Niacin to Improve Blood Flow in People With Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): Niacin-ER; Placebo; L-NMMA; Acetylcholine
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 500 mg daily for 4 weeks, 1000 mg daily for 4 weeks, and 1500 mg daily for 4 weeks; 500 mg daily for 4 weeks, 1000 mg daily for 4 weeks, and 1500 mg daily for 4 weeks
Intervention MeSH terms: Niacin; Acetylcholine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Acetylcholine; Forearm Blood Flow; HDL; L-NMMA; Sickle Cell Anemia; Sickle Cell Disease