ENTHRALL: Effect of Niacin on Transport of HDL and Relationship to Atherogenic Lipoproteins and Lipolysis

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01250990
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 22
• Location: 1
• Arms: 2
• Duration (Months): 5.9
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

This study looks at whether niacin improves reverse cholesterol transport (RCT) in healthy volunteers. 3H-Cholesterol will be used to measure RCT by analyzing changes in the tracer activity in total plasma, lipoproteins, red blood cells (RBCs) and stool. The hypothesis is that niacin augments reverse cholesterol transport.

Condition or Disease	Intervention/Treatment	Phase
Dyslipidemias	Drug: Niacin; Other: Placebo	N/A

Detailed Description

The study will use 3H-cholesterol bound to albumin (particulate cholesterol) to assess the ability of high density lipoprotein (HDL) to transport cholesterol to the liver to be eliminated. This process is called Reverse Cholesterol transport and is one of the main mechanisms by which HDL protect against atherosclerotic cardiovascular disease. The availability of a method to assess RCT is important for the development of new drugs which affect RCT and may result in useful treatments for atherosclerosis.

This study will evaluate the use of radiolabeled particulate cholesterol administered intravenously in association with albumin, as a method to study reverse cholesterol transport (RCT) in humans before and after treatment by niacin by analyzing changes in the tracer activity in total plasma and lipoproteins. The study population is healthy volunteers.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: A Randomized, Double-Blind, Placebo Controlled Study Evaluating the Effects Of Niacin On Reverse Cholesterol Transport As Measured Using [1,2-3H]-Cholesterol (3H-cholesterol) in Healthy Volunteers.
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Niacin Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.	Drug: Niacin; Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.; Other Names: Niacor and Niaspan
Placebo Comparator: Placebo Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that.	Other: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin [Baseline and 12 weeks]

   Subjects were injected with a bolus of 3-H cholesterol mixed with human serum albumin as an intravenous bolus. This injected labelled cholesterol is taken up by macrophages. The rate of appearance of labelled cholesterol in plasma HDL- cholesterol is a measure of reverse cholesterol transport. We assessed HDL cholesterol enrichment as percent of injected tritiated tracer appearing in plasma total HDL cholesterol between 60 and 240 minutes post-injection expressed as percent 3-H cholesterol/mol HDL cholesterol/hour. The tracer study was performed at baseline and after 12 weeks of niacin or placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Men and women between the ages of 18 and 75 inclusive

• HDL cholesterol >= 25 mg/dL in all subjects, and <= 60 mg/dL in men and <= 70 mg/dL in women

• Women must be of non-childbearing potential. They must have been surgically sterilized at least 6 months prior to screening or be postmenopausal. Postmenopausal women must have no regular menstrual bleeding for at least 2 years prior to inclusion.

• Subjects must be in good overall health.

• Subjects must be able to comprehend and willing to provide a signed Institutional Regulatory Board (IRB) approved Informed Consent Form.

• Subjects must be willing to comply with all study-related procedures.

• Subjects must weigh at least 140 pounds to participate in the HDL kinetics Substudy.

Exclusion Criteria:

• Clinically-manifest cardiovascular disease, including coronary disease, cerebrovascular disease, or peripheral vascular disease

• History of diabetes mellitus or fasting glucose > 126 mg/dL at the screening visit

• Presence of New York Heart Association (NYHA) Class III or IV chronic heart failure or unstable angina pectoris

• History of any other endocrine disease

• History of a non-skin malignancy within the previous 5 years

• Anemia defined as hemoglobin less than 12 g/dL

• Renal insufficiency as defined by creatinine ³ 1.3 mg/dl

• Any major active rheumatologic, pulmonary, or dermatologic disease or inflammatory condition

• Uncontrolled hypertension (Systolic >160 mm Hg and/or Diastolic >100 mmHg on two consecutive measurements

• Use of warfarin, or any known coagulopathy and /or elevated Prothrombin time/Partial Thromboplastin Time (PT/PTT) >1.5 x upper limit of normal (ULN)

• Self-reported history of Human immunodeficiency virus (HIV) positive

• Previous organ transplantation

• Clinical evidence of liver disease or liver injury as indicated by abnormal liver function tests such as Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x ULN, or self-reported history of positive for Hepatitis B or Hepatitis C

• Any major surgical procedure that occurred within the previous 3 months of the screening visit

• History of illicit drug abuse (< 1 year)

• Regular use of alcoholic beverages (> 2 drinks/day)

• Body mass index (BMI) > 35 kg/m2 or < 18.5 kg/m2

• Administration of an investigational drug within 6 weeks prior to the screening visit

• Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study will be excluded.

• Use of daily lipid-altering therapy prior to the initiation of study medication is exclusionary under the following circumstances (washout of non-statins is permitted):

• Statins within 4 weeks

• Niacin > 250 mg/ day within 6 weeks: Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, or supplemental niacin

• Fibrates within 12 weeks: fenofibrate (Antara, Lofibra, Tricor, Triglide), gemfibrozil (Lopid), or clofibrate

• Enterically active lipid-altering drugs within 4 weeks: colestipol (Colestid), cholestyramine (Questran), colesevelam (Welchol), ezetimibe (Zetia, Vytorin), orlistat (Xenical, Alli)

• Red yeast rice

• Fish oil > 2 g/day within 4 weeks: Lovaza (née Omacor), numerous supplements

• Altered dose of a selective estrogen receptor modulator (SERM) within 4 weeks

• History of severe intolerance of niacin

• Men who plan to conceive a child within 3 months of the conclusion of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Richard Dunbar, MD MSTR, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Richard Dunbar, Research Associate Professor, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01250990
• Other Study ID Numbers: 811956; K23HL091130
• First Posted: Dec 1, 2010
• Last Update Posted: Jul 28, 2016
• Last Verified: Jun 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Richard Dunbar, Research Associate Professor, University of Pennsylvania: Niacin; HDL; Reverse cholesterol transport
• Additional relevant MeSH terms: Dyslipidemias; Niacin

Study Results

Participant Flow

Arm/Group Title	Niacin	Placebo
Arm/Group Description	Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated. Niacin: Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.	Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that. Placebo: Placebo
Period Title: Overall Study
STARTED	11	11
COMPLETED	7	9
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Niacin	Placebo	Total
Arm/Group Description	Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated. Niacin: Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.	Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that. Placebo: Placebo	Total of all reporting groups
Overall Participants	11	11	22
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	11 100%	22 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	11 100%	11 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Rate of Appearance of 3H Cholesterol in the Total HDL Fraction Before and After 12 Weeks of Treatment With Niacin
Description	Subjects were injected with a bolus of 3-H cholesterol mixed with human serum albumin as an intravenous bolus. This injected labelled cholesterol is taken up by macrophages. The rate of appearance of labelled cholesterol in plasma HDL- cholesterol is a measure of reverse cholesterol transport. We assessed HDL cholesterol enrichment as percent of injected tritiated tracer appearing in plasma total HDL cholesterol between 60 and 240 minutes post-injection expressed as percent 3-H cholesterol/mol HDL cholesterol/hour. The tracer study was performed at baseline and after 12 weeks of niacin or placebo.
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Of the 22 subjects enrolled, only subjects who completed the baseline and 12 week reverse cholesterol transport studies were included in the final outcome analysis.

Arm/Group Title	Niacin	Placebo
Arm/Group Description	Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated. Niacin: Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.	Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that. Placebo: Placebo
Measure Participants	7	9
Pre-treatment	3.24	4.16
Post-treatment	2.61	3.72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Niacin, Placebo
	Comments	This is a pilot study to assess the effects of niacin on reverse cholesterol transport. The null hypothesis is that niacin has no effect on reverse cholesterol transport.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments	p value is for comparison between changes in reverse cholesterol transport in niacin versus placebo groups after 12 weeks of treatment.
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	6 months
Arm/Group Title	Niacin		Placebo
Arm/Group Description	Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated. Niacin: Niacin taken orally for 12 weeks at the highest tolerated dose (up to 6 grams), and at least 2 grams daily and up to the maximum approved dose. Subjects will initiate therapy with Niaspan and will advance to Niacor as tolerated.		Placebo tablet with 50 mg niacin for the first 4 weeks to maintain blinding of the study team and subjects, changed to pure placebo after that. Placebo: Placebo
All Cause Mortality
	Niacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Niacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Niacin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.