A Study of the Efficacy and Safety of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-832)

A Phase III, Randomized, Active Comparator-controlled, Clinical Trial to Study the Efficacy and Safety of MK-0653H in Japanese Patients With Hypercholesterolemia.

This study will evaluate the efficacy and safety and tolerability of 2 dose levels of MK-0653H in Japanese participants. The primary hypotheses are that the administration of MK-0653H is safe and tolerable and that MK-0653H is superior to single entity of Ezetimibe and Rosuvastatin in percent reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) after 12 weeks of treatment.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Ezetimibe 10 mg; Drug: Placebo for Rosuvastatin; Drug: Rosuvastatin 2.5 mg; Drug: Placebo for Ezetimibe

• Study Type: Interventional
• Enrollment (Actual): 321
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Japanese
• Outpatient with hypercholesterolemia
• Female participant who is of reproductive potential has to agree to remain abstinent or use (or partner use) two acceptable methods of birth control from date of signed informed consent to the 14 days after the last dose of study drug
• Will maintain a stable diet that is consistent with the Japan Atherosclerosis Society Guideline 2012 (JAS 2012) for prevention of atherosclerotic cardiovascular diseases for the duration of the study

Exclusion Criteria:

• Uncontrolled hypertension (treated or untreated)
• Uncontrolled type 1 or type 2 diabetes mellitus
• History of coronary artery disease (CAD), CAD-equivalent disease
• Familial hypercholesterolemia or has undergone LDL apheresis
• Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins
• Has had a gastrointestinal tract bypass, or other significant intestinal malabsorption
• History of cancer within the past 5 years (except for successfully treated dermatological basal cell or squamous cell carcinoma or in situ cervical cancer)
• Human Immunodeficiency Virus (HIV) positive
• History of drug/ alcohol abuse within the past 5 years or psychiatric illness not adequately controlled and stable on pharmacotherapy
• Consumes more than 25 g of alcohol per day
• Currently following an excessive weight reduction diet
• Currently engages in a vigorous exercise regimen (e.g.; marathon training, body building training etc.) or intends to start training during the study
• Hypersensitivity or intolerance to Ezetimibe or Rosuvastatin
• Myopathy or rhabdomyolysis with Ezetimibe or any statin
• Pregnant or lactating
• Taking any other investigational drugs and/or has taken any investigational drugs within 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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ezetimibe 10 mg; 1 Ezetimibe 10 mg tablet and 2 Rosuvastatin placebo capsules once daily for 12 weeks	Drug: Ezetimibe 10 mg; Drug: Placebo for Rosuvastatin
Active Comparator: Rosuvastatin 2.5 mg; 1 Rosuvastatin 2.5 mg capsule, 1 Rosuvastatin placebo capsule and 1 Ezetimibe placebo tablet once daily for 12 weeks.	Drug: Placebo for Rosuvastatin; Drug: Rosuvastatin 2.5 mg; Drug: Placebo for Ezetimibe
Active Comparator: Rosuvastatin 5.0 mg; 2 Rosuvastatin 2.5 mg capsules and Ezetimibe placebo tablet once daily for 12 weeks.	Drug: Rosuvastatin 2.5 mg; Drug: Placebo for Ezetimibe
Experimental: Ezetimibe 10 mg+ Rosuvastatin 2.5 mg; 1 Ezetimbie 10 mg tablet, 1 Rosuvastatin 2.5 mg capsule and 1 Rosuvastatin placebo capsule once daily for 12 weeks.	Drug: Ezetimibe 10 mg; Drug: Placebo for Rosuvastatin; Drug: Rosuvastatin 2.5 mg
Experimental: Ezetimibe 10 mg+ Rosuvastatin 5.0 mg; 1 Ezetimbie 10 mg tablet and 2 Rosuvastatin 2.5 mg capsules once daily for 12 weeks.	Drug: Ezetimibe 10 mg; Drug: Rosuvastatin 2.5 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Experience 1 or More Gallbladder-related AEs	Gallbladder-related AEs included Bile Duct Obstruction, Bile Duct Stone, Bile Duct Stenosis, Biliary Colic, Cholangitis, Cholecystectomy, Cholecystitis, Cholelithiasis, Gallbladder Disorder, Gallbladder Perforation, Hepatic Pain, and Hydrocholecystis.	up to 14 weeks
Percentage of Participants Who Experience 1 or More Allergic Reaction or Rash AEs	Allergic Reaction or Rash AEs included Allergy to Arthropod Sting, Anaphylactoid Reaction, Anaphylactic Reaction, Anaphylatic Shock, Anaphylactoid Shock, Angioedema, Conjunctivitis Allergic, Contrast Media Reaction, Dermatitis, Dermatitis Allergic, Dermatitis Atopic, Dermatitis Bullous, Dermatitis Contact, Dermatitis Psoriasiform, Drug Hypersensitivity, Eczema, Eosinophila, Erythema, Eye Allergy, Face Oedema, Hypersensitivity, Mechanical Urticaria, Palmar Erythema, Periorbital Oedema, Photodermatosis, Photosensitivity Allergic reaction, Photosensitivity Reaction, Pigmentation Disorder, Pruritus, Pruritus Generalised, Rash, Rash Erythematous, Rash Follicular, Rash Generalised, Rash Maculo-Papular, Rash Papulosquamous, Rash Pruritic, Rash Pustular, Rash Vesicular, Rhinitis, Rhinitis Allergic, Rosacea, Skin Exfoliation, Skin Disorder, Skin Hyperpigmentation, Skin Lesion, Skin Mass, Skin Ulcer, Subcutaneous Nodule, Swelling Face, Systemic Lupus Erythematosus Rash, Urticaria.	up to 14 weeks
Percentage of Participants Who Experience 1 or More Hepatitis-related AEs	Hepatitis-related AEs included Cholestasis, Cytolytic Hepatitis, Hepatic Cyst, Hepatic Failure, Hepatic Lesion, Hepatic Necrosis, Hepatitis, Hepatitis Cholestatic, Hepatitis Fulminant, Hepatitis Infectious, Hepatocellular Injury, Hepatomegaly, Jaundice, Jaundice Cholestatic.	up to 14 weeks
Percentage Change From Baseline in Low-density Lipoprotein-cholesterol (LDL-C)	Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. Results were reported as a M-estimate.	Baseline and Week 12
Percentage of Participants Who Experience at Least 1 Adverse Event (AE)	An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized	up to 14 weeks
Percentage of Participants Who Had Study Drug Discontinued Due to Adverse Event	An AE was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. The percentage of participants that had study drug discontinued due to an AE was summarized.	up to 12 weeks
Percentage of Participants Who Experience 1 or More Gastrointestinal-related AEs	Gastrointestinal-related AEs included all preferred terms within system organ class of Gastrointestinal Disorders except Chapped Lips and Toothache.	up to 14 weeks
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) ≥3 Times Upper Normal Limit (ULN)	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT that were 3 x ULN or greater were recorded. The ALT ULN was 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Consecutive Elevations in Aspartate Aminotransferase (AST) ≥3 Times Upper Normal Limit (ULN)	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of AST that were 3 x ULN or greater were recorded. The AST ULN was 40 U/L..	up to 12 weeks
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) ≥3 Times Upper Normal Limit (ULN)	Participants had ALT and AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT and/or AST that were 3 x ULN or greater were recorded. The ALT and AST ULNs were 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Elevation in Alanine Aminotransferase (ALT) ≥5 Times Upper Normal Limit (ULN)	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessments of ALT that was 5x ULN or greater were recorded. The ALT ULN was 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Elevation in Aspartate Aminotransferase (AST) ≥5 Times Upper Normal Limit (ULN)	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had an assessments of AST that was 5x ULN or greater were recorded. The AST ULN was 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Elevation in Alanine Aminotransferase (ALT) ≥10 Times Upper Normal Limit (ULN)	Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessments of ALT that was 10x ULN or greater were recorded. The ALT ULN was 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Elevation in Aspartate Aminotransferase (AST) ≥10 Times Upper Normal Limit (ULN)	Participants had AST levels assessed throughout the 12 week treatment period. Participants who had an assessments of AST that was 10x ULN or greater were recorded. The AST ULN was 40 U/L.	up to 12 weeks
Percentage of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) ≥10 Times Upper Normal Limit (ULN)	Participants had ALT and AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of ALT and/or AST that were 10x ULN or greater were recorded. The ALT and AST ULNs were 40 U/L.	up to 12 weeks
Percentage of Participants With Potential Hy's Law Condition	Percentage of Participants with Potential Hy's Law Condition (defined as serum ALT or serum AST elevations >3xULN, with serum alkalinephosphatase <2xULN and total bilirubin (TBL) ≥2xULN) was summarized. The ALT and AST ULNs were 40 U/L. The ULN for alkaline phosphatase was 359 IU/L and the ULN for total bilirubin was 1.2 mg/dL.	up to 12 weeks
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN	Participants had creatine phosphokinase (CK) levels assessed throughout the 12 week treatment period. Participants who had any CK level that was ≥10 x ULN were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.	up to 12 weeks
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN With Muscle Symptoms	Participants had CK levels assessed throughout the 52 week treatment period. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.	up to 12 weeks
Percentage of Participants Who Experience Elevations in Creatine Kinase (CK) ≥10 Times ULN and Drug-Related Muscle Symptoms	Participants had CK levels assessed throughout the 52 week treatment period. Participants who had any CK level that was ≥10 x ULN and had associated muscle symptoms present within +/- 7 days that were reported as at least possibly-related to study drug were recorded. The CK ULNs for males and females were 287 IU/L and 163 IU/L, respectively.	up to 12 weeks

Collaborators and Investigators

• Sponsor: Organon and Co

Publications and helpful links

General Publications

• Teramoto T, Yokote K, Nishida C, Oshima N, Takase T. A phase III clinical trial to study the efficacy and safety of ezetimibe plus rosuvastatin combination therapy in Japanese patients with hypercholesterolemia - A randomized, double-blind comparative study. J Clin Therapeut Med. 2017;33(11):881-896.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2016
• Primary Completion (Actual): January 18, 2017
• Study Completion (Actual): January 18, 2017

Study Registration Dates

• First Submitted: April 13, 2016
• First Submitted That Met QC Criteria: April 13, 2016
• First Posted (Estimate): April 18, 2016

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Ezetimibe
• Other Study ID Numbers: 0653H-832; 163336 (Registry Identifier: JAPIC-CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf