A Long-term Study of ERN/LRPT (Extended Release Niacin/Laropiprant [MK0524A]) in Patients With Dyslipidemia (0524A-102)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00961636
• Collaborator: (none)
• Enrollment: 1,152
• Arms: 3
• Duration (Months): 15

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy of laropiprant (LRPT) to reduce flushing symptoms beyond 6 months and will measure the impact of withdrawal of laropiprant in patients following 20 weeks of stable maintenance therapy.

Condition or Disease	Intervention/Treatment	Phase
Dyslipidemia	Drug: ER niacin (+) laropiprant (ERN/LRPT); Drug: ER niacin (+) laropiprant (ERN/LRPT); Drug: Extended-release niacin (ERN); Drug: Placebo to ERN/LRPT	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1152 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Worldwide, Multicenter, Double-Blind, Randomized, Parallel, Placebo-Controlled Study to Evaluate the Long-term Efficacy, Safety and Tolerability of ERN/LRPT in Patients With Dyslipidemia
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ERN/LRPT One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks	Drug: ER niacin (+) laropiprant (ERN/LRPT); One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks
Experimental: ERN/LRPT then ERN One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.	Drug: ER niacin (+) laropiprant (ERN/LRPT); One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks.; Drug: Extended-release niacin (ERN); Two 1g tablets ERN (2g total) once daily for 12 weeks.
Placebo Comparator: Placebo One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.	Drug: Placebo to ERN/LRPT; One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks

Outcome Measures

Primary Outcome Measures

1. Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period [Week 21 to Week 32]

   Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assessed the overall severity of the flushing experience, using a scale of 0 (no symptom) to 10 (extreme). The number of days/week was derived as: 7*(total number of days with GFSS ≥4 across Weeks 21-32 divided by the total number of days with nonmissing GFSS across the same period). The number of days/week with a GFSS ≥4 for each participant was listed in 1 of the following 6 categories: 0, >0 to 0.5, >0.5 to 1, >1 to 2, >2 to 3, and >3 days per week.

Secondary Outcome Measures

1. Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period [Week 21 to Week 32]

   Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assesses the overall severity of the flushing experience (including redness, warmth, tingling, or itching) using a scale with response categories of None, Mild, Moderate, Severe, and Extreme. The categories were supplemented with numbers 0 to 10 to allow for greater precision within each category (None=0, Mild=1-3, Moderate=4-6, Severe=7-9, Extreme=10). The daily response was recorded in the morning, and reflected the symptoms experienced during the previous 24 hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient is a male, or a female who is unlikely to conceive, as indicated by meeting at least one of the following conditions: (a) Patient is a male.(b) Patient is a female of reproductive potential and either agrees to remain abstinent (if this form of birth control is accepted by local regulatory agencies and review committees as the sole method of birth control) or use (or have their partner use) 2 acceptable methods of birth control within the projected duration of the study.(c) Patient is a female who is not of reproductive potential and therefore eligible to participate in this study without requiring the use of contraception.

• Lipid-modifying therapy (LMT) is appropriate for the patient

• Patient meets one of the following criteria based on the National Cholesterol Education Program Adult Treatment Panel III guidelines : 1) High risk and is on a statin with LDL-cholesterol (LDL-C) <100 mg/dL or intolerant to statins with LDL-C <120 mg/dL; 2) Multiple risk with LDL-C <130 mg/dL; 3) Low risk with LDL-C <190 mg/dL

• Patient has triglyceride levels <500 mg/dL

Exclusion Criteria:

• Patient is pregnant, breast-feeding, or expecting to conceive

• Patient has a history of cancer within 5 years of screening (except certain skin and cervical cancers)

• Female patient plans to donate eggs during the study

• Male patient plans to donate sperm during the study

• Patient has or has a history of any condition, therapy, or lab abnormality that might confound the study results, interfere with participation for the full duration of the study, or make participation in the study not in the patient's best interest

• Patient has donated or received blood within 8 weeks of screening or plans to donate/receive blood during and 8 weeks after the study

• Patient is experiencing menopausal hot flashes

• Patient has chronic heart failure, uncontrolled cardiac arrhythmias, or poorly controlled hypertension

• Patient has type 1 or 2 diabetes and is poorly-controlled, newly diagnosed, has recently had repeated hypoglycemia, or is taking new or recently adjusted antidiabetic medication

• Patient has uncontrolled metabolic or endocrine disease that influences serum lipids or lipoproteins

• Patient has kidney disease

• Patient had active peptic ulcers within 3 months of screening

• Patient has a history of heart attack, stroke, heart bypass surgery, angina, or angioplasty within 3 months of screening

• Patient is human immunodeficiency virus (HIV) positive

• Patient is taking or has taken niacin >50 mg daily within 6 weeks of screening

• Patient has had a change to type or dose of LMT regimen within 6 weeks of Visit 1

• Patient is taking a statin and a fibrate at screening

• Patient is taking a long acting non-steroidal anti-inflammatory drug (NSAID), such as naproxen or aspirin >100 mg per day at screening

• Patient has arterial bleeding

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00961636
• Other Study ID Numbers: 0524A-102; 2009_634
• First Posted: Aug 19, 2009
• Last Update Posted: Feb 16, 2015
• Last Verified: Jan 1, 2015

• Additional relevant MeSH terms: Dyslipidemias; Niacin; Niacinamide; Nicotinic Acids

Study Results

Participant Flow

Arm/Group Title	ERN/LRPT	ERN/LRPT Then ERN	Placebo
Arm/Group Description	One 1g/20 mg tablet Extended -release niacin (+) laropiprant (ERN/LRPT) once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks	One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.	One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.
Period Title: Overall Study
STARTED	463	456	233
COMPLETED	356	325	201
NOT COMPLETED	107	131	32

Baseline Characteristics

Arm/Group Title	ERN/LRPT	ERN/LRPT Then ERN	Placebo	Total
Arm/Group Description	One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks	One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.	One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.	Total of all reporting groups
Overall Participants	463	456	233	1152
Age, Customized (Number) [Number]
< 65 years	334 72.1%	328 71.9%	166 71.2%	828 71.9%
>=65 years	129 27.9%	128 28.1%	67 28.8%	324 28.1%
Sex: Female, Male (Count of Participants)
Female	184 39.7%	144 31.6%	87 37.3%	415 36%
Male	279 60.3%	312 68.4%	146 62.7%	737 64%

Outcome Measures

1. Primary Outcome

Title	Number Participants With Days Per Week With Global Flushing Severity Score (GFSS) ≥4 Partitioned Into 6 Categories During the Postwithdrawal Period
Description	Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assessed the overall severity of the flushing experience, using a scale of 0 (no symptom) to 10 (extreme). The number of days/week was derived as: 7*(total number of days with GFSS ≥4 across Weeks 21-32 divided by the total number of days with nonmissing GFSS across the same period). The number of days/week with a GFSS ≥4 for each participant was listed in 1 of the following 6 categories: 0, >0 to 0.5, >0.5 to 1, >1 to 2, >2 to 3, and >3 days per week.
Time Frame	Week 21 to Week 32

Outcome Measure Data

Analysis Population Description

Analysis performed using the Full Analysis Set (FAS) population which included all randomized participants that did not have a withdrawal visit and/or did not have at least 1 GFSS score during the post-withdrawal period (Weeks 21 to 32).

Arm/Group Title	ERN/LRPT	ERN/LRPT Then ERN	Placebo
Arm/Group Description	One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks	One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.	One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.
Measure Participants	362	354	207
0 Days per week	291 62.9%	181 39.7%	188 80.7%
>0 to ≤ 0.5 Days per week	43 9.3%	74 16.2%	7 3%
>0.5 to ≤1 Days per week	3 0.6%	32 7%	4 1.7%
>1.0 to ≤2 Days per week	8 1.7%	30 6.6%	3 1.3%
>2 to ≤3 Days per week	1 0.2%	17 3.7%	1 0.4%
>3 Days per week	16 3.5%	20 4.4%	4 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERN/LRPT, ERN/LRPT Then ERN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The closed ordered testing procedure was applied to the efficacy hypotheses. If statistical significance was achieved for the primary hypothesis, then the secondary hypothesis was tested. All tests were performed at significance level 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel (CMH) test was stratified by country

2. Secondary Outcome

Title	Number of Participants With Maximum GFSS ≥4 During the Post-withdrawal Period
Description	Flushing symptoms were recorded using participant's response to the Global Flushing Severity Score (GFSS), which assesses the overall severity of the flushing experience (including redness, warmth, tingling, or itching) using a scale with response categories of None, Mild, Moderate, Severe, and Extreme. The categories were supplemented with numbers 0 to 10 to allow for greater precision within each category (None=0, Mild=1-3, Moderate=4-6, Severe=7-9, Extreme=10). The daily response was recorded in the morning, and reflected the symptoms experienced during the previous 24 hours.
Time Frame	Week 21 to Week 32

Outcome Measure Data

Analysis Population Description

Analysis performed using the Full Analysis Set (FAS) population which included all randomized participants that did not have a withdrawal visit and/or did not have at least 1 GFSS score during the post-withdrawal period (Weeks 21 to 32).

Arm/Group Title	ERN/LRPT	ERN/LRPT Then ERN	Placebo
Arm/Group Description	One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks	One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.	One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.
Measure Participants	362	354	207
Number [Participants]	71 15.3%	173 37.9%	19 8.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ERN/LRPT, ERN/LRPT Then ERN
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The closed ordered testing procedure was applied to the efficacy hypotheses. If statistical significance was achieved for the primary hypothesis, then the secondary hypothesis was tested. All tests were performed at significance level 0.05.
	Method	Unconditional Miettinen and Nurminen
	Comments

Adverse Events

Adverse Event Reporting Description	Of 1152 randomized participants, 1148 participants took at least one dose of study medication and were included in the analyses of safety.
Arm/Group Title	ERN/LRPT		ERN/LRPT Then ERN		Placebo
Arm/Group Description	One 1g/20 mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 28 weeks		One 1g/20mg tablet ERN/LRPT once daily for 4 weeks, then two 1g/20 mg tablets daily (2g/40 mg total) for 16 weeks then Two 1g tablets ERN (2g total) once daily for 12 weeks.		One tablet placebo to ERN/LRPT once daily for 4 weeks, then two tablets placebo to ERN/LRPT daily for 28 weeks.
All Cause Mortality
	ERN/LRPT		ERN/LRPT Then ERN		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	ERN/LRPT		ERN/LRPT Then ERN		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/461 (3.7%)		34/455 (7.5%)		13/232 (5.6%)
Cardiac disorders
Angina pectoris	0/461 (0%)	0	1/455 (0.2%)	2	0/232 (0%)	0
Angina unstable	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Atrial fibrillation	0/461 (0%)	0	2/455 (0.4%)	2	0/232 (0%)	0
Cardiac failure	0/461 (0%)	0	1/455 (0.2%)	2	0/232 (0%)	0
Cardiac failure congestive	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Coronary artery disease	0/461 (0%)	0	2/455 (0.4%)	2	0/232 (0%)	0
Myocardial infarction	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Supraventricular tachycardia	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Ventricular tachycardia	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Ear and labyrinth disorders
Cerumen impaction	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Endocrine disorders
Goitre	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Eye disorders
Optic ischaemic neuropathy	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Gastrointestinal disorders
Gastric ulcer haemorrhage	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Haemorrhoids	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
General disorders
Device malfunction	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Non-cardiac chest pain	0/461 (0%)	0	1/455 (0.2%)	1	1/232 (0.4%)	1
Hepatobiliary disorders
Cholelithiasis	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Immune system disorders
Drug hypersensitivity	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Infections and infestations
Cellulitis	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Diverticulitis	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
H1N1 influenza	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Pneumonia	0/461 (0%)	0	1/455 (0.2%)	1	1/232 (0.4%)	1
Post procedural infection	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Post procedural sepsis	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Pyelonephritis	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Urosepsis	1/461 (0.2%)	1	1/455 (0.2%)	1	0/232 (0%)	0
Injury, poisoning and procedural complications
Clavicle fracture	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Concussion	0/461 (0%)	0	1/455 (0.2%)	1	1/232 (0.4%)	1
Foreign body	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Humerus fracture	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Joint injury	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Limb injury	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Post procedural haematoma	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Tendon rupture	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Traumatic brain injury	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Intervertebral disc protrusion	2/461 (0.4%)	2	0/455 (0%)	0	0/232 (0%)	0
Musculoskeletal pain	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Tendon disorder	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Intraocular melanoma	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Prostate cancer	2/461 (0.4%)	2	2/455 (0.4%)	2	0/232 (0%)	0
Tongue cancer metastatic	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Nervous system disorders
Cerebral haemorrhage	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Epileptic aura	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Haemorrhage intracranial	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Headache	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Syncope	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Transient ischaemic attack	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Psychiatric disorders
Alcoholism	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Major depression	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Renal and urinary disorders
Nephrolithiasis	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Urinary incontinence	1/461 (0.2%)	1	0/455 (0%)	0	0/232 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Pulmonary embolism	1/461 (0.2%)	1	1/455 (0.2%)	1	0/232 (0%)	0
Skin and subcutaneous tissue disorders
Drug eruption	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Vascular disorders
Arteriosclerosis	0/461 (0%)	0	0/455 (0%)	0	1/232 (0.4%)	1
Thrombophlebitis	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Thrombophlebitis superficial	0/461 (0%)	0	1/455 (0.2%)	1	0/232 (0%)	0
Other (Not Including Serious) Adverse Events
	ERN/LRPT		ERN/LRPT Then ERN		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	136/461 (29.5%)		162/455 (35.6%)		37/232 (15.9%)
Infections and infestations
Nasopharyngitis	33/461 (7.2%)	40	34/455 (7.5%)	35	11/232 (4.7%)	12
Nervous system disorders
Paraesthesia	23/461 (5%)	53	28/455 (6.2%)	65	6/232 (2.6%)	6
Skin and subcutaneous tissue disorders
Pruritis	51/461 (11.1%)	67	66/455 (14.5%)	116	17/232 (7.3%)	18
Vascular disorders
Flushing	52/461 (11.3%)	77	85/455 (18.7%)	130	7/232 (3%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publications derived from this study should include input from the investigator(s) and Sponsor personnel. Subsequent to the multicenter publication, or 24 months after completion of the study, whichever comes first, an investigator and/or his/her colleagues may publish the results for their study site independently. The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation.