Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (HUPrevent)
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|ClinicalTrials.gov Identifier: NCT01389024|
Recruitment Status : Active, not recruiting
First Posted : July 7, 2011
Last Update Posted : October 8, 2019
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease Stroke||Drug: Hydroxyurea Drug: Placebo||Phase 2|
Stroke, silent cerebral infarct (SCI), and cognitive impairment are frequent and highly morbid complications of sickle cell disease (SCD) in children. Current approaches to the prevention and treatment of neurological complications in SCD include screening by transcranial Doppler ultrasound (TCD) to identify children with elevated cerebral blood flow velocity who are at increased risk for strokes; these children are then typically treated with chronic transfusions indefinitely. Hydroxyurea (HU) may have beneficial effects on central nervous system (CNS) complications in SCD and reduces the frequency of painful crisis, acute chest syndrome and transfusion. The safety of HU in infants and children has been suggested in a National Institutes of Health (NIH) sponsored phase III trial; however, the exact indications for the use of HU in children remain unclear, as well as its efficacy in preventing central nervous system (CNS) complications of SCD. Our preliminary data suggest that, if the cumulative frequency of abnormal TCD, SCI and stroke could be reduced by 50%, the majority of pediatric hematologists would prescribe HU to all young children with SCD. The long term goal of this project is to perform a primary prevention trial to demonstrate the neuroprotective effect of HU and broaden the indications for HU in children. The goals of this proposal are to: 1) conduct an internal pilot randomized placebo-controlled trial of HU to reduce the CNS complications of SCD (the term internal pilot is used, as the results from the participants in the pilot will be analyzed as part of a definitive phase III trial to follow); 2) demonstrate the safety of hydroxyurea and study procedures in young children with SCD; and 3) create the leadership, network of clinical centers and other procedures necessary to conduct a definitive phase III trial demonstrating the efficacy of HU for primary prevention of the neurological complications of SCD.
The primary endpoint for the internal pilot and definitive phase III trials will be the development of abnormal TCD, SCI, TIA or stroke. To begin the internal pilot trial, the investigators obtained Clinical and Translational Science Award (CTSA) support at Johns Hopkins and Washington University; these sites will screen 40 participants 9-48 months of age and randomly assign and follow 20 participants for three years. Four additional centers (Children's Hospital of Philadelphia, Vanderbilt University,Children's Hospital Medical Center, Cincinnati and the University of Alabama, Birmingham) began enrollment (up to 20 patients screened and 10 participants randomly assigned per site), to provide a total of 80 participants screened, 40 randomly assigned, and a minimum of 70 participant years of follow-up. Additional sites have been added. Participants must have TCD measurements that are well below transfusion thresholds and magnetic resonance imaging (MRI) of the brain without evidence of SCI. Participants in the internal pilot will continue into a phase III trial, to complete 3 years on HU or placebo. The information from the internal pilot trial will be used to improve the design of the definitive phase III trial. The results of these studies could lead to true primary prevention of CNS complications of SCD, including abnormal TCD, SCI, neurocognitive impairment and stroke. In doing so, this study could also reduce the burden of chronic transfusions and change clinical practice by broadening the indications for HU.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children|
|Study Start Date :||October 2011|
|Estimated Primary Completion Date :||August 2020|
|Estimated Study Completion Date :||August 2020|
treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC <4000
Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.
Placebo Comparator: Placebo
Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day
Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Other Name: Sugar
- Central Nervous System Complications [ Time Frame: 3 years ]A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.
- Proportion of participants with severe adverse events attributed to study procedures [ Time Frame: 3 years ]We will evaluate the safety of study procedures including the sedation required to obtain magnetic resonance imaging (MRI) of the brain in young children and administration of hydroxyurea.
- Proportion of participants undergoing randomization [ Time Frame: 6 months ]We will evaluate the proportion of screened participants that undergo randomization to hydroxyurea or placebo
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01389024
|United States, Alabama|
|University of Alabama|
|Birmingham, Alabama, United States, 35233|
|United States, Maryland|
|Baltimore, Maryland, United States, 21215|
|Johns Hopkins Hospital|
|Baltimore, Maryland, United States, 21287|
|United States, Missouri|
|Mercy Children's Hospital|
|Kansas City, Missouri, United States, 64108|
|St. Louis Children's Hospital|
|Saint Louis, Missouri, United States, 63110|
|United States, New York|
|New York, New York, United States, 10032|
|United States, Pennsylvania|
|Children's Hospital of Philadelphia|
|Philadelphia, Pennsylvania, United States, 19104|
|Principal Investigator:||James F. Casella, MD||Johns Hopkins University|