Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease

Study Overview
=================
Brief Summary
-----------------
This is a pilot study of hydroxyurea versus placebo to reduce central nervous system complications (abnormally fast blood flow to the brain, silent cerebral infarct or stroke) in young children with sickle cell disease. The investigators plan to identify children 12 to 48 months old without central nervous system complications and randomly assign 20 to treatment with hydroxyurea and 20 to treatment with placebo for 36 months. Neither the study doctors nor the participants will know which treatment they are receiving.

Detailed Description
-----------------
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, transient ischemic attack (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.

Official Title
-----------------
Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children

Conditions
-----------------
Sickle Cell Disease, Stroke

Intervention / Treatment
-----------------
* Drug: Hydroxyurea
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Screening Participant must have sickle cell anemia (hemoglobin SS) or sickle Beta-zero (null) thalassemia (hemoglobin S-B0) as confirmed at the local institution by hemoglobin analysis after six months of age. Participant must be 9 to 48 months of age. All screening procedures except MRI can be completed between 9 and 12 months of age, with the exception of the MRI, for which the child must have reached the age of 12 months. Informed consent must be signed by the participant's legally authorized guardian acknowledging written consent to join the study. Exclusion Criteria for Screening History of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke. Other neurological problems, such as neurofibromatosis, lead poisoning, non-febrile seizure disorder, or tuberous sclerosis. Known human immunodeficiency virus (HIV) infection. Treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipated treatment during the course of the study. Chronic blood transfusion therapy, ongoing or planned. Poor adherence likely per his/her hematologist and study coordinator based on previous compliance in clinic appointments and following advice. Presence or planned permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth), which their physicians believe will interfere with the MRI of the brain. History of two or more TCD studies with a velocity ≥ 200 cm/sec by the non-imaging technique, or ≥185 cm/sec for the imaging technique or a indeterminate TCD. Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions. Other significant organ system dysfunction Known allergy or intolerance of hydroxyurea Significant prematurity (gestational age of < 32 weeks) Inclusion Criteria for MRI of the Brain with Sedation 1. The parents or guardians must provide consent for sedation. Exclusion Criteria for MRI of the Brain with Sedation Failure to pass MRI screening checklist Obstructive sleep apnea (OSA) and receiving therapy [e.g. continuous positive airway pressure], or being evaluated or followed by a specialist for management of severe OSA Less than 12 months of age. Allergic reactions such as urticaria or bronchospasm or previous adverse reactions to propofol, eggs, or soy products, if used at the participating center. Allergy or previous adverse reaction to pentobarbital, if used at the participating center Known major chromosomal abnormalities Known airway abnormalities that would increase the risk of sedation/anesthesia. Temporary Exclusions Room air oxygen saturation greater than or equal to 5% below the participant's baseline on the day of the MRI with sedation. Room air oxygen saturation <90% on the day of the MRI with sedation. Hemoglobin <6.5 g/dl (must be measured within 30 days of MRI). Temperature >38˚ C on the day of sedation 8. Upper or lower respiratory infection, active bronchospasm, acute chest syndrome, splenic sequestration or other acute complications of sickle cell disease other than pain in the last 4 weeks (from resolution of symptoms) 9. Pain crisis within two weeks requiring treatment with opiates Inclusion Criteria for Randomization Participant must be 12 to 54 months of age Participant must have successfully completed screening procedures (TCD, MRI of the brain, neurology exam, and cognitive evaluation) Exclusion Criteria for Randomization Participants whose MRI show a silent or overt cerebral infarct. Participants who have a non-imaging TCD study with a velocity ≥ 185 cm/sec or a TCD that is indeterminate. Participants with abnormal kidney function (creatinine > 0.8 mg/dl) Significant cytopenias [absolute neutrophil count (ANC) <1500/ul, platelets <150,000/ul, reticulocytes <80,000/ul, unless the hemoglobin is > 9 g/dl]. Cytopenias will be considered transient exclusions.

Ages Eligible for Study
-----------------
Minimum Age: 12 Months
Maximum Age: 54 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxyurea<br>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 Absolute Neutrophil Count (ANC) <4000 | Drug: Hydroxyurea<br>* 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.<br>* Other names: Hydrea;|
| Placebo Comparator: Placebo<br>Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day | Drug: Placebo<br>* 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.<br>* Other names: Sugar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Randomized Participants With Central Nervous System Complications | A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe Adverse Events (SAE) Attributed to Study Procedures | Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed. | 3 years | 
| Severe Adverse Events (SAE) Attributed to Sedated MRIs | Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed. | 3 years | 
| Number of Participants Randomized | We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo. | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sickle cell disease, stroke, silent cerebral infarct, children