Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (HUPrevent)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01389024
Recruitment Status : Recruiting
First Posted : July 7, 2011
Last Update Posted : July 18, 2018
Sponsor:
Collaborators:
National Center for Research Resources (NCRR)
Washington University School of Medicine
Vanderbilt University School of Medicine
University of Alabama at Birmingham
Children's Hospital of Philadelphia
Medical University of South Carolina
RTI International
Columbia University
Children's Mercy Hospital Kansas City
Sinai Hospital of Baltimore
Information provided by (Responsible Party):
Johns Hopkins University

Tracking Information
First Submitted Date  ICMJE June 30, 2011
First Posted Date  ICMJE July 7, 2011
Last Update Posted Date July 18, 2018
Study Start Date  ICMJE October 2011
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 6, 2011)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01389024 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2011)
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2011)
  • 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 an 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease
Official Title  ICMJE Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children
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, 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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Sickle Cell Disease
  • Stroke
Intervention  ICMJE
  • Drug: Hydroxyurea
    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.
    Other Names:
    • Droxia
    • Hydrea
  • Drug: Placebo
    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
Study Arms  ICMJE
  • Experimental: Hydroxyurea
    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
    Intervention: Drug: Hydroxyurea
  • Placebo Comparator: Placebo
    Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 6, 2011)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2019
Estimated Primary Completion Date August 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Screening

  1. 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.
  2. 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.
  3. Informed consent must be signed by the participant's legally authorized guardian acknowledging written consent to join the study.

Exclusion Criteria for Screening

  1. History of a focal neurologic event lasting more than 24 hours with medical documentation or a history of prior overt stroke.
  2. Other neurological problems, such as neurofibromatosis, lead poisoning, non-febrile seizure disorder, or tuberous sclerosis.
  3. Known human immunodeficiency virus (HIV) infection.
  4. Treatment with anti-sickling drugs or hydroxyurea within 3 months or anticipated treatment during the course of the study.
  5. Chronic blood transfusion therapy, ongoing or planned.
  6. Poor adherence likely per his/her hematologist and study coordinator based on previous compliance in clinic appointments and following advice.
  7. 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.
  8. 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.
  9. 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.
  10. Other significant organ system dysfunction
  11. Known allergy or intolerance of hydroxyurea
  12. 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

  1. Failure to pass MRI screening checklist
  2. 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
  3. Less than 12 months of age.
  4. Allergic reactions such as urticaria or bronchospasm or previous adverse reactions to propofol, eggs, or soy products, if used at the participating center.
  5. Allergy or previous adverse reaction to pentobarbital, if used at the participating center
  6. Known major chromosomal abnormalities
  7. Known airway abnormalities that would increase the risk of sedation/anesthesia.

    Temporary Exclusions

  8. Room air oxygen saturation greater than or equal to 5% below the participant's baseline on the day of the MRI with sedation.
  9. Room air oxygen saturation <90% on the day of the MRI with sedation.
  10. Hemoglobin <6.5 g/dl (must be measured within 30 days of MRI).
  11. 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

  1. Participant must be 12 to 54 months of age
  2. Participant must have successfully completed screening procedures (TCD, MRI of the brain, neurology exam, and cognitive evaluation)

Exclusion Criteria for Randomization

  1. Participants whose MRI show a silent or overt cerebral infarct.
  2. Participants who have a non-imaging TCD study with a velocity ≥ 185 cm/sec or a TCD that is indeterminate.
  3. Participants with abnormal kidney function (creatinine > 0.8 mg/dl)
  4. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 54 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Diane Weiss, BA 410-955-6132 dweiss14@jhmi.edu
Contact: James F. Casella, MD 410-955-6132 jcasella@jhmi.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01389024
Other Study ID Numbers  ICMJE NA_00041623
3UL1RR025005 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Johns Hopkins University
Study Sponsor  ICMJE Johns Hopkins University
Collaborators  ICMJE
  • National Center for Research Resources (NCRR)
  • Washington University School of Medicine
  • Vanderbilt University School of Medicine
  • University of Alabama at Birmingham
  • Children's Hospital of Philadelphia
  • Medical University of South Carolina
  • RTI International
  • Columbia University
  • Children's Mercy Hospital Kansas City
  • Sinai Hospital of Baltimore
Investigators  ICMJE
Principal Investigator: James F. Casella, MD Johns Hopkins University
PRS Account Johns Hopkins University
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP