Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease

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.

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.