Novel Use of Hydroxyurea in an African Region with Malaria (NOHARM): A Randomized Controlled Trial
Bibliographic record
Abstract
Abstract Background. Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic settings such as sub-Saharan Africa, where the greatest sickle cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, through upregulation of intracellular adhesion molecule 1 (ICAM-1) that facilitates parasite adhesion to endothelium. In addition, hydroxyurea-associated neutropenia could worsen infections that occur in low-resource settings. Methods. NOHARM (NCT01976416) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda. Children between the ages of 1.00-3.99 years were enrolled, and then received 12-months of blinded treatment with either hydroxyurea or placebo at 20 ± 2.5 mg/kg/day, with dose adjustments in both arms for weight gain and hematological toxicities. All participants received standard care for SCA including folic acid, penicillin prophylaxis, and pneumococcal vaccination. For malaria prophylaxis, children received insecticide-treated mosquito nets and monthly sulphadoxine-pyrimethamine. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events, clinical and laboratory effects, and hematological toxicities. After completing the blinded treatment phase, all participants were offered open-label hydroxyurea, as per local Ethics Committee recommendations. Results. Study participants (median age 2.2 years) received either hydroxyurea (N=104) or placebo (N=103) for 12-months. Malaria occurred at a low rate throughout the study. The malaria incidence did not differ between children on hydroxyurea [0.05 episodes/child/year, 95% CI (0.02, 0.13)] versus placebo [0.07 episodes/child/year (0.03, 0.16)]. The hydroxyurea/placebo malaria incidence rate ratio was 0.7 [(0.2, 2.7), p=0.61], and time to infection did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%, p=0.001). For individual clinical events, vaso-occlusive pain and hospitalizations were significantly less frequent with hydroxyurea than placebo; the number needed to treat to prevent one hospitalization was 6.4, while the number needed to treat to prevent a SCA-related event was 2.5. Serious adverse events, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Specifically, low hemoglobin (<6.0 g/dL) occurred more frequently in children receiving placebo than hydroxyurea, while the frequencies of neutropenia, thrombocytopenia and reticulocytopenia did not differ significantly between treatment arms. Three deaths occurred (two hydroxyurea, one placebo, none from malaria). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, along with decreased leukocytes, neutrophils, and reticulocytes. Conclusions. In this prospective randomized double-blinded placebo-controlled trial of young children with SCA living in Uganda, hydroxyurea therapy was both safe and efficacious. Based on these NOHARM data, hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased risk for severe malaria, infections, or adverse events. Hydroxyurea provides predicted SCA-related laboratory and clinical efficacy, but the optimal dosing and monitoring regimens for affected children in Africa remain undefined. Disclosures Ware: Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Global Blood Therapeutics: Consultancy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".