Efficacy and Safety of Extended Release (ER) Niacin/Laropiprant When Added to Ongoing Lipid-Modifying Therapy in Patients With High Cholesterol or Abnormal Lipid Levels (MK-0524A-133)

A Worldwide, Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled 12-Week Study to Evaluate the Efficacy and Safety of Extended Release (ER) Niacin/Laropiprant When Added to Ongoing Lipid-Modifying Therapy in Patients With Primary Hypercholesterolemia or Mixed Dyslipidemia

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01274559

Enrollment

1173

Registered

2011-01-11

Start date

2011-03-01

Completion date

2013-02-26

Last updated

2024-05-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Mixed Dyslipidemia, Primary Hypercholesterolemia

Keywords

MK-0524A/ER, Hypercholesterolemia, Dyslipidemia, Niacin, Laropiprant

Brief summary

This is a multicenter, randomized, double-blind, placebo-controlled study in participants with primary hypercholesterolemia or mixed dyslipidemia, and elevated low density lipoprotein-cholesterol (LDL-C) to assess the efficacy and safety of extended release (ER) niacin/laropiprant \[ERN/LRPT (MK-0524A)\] when added to the following ongoing lipid-modifying therapy (LMT): simvastatin, atorvastatin, rosuvastatin monotherapy, ezetimibe/simvastatin fixed dose combination (FDC), or any statin co-administered with ezetimibe. The study is based on the hypothesis that ERN/LRPT 2 g daily will be superior to placebo at lowering LDL-C at Week 12 of treatment.

Interventions

DRUGExtended-release niacin/laropiprant (ERN/LRPT)

1 oral 1 g tablet of ERN/LRPT to be taken with food in the evening or at bedtime for the first 4 weeks of treatment; then 2 oral 1g tablets of ERN/LRPT to be taken together in the evening or at bedtime with food for the next 8 weeks. Each 1g tablet contains 1g ERN and 20 mg LRPT

DRUGPlacebo

1 oral 1 g tablet of placebo to be taken with food in the evening or at bedtime for the first 4 weeks of treatment; then 2 oral 1g tablets of placebo to be taken together in the evening or at bedtime with food for the next 8 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Has a history of primary hypercholesterolemia or mixed dyslipidemia. * Must meet one of the risk categories (very high, high or moderate and corresponding LDL-C criteria at Visit 2. * Has TG levels \<500 mg/dL (\<5.65 mmol/L). * Has been on a stable dose of one of the following lipid-modifying therapies (LMTs)for at least 6 weeks prior to Visit 1, and agrees to remain on the same type and dose of LMT for the duration of the study: * Monotherapy: any statin * Combination Therapy: ezetimibe/simvastatin in the same tablet * Co-administration Therapy: any statin co-administered with ezetimibe * Is male or female and ≥18 years of age on day of signing informed consent. * A female must meet ONE of the following: * Of reproductive potential and agrees to remain abstinent or use (or have their partner use) 2 acceptable methods of birth control for the study duration. * Not of reproductive potential is eligible without requiring the use of contraception. Definition of not of reproductive potential: one who has either of the following: * reached natural menopause, defined as: 6 months of spontaneous amenorrhea with serum FSH levels (at Visit 1) in the postmenopausal range (per central lab) or 12 months of spontaneous amenorrhea.Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa). * 6 weeks post surgical hysterectomy, or bilateral oophorectomy with or without hysterectomy. * Bilateral tubal ligation without subsequent restorative procedure. * Understands the study's procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.

Exclusion criteria

\- Has taken a prohibited LMT within 6 weeks of Visit 1. Examples of prohibited LMT include bile acid sequestrants, fibrates (monotherapy, coadministration or combination with other LMT), niacin \>50 mg, and red yeast rice products. * Has had a change to the type or dose of acceptable LMT regimen within 6 weeks of Visit 1. * Is pregnant, breastfeeding, or expecting to conceive during the study including the 14-day poststudy follow-up. * Has a history of malignancy ≤5 years prior to signing informed consent, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. * Female who is expecting to donate eggs during the study, including the 14-day follow-up. * Is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study. * Has participated in a study, including post-study follow-up, with an investigational compound (non-lipid-modifying) within 30 days of Visit 1 or a lipid-modifying compound (investigational or marketed), within 6 weeks of Visit 1. * Has donated and/or received blood as follows: * donated blood products or has had phlebotomy of \>300 mL within 8 weeks prior to signing informed consent. * intends to give or receive blood products during the study. * intends to donate more than 250 mL of blood products within 8 weeks following the last study visit. * Has the following exclusionary laboratory values at Visit 2 * Creatinine clearance (eGFR) \<30 mL/min (0.50 mL/s) * ALT (SGPT) \>1.5 x ULN * AST (SGOT) \>1.5 x ULN * CK \>2 x ULN * Has used recreational or illicit drugs within 1 year of signing informed consent. * Was \<80% compliant with LMT or placebo at Visit 2, AND in the opinion of the investigator, is believed to be unable to maintain at least 80% compliance with dosing during the active treatment period. * Has chronic heart failure defined by the New York Heart Association (NYHA) Classes III or IV, uncontrolled cardiac arrhythmias, or poorly controlled hypertension (systolic blood pressure \>160 mm Hg or diastolic \>100 mm Hg). * Has Type 1 or Type 2 diabetes mellitus and meets one or more of the following criteria: * Is poorly controlled (HbA1C \>8.0% at Visit 1) * Is newly diagnosed (within 3 months of Visit 1) * Has recently experienced repeated hypoglycemia or unstable glycemic control (within 3 months of Visit 1). * Is taking new or recently adjusted antidiabetic pharmacotherapy (with the exception of ± ≤ 10 units of insulin) within 3 months of Visit 1. * Has uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins (i.e., secondary causes of hyperlipidemia such as hyper- or hypothyroidism. * Has nephrotic syndrome or other clinically significant renal disease. * Has active peptic ulcer disease within 3 months of Visit 1. * Has a history of hypersensitivity or allergic reaction to niacin or niacin containing products. * Has history of myocardial infarction, stroke, coronary artery bypass surgery or other revascularization procedure, unstable angina or angioplasty within 3 months of Visit 1. * Has arterial bleeding. * Has a history of ileal bypass, gastric bypass or other significant condition associated with malabsorption or rapid weight loss within 18 months of Visit 1. * Has active or chronic hepatobiliary or hepatic disease. * Is Chinese and is on simvastatin 80 mg or a product containing simvastatin 80 mg at Visit 1. * Is receiving treatment with systemic steroids (intravenous, injected, and oral steroids) OR systemic anabolic agents. * Consumes more than 3 alcoholic drinks on any given day or more than 14 drinks per week. * Is taking the following antioxidant vitamins each day: * Vitamin C in excess of 1500 mg * Vitamin E in excess of 45 IU for men, 36 IU for women * Beta Carotene 15000 IU for men, 12000 IU for women

Design outcomes

Primary

Measure	Time frame
Percent Change From Baseline at Week 12 in Low Density Lipoprotein-Cholesterol (LDL-C)	Baseline and Week 12

Secondary

Measure	Time frame	Description
Percent Change From Baseline in HDL-C at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Triglyceride (TG) at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Non-HDL-C at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Apo B:Apolipoprotein A-I (Apo A-I) at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Total Cholesterol (TC):HDL-C at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Lipoprotein a [Lp(a)] at Week 12	Baseline and Week 12	—
Percent Change From Baseline in Apo A-I at Week 12	Baseline and Week 12	—
Percent Change From Baseline in TC at Week 12	Baseline and Week 12	—
Percent Change From Baseline in LDL-C at Week 4	Baseline and Week 4	—
Percent Change From Baseline in LDL-C:High-density Lipoprotein Cholesterol (HDL-C) at Week 12	Baseline and Week 12	—
Percent Change From Baseline in HDL-C at Week 4	Baseline and Week 4	—
Percent Change From Baseline in TG at Week 4	Baseline and Week 4	—
Percent Change From Baseline in Non-HDL-C at Week 4	Baseline and Week 4	—
Percent Change From Baseline in Apo B at Week 4	Baseline and Week 4	—
Percent Change From Baseline in Apo B:Apo A-I at Week 4	Baseline and Week 4	—
Percent Change From Baseline in TC:HDL-C at Week 4	Baseline and Week 4	—
Percent Change From Baseline in Lp(a) at Week 4	Baseline and Week 4	—
Percent Change From Baseline in Apo A-I at Week 4	Baseline and Week 4	—
Percent Change From Baseline in TC at Week 4	Baseline and Week 4	—
Number of Participants Who Achieve LDL-C Target Levels at Week 12 of Treatment	Baseline and 12 weeks	assessed as per National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and European Society of Cardiology (ESC) treatment guidelines
Percent Change From Baseline in LDL-C:HDL-C at Week 4	Baseline and Week 4	—

Participant flow

Pre-assignment details

Phase 3 study HPS2-THRIVE (NCT00461630) did not meet its primary endpoint of reduction of major vascular events and had a significant increase in the incidence of some types of non-fatal serious adverse events. As a result, MK-0524A-133 was discontinued. Only individual data were obtained; none of the planned efficacy outcomes were summarized.

Participants by arm

Arm	Count
Extended-release Niacin/Laropiprant ERN/LRPT 1 g (1 tablet for 4 wks) followed by ERN/LRPT 2 g (2 tablets for 8 wks); Each 1-g tablet contains 1 g of ER niacin and 20 mg of laropiprant.	587
Placebo Matching 1 g Placebo (1 tablet for 4 wks) followed by 2 g placebo (2 tablets for 8 weeks)	586
Total	1,173

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	57	13
Overall Study	Death	1	1
Overall Study	Lost to Follow-up	3	3
Overall Study	Non-compliance with Study Drug	2	4
Overall Study	Physician Decision	2	1
Overall Study	Protocol Violation	28	23
Overall Study	Study Terminated by Sponsor	79	87
Overall Study	Withdrawal by Subject	25	13

Baseline characteristics

Characteristic	Extended-release Niacin/Laropiprant	Placebo	Total
Age, Customized 21 to 30 years	1 Participants	2 Participants	3 Participants
Age, Customized 31 to 40 years	9 Participants	12 Participants	21 Participants
Age, Customized 41 to 50 years	63 Participants	62 Participants	125 Participants
Age, Customized 51 to 60 years	182 Participants	168 Participants	350 Participants
Age, Customized 61 to 70 years	209 Participants	232 Participants	441 Participants
Age, Customized 71 to 80 years	108 Participants	98 Participants	206 Participants
Age, Customized >80 years	15 Participants	12 Participants	27 Participants
Sex: Female, Male Female	239 Participants	243 Participants	482 Participants
Sex: Female, Male Male	348 Participants	343 Participants	691 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	101 / 572	16 / 572
serious Total, serious adverse events	23 / 572	16 / 572