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

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Niacin
* Drug: Aspirin
* Drug: Fenofibrate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Extended-release niacin with aspirin<br> | Drug: Niacin<br>* 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)<br>Drug: Aspirin<br>* Aspirin 325 mg will be given by mouth in the evening with extended-release niacin through week 24.<br>|
| Experimental: Arm B: Fenofibrate<br> | Drug: Fenofibrate<br>* Fenofibrate will be administered as 200 mg by mouth once daily for 24 weeks.<br>|

What is the study measuring?
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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 |