Protocol Number: 03-CC-0127

Title:

Evaluation of Potential Synergy of Combining Hydroxyurea with Nitric Oxide Donors on Fetal Hemoglobin Synthesis in Patients with Sickle Cell Anemia

Number:

03-CC-0127

Summary:

Patients with sickle cell disease have abnormal hemoglobin (the protein in red blood cells that carries oxygen to the body). This abnormality causes red blood cells to take on a sickle shape, producing disease symptoms. Fetal hemoglobin, a type of hemoglobin present in fetuses and babies, can prevent red cells from sickling. The drug hydroxyurea increases fetal hemoglobin production in patients with sickle cell disease by making a molecule called nitric oxide. The drugs L-arginine and Sildenafil (Viagra) increase the amount or the effect of nitric oxide. This study will evaluate:

- The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease;

- The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease; and

- The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease. (Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease, and this condition increases the risk of dying from the disease.)

Patients with hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype may be eligible for this study.

Before starting treatment, patients will have a complete medical history and physical examination. All patients will take hydroxyurea once a day every day by mouth for at least 2 months. They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea, and will have blood drawn through a catheter (plastic tube placed in a vein) every hour for 6 hours for tests to determine nitric oxide levels. After discharge, they will return to the clinic once every 2 weeks to check for treatment side effects and for blood tests to monitor hemoglobin and fetal hemoglobin levels. After fetal hemoglobin levels have been stable for 2 months, patients will be admitted to the Clinical Center for their first dose of L-arginine (for men) or Sildenafil (for women). Again, blood samples will be collected through a catheter once an hour for 6 hours. If there are no complications, patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been stable for at least 2 months. Patients will return to the clinic for blood tests every week for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to check for treatment side effects.

Patients will have eye examinations before and during treatment. Some patients with sickle cell disease develop abnormalities in the blood vessels of the eye. Also, Sildenafil can cause temporary changes in color vision. Rarely, more serious eye problems can occur, such as bleeding from the eye blood vessels or damage to the retina-a layer of tissue that lines the back of the eye. Patients will also have an echocardiogram (ultrasound of the heart) before beginning treatment, after hydroxyurea treatment, and after 1 and 3 months of combined treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the lungs.

Patients who develop complications from L-arginine or Sildenafil may continue in the study on hydroxyurea alone. Patients whose fetal hemoglobin levels increase with the combination therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them.

Sponsoring Institute:

Warren G. Magnuson Clinical Center (CC)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

A total of 50 patients with homozygous sickle cell disease or other sickling disorders (e.g., B(0) or B(+) Thalassemia/Sickle) whom are greater than 15 years of age will be eligible for treatment.

Patients currently being followed on an NIH study or at Howard University on stable doses of hydroxyurea are also eligible.

Patients must have documented hemoglobin S-only, S-beta-thalassemia, or other sickle cell disease genotype. Only patients with hemoglobin S-only will be considered in the primary analysis.

Patients must have relatively well preserved renal and hepatic function (creatinine less than 1.6 mg/dl and normal liver function test less than 5 X normal ALT).

Evidence of severe sickle cell anemia will include one or more of the following: recurrent pain crisis (greater than or equal to 2 ER visits per year), recurrent acute chest syndrome (a lung problem like pneumonia), hospitalizations, leg ulceration, priapism, aseptic necrosis of the hip, and/or pulmonary hypertension.

Patients must be able to provide informed consent.

EXCLUSION CRITERIA:

Patients who have hemoglobin S and A (trait) or hemoglobin A-only (non-sickle cell).

Patients must not be on a chronic transfusion program, defined as regular transfusions every 2-8 weeks.

Patients must not be pregnant or breast feeding.

Patients on chronic nitrates, such as nitroglycerin.

Special Instructions: Currently Not Provided

Keywords:

Fetal Hemoglobin Induction

L-Arginine

Nitric Oxide Therapy

Sickle Cell Disease

Sildenafil (Viagra)

Recruitment Keywords:

Sickle Cell Anemia

Conditions:

Sickle Cell Anemia

Investigational Drug(s):

Hydroxyurea

L-Arginine

Sildenafil

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Rodgers GP, et al. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med. 1990 Apr 12;322(15):1037-45. PMID: 1690857

Goldberg MA, et al. Treatment of sickle cell anemia with hydroxyurea and erythropoietin. N Engl J Med. 1990 Aug 9;323(6):366-72. PMID: 1695325

Charache S, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.

Blood. 1992 May 15;79(10):2555-65.

PMID: 1375104

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

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