MK-0524B Lipid Study (MK-0524B-063)

Study Overview
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Brief Summary
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This is a 20-week clinical trial in participants with primary hypercholesterolemia or mixed dyslipidemia to demonstrate the effect of MK-0524B compared to MK-0524A + Simvastatin on lipid values.

Official Title
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A Multicenter, Randomized, Double-Blind, Crossover Design Study to Evaluate the Lipid-Altering Efficacy and Safety of MK-0524B Combination Tablet Compared to MK-0524A + Simvastatin Coadministration in Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia

Conditions
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Primary Hypercholesterolemia, Mixed Dyslipidemia

Intervention / Treatment
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* Drug: Comparator: simvastatin
* Drug: MK-0524A
* Drug: Placebo
* Drug: MK-0524B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: has primary hypercholesterolemia or mixed dyslipidemia based on medical history (previous diagnosis), historic lipid values, or as otherwise determined through optional lipid measurements at screening visit meets one of the following triglyceride (TG) criteria: is on niacin, statin, or fibrate and has TG <500 mg/dL at or within 6 months of washout is not on any lipid altering therapy or is on lipid altering therapy other than niacin, statin, or fibrate and has TG <600 mg/dL at or within 6 months of screening Exclusion Criteria: is high risk (coronary heart disease [CHD] or CHD risk equivalent) AND is on a statin is pregnant or breast-feeding, or expecting to conceive during the study including the 14-day post study follow-up has Type 1 or Type 2 diabetes mellitus and is on statin therapy, is poorly controlled, is newly diagnosed (within 3 months of Visit 1), has recently experienced repeated hypoglycemia or unstable glycemic control or is taking new or recently adjusted anti-diabetic medications (with the exception of +/- 10 units of insulin) within 3 months of Visit 1 has the following conditions: chronic heart failure, uncontrolled/unstable cardiac arrhythmias, unstable hypertension, active or chronic hepatobiliary disorder or hepatic disease, human immunodeficiency virus (HIV) positive, gout (within 1 year)

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 1.8g/20mg→MK-0524A 2g+Simvastatin 20mg<br>After a 2-week placebo run-in, participants will receive MK-0524B (0.9 g/simvastatin 10 mg) for 4 weeks, then MK-0524B 1.8g /20 mg combination tablet for 8 weeks. Participant is then co-administered MK-0524A 2 g + simvastatin 20 mg for 8 weeks. | Drug: Comparator: simvastatin<br> <br> * Other names: MK0733;Drug: MK-0524A<br>* Extended-release(ER) niacin/Laropiprant (MK-0524) Combination tablet<br>Drug: Placebo<br> <br> Drug: MK-0524B<br> <br> |
| Experimental: Sequence 2: MK-0524A 2g+Simvastatin 20mg →MK-0524B 1.8g/20mg<br>After a 2-week placebo run-in, participants will be co-administered MK-0524A 1g + simvastatin 10 mg for 4 weeks, then co-administered MK-0524A 2g +simvastatin 20 mg for 8 weeks. Participant then receives MK-0524B 1.8 g/20 mg combination tablet for 8 weeks. | Drug: Comparator: simvastatin<br> <br> * Other names: MK0733;Drug: MK-0524A<br>* Extended-release(ER) niacin/Laropiprant (MK-0524) Combination tablet<br>Drug: Placebo<br> <br> Drug: MK-0524B<br> <br> |
| Experimental: Sequence 3: MK-0524B 1.8g/40mg→MK-0524A 2g+Simvastatin 40mg<br>After a 2-week placebo run-in, participants will receive MK-0524B 0.9g/40 mg combination tablet for 4 weeks, then MK-0524B 1.8g /40 mg combination tablet for 8 weeks. Participant is then co-administered MK-0524A 2 g + simvastatin 40 mg for 8 weeks. | Drug: Comparator: simvastatin<br> <br> * Other names: MK0733;Drug: MK-0524A<br>* Extended-release(ER) niacin/Laropiprant (MK-0524) Combination tablet<br>Drug: Placebo<br> <br> Drug: MK-0524B<br> <br> |
| Experimental: Sequence 4: MK-0524A 2g+Simvastatin 40mg →MK-0524B 1.8g/40mg<br>After a 2-week placebo run-in, participants will be co-administered MK-0524A 1g + simvastatin 40 mg for 4 weeks, then co-administration MK-0524A 2g +simvastatin 40 mg for 8 weeks. Participant then receives MK-0524B 1.8 g/40 mg combination tablet for 8 weeks. | Drug: Comparator: simvastatin<br> <br> * Other names: MK0733;Drug: MK-0524A<br>* Extended-release(ER) niacin/Laropiprant (MK-0524) Combination tablet<br>Drug: Placebo<br> <br> Drug: MK-0524B<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) | Blood samples taken at baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment during each period to determine the LDL-C levels. The change from baseline after 8 weeks of treatment was recorded. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) | Blood samples taken at baseline (Week 4 for Period II; Week 12 for Period III) and after 8 weeks of treatment during each period to determine the HDL-C levels. The change from baseline after 8 weeks of treatment was recorded. | 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 ) 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 ULNs for males and females were 43 U/L and 36 U/L, respectively. The ALT ULNs for males and females were 40 U/L and 33 U/L, respectively. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants With Creatine Kinase (CK) >=10 x ULN | Participants had CK levels assessed during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of CK that was 10 x ULN or greater were recorded. The ULNs for males and females were 207 U/L and 169 U/L, respectively. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants With CK >=10 x ULN With Muscle Symptoms | Participants had CK levels assessed during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of CK that was 10 x ULN or greater and had associated muscle symptoms present within +/- 7 days were recorded. The ULNs for males and females were 207 U/L and 169 U/L, respectively. | up 20 weeks (12 weeks in Period 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 during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had an assessment of CK that was 10 x ULN or greater and had associated muscle symptoms present within +/- 7 days that were reported as at least possibly related to study drug were recorded. The ULNs for males and females were 207 U/L and 169 U/L, respectively. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants With New Diagnosis of Impaired Fasting Blood Glucose | Participants had fasting glucose levels assessed during Period I (4 weeks ) throughout each 8 week treatment period (20 weeks total). Participants who had the new diagnosis of impaired fasting blood glucose were recorded. A pre-defined set of MedDRA terms was used to identify participants whose glycemic status became 'impaired' during the course of treatment (from clinical adverse experience reports). The MedDRA terms were as follows: blood glucose increased, blood glucose abnormal, glucose tolerance decreased, glucose tolerance test abnormal, carbohydrate tolerance decreased, glucose tolerance impaired, hyperglycaemia, impaired fasting glucose, impaired insulin secretion, metabolic syndrome, insulin resistance, insulin resistance syndrome. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants With New Diagnosis of Diabetes | Participants who with newly diagnosed of diabetes were recorded. A participant was classified as having new onset diabetes if they experienced an adverse Event (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 Period I/II and 8 weeks in Period III) | 
| Percentage of Participants With Worsening of the Pre-existing Conditions of Diabetes in Participants With Diabetes at Baseline | Participants with diabetes at baseline and who experienced a worsening of the diabetes identified through adverse event reports using a pre-defined set of terms and/or increasing dose/adding a new anti-diabetic medication. | up 20 weeks (12 weeks in Period 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 as cardiovascular events were recorded | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Experience at Least 1 Clinical 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. A clinical AE was an AE reported as a result of a clinical examination or reported by the participant. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Experience at Least 1 Laboratory 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. A laboratory AE was an AE reported as a result of a laboratory assessment or test | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Were Discontinued From the Study Due to a Clinical 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. A clinical AE was an AE reported as a result of a clinical examination or reported by the participant. Participants who were discontinued from the study due to a clinical AE were recorded. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Were Discontinued From the Study Due to a Laboratory 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. A laboratory AE was an AE reported as a result of a laboratory assessment or test. Participants who were discontinued from the study due to a laboratory AE were recorded. | up 20 weeks (12 weeks in Period I/II and 8 weeks in Period III) | 
| Percentage of Participants Who Experience at Least 1 Hepatitis-related Non-serious Clinical 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. Non-serious 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 Period I/II and 8 weeks in Period III) | 
| Percentage Change From Baseline in LDL-C at Week 4 | Blood samples taken at baseline (Day1 of Period I) and after 4 weeks of treatment to determine the LDL-C levels. The change from baseline after 4 weeks of treatment was recorded. | Baseline (Day1 of Period I) and Week 4 | 
| Percentage Change From Baseline in HDL-C at Week 4 | Blood samples taken at baseline (Day1 of Period I) and after 4 weeks of treatment to determine the HDL-C levels. The change from baseline after 4 weeks of treatment was recorded. | Baseline (Day1 of Period I) and Week 4 |