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Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized,
James F Casella1, Dana K Furstenau1, Robert J Adams2
1Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Insights
Hydroxyurea shows promise in preventing central nervous system (CNS) injury in children with sickle cell disease (SCD). This pilot study suggests a significant reduction in CNS injury incidence with hydroxyurea treatment.
Area of Science:
- Neurology
- Hematology
- Pediatrics
Background:
- Central nervous system (CNS) injury is a frequent complication in sickle cell disease (SCD), impacting children early in life.
- While hydroxyurea is a known treatment for SCD, high-quality randomized trial data on its neuroprotective effects are limited.
- The HU Prevent trial aimed to assess the feasibility and efficacy of hydroxyurea in preventing CNS injury in young children with SCD.
Purpose of the Study:
- To evaluate the neuroprotective effect of dose-escalated hydroxyurea compared to placebo in preventing CNS injury in children with SCD.
- To assess the incidence of a composite primary outcome and a secondary Stroke Consequences Risk Score (SCRS).
Main Methods:
- A randomized, double-blind, placebo-controlled, phase II feasibility/pilot trial (HU Prevent) involving children aged 12-48 months with HbSS or HbS-β0-thalassemia.
- Participants received either dose-escalated hydroxyurea or placebo, with regular neurological examinations, MRI, and cerebral blood flow velocity assessments.
- The primary outcome was a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke.
Main Results:
- One participant in the hydroxyurea group experienced a primary outcome event versus four in the placebo group, indicating an approximate 80% reduction in incidence.
- The mean Stroke Consequences Risk Score (SCRS) was significantly lower in the hydroxyurea group (0.078) compared to the placebo group (0.312), p=0.072.
- No serious adverse events were directly attributed to hydroxyurea; three serious adverse events were related to sedation during MRI procedures.
Conclusions:
- Hydroxyurea demonstrated a potential profound neuroprotective effect in children with SCD, significantly reducing the incidence of CNS injury.
- The findings support the need for a definitive phase III study to confirm these results and advocate for early hydroxyurea use in infants with SCD.
- Further research is warranted to establish hydroxyurea as a standard preventative therapy for CNS complications in pediatric SCD.
Abstract:
Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-β0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.
