Novel Dose Escalation to Predict Treatment With Hydroxyurea

To be eligible to participate in this study, patients must have decided that they want to
begin hydroxyurea therapy. Patients choosing to participate in this study will be assigned
randomly (like flipping a coin) to one of two hydroxyurea treatment groups. Both groups of
patients will receive hydroxyurea treatment, but the determination of the starting
hydroxyurea dose will be different between the two groups:

1. Group 1: The standard (dose increase) group: Patients assigned to this group will be
treated following the method that is currently standard for all patients starting
hydroxyurea at our institution. All patients will be started at a dose of 20 milligrams
per kilogram of body weight. Dose changes will be made every eight weeks until the
patient is judged to be at his or her MTD.

2. Group 2: The alternative (dose-prediction) group: Patients assigned to this group will
have their predicted MTD determined using our dose-prediction equation and will be
started directly at this dose.

Patients in both groups will be assessed monthly to see if they are having any side effects
to hydroxyurea. We will also check to see if the MTD has been reached. Once it is decided
that the patient has reached their maximum dose, they will continue to be monitored for two
additional clinic visits (approximately eight additional weeks) to complete collection of
end-of-study biological blood and urine samples and to ensure that there is no late harmful
effects from hydroxyurea. The maximum time the patient will be on the study is 12 months
after starting hydroxyurea therapy.

Patients will also be asked to participate in optional associated studies.

Biologic studies: The purpose of these studies is to determine the effect of hydroxyurea
therapy on blood and urine markers that may be increased or decreased because of sickle cell
disease. Patients participating in these studies will have one blood sample of 2 teaspoons
(10 milliliters) and a urine sample collected before starting hydroxyurea therapy. Another
blood and urine sample will be collected when they complete the study. These samples will be
used to analyze markers associated with the following disease processes in sickle cell
disease:

1. inflammation, blood vessel damage and oxidative stress.

2. blood viscosity.

3. early kidney disease.

4. early brain disease.

5. altered function of white blood cells, red blood cells, and platelets.

Inclusion Criteria:

1. A severe form of sickle cell disease (HbSS or HbS beta-zero thalassemia)

2. Age range of 1.0-15.99 years, inclusive, at the time of enrollment

3. A decision by the subject's family and primary clinician to initiate hydroxyurea
therapy, made independently of recruitment for the study (not applicable for the
biological arm patients)

4. Informed consent and assent (as applicable) obtained from parent/guardian and child.

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

Exclusion Criteria:

1. Documented clinical stroke or transient ischemic attack (TIA).

2. Known severe vasculopathy or moya-moya disease on brain imaging studies

3. Asparagine aminotransferase (AST) or alanine aminotransferase (ALT) greater than three
times upper limit of normal or serum creatinine greater than 0.8 mg/dl

4. Current participation in other interventional trials. Subjects must have been off any
alternative therapy for at least three months prior to enrollment in this study

5. Erythrocyte transfusion within the prior 2 months

6. Any condition or chronic illness that in the opinion of the primary clinician makes
participation in the trial ill advised

7. Inability or unwillingness to complete required studies

8. Pregnancy or unwillingness to use a medically acceptable form of contraception if
sexually active (male OR female)

Patients excluded from participation due to laboratory abnormalities, participation in
other interventional trials, or recent transfusions may be re-screened at a later date