A Clinical Trial to Assess the Efficacy and Safety of MK-0653C in Japanese Participants With Hypercholesterolemia (MK-0653C-383)

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of MK-0653C (Ezetimibe [EZ] 10 mg/Atorvastatin [Atora] 10mg or 20 mg) compared to EZ 10 mg, Atora 10 mg, or Atora 20 mg alone when administered to Japanese participants with hypercholesterolemia. The primary hypothesis is that MK-0653C (EZ 10 mg/Atorva 10 mg) is superior to EZ 10 mg and is superior to Atorva 10 mg and that MK-0653C (EZ 10 mg/Atorva 20 mg) is superior to EZ 10 mg and is superior to Atorva 20 mg in percent change from baseline in low-density lipoprotein cholesterol (LDL-C) after 12 weeks of treatment.

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

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Ezetimibe 10 mg
* Drug: Atorvastatin 10 mg
* Drug: Placebo for Ezetimibe 10 mg tablet
* Drug: Placebo for Atorvastatin 10 mg capsule
* Behavioral: Diet control/Daily Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese outpatient with hypercholesterolemia. Females must be non-reproductive potential or 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 Agree to maintain a stable diet that is consistent with the Japan Atherosclerosis Society Guideline 2012 (JAS2012) for prevention of atherosclerotic cardiovascular diseases for the duration of the study Exclusion Criteria: Uncontrolled hypertension Type 1 or uncontrolled type 2 diabetes mellitus (treated or untreated) History of coronary artery disease (CAD) Homozygous familial hypercholesterolemia or has undergone LDL apheresis 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 Consumes more than 1L of grapefruit juice per day Currently following an excessive weight reduction diet Engaging 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 atorvastatin History of 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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ezetimibe 10 mg<br>1 ezetimide 10 mg tablet, 2 atorvastatin 10 mg placebo capsules orally once daily for 12 weeks. | Drug: Ezetimibe 10 mg<br> <br> Drug: Placebo for Atorvastatin 10 mg capsule<br> <br> Behavioral: Diet control/Daily Exercise<br>* Diet and Daily exercise program as per Japan Atherosclerosis Society Guideline 2012 (JAS2012)<br>|
| Active Comparator: Atorvastatin 10 mg<br>1 atorvastatin 10 mg capsule, 1 ezetimide 10 mg placebo tablet, and 1 atorvastatin 10 mg placebo capsule orally once daily for 12 weeks. | Drug: Atorvastatin 10 mg<br> <br> Drug: Placebo for Ezetimibe 10 mg tablet<br> <br> Drug: Placebo for Atorvastatin 10 mg capsule<br> <br> Behavioral: Diet control/Daily Exercise<br>* Diet and Daily exercise program as per Japan Atherosclerosis Society Guideline 2012 (JAS2012)<br>|
| Active Comparator: Atorvastatin 20 mg<br>2 atorvastatin 10 mg capsules and 1 ezetimide 10 mg placebo tablet orally, once daily for 12 weeks. | Drug: Atorvastatin 10 mg<br> <br> Drug: Placebo for Ezetimibe 10 mg tablet<br> <br> Behavioral: Diet control/Daily Exercise<br>* Diet and Daily exercise program as per Japan Atherosclerosis Society Guideline 2012 (JAS2012)<br>|
| Experimental: Ezetimibe 10 mg + Atorvastatin 10 mg<br>1 Ezetimibe 10 mg tablet, 1 atorvastatin 10 mg capsule and 1 atorvastatin 10 mg placebo capsule orally, once daily for 12 weeks | Drug: Ezetimibe 10 mg<br> <br> Drug: Atorvastatin 10 mg<br> <br> Drug: Placebo for Atorvastatin 10 mg capsule<br> <br> Behavioral: Diet control/Daily Exercise<br>* Diet and Daily exercise program as per Japan Atherosclerosis Society Guideline 2012 (JAS2012)<br>|
| Experimental: Ezetimibe 10 mg + Atorvastatin 20 mg<br>1 Ezetimibe 10 mg tablet and 2 atorvastatin 10 mg capsules orally, once daily for 12 weeks | Drug: Ezetimibe 10 mg<br> <br> Drug: Atorvastatin 10 mg<br> <br> Behavioral: Diet control/Daily Exercise<br>* Diet and Daily exercise program as per Japan Atherosclerosis Society Guideline 2012 (JAS2012)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 12 | Participants had LDL-C levels assessed at baseline and after 12 weeks of study drug administration. The change from baseline was calculated. | Baseline and Week 12 | 
| Percentage of Participants Who Experience 1 or More Gastrointestinal-related Adverse Events (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 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 of Participants Who Experience Consecutive Elevations in Alanine Aminotransferase (ALT) ≥3 Times Upper Limit of Normal (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 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 ALT and/or AST ≥3 Times 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 Consecutive Elevations in ALT ≥5 Times ULN | Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessment 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 Consecutive Elevations in AST ≥5 Times ULN | Participants had AST levels assessed throughout the 12 week treatment period. Participants who had an assessment of AST that was 5x ULN or greater were recorded. AST ULN was 40 U/L. | up to 12 weeks | 
| Percentage of Participants Who Have Consecutive Elevations in ALT and/or AST ≥5 Times 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 5 x ULN or greater were recorded. The ALT and AST ULNs were 40 U/L. | up to 12 weeks | 
| Percentage of Participants Who Experience Consecutive Elevations in ALT ≥10 Times ULN | Participants had ALT levels assessed throughout the 12 week treatment period. Participants who had an assessment 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 Consecutive Elevations in AST ≥10 Times ULN | Participants had AST levels assessed throughout the 12 week treatment period. Participants who had 2 consecutive assessments of AST that were 10x ULN or greater were recorded. The AST ULN was 40 U/L. | up to 12 weeks | 
| Percentage of Participants Who Have Consecutive Elevations in ALT and/or AST ≥10 Times 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 alkaline phosphatase <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 Have Elevations in Creatine Kinase (CK) ≥10xULN | 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 Have Elevations in CK ≥10xULN With Muscle Symptoms | Participants had CK levels assessed throughout the 12 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 Have Elevations in CK ≥10xULN and Drug-Related Muscle Symptoms | Participants had CK levels assessed throughout the 12 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 |