Mixed Dyslipidemia, Primary Hypercholesterolemia
Conditions
Keywords
Low-density lipoprotein, LDL, High-density lipoprotein, HDL, Niacin, Lipid modifying therapy, Cholesterol, High cholesterol, Triglycerides
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 /20 mg is equivalent to ERN/LRPT 2 g coadministered with simvastatin 20 mg in reducing low-density lipoprotein cholestrol (LDL-C).
Interventions
DRUGSIM-matching placebo
Placebo for simvastatin 10 mg oral tablet taken once daily
DRUGER niacin/laropiprant (ERN/LRPT)
ER niacin 1 g/laropiprant 20 mg oral tablet taken once daily
DRUGER niacin/laropiprant/simvastatin (ERN/LRPT/SIM)
ER niacin 1 g/laropiprant 20 mg/simvastatin 10 mg oral tablet taken once daily
DRUGSimvastatin (SIM)
Simvastatin 10 mg oral tablet taken once daily
DRUGPlacebo Run-In
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
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) Blood Levels | Baseline and Week 12 and Week 20 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) Blood Levels | Baseline and Week 12 and Week 20 | 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. |
Participant flow
Pre-assignment details
Sequence 1 (randomized) = 577; Sequence 2 (randomized) = 562
Participants by arm
| Arm | Count |
|---|---|
| ERN/LRPT/SIM → ERN/LRPT+SIM (Sequence 1) Study drug was administered as extended-release niacin/laropiprant/simvastatin combination (ERN/LRPT/SIM) during Period I and II for 12 weeks and extended-release niacin/laropiprant (ERN/LRPT) + simvastatin (SIM) during Period III for 8 weeks. | 577 |
| ERN/LRPT+SIM → ERN/LRPT/SIM (Sequence 2) Study drug was co-administered as extended-release niacin/laropiprant (ERN/LRPT) + simvastatin (SIM) (ERN/LRPT + SIM) during Periods I and II for 12 weeks and extended-release niacin/laropiprant/simvastatin combination (ERN/LRPT/SIM) during Period III for 8 weeks. | 562 |
| Total | 1,139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period I and II | Adverse Event | 63 | 43 |
| Period I and II | Lost to Follow-up | 3 | 5 |
| Period I and II | Noncompliance with Study Drug | 1 | 1 |
| Period I and II | Physician Decision | 2 | 1 |
| Period I and II | Protocol Violation | 9 | 10 |
| Period I and II | Study Terminated by Sponsor | 406 | 415 |
| Period I and II | Withdrawal by Subject | 9 | 4 |
| Period III | Adverse Event | 0 | 2 |
| Period III | Lost to Follow-up | 1 | 0 |
| Period III | Protocol Violation | 0 | 1 |
| Period III | Study Terminated by Sponsor | 77 | 76 |
Baseline characteristics
| Characteristic | ERN/LRPT/SIM → ERN/LRPT+SIM (Sequence 1) | ERN/LRPT+SIM → ERN/LRPT/SIM (Sequence 2) | Total |
|---|---|---|---|
| Age, Continuous | 56.2 Years STANDARD_DEVIATION 10.44 | 56.4 Years STANDARD_DEVIATION 10.44 | 56.3 Years STANDARD_DEVIATION 10.43 |
| Sex: Female, Male Female | 345 Participants | 332 Participants | 677 Participants |
| Sex: Female, Male Male | 232 Participants | 230 Participants | 462 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 103 / 567 | 95 / 554 | 0 / 83 | 0 / 82 |
| serious Total, serious adverse events | 11 / 567 | 5 / 554 | 0 / 83 | 1 / 82 |
Outcome results
Primary
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.
Time frame: Baseline and Week 12 and Week 20
Population: Completers Population - participants that completed the study, have respective endpoint data available at baseline, end of period II and end of period III and were not off study drug more than 3 days prior to their period II and period III observations.
Secondary
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.
Time frame: Baseline and Week 12 and Week 20
Population: Completers Population - participants that completed the study, have respective endpoint data available at baseline, end of period II and end of period III and were not off study drug more than 3 days prior to their period II and period III observations.