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

Phase 3

Terminated

Conditions: Primary Hypercholesterolemia
Dyslipidemia

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

Registration Number: NCT01294683

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 977

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 1: MK-0524B 2g/40g→MK-0524A 2g + Simvastatin 40 mg	Simvastatin	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.
Sequence 1: MK-0524B 2g/40g→MK-0524A 2g + Simvastatin 40 mg	Extended Release (ER) niacin/laropiprant/simvastatin (N/LRPT/SIM)	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.
Sequence 1: MK-0524B 2g/40g→MK-0524A 2g + Simvastatin 40 mg	Extended Release (ER) niacin/laropiprant (N/LRPT)	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.
Sequence 1: MK-0524B 2g/40g→MK-0524A 2g + Simvastatin 40 mg	Placebo	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.
Sequence 2: MK-0524A 2g + Simvastatin 40 mg→ MK-0524B 2g/40g	Extended Release (ER) niacin/laropiprant/simvastatin (N/LRPT/SIM)	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.
Sequence 2: MK-0524A 2g + Simvastatin 40 mg→ MK-0524B 2g/40g	Simvastatin	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.
Sequence 2: MK-0524A 2g + Simvastatin 40 mg→ MK-0524B 2g/40g	Extended Release (ER) niacin/laropiprant (N/LRPT)	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.
Sequence 2: MK-0524A 2g + Simvastatin 40 mg→ MK-0524B 2g/40g	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)	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)	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C)	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)	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.
Percentage of Participants With Elevations in ALT and/or AST of >=10 x ULN	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With Consecutive Elevations in Alanine Aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) of >=3 x Upper Limit of Normal (ULN)	Up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With Elevations in ALT and/or AST of >=5 x ULN	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With Creatine Kinase (CK) >=10 x ULN	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With CK >=10 x ULN With Muscle Symptoms - Drug Related	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants Who Experienced at Least 1 Hepatitis-related Adverse Event (AE)	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With New Onset of Diabetes	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants With a Confirmed Adjudicated Cardiovascular Event	up 20 weeks (12 weeks in Periods I/II and 8 weeks in Period III)	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.
Percentage of Participants Who Experienced at Least 1 AE	up 22 weeks (12 weeks in Periods I/II and 10 weeks in Period III)	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.
Percentage of Participants Who Were Discontinued From the Study Due to an AE	up 22 weeks (12 weeks in Periods I/II and 10 weeks in Period III)	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.