Endothelial Function, Lipoproteins, and Inflammation With Low HDL Cholesterol in HIV: ER Niacin Versus Fenofibrate

Effect of HDL-Raising Therapies on Endothelial Function, Lipoproteins, and Inflammation in HIV-infected Subjects With Low HDL Cholesterol: A Phase II Randomized Trial of Extended Release Niacin vs. Fenofibrate

This study is being done with people with HIV infection who have low levels of HDL-C. HDL-C is a type of "good" cholesterol. People with low HDL-C have a higher risk of heart disease and may have problems with how their blood vessels relax. The endothelium is the inner lining of all blood vessels, such as arteries and veins. When the endothelium is not working properly, the blood vessels have trouble expanding properly, which contributes to the development of heart and blood vessel disease.

The main purpose of this study is to see if taking either extended-release niacin or fenofibrate for 24 weeks will help blood vessels work better by improving endothelial function and increasing HDL-C. Niacin and fenofibrate are medications that raise HDL-C. This study will also help determine how safe extended-release niacin and fenofibrate are.

The analysis is an as-treated analysis of participants who completed study treatment and had a week 24 BART scan. Safety analyses include all participants

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Niacin; Drug: Aspirin; Drug: Fenofibrate

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama Therapeutics CRS (5801)
  • California
    • Los Angeles, California, United States, 90033-1079
      • University of Southern California (1201)
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS (601)
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS (603)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS (6101)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS (2701)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School-Adult Clinical Research Ctr. CRS (31477)
  • New York
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS (401)
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • Unc Aids Crs (3201)
    • Durham, North Carolina, United States, 27710
      • Duke Univ. Med. Ctr. Adult CRS (1601)
    • Greensboro, North Carolina, United States, 27401
      • Moses H. Cone Memorial Hospital CRS (3203)
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS (2401)
    • Cleveland, Ohio, United States, 44106
      • Case CRS (2501)
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS (1401)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infection
• Currently on continuous ART for ≥48 weeks.
• CD4+ cell count ≥100/mm3 obtained within 60 days prior to study entry.
• Most recent HIV-1 RNA below the limit of detection using an ultrasensitive licensed or FDA-approved assay obtained within 60 days prior to study entry.
• Certain laboratory values obtained within 60 days prior to study entry (as indicated in the protocol).
• HDL-C ≤ 40 mg/dL for men or ≤ 50 mg/dL for women within 60 days prior to study entry by any local assay.
• Fasting triglycerides 150-800 mg/dL within 60 days prior to study entry, (initially 200-800 mg/dL, amended during study conduct).
• LDL-C < 160 mg/dL within 60 days prior to study entry.
• For women of reproductive potential, negative serum or urine pregnancy test with a sensitivity of 15-25 mIU/mL within 60 days prior to entry.
• Female subjects of reproductive potential must agree to use a reliable method of contraception while receiving study drug and for 6 weeks after stopping study drug.

Exclusion Criteria:

• Anticipation of changing ART.
• Intent to initiate or change the dose of lipid-lowering drugs or antihypertensives during study.
• Active acute infection or other serious illness requiring systemic treatment and/or hospitalization until subject either completes or is clinically stable on therapy in the opinion of the site investigator.
• Untreated hypogonadism
• History of physician-diagnosed diabetes mellitus or currently taking glucose-lowering medication, (amended during study conduct to allow well-controlled diabetics who are diet controlled or on stable antidiabetic treatment of metformin, sulfonylurea, meglitinides or alpha-glucosidase inhibitors).
• Hormonal anabolic therapies within 90 days prior to study entry.
• Uncontrolled hypertension within 60 days of study entry.
• Acute symptoms of gout within 60 days prior to study entry.
• Active peptic ulcer disease as defined by a health care professional. Treatment for gastroesophageal reflux disease (GERD) is not exclusionary.
• Documented untreated hypothyroidism per subject's medical records.
• Use of thyroid hormone supplements other than for treatment of hypothyroidism within 30 days prior to entry.
• Active or symptomatic gallbladder disease within 1 year of study entry.
• Active cancer requiring systemic chemotherapy or radiation within 1 year of study entry.
• Lipid-lowering agents within 30 days prior to study entry.
• Use of fish oil with DHA/EPA >1000 mg/day within 30 days prior to entry.
• Niacin or niacin-containing products that contain >100 mg daily within 30 days prior to study entry.
• Use of vitamin E supplements greater than 200 IU/day within 30 days prior to entry.
• Use of vitamin C supplements greater than 250 mg/day within 30 days prior to entry.
• Use of systemic cancer chemotherapy, immunomodulators (e.g., growth factors, immune globulin, interleukins, and interferons) within 90 days prior to study entry.
• Any systemic glucocorticoid above replacement levels, defined as the equivalent of ≥ 7.5 mg of prednisone daily, within 60 days prior to study entry.
• Allergy, sensitivity, or severe intolerance to both aspirin and naproxen (Aleve, Naprosyn).
• Symptomatic pancreatitis with hospitalization.
• Pregnancy or currently breastfeeding.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Currently taking or anticipation of starting medication during the study for hepatitis C including interferon and ribavirin.
• Documented history of macular edema.
• Current severe congestive heart failure (New York Heart Association [NYHA] Class III or IV).
• History of or current diagnosis of coronary artery disease, angina pectoris, myocardial infarction, previous coronary artery intervention (stenting, angioplasty), peripheral arterial disease (claudication, peripheral arterial angioplasty, or peripheral arterial bypass procedure), cerebrovascular disease (stroke or transient ischemic attack with documented carotid or aortic atherosclerosis), or abdominal aortic aneurysm.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Extended-release niacin with aspirin	Drug: Niacin; Extended-release niacin will be given with aspirin 325 mg by mouth in the evening and dose-escalated as follows: 500 mg once daily for 4 weeks, 1000 mg once daily for 4 weeks, then 1500 mg once daily for 16 weeks (through week 24); Drug: Aspirin; Aspirin 325 mg will be given by mouth in the evening with extended-release niacin through week 24.
Experimental: Arm B: Fenofibrate	Drug: Fenofibrate; Fenofibrate will be administered as 200 mg by mouth once daily for 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in Relative FMD (%)	The absolute change in maximum relative flow mediated dilation (FMD) (%) of the brachial artery from baseline to week 24.	0 and 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cholesterol	Absolute change in total cholesterol from week 0 to week 24.	0 and 24 weeks
Change in Triglycerides	Change in Triglycerides (mg/dL) from week 0 to week 24.	0 and 24 weeks
Men: Change in HDL Cholesterol	Among men, change in HDL Cholesterol (mg/dL) from week 0 to week 24.	0 and 24 weeks
Women: Change in HDL Cholesterol	Among women, change in HDL cholesterol (mg/dL) from week 0 to week 24.	0 and 24 weeks
Change in HDL Particles	Change in total HDL particles from week 0 to week 24	0 and 24 weeks
Change in Non-HDL Cholesterol	Change in non-HDL Cholesterol (mg/dL) from week 0 to week 24.	0 and 24 weeks
Change in LDL Cholesterol	Change in LDL cholesterol (mg/dL) from week 0 to week 24.	0 and 24 weeks
Change in Small LDL Particles	Change in Small LDL particles from week 0 to week 24.	0 and 24 weeks
Change in Large HDL Particles	Change in Large HDL Particles from week 0 to week 24	0 and 24 weeks
Change in HOMA-IR	Absolute change from week 0 to week 24 in insulin resistance as estimated by HOMA-IR	0 and 24 weeks
Change in IL-6	Change in IL-6 from week 0 to week 24	0 and 24 weeks
Change in C-reactive Protein (CRP)	Change in C-reactive protein from week 0 to week 24.	0 and 24 weeks
Change in D-Dimer	Change in D-Dimer from week 0 to week 24	0 and 24 weeks

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Michael P Dube, MD, University of Southern California; Study Chair: James H Stein, MD, University of Wisconsin School of Medicine and Public Health (Northwestern University CRS)

Publications and helpful links

General Publications

• International Conference on Harmonisation. E2A: Clinical Safety Data Management : Definitions and Standards for Expedited Reporting. Website: http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/clinical-safety-data-management-definitions-and-standards-for-expedited-reporting.html. Accessed May 24, 2011.
• Dube MP, Chan ES, Lake JE, Williams B, Kinslow J, Landay A, Coombs RW, Floris-Moore M, Ribaudo HJ, Yarasheski KE. A Randomized, Double-blinded, Placebo-controlled Trial of Sitagliptin for Reducing Inflammation and Immune Activation in Treated and Suppressed Human Immunodeficiency Virus Infection. Clin Infect Dis. 2019 Sep 13;69(7):1165-1172. doi: 10.1093/cid/ciy1051.
• Dube MP, Komarow L, Fichtenbaum CJ, Cadden JJ, Overton ET, Hodis HN, Currier JS, Stein JH; AIDS Clinical Trials Group A5293 Study Team. Extended-Release Niacin Versus Fenofibrate in HIV-Infected Participants With Low High-Density Lipoprotein Cholesterol: Effects on Endothelial Function, Lipoproteins, and Inflammation. Clin Infect Dis. 2015 Sep 1;61(5):840-9. doi: 10.1093/cid/civ385. Epub 2015 May 15.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: August 30, 2011
• First Submitted That Met QC Criteria: August 30, 2011
• First Posted (Estimate): August 31, 2011

Study Record Updates

• Last Update Posted (Estimate): February 3, 2016
• Last Update Submitted That Met QC Criteria: January 4, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Aspirin; Fenofibrate; Niacin
• Other Study ID Numbers: ACTG A5293; 1U01AI068636 (U.S. NIH Grant/Contract)