Neurocognitive gains among Ugandan children with sickle cell anemia on hydroxyurea: 18-month interim trial results.

Children with sickle cell anemia (SCA) frequently develop progressive neurocognitive impairment. We aimed to determine effects of hydroxyurea therapy on neurocognitive function in Ugandan children with SCA by comparing levels at enrollment to a planned 18-month interim assessment. Ugandan children (N = 264) aged 3 to 9 years attending SCA clinic were enrolled and treated in a 30-month, single-arm, open-label trial with escalation to maximum tolerated dose. Sibling controls (N = 110) without SCA underwent parallel neurocognitive testing to establish age-normalized z scores for comparison. At enrollment, mean participant age was 5.6 ± 1.2 years, with comparable socioeconomic status and caregiver education vs. controls. Month 18 mean daily hydroxyurea dose was 25.4 mg/kg. We found significantly improved participant z scores vs. baseline in all 3 neurocognitive domains tested: cognition: -0.54 ± 1.10 vs. -0.07 ± 1.16, P < .001; attention: -0.07 ± 1.01 vs. 0.27 ± 0.84, P < .001; and executive function: -0.06 ± 0.62 vs. 0.08 ± 0.72, P = .010. No month-18 measures differed from controls. Participants with SCA and cognitive impairment declined from 8.7% at enrollment to 4.0%, vs. 1.6% of controls; with decreased mean TCD velocity. Improved neurocognitive treatment z-scores were associated with higher baseline scores and socioeconomic status, hydroxyurea-associated lower TCD velocity, and hematological-induced effects, eg higher hemoglobin. Despite improvement, unadjusted neurocognitive scores remained negatively associated with age. Hydroxyurea therapy improved SCA neurocognitive function in sub-Saharan children, potentially aided by practice effects. Early treatment is needed for optimal impact. Our ongoing trial will assess impact from longer-term hydroxyurea therapy. This trial was registered at www.ClinicalTrials.gov as #NCT04750707.