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

Autor: Casella JF; Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Furstenau DK; Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Adams RJ; Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, USA., Brambilla DJ; Research Triangle Institute (RTI) International, Rockville, Maryland, USA., Lebensburger JD; Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Fehr JJ; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, USA., Jordan LC; Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA., King AA; Division of Pediatric Hematology/Oncology, Washington University and St. Louis Children's Hospital, St. Louis, Missouri, USA., Ichord RN; Department of Neurology and Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., McKinstry RC; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA., Kraut MA; Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Shaw DW; Department of Radiology, Seattle Children's Hospital, Seattle, Washington, USA., White DA; Department of Psychological Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, USA., Whyte-Stewart DA; Division of Nonmalignant Hematology, Food and Drug Administration (FDA), Silver Spring, Maryland, USA., Avadhani R; Department of Neurology and Neurosurgery, BIOS Clinical Trials Coordinating Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Barron-Casella EA; Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Cannon AD; Department of Neuropsychology, Kennedy Krieger Institute, Baltimore, Maryland, USA., Eaton CK; Biostatistics, Epidemiology, and Data Management Core, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA., Riekert KA; Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Shay JE; Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Smith-Seidel CA; Department of Psychology, Martinsburg Veterans Affairs Medical Center (VAMC), Martinsburg, West Virginia, USA., Weiss DC; Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Ostapkovich ND; Department of Neurology and Neurosurgery, BIOS Clinical Trials Coordinating Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Vermillion K; Vanderbilt Institute for Clinical and Translational Research (VICTR), Vanderbilt University Medical Center, Nashville, Tennessee, USA., Treine KE; Department of Neurology and Neurosurgery, BIOS Clinical Trials Coordinating Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Kingsbury CE; Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Strouse JJ; Department of Medicine and Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA., Thompson RE; Department of Biostatistics, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA., Hanley DF; Department of Neurology and Neurosurgery, BIOS Clinical Trials Coordinating Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: American journal of hematology [Am J Hematol] 2024 Oct; Vol. 99 (10), pp. 1906-1916. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1002/ajh.27423
Abstrakt: 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-β 0 -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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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