This proposal is for a randomized double-blind controlled trial of hydroxyurea, to determine whether crisis attack rates in patients with sickle cell anemia can be reduced by at least 50%. Recurrent painful crises are the most disabling feature of the disease, interfering with education, vocational training, job retention and psychosocial development. Polymerization of sickle hemoglobin within deoxygenated red cells makes them rigid; vasocclusive lesions produced by non-deformable red cells are the cause of painful crises. Fetal hemoglobin (HbF) interferes with polymerization. Clinical observations suggest that if Hb F levels exceed 15%, patients have fewer crises. Our preliminary results indicate that at least half of group of patients treated with hydroxyurea can achieve that level within 1 year. The only toxicity encountered has been mild, readily reversible bone marrow depression. Approximately 296 patients will be recruited from 17 clinics. Drug doses will be gradually increased from 15 mg/kg to the maximum level tolerated by each patient; placebo doses will be manipulated in the same fashion. All persons with direct patient contact will be blinded. Each crisis reported will be reviewed by an external committee to assure that it meets study criteria. The preliminary analysis will be a comparison of crisis attack rates in the treated and control groups. Secondary analyses will include comparison of changes in clinical condition (pain severity and duration and psychosocial status) with changes in Hb F production, complications of the disease in the two groups, and reasons for non-compliance with either regimen. A clinical trial is necessary at this time because clinician are already using hydroxyurea to treat sickle cell disease, without proof of efficacy. The drug can be used safely, but careful monitoring is needed, and the cost and inconvenience of that monitoring demand that efficacy be proven.
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