Stroke occurs in about 10% of pediatric patients with Sickle Cell Disease (Hb SS) and is a major cause of morbidity. The 46-90% rate of recurrence can be reduced to less than 10% by chronic blood transfusion. Secondary prevention programs based on transfusion have become the standard of care, but most patients have already suffered irreversible brain injury. Prevention of first stroke is now possible using transcranial Doppler (TCD) ultrasound which can detect arterial abnormalities which place these children at high risk for cerebral infarction. Prediction is based on the detection of high arterial blood flow rates which are associated with arterial narrowing and subsequent cerebral infarction. Combining predictive screening and a potentially effective treatment, prevention of stroke before brain injury occurs is now possible. A randomized, controlled trial is needed to determine if first stroke in high risk children is significantly reduced by prophylactic transfusion. This randomized, controlled, multicenter trial of efficacy of periodic blood transfusion will test the hypothesis that reduction of sickle hemoglobin to 30% or less with transfusion will reduce first time stroke by at least 70% compared to supportive medical care. Primary endpoints will be clinically evident symptoms of cerebral infarction with consistent findings on Magnetic Resonance Imaging (MRI), symptomatic intracranial hemorrhage and death from any cause; secondary endpoints will be asymptomatic brain lesions, detected by MR in brain areas not implicated in primary endpoints. Hematologic characteristics of the high risk group will be analyzed and serum and DNA samples frozen for future analyses. Study design calls for 6-month start-up, TCD screening and randomization conducted during months 6-24, and observation for stroke from entry through month 54. TCD will be interpreted blindly. Endpoints will be adjudicated and MRIs interpreted centrally by blinded panels. Sample size calculation is based on prospective data relating to TCD velocity to risk of stroke and a randomization criterion associated with a 46% risk of cerebral infarction over 36 months of observation. Sample size (60 each group) is sufficient to detect 70% reduction in the primary endpoint of stroke at 90% power allowing for up to a 10% dropout. The pool of asymptomatic children to be screened at the 12 centers participating in this trial is two times that needed to find the 120 patients. Random TCD screening at four centers suggests prevalence rates of the high risk state comparable to those reported by this investigative team in the pilot study on which trial assumptions are based. This trial is significant because it will determine if transfusion is effective in the primary prevention of stroke in Hb SS children at risk for stroke. Primary prevention is preferable to secondary prevention because it intervenes before the occurrence of brain injury. Secondary aims may further understanding of the effects of transfusion on the brain and guide future research into the cause(s) of cerebrovascular involvement in Hb SS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
1U10HL052016-01
Application #
2229119
Study Section
Clinical Trials Review Committee (CLTR)
Project Start
1994-07-15
Project End
1999-06-30
Budget Start
1994-07-15
Budget End
1995-06-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
New England Research Institute
Department
Type
DUNS #
153914080
City
Watertown
State
MA
Country
United States
Zip Code
02472
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Hyacinth, Hyacinth I; Adams, Robert J; Voeks, Jenifer H et al. (2014) Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk. Am J Hematol 89:47-51
Hyacinth, Hyacinth I; Gee, Beatrice E; Adamkiewicz, Thomas V et al. (2012) Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia. Cytokine 60:302-8
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Abboud, Miguel R; Cure, Joel; Granger, Suzanne et al. (2004) Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study. Blood 103:2822-6
Adams, Robert J; Brambilla, Donald J; Granger, Suzanne et al. (2004) Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Blood 103:3689-94
Hsu, Lewis L; Miller, Scott T; Wright, Elizabeth et al. (2003) Alpha Thalassemia is associated with decreased risk of abnormal transcranial Doppler ultrasonography in children with sickle cell anemia. J Pediatr Hematol Oncol 25:622-8
Kral, Mary C; Brown, Ronald T; Nietert, Paul J et al. (2003) Transcranial Doppler ultrasonography and neurocognitive functioning in children with sickle cell disease. Pediatrics 112:324-31
Miller, S T; Wright, E; Abboud, M et al. (2001) Impact of chronic transfusion on incidence of pain and acute chest syndrome during the Stroke Prevention Trial (STOP) in sickle-cell anemia. J Pediatr 139:785-9

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