This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Rationale: Central nervous systems (CNS) complications including stroke and cognitive impairment cause significant morbidity and mortality in patients with sickle cell disease (SCD). Measurement of timed -averaged mean maximum blood flow velocity (TAMV) in the major cerebral arteries by transcranial Doppler (TCD) can identify children at risk for overt stroke. However, 20% of children with SCD have clinically silent cerebral ischemia that is not identified by TCD. These 'silent' cerebral infarcts are associated with significant cognitive impairment that may be prevented by monthly transfusions of sickle negative blood.Proposal: The Silent Infarct Transfusion (SIT) Trial is Phase III randomized controlled trial comparing monthly transfusions of sickle negative blood to usual care for children with SCD and silent infarct. We hypothesize that prophylactic transfusion therapy will result in at least 86% reduction in the proportion of patients with clinically evident strokes or new or progressive silent cerebral infarcts. We will evaluate the effect of transfusion on general intellectual abilities and the overall benefits and risks of transfusion therapy in this population. In addition, we will develop a repository for genetic studies of SCD.Methods: We will screen 1880 patients =6 and <13 years of age with sickle cell anemia (HbSS) or sickle ?-null thalassemia (HbSB0) from 23 centers. All patients (approximately 148 children at Johns Hopkins) will be screened by brain MRI including T1, T2, and diffusion weighted, and fluid attenuated inversion recovery (FLAIR) images, and time of flight magnetic resonance angiography (MRA); provide venous blood for the genetic repository; and complete a detailed demographic and phenotype form. We will identify about 375 patients with ischemic changes on MRI (25 at Hopkins). These children will be evaluated for established indications for transfusion (overt stroke, abnormal TCD), and receive further education about the intervention portion of the trial. We plan to randomize 102 children to each arm (monthly transfusion for 3 years versus routine care). All children will have another MRI and focused neuropsychological assessment immediately before randomization. The neuropsychological assessment will be repeated 12 to 18 months and 3 years later; the MRI will be repeated 3 years later. All MRIs will be reviewed centrally by at least 2 of the 3 study radiologists, both to identify infarct-like lesions prior to randomization and for study endpoints. Parents and medical providers will complete questionnaires to estimate the value of various health outcomes at the beginning and end of the study.Implications: This study will answer several important questions about transfusion therapy in children with SCD. It will provide a precise estimate of the efficacy of transfusion to prevent new or progressive silent infarct in children with SCD and silent infarct. We will also be able to detect changes in general intellectual abilities between the two groups The SIT trial will rigorously evaluate the benefits and risks of transfusion in children with SCD.
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