Efficacy and Safety of Extended-Release Niacin/ Laropiprant/Simvastatin Tablets in Participants With Hypercholesterolemia or Mixed Dyslipidemia (MK-0524B-143)

Study Overview
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Brief Summary
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This study is being done to find out if tablets containing extended release (ER) niacin, laropiprant, and simvastatin (ERN/LRPT/SIM) are as effective as tablets containing ER niacin and laropiprant taken with simvastatin tablets (ERN/LRPT + SIM) for lowering high cholesterol and high lipid levels in the blood. The primary hypothesis is that ERN/LRPT/SIM 2 g /20 mg is equivalent to ERN/LRPT 2 g coadministered with simvastatin 20 mg in reducing low-density lipoprotein cholestrol (LDL-C).

Official Title
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A Phase III Multicenter, Double-Blind, Crossover Design Study to Evaluate Lipid-Altering Efficacy and Safety of 1 g/10 mg Extended-Release Niacin/Laropiprant/Simvastatin Combination Tablets in Patients With Primary Hypercholesterolemia or Mixed Dyslipidemia

Conditions
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Primary Hypercholesterolemia, Mixed Dyslipidemia

Intervention / Treatment
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* Drug: ER niacin/laropiprant (ERN/LRPT)
* Drug: ER niacin/laropiprant/simvastatin (ERN/LRPT/SIM)
* Drug: Simvastatin (SIM)
* Drug: Placebo Run-In
* Drug: SIM-matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Has a history of primary hypercholesterolemia or mixed dyslipidemia and meets LDL-C and triglyceride criteria. Is high risk coronary heart disease (CHD) and has LDL-C ≤190 mg/dL (≤4.91 mmol/L). Is not high risk CHD and has LDL-C ≤240 mg/dL (≤6.21 mmol/L). Exclusion criteria: Is pregnant or breast-feeding, or expecting to conceive or donate eggs or sperm during the study. Has a history of malignancy within ≤5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Consumes more than 3 alcoholic drinks per day (14 per week). Is a high risk CHD patient on lipid modifying therapy (LMT). Is on any LMT with equivalent or greater LDL-C-lowering efficacy than simvastatin 40 mg. Has Type 1 or Type 2 diabetes mellitus that is poorly controlled, or on statin therapy. Currently engages in vigorous exercise or is on an aggressive diet regimen. Has uncontrolled endocrine or metabolic disease, uncontrolled gout, kidney or hepatic disease, heart failure, recent peptic ulcer disease, hypersensitivity or allergic reaction to niacin or simvastatin, recent heart attack, stroke or heart surgery. Is human immunodeficiency virus (HIV) positive. Has taken niacin >50 mg/day, bile-acid sequestrants, 3-hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA) reductase inhibitors, ezetimibe, Cholestin™ [red yeast rice] and other red yeast products within 6 weeks, or fibrates within 8 weeks of randomization visit (Visit 3). Note: Fish oils, phytosterol margarines and other non-prescribed therapies are allowed provided participant has been on a stable dose for 6 weeks prior to Visit 2 and agrees to remain on this dose for the duration of the study. Is currently receiving cyclical hormonal contraceptives or intermittent use of hormone replacement therapies (HRTs) (e.g., estradiol, medroxyprogesterone, progesterone). Note: Participants who have been on a stable dose of non-cyclical HRT or hormonal contraceptive for greater than 6 weeks prior to Visit 1 are eligible if they agree to remain on the same regimen for the duration of the study. Is taking prohibited medications such as systemic corticosteroids, potent inhibitors of Cytochrome P450 3A4 (CYP3A4), cyclosporine, danazol, or fusidic acid. Consumes >1 quart of grapefruit juice/day. Requires warfarin treatment and has not been on a stable dose with a stable International Normalized Ratio (INR) for at least 6 weeks prior to Visit 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ERN/LRPT/SIM → ERN/LRPT+SIM<br>Weeks 0-4 (Period 1): Participants will take ERN/LRPT/SIM 1 g/10 mg and SIM-matching placebo tablets daily; Weeks 5-12 (Period 2): Participants will be advanced to ERN/LRPT/SIM 2 g/20 mg and SIM-matching placebo tablets daily; Weeks 13-20 (Period III): Participants will crossover to ERN/LRPT 2 g + SIM 20 mg coadministration treatment. | Drug: ER niacin/laropiprant (ERN/LRPT)<br>* ER niacin 1 g/laropiprant 20 mg oral tablet taken once daily<br>* Other names: MK-0524B;Drug: ER niacin/laropiprant/simvastatin (ERN/LRPT/SIM)<br>* ER niacin 1 g/laropiprant 20 mg/simvastatin 10 mg oral tablet taken once daily<br>* Other names: MK-0524A, Tredaptive™;Drug: Simvastatin (SIM)<br>* Simvastatin 10 mg oral tablet taken once daily<br>* Other names: Zocor®;Drug: Placebo Run-In<br>* Placebo matches both ER niacin 1 g/laropiprant 20 mg oral tablet and ER niacin 1 g/laropiprant 20 mg/simvastatin 10 mg oral tablet; placebo is taken once daily<br>Drug: SIM-matching placebo<br>* Placebo for simvastatin 10 mg oral tablet taken once daily<br>|
| Active Comparator: ERN/LRPT+SIM → ERN/LRPT/SIM<br>Weeks 0-4 (Period I): Participants will take ERN/LRPT co-administered with SIM (ERN/LRPT 1g + SIM 10 mg tablets) daily; Weeks 5-12 (Period II): Participants will be advanced to ERN/LRPT 2 g + SIM 20 mg daily; Weeks 13-20 (Period III): Participants will crossover to the ERN/LRPT/SIM 2 g/20 mg combination treatment and SIM-matching placebo tablets. | Drug: ER niacin/laropiprant (ERN/LRPT)<br>* ER niacin 1 g/laropiprant 20 mg oral tablet taken once daily<br>* Other names: MK-0524B;Drug: ER niacin/laropiprant/simvastatin (ERN/LRPT/SIM)<br>* ER niacin 1 g/laropiprant 20 mg/simvastatin 10 mg oral tablet taken once daily<br>* Other names: MK-0524A, Tredaptive™;Drug: Simvastatin (SIM)<br>* Simvastatin 10 mg oral tablet taken once daily<br>* Other names: Zocor®;Drug: Placebo Run-In<br>* Placebo matches both ER niacin 1 g/laropiprant 20 mg oral tablet and ER niacin 1 g/laropiprant 20 mg/simvastatin 10 mg oral tablet; placebo is taken once daily<br>Drug: SIM-matching placebo<br>* Placebo for simvastatin 10 mg oral tablet taken once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Blood Levels | Due to study termination caused by the decision to stop the development of the combination tablet, sufficient data were not available to perform the planned efficacy analysis, which is based on the cross-over data collected in period II and III. | Baseline and Week 12 and Week 20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) Blood Levels | Due to study termination caused by the decision to stop the development of the combination tablet, sufficient data were not available to perform the planned efficacy analysis, which is based on the cross-over data collected in period II and III. | Baseline and Week 12 and Week 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low-density lipoprotein, LDL, High-density lipoprotein, HDL, Niacin, Lipid modifying therapy, Cholesterol, High cholesterol, Triglycerides