Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease
Information source: Johns Hopkins University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Sickle Cell Disease; Stroke
Intervention: Hydroxyurea (Drug); Placebo (Drug)
Phase: Phase 2
Status: Recruiting
Sponsored by: Johns Hopkins University Official(s) and/or principal investigator(s): James F. Casella, MD, Principal Investigator, Affiliation: Johns Hopkins University
Overall contact: Diane Weiss, BA, Phone: 410-955-6132, Email: dweiss14@jhmi.edu
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.
Clinical Details
Official title: Hydroxyurea to Prevent Central Nervous System (CNS) Complications of Sickle Cell Disease in Children
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Prevention
Primary outcome: Central Nervous System Complications
Secondary outcome: Proportion of participants with severe adverse events attributed to study proceduresProportion of participants undergoing randomization
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
Minimum age: 12 Months.
Maximum age: 54 Months.
Gender(s): Both.
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.
Locations and Contacts
Diane Weiss, BA, Phone: 410-955-6132, Email: dweiss14@jhmi.edu
University of Alambama, Birmingham, Alabama 35233, United States; Recruiting Jeanie Dumas, Phone: 205-939-9285, Email: Jeanine.Dumas@childrensal.org Jeffrey Lebensberger, MD, Phone: 410-639-6662, Email: jlebensburger@peds.uab.edu Jeffrey Lebensburger, MD, Principal Investigator
Johns Hopkins Hospital, Baltimore, Maryland 21287, United States; Recruiting Diane Weiss, BA, Phone: 410-955-6132, Email: dweiss14@jhmi.edu John J Strouse, MD, PhD, Phone: 410-614-6102, Email: jstrous1@jhmi.edu John J Strouse, MD, PhD, Sub-Investigator
St. Louis Children's Hospital, St. Louis, Missouri 63110, United States; Recruiting Alison King, MD, MPH, Phone: 314-286-1601, Email: king_a@wustl.edu Alison King, MD, MPH, Principal Investigator
Cincinnati Children's Hospital, Cincinnati, Ohio 45229, United States; Recruiting Adriane Hausfeld, Phone: 513-803-3236, Email: Adriane.Hausfeld@cchmc.org Charles Quinn, MD, MHS, Email: Charles.Quinn@cchmc.org Charles Quinn, MD, MHS, Principal Investigator
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Recruiting Helen Stanley, Phone: 267-426-5602, Email: stanleyh1@email.chop.edu Janet Kwiatkowski, MD, MHS, Phone: 215-590-5286, Email: Kwiatkowski@email.chop.edu Janet Kwiatkowski, MD, MHS, Principal Investigator
Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States; Recruiting Michael R DeBaun, MD, MPH, Phone: 615-936-2540, Email: m.debaun@vanderbilt.edu Jackie Harris, RN, Phone: 615-936-1767, Email: jacqueline.b.harris@Vanderbilt.Edu Michael R DeBaun, MD, MPH, Principal Investigator
Additional Information
Related publications: Kwiatkowski JL, Zimmerman RA, Pollock AN, Seto W, Smith-Whitley K, Shults J, Blackwood-Chirchir A, Ohene-Frempong K. Silent infarcts in young children with sickle cell disease. Br J Haematol. 2009 Aug;146(3):300-5. doi: 10.1111/j.1365-2141.2009.07753.x. Epub 2009 Jun 4. Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE. Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood. 2007 Aug 1;110(3):1043-7. Epub 2007 Apr 11. Strouse JJ, Cox CS, Melhem ER, Lu H, Kraut MA, Razumovsky A, Yohay K, van Zijl PC, Casella JF. Inverse correlation between cerebral blood flow measured by continuous arterial spin-labeling (CASL) MRI and neurocognitive function in children with sickle cell anemia (SCA). Blood. 2006 Jul 1;108(1):379-81. Epub 2006 Mar 14. Casella JF, King AA, Barton B, White DA, Noetzel MJ, Ichord RN, Terrill C, Hirtz D, McKinstry RC, Strouse JJ, Howard TH, Coates TD, Minniti CP, Campbell AD, Vendt BA, Lehmann H, Debaun MR. Design of the silent cerebral infarct transfusion (SIT) trial. Pediatr Hematol Oncol. 2010 Mar;27(2):69-89. doi: 10.3109/08880010903360367.
Starting date: October 2011
Last updated: October 24, 2013
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