 days of treatment to assess the percentage of participants who have an LDL-C <70 mg/dL and ≥50% reduction from baseline at day 56. The percentage of participants who have LDL-C <70 mg/dL and ≥50% reduction from baseline is reported.	Baseline and Day 56
Percentage of Participants Who at Day 56 Have an LDL-C <55 mg/dL and ≥50% Reduction From Baseline	Blood samples were collected at baseline and after 56 days of treatment to assess the percentage of participants who have an LDL-C <55 mg/dL and ≥50% reduction from baseline at day 56. The percentage of participants who have LDL-C <55 mg/dL and ≥50% reduction from baseline is reported.	Baseline and Day 56
Percentage of Participants With ≥1 Adverse Event (AE)	An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE is reported.	Up to approximately 147 days
Percentage of Participants Discontinuing From Study Intervention Due to AE	An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to an AE is reported.	Up to approximately 91 days

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2024
• Primary Completion (Actual): February 14, 2025
• Study Completion (Actual): March 28, 2025

Study Registration Dates

• First Submitted: June 4, 2024
• First Submitted That Met QC Criteria: June 4, 2024
• First Posted (Actual): June 10, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Hypercholesterolemia; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azetidines; Azetines; Ezetimibe; 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; MK-0616
• Other Study ID Numbers: 0616-018; MK-0616-018 (Other Identifier: MSD); U1111-1290-3888 (Registry Identifier: UTN); 2023-504920-25-00 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No