Niacin to Improve Blood Flow in People With Sickle Cell Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT00508989
First received: July 27, 2007
Last updated: March 14, 2014
Last verified: March 2014
  Purpose

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:

  • Flow-mediated dilation (FMD): An ultrasound picture of the artery in the forearm is obtained. A blood pressure cuff is then placed on the upper arm and inflated for 5 minutes. After the pressure cuff is released, the ultrasound is repeated.
  • Peripheral artery tonometry (PAT): A sensor is placed on the subject s finger. The sensor puts pressure on the finger and measures blood flow.
  • 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:

    • Sodium nitroprusside causes blood vessels to dilate and increases blood flow to the heart.
    • Acetylcholine causes blood vessels to dilate and slows heart rate.
    • LNMMA decreases blood flow by blocking the production of nitric oxide.

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:

  • Weeks 2, 6 and 10: Brief medical history, review of medication side effects and blood tests.
  • Weeks 4 and 8: Physical examination, brief medical history, review of medication side effects and blood tests, repeat FMD and PAT blood flow studies and 6-minute walk test.
  • Week 12: Same as weeks 4 and 8 plus standard blood flow studies and echocardiogram....

Condition Intervention Phase
Sickle Cell Disease
Drug: Niacin-ER
Drug: Placebo
Drug: L-NMMA
Drug: Acetylcholine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Niacin Therapy to Improve Endothelial Function in Sickle Cell Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The Effect of niacin-ER on endothelial dysfunction in the sickle cell. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Effect of niacin therapy on HDL and apo A-I levels in subjects with sickle cell disease. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: July 2007
Study Completion Date: April 2011
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 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
Placebo Comparator: 2 Drug: Placebo
500 mg daily for 4 weeks, 1000 mg daily for 4 weeks, and 1500 mg daily for 4 weeks

Detailed Description:

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, microvascular 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. Another 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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Males or females 18 to 65 years of age.
  • Diagnosis of sickle cell disease (electrophoretic or HPLC documentation of hemoglobin S only phenotype is required).
  • Hemoglobin greater than 5.5 grams per deciliter
  • Absolute reticulocyte count greater than 95,000 microliters if hemoglobin is less than 9.0 grams per deciliter.
  • An apoA-1 level lower than 99 milligrams per deciliter (median value among sickle cell subjects), or HDL-C level below 39 milligrams per deciliter (median value amongst our sickle cell cohort).

EXCLUSION CRITERIA:

  • Acute pain crisis requiring intravenous analgesics within the last week.
  • Current pregnancy or lactation.
  • Hemoglobin SC disease, or hemoglobin A greater than 20%
  • Conditions that may independently affect endothelial function:

    1. Diabetes mellitus
    2. Cigarette smoking within one month
    3. Uncontrolled hypertension
  • Serum creatinine greater than 2.0 milligram per deciliter
  • Serum alanine aminotransferase (ALT) greater than 3 times the upper limit of normal. (AST elevation will not be used as an exclusion criterion, since this is elevated in normal sickle cell subjects due to red cell lysis, even without liver injury)
  • Uric acid level greater than 8 or history of gout
  • History of GI bleeding within the past 6 months
  • Active peptic ulcer disease
  • Hemoglobin less than or equal to 5.5 grams per deciliter; however, subjects may return for evaluation at a later date.
  • No aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) for 1 week prior to forearm blood flow assessment and no caffeine the day of each forearm blood flow study. Subjects on opiates or acetaminophen will not be excluded.
  • Subjects taking sildenafil, vardenafil, tadalafil, L-arginine, fibrates (e.g., clofibrate, gemfibrozil, or fenofribrate) or inhaled nitric oxide within the last week will be excluded from the study.
  • Subjects taking any statin drug (e.g., fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin) within the last four weeks will be excluded from the study.
  • Subjects taking prostaglandins such as epoprostenol or treprostinil will be excluded from the study.
  • Subjects with significant cardiac disease and/or known peripheral Arterial disease.
  • Subjects with significant hypotension.
  • Women who do not use birth control while participating in this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00508989

Locations
United States, District of Columbia
Howard University Hospital
Washington, District of Columbia, United States, 20060
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: John F Tisdale, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT00508989     History of Changes
Other Study ID Numbers: 070196, 07-H-0196
Study First Received: July 27, 2007
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Acetylcholine
Forearm Blood Flow
HDL
L-NMMA
Sickle Cell Anemia
Sickle Cell Disease

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Acetylcholine
Niacin
Nicotinic Acids
Niacinamide
Omega-N-Methylarginine
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cholinergic Agonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 31, 2014