After patient enrollment, a two-month pre-hydroxyurea evaluation phase will be used to perform baseline evaluations including nutritional and infectious assessments, and to provide supplements or treatments as deemed necessary. After the pre-hydroxyurea evaluation and supplementation phase, hydroxyurea dosing will be administered as a single daily dose, using capsules provided as a monthly supply in 200mg, 300mg, 400mg, or 500mg sizes.

Hydroxyurea will begin at 15-20 mg/kg PO daily. Six months of treatment will be given at the fixed dose, followed by another six months with dose escalation (2.5-5.0 mg/kg increments every 8 weeks) as tolerated to 20-30 mg/kg/day or MTD. The dose escalation phase will continue through the 12-month evaluation, after which hydroxyurea will continue in maintenance phase until the common treatment termination date. The daily dose will be calculated using available capsule sizes and a goal of 15-20 (17.5 ± 2.5) mg/kg/day based on weight. After 6 months of treatment, hydroxyurea will be titrated according to myelosuppression, and will be increased to 20-30 mg/kg/day or the maximum tolerated dose (MTD). Hydroxyurea dose escalation will occur in 5.0 ± 2.5 mg/kg/day increments.

An expected toxicity rate of 20% and acceptable toxicity rate of 30% were used for statistical calculations. After 53 participants at each site complete 3 months of therapy, if ≤ 15 participants have hematologic toxicity there is no early evidence against safety. If ≥ 15 of the initial participants experience toxicity, this is early evidence against safety. Future participants will begin at a lower dose of hydroxyurea (10 ± 2.5 mg/kg), with another 53 participants recruited of the same safety analysis. Upon final analysis of 133 participants at the same starting dose, safety for fixed-dose hydroxyurea can be concluded.

The efficacy of hydroxyurea will be primarily assessed through fetal hemoglobin (HbF), comparing treatment with baseline values. Additional measures of laboratory efficacy will include changes in Hb, MCV, WBC, ANC, ARC, and bilirubin. Clinical events such as vaso-occlusive pain will be captured as secondary outcomes.

Hydroxyurea administered at 15-20 mg/kg/ day as a single daily dose.

An expected toxicity rate of 20% and acceptable toxicity rate of 30% were used for statistical calculations. After 53 participants at each site complete 3 months of therapy, if ≤ 15 participants have hematologic toxicity there is no early evidence against safety. If ≥ 15 of the initial participants experience toxicity, this is early evidence against safety. Future participants will begin at a lower dose of hydroxyurea (10 ± 2.5 mg/kg), with another 53 participants recruited of the same safety analysis. Upon final analysis of 133 participants at the same starting dose, safety for fixed-dose hydroxyurea can be concluded.

N= number of participants analyzed for toxicity during the first 3 months of trial therapy

Hydroxyurea administered at 15-20 mg/kg/ day as a single daily dose.