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Sponsored by: |
National Heart, Lung, and Blood Institute (NHLBI) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00508989 |
This study will determine whether niacin can improve blood flow in people with sickle cell disease, in which abnormal red blood cells interfere with blood flow to cause the disease symptoms. Niacin, a drug that has been used to increase HDL (good cholesterol) levels, improves blood flow in people without sickle cell disease. This study will see if it can do the same in people with the disease.
Patients with sickle cell disease between 18 and 65 years of age may be eligible for this study.
Candidates are screened with a medical history, physical examination, blood tests, echocardiogram and 6-minute walk test of exercise capacity.
Participants have the following baseline blood flow studies:
Standard forearm blood flow test: Small tubes are placed in the artery of the forearm at the inside of the elbow. Saline is infused into one tube. Pressure cuffs are applied to the wrist and upper arm. A strain gauge (rubber band device) is placed around the forearm. When the cuffs are inflated, blood flows into the arm, stretching the strain gauge, and the flow measurement is recorded. Blood samples are collected from the tube in the artery to measure blood counts, proteins and other chemicals. At various times, small doses of the following drugs are administered through the tube in the vein:
Blood flow is measured after each dose of the different drugs. There are rest periods between injections of the different drugs. Pictures of the forearm are taken during the studies using an infrared camera and computer.
-Drug Treatment. Participants are assigned to take three 4-week courses of niacin or placebo. They return to the Clinical Center at the following intervals from the time they start the test drug for followup:
Condition | Intervention | Phase |
---|---|---|
Sickle Cell Disease |
Drug: Niacin-ER Drug: Placebo Drug: L-NMMA Drug: Acetylcholine |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study |
Official Title: | Niacin Therapy to Improve Endothelial Function in Sickle Cell Disease |
Estimated Enrollment: | 60 |
Study Start Date: | July 2007 |
Arms | Assigned Interventions |
---|---|
1: Experimental |
Drug: Niacin-ER
500 mg daily for 4 weeks, 1000 mg daily for 4 weeks, and 1500 mg daily for 4 weeks
Drug: L-NMMA
N/A
Drug: Acetylcholine
N/A
|
2: Placebo Comparator |
Drug: Placebo
500 mg daily for 4 weeks, 1000 mg daily for 4 weeks, and 1500 mg daily for 4 weeks
|
Sickle cell disease is an autosomal recessive disorder and the most common genetic disease affecting African-Americans. Approximately 0.15 percent of African-Americans are homozygous for sickle cell disease, and 8 percent have sickle cell trait. Hemoglobin S polymerization leads to red cell rigidity, micro vascular obstruction, inflammation, and end-organ ischemic injury. Our published data indicate that up to 50 percent of sickle cell patients have vascular dysfunction due to impaired bioavailability of endogenous nitric oxide, due in large part to scavenging of nitric oxide by cell-free hemoglobin. We recently have completed studies that directly demonstrate endothelial dysfunction in patients with sickle cell disease, characterized by decreased ACh dependent vasorelaxation in forearm blood flow studies, distinct from the nitric oxide resistance above. Further, we have found in sickle cell patients a new association between low levels of apoA-I, pulmonary hypertension and endothelial dysfunction. Raising levels of HDL, and therefore apoA-1, could have the effect of ameliorating the endothelial dysfunction characteristic of sickle cell disease by affecting endothelium dependent vasorelaxation. Therapies directed at restoring HDL in these patients may be beneficial.
HDL is thought to promote vascular health in a variety of ways, some of which are unrelated to lipid transport. One of the best-known mechanisms relates to efflux of cholesterol from atherosclerotic plaque, yet HDL is thought to have several antithrombotic and anti-inflammatory effects. In vitro HDL attenuates formation of oxidized LDL and inhibits endothelial cell expression of inflammatory cell adhesion molecules. It is also thought to mediate NO production via stimulation of eNOS, thereby modulating endothelial function. In a study of subjects with atherosclerosis, low HDL levels correlated with impaired vasomotor relaxation via brachial artery FMD. Study utilizing recombinant HDL cholesterol infused into brachial arteries of hypercholesterolemic men resulted in increased acetylcholine mediated blood flow that was inhibited by the infusion of L-NAME, an eNOS inhibitor, suggesting that HDL increased blood flow via an eNOS dependent mechanism. This may have implications not only for subjects with atherosclerosis, but also for those with sickle cell disease and endothelial dysfunction.
We propose that niacin therapy could improve vascular reactivity in response to acetylcholine. Several options for increasing HDL levels have been previously utilized in forearm flow studies using venous occlusion plethysmography or flow-mediated dilation. Reconstituted HDL (rHDL), apoA-1 mimetics and niacin therapy were all shown to improve endothelial dysfunction, and proved safe and effective.
This trial will aim to 1) establish the effects of niacin treatment on raising HDL levels in subjects with sickle cell disease, 2) investigate whether niacin treatment would result in improvement of endothelial-dependent relaxation via venous occlusion plethysmography, and 3) compare the efficacy of peripheral arterial tonometry measurements to venous occlusion plethysmography and flow-mediated dilation as indicators of vascular dysfunction.
Ages Eligible for Study: | 18 Years to 65 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
EXCLUSION CRITERIA:
Conditions that may independently affect endothelial function:
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, District of Columbia | |
Howard University Hospital | Recruiting |
Washington, District of Columbia, United States, 20060 | |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 |
Responsible Party: | National Institutes of Health ( Mark T. Gladwin, M.D./National Heart, Lung, and Blood Institute ) |
Study ID Numbers: | 070196, 07-H-0196 |
Study First Received: | July 27, 2007 |
Last Updated: | November 11, 2008 |
ClinicalTrials.gov Identifier: | NCT00508989 |
Health Authority: | United States: Federal Government |
Acetylcholine Forearm Blood Flow HDL |
L-NMMA Sickle Cell Anemia Sickle Cell Disease |
Hematologic Diseases Anemia Anemia, Hemolytic Sickle cell anemia Anemia, Hemolytic, Congenital Nicotinic Acids Genetic Diseases, Inborn |
Hemoglobinopathies Omega-N-Methylarginine Acetylcholine Hemoglobinopathy Anemia, Sickle Cell Niacin |
Antimetabolites Neurotransmitter Agents Vasodilator Agents Vitamin B Complex Molecular Mechanisms of Pharmacological Action Growth Substances Antilipemic Agents |
Physiological Effects of Drugs Cardiovascular Agents Cholinergic Agents Pharmacologic Actions Therapeutic Uses Vitamins Micronutrients |