A Study to Evaluate Efficacy and Safety of Extended-Release Niacin + Laropiprant + Simvastatin in Participants With Primary Hypercholesterolemia or Mixed Dyslipidemia (MK-0524B-118)

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/40 mg is equivalent to ERN/LRPT 2 g co-administered with simvastatin 40 mg in reducing low-density lipoprotein cholesterol (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 Extended-Release Niacin/Laropiprant/Simvastatin Combination Tablet in Patients With Primary Hypercholesterolemia or Mixed Dyslipidemia

Conditions
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Dyslipidemia, Primary Hypercholesterolemia

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Extended Release (ER) niacin/laropiprant/simvastatin (N/LRPT/SIM)
* Drug: Extended Release (ER) niacin/laropiprant (N/LRPT)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Participant has a history of primary hypercholesterolemia or mixed dyslipidemia and meets LDL-C and triglyceride criteria. Visit 2: Participant is high risk coronary heart disease (CHD) or CHD risk-equivalent. Exclusion Criteria Participant is pregnant or breast-feeding, or expecting to conceive during the study. Participant has a history of malignancy. Participant consumes more than 3 alcoholic drinks per day (14 per week). Participant is high risk CHD patient on statin therapy or any patient on statin therapy equivalent to 80 mg simvastatin. Participant with Type 1 or Type 2 diabetes mellitus that is poorly controlled, or on statin therapy. Participant currently engages in vigorous exercise or is on an aggressive diet regimen. Participant 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. Participant is human immunodeficiency virus (HIV) positive. Participant has taken niacin >50 mg/day, bile-acid sequestrants, hydroxymethyl glutaryl 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. Participant 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. Participant is taking prohibited medications such as systemic corticosteroids, itraconazole or ketoconazole, erythromycin, clarithromycin, or telithromycin, nefazodone, HIV protease inhibitors, verapamil, amiodarone, cyclosporine, danazol, diltiazem or fusidic acid. Participant consumes >1 quart of grapefruit juice/day.

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: Sequence 1: MK-0524B 2g/40g→MK-0524A 2g + Simvastatin 40 mg<br>After a 2-week placebo run-in, participants received extended release (ER) niacin/laropiprant (N/LRPT) 1 g/20 mg combination tablet (MK-0524B) once daily for 4 weeks, then ERN/LRPT/Simvastatin (SIM) 2 g/40 mg combination tablet once daily for 8 weeks. Participants then received ERN/LRPT 2 g (MK-0524A) co-administered with SIM 40 mg once daily for 8 weeks. | Drug: Simvastatin<br> <br> * Other names: Zocor;Drug: Extended Release (ER) niacin/laropiprant/simvastatin (N/LRPT/SIM)<br> <br> * Other names: MK-0524B;Drug: Extended Release (ER) niacin/laropiprant (N/LRPT)<br> <br> * Other names: MK-0524A;Drug: Placebo<br> <br> |
| Experimental: Sequence 2: MK-0524A 2g + Simvastatin 40 mg→ MK-0524B 2g/40g<br>After a 2-week placebo run-in, participants received ERN/LRPT 1 g (MK-0524A) co-administered with SIM 20 mg once daily for 4 weeks then received ERN/LRPT 2 g (MK-0524A) co-administered with SIM 40 mg once daily for 8 weeks. Participants then received ERN/LRPT/SIM 2 g/40 mg combination tablets (MK-0524B) once daily for 8 weeks. | Drug: Simvastatin<br> <br> * Other names: Zocor;Drug: Extended Release (ER) niacin/laropiprant/simvastatin (N/LRPT/SIM)<br> <br> * Other names: MK-0524B;Drug: Extended Release (ER) niacin/laropiprant (N/LRPT)<br> <br> * Other names: MK-0524A;Drug: Placebo<br> <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 samples were taken at baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment (Week 12 for Period II and Week 20 for Period III) to determine the LDL-C levels. The change from baseline after 8 weeks of treatment was recorded. Results from recent studies indicated that the combination tablet formulations used in the study did not meet the pre-specified pharmacokinetic bounds used to establish the equivalence of the combination tablet (MK-0524B; ERN/LRPT/SIM) to the coadministration of MK-0524A (ERN/LRPT) and SIM. Therefore, efficacy data were not analyzed, as the study was stopped early. Only safety data were evaluated. | Baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment (Week 12 for Period II and Week 20 for Period III) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) | Blood samples were taken at baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment (Week 12 for Period II and Week 20 for Period III) to determine the HDL-C levels. The change from baseline after 8 weeks of treatment was recorded. Results from recent studies indicated that the combination tablet formulations used in the study did not meet the pre-specified pharmacokinetic bounds used to establish the equivalence of the combination tablet (MK-0524B; ERN/LRPT/SIM) to the coadministration of MK-0524A (ERN/LRPT) and SIM. Therefore, efficacy data were not analyzed, as the study was stopped early. Only safety data were evaluated. | Baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment during each period (Week 12 for Period II and Week 20 for Period III) | 
| Percentage of Participants With Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) of >=3 x Upper Limit of Normal (ULN) | Participants had AST and ALT levels assessed during Period I (4 weeks ) and throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of either AST or ALT that was 3 x ULN or greater were recorded. The AST UNLs for males and females were 43 U/L and 36 U/L, respectively. The ALT UNLs for males and females were 40 U/L and 33 U/L, respectively. | Up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With Elevations in ALT and/or AST of >=5 x ULN | Participants had AST and ALT levels assessed during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of either AST or ALT that was 5 x ULN or greater were recorded. The AST UNLs for males and females were 43 U/L and 36 U/L, respectively. The ALT UNLs for males and females were 40 U/L and 33 U/L, respectively. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With Elevations in ALT and/or AST of >=10 x ULN | Participants had AST and ALT levels assessed during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of either AST or ALT that was 10 x ULN or greater were recorded. The AST UNLs for males and females were 43 U/L and 36 U/L, respectively. The ALT UNLs for males and females were 40 U/L and 33 U/L, respectively. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With Creatine Kinase (CK) >=10 x ULN | Participants had CK levels assessed throughout the treatment periods. Participants who had any CK level that was >=10 x ULN were recorded. The UNLs for males and females were 207 U/L and 169 U/L, respectively. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With CK >=10 x ULN With Muscle Symptoms - Drug Related | Participants had CK levels assessed throughout the treatment periods. 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 UNLs for males and females were 207 U/L and 169 U/L, respectively. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Experienced at Least 1 Hepatitis-related Adverse Event (AE) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. Hepatitis-related AEs were identified by a collective review using the following pre-specified set of preferred terms: cholestasis, hepatic necrosis, hepatocellular damage, cytolytic hepatitis, hepatitis, hepatomegaly, jaundice, hepatic failure, hepatitis cholestatic, jaundice cholestatic, hepatitis fulminant, hyperbilirubinaemia, jaundice hepatocellular, ocular icterus, yellow skin, hepatic function abnormal, acute hepatic failure, subacute hepatic failure, hepatitis acute, hepatitis toxic, hepatotoxicity, and mixed hepatocellular-cholestatic injury. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With New Onset of Diabetes | Participants who with newly diagnosed of diabetes were recorded. A participant was classified as having new onset diabetes if they experienced an AE related to a diagnosis of diabetes (based on a pre-defined set of Medical Dictionary for Regulatory Activities [MedDRA] terms), or if they started taking an anti-diabetic medication during the course of the study. The MedDRA terms were as follows: diabetes mellitus, diabetes mellitus insulin-dependent, diabetes mellitus non-insulin dependent, insulin-requiring type II diabetes mellitus, insulin resistant diabetes, diabetes with hyperosmolarity, latent autoimmune diabetes in adults. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants With a Confirmed Adjudicated Cardiovascular Event | Select serious adverse cardiovascular events and all-cause mortality that occurred during the treatment phase of the study were adjudicated by an expert committee external to the sponsor. Those events confirmed by the committee a cardiovascular events were recorded. | up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Experienced at Least 1 AE | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. | up 22 weeks (12 weeks in Periods I/II and 10 weeks in Period III) | 
| Percentage of Participants Who Were Discontinued From the Study Due to an AE | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which was temporally associated with the use of the product, was also an AE. Participants who were discontinued from the study due to an AE were recorded. | up 22 weeks (12 weeks in Periods I/II and 10 weeks in Period III) | 

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