| Control Group |
Placebo |
Participants will initially be administered placebo at a dose of 20.0 ± 2.5 mg/kg/day averaged over the course of a week which is typically a low but effective dose. The hydroxyurea dose will then be escalated to MTD if they meet predesignated haematological criteria. In order to increase the dose all of the following must be true: ANC > 3.0 x 109/L, Hb > 7.0 g/dL, ARC > 80 x 109/L, platelets > 100 x 109/L. Dosing flexibility is permitted to allow for rounding to available tablet strengths. Placebo will be escalated at a similar rate to hydroxyurea participants in order to maintain the blind. |
Hydroxyurea or placebo will be provided in equal 1:1 randomization, stratified for age, during the first 12 months of study participation. After Month 12, hydroxyurea will be provided for study participants for the duration of the study. |
Placebo will be provided in 1000 mg tablets (scored in 250 mg) and 100 mg tablets (scored in 50 mg). Participants will receive their dose at each scheduled clinic visit based on treatment assignment and weight. |
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Placebo |
| Experimental Group |
Hydroxyurea |
Participants will initially be administered hydroxyurea at a dose of 20.0 ± 2.5 mg/kg/day averaged over the course of a week which is typically a low but effective dose. The hydroxyurea dose will then be escalated to MTD if they meet predesignated haematological criteria. In order to increase the dose all of the following must be true: ANC > 3.0 x 109/L, Hb > 7.0 g/dL, ARC > 80 x 109/L, platelets > 100 x 109/L. Dosing flexibility is permitted to allow for rounding to available tablet strengths. |
Participants will receive oral hydroxyurea for twelve (12) months, followed by an opportunity for subsequent open label treatment. |
Hydroxyurea is a cytotoxic, antimetabolic, and antineoplastic agent used for several decades to treat a variety of medical disorders, most notably myeloproliferative neoplasms, chronic myelogenous leukemia, and HIV. The efficacy of hydroxyurea for these varied medical conditions is due to its mechanism of action as a potent inhibitor of ribonucleotide reductase, a ubiquitous intracellular enzyme that converts ribonucleotides to deoxyribonucleotides, which are required for DNA synthesis and repair.
The first clinical application of hydroxyurea for patients with SCA was reported in 1984, when Platt and colleagues demonstrated a rapid and dramatic increase in HbF-containing reticulocytes without significant bone marrow toxicity. This and other 'proof-of-principle' experiments led to a critical phase I/II study of adults with SCA treated with hydroxyurea at maximum tolerated dose (MTD), which demonstrated significant dose-dependent increases in hemoglobin and HbF along with concurrent reduction in total white blood cell count, neutrophils, and reticulocytes. Similar results were observed in phase I/II studies involving school-age children, toddlers, and infants, all documenting the safety, laboratory benefits, and clinical efficacy of hydroxyurea for young patients with SCA. A pivotal Phase III trial of adults with SCA, using a randomized, double-blinded, placebo-controlled study design, proved the clinical efficacy of hydroxyurea for reduction of vaso-occlusive pain, acute chest syndrome, transfusions, and hospitalizations.
The phase III study of hydroxyurea in infants (BABY HUG) has recently been completed; although equivocal benefits for organ protection were observed during the 2-year treatment period, significant laboratory efficacy and clear clinical benefits for reducing pain, acute chest syndrome, hospitalizations, and transfusions were demonstrated. Three reports have documented the benefits of hydroxyurea
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