Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa
| Autor: | Adam Lane, Teresa Latham, Chandy C. John, Robert O. Opoka, Christopher M. Ndugwa, Heather Hume, Catherine Nabaggala, Phillip Kasirye, Russell E. Ware |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Pediatrics medicine.medical_specialty Sub saharan Anemia Anemia Sickle Cell 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Double-Blind Method Antisickling Agents hemic and lymphatic diseases parasitic diseases Dose escalation Humans Hydroxyurea Medicine Uganda Prospective Studies 030212 general & internal medicine Malaria epidemiology Peripheral Vascular Diseases Dose-Response Relationship Drug business.industry Incidence Incidence (epidemiology) General Medicine medicine.disease Sickle cell anemia Malaria Child Preschool Female business |
| Zdroj: | New England Journal of Medicine. 382:2524-2533 |
| ISSN: | 1533-4406 0028-4793 |
| DOI: | 10.1056/nejmoa2000146 |
| Popis: | Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P0.001). Children in the dose-escalation group had fewer sickle cell-related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia.Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children's Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.). |
| Databáze: | OpenAIRE |
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