Sparing Conversion to Abnormal TCD (Transcranial Doppler) Elevation (SCATE)

Results from previous studies confirm an increased risk of stroke among children with
conditional TCD velocities. In addition, studies suggest that patients who were on
observation alone, converted from conditional TCD (moderate risk category) to an abnormal
TCD (with a much higher risk for primary stroke) within 30 months of initial identification
of the conditional TCD velocity; this conversion led to initiation of chronic and indefinite
transfusions in all cases. Preliminary data suggests that the risk of conversion to abnormal
TCD velocities will be lower for subjects with conditional TCD velocities on hydroxyurea by
at least three-fold. This important difference in conversion risk rate suggests that an
alternative treatment could have a substantial and beneficial impact on patients with
elevated TCD velocities.

An alternative treatment could protect the brain of patients with SCA and conditional TCD
velocities who are at increased risk for stroke. The avoidance of chronic blood transfusions
would be a great benefit for all children with sickle cell disease, especially those in
developing countries where the blood supply may be less safe (in comparison with that in the
US) or unavailable, and very costly.

Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia,
HbSD, HbSOArab)

2. Age: ≥ 2 and < 11 years of age, at the time of enrollment

3. Conditional TCD Velocity (170 - 199cm/sec) by Transcranial Doppler ultrasonography
examination within 3 months of enrollment

4. Parent or guardian willing and able to provide informed consent

5. Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria:

1. Prior abnormal TCD Velocity

2. History of clinical stroke

3. Inability to take or tolerate daily oral hydroxyurea, including

- Known allergy to hydroxyurea therapy

- Known positive serology to HIV infection

- Known malignancy

- Current lactation

4. Abnormal laboratory values at initial evaluation (temporary exclusions):

- Hemoglobin concentration < 6.0 gm/dL

- Absolute reticulocyte count < 100 x 10^9/L with a hemoglobin concentration < 8.0
gm/dL

- WBC count < 3.0 x 10^9/L

- Absolute neutrophil count (ANC) < 1.0 x 10^9/L

- Platelet count < 100 x 10^9/L

5. Current use of therapeutic agents for sickle cell disease (e.g., hydroxyurea,
arginine, decitabine, magnesium, chronic transfusions). Subjects must be off
therapeutic agents for sickle cell disease for at least 3 months prior to enrollment.

6. Current participation in other therapeutic clinical trials

7. Serum creatinine more than twice the upper limit for age OR ≥ 1.0 mg/dL

8. Any condition or chronic illness, which in the opinion of the clinical investigator
makes participation ill-advised

9. Pregnancy (for post-menarchal females only)

10. Erythrocyte transfusion within the past 2 months

11. Previous stem cell transplant or other myelosuppressive therapy