Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

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-ß0-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.

Proteomic discovery in sickle cell disease: Elevated neurogranin levels in children with sickle cell disease.

PURPOSE: Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes stroke and silent cerebral infarct (SCI). Our aim was to identify markers of brain injury in SCD. EXPERIMENTAL DESIGN: Plasma proteomes were analyzed using a sequential separation approach of hemoglobin (Hb) and top abundant plasma protein depletion, followed by reverse phase separation of intact proteins, trypsin digestion, and tandem mass spectrometry. We compared plasma proteomes of children with SCD with and without SCI in the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) to age-matched, healthy non-SCD controls. RESULTS: From the SCD group, 1172 proteins were identified. Twenty-five percent (289/1172) were solely in the SCI group. Twenty-five proteins with enriched expression in the human brain were identified in the SCD group. Neurogranin (NRGN) was the most abundant brain-enriched protein in plasma of children with SCD. Using a NRGN sandwich immunoassay and SIT Trial samples, median NRGN levels were higher at study entry in children with SCD (0.28 ng/mL, N = 100) compared to control participants (0.12 ng/mL, N = 25, p < 0.0004). CONCLUSIONS AND CLINICAL RELEVANCE: NRGN levels are elevated in children with SCD. NRGN and other brain-enriched plasma proteins identified in plasma of children with SCD may provide biochemical evidence of neurological injury.