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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by Johns Hopkins University
Sponsor:
Collaborators:
Washington University School of Medicine
Vanderbilt University School of Medicine
University of Alabama at Birmingham
Children's Hospital of Philadelphia
Children's Hospital Medical Center, Cincinnati
Medical University of South Carolina
RTI International
Information provided by (Responsible Party):
James Casella, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01389024
First received: June 30, 2011
Last updated: October 24, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Stroke
Drug: Hydroxyurea
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Prevention
Official Title: Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Central Nervous System Complications [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.


Secondary Outcome Measures:
  • Proportion of participants with severe adverse events attributed to study procedures [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    We will evaluate the proportion of screened participants that undergo randomization to hydroxyurea or placebo


Estimated Enrollment: 40
Study Start Date: October 2011
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hydroxyurea 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
Placebo Comparator: Placebo
Sucrose placebo
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

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 or stroke. To begin the internal pilot trial, the investigators have 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) will begin 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. 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.

  Eligibility

Ages Eligible for Study:   12 Months to 54 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01389024

Contacts
Contact: Diane Weiss, BA 410-955-6132 dweiss14@jhmi.edu
Contact: James F. Casella, MD 410-955-6132 jcasella@jhmi.edu

Locations
United States, Alabama
University of Alambama Recruiting
Birmingham, Alabama, United States, 35233
Contact: Jeanie Dumas    205-939-9285    Jeanine.Dumas@childrensal.org   
Contact: Jeffrey Lebensberger, MD    410-639-6662    jlebensburger@peds.uab.edu   
Principal Investigator: Jeffrey Lebensburger, MD         
United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21287
Contact: Diane Weiss, BA    410-955-6132    dweiss14@jhmi.edu   
Contact: John J Strouse, MD, PhD    410-614-6102    jstrous1@jhmi.edu   
Sub-Investigator: John J Strouse, MD, PhD         
United States, Missouri
St. Louis Children's Hospital Recruiting
St. Louis, Missouri, United States, 63110
Contact: Alison King, MD, MPH    314-286-1601    king_a@wustl.edu   
Principal Investigator: Alison King, MD, MPH         
United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Adriane Hausfeld    513-803-3236    Adriane.Hausfeld@cchmc.org   
Contact: Charles Quinn, MD, MHS       Charles.Quinn@cchmc.org   
Principal Investigator: Charles Quinn, MD, MHS         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Helen Stanley    267-426-5602    stanleyh1@email.chop.edu   
Contact: Janet Kwiatkowski, MD, MHS    215-590-5286    Kwiatkowski@email.chop.edu   
Principal Investigator: Janet Kwiatkowski, MD, MHS         
United States, Tennessee
Vanderbilt University School of Medicine Recruiting
Nashville, Tennessee, United States, 37232
Contact: Michael R DeBaun, MD, MPH    615-936-2540    m.debaun@vanderbilt.edu   
Contact: Jackie Harris, RN    615-936-1767    jacqueline.b.harris@Vanderbilt.Edu   
Principal Investigator: Michael R DeBaun, MD, MPH         
Sponsors and Collaborators
Johns Hopkins University
Washington University School of Medicine
Vanderbilt University School of Medicine
University of Alabama at Birmingham
Children's Hospital of Philadelphia
Children's Hospital Medical Center, Cincinnati
Medical University of South Carolina
RTI International
Investigators
Principal Investigator: James F. Casella, MD Johns Hopkins University
  More Information

Publications:
Responsible Party: James Casella, Rainey Professor of Pediatric Hematology, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01389024     History of Changes
Other Study ID Numbers: NA_00041623, 3UL1RR025005
Study First Received: June 30, 2011
Last Updated: October 24, 2013
Health Authority: United States: Institutional Review Board
United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
sickle cell disease
stroke
silent cerebral infarct
children

Additional relevant MeSH terms:
Anemia, Sickle Cell
Stroke
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Hydroxyurea
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on July 24, 2014