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

Phase 3

Terminated

Brief Summary: The primary goal of the Phase III SCATE trial is to compare 30 months of alternative therapy (hydroxyurea) to standard care (observation) in children with sickle cell anemia and conditional (170 - 199cm/sec) Transcranial Doppler (TCD) velocities. For the alternative regimen (hydroxyurea) to be declared superior to the standard treatment regimen (observation), the hydroxyurea-treated group must have a three-fold reduction in the incidence of conversion to abnormal TCD velocities (≥ 200 cm/sec), compared to the standard treatment arm.

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSD, HbSOArab)
Age: ≥ 2 and < 11 years of age, at the time of enrollment
Conditional TCD Velocity (170 - 199cm/sec) by Transcranial Doppler ultrasonography examination within 3 months of enrollment
Parent or guardian willing and able to provide informed consent
Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria

Prior abnormal TCD Velocity
History of clinical stroke
Inability to take or tolerate daily oral hydroxyurea, including
- Known allergy to hydroxyurea therapy
- Known positive serology to HIV infection
- Known malignancy
- Current lactation
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
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.
Current participation in other therapeutic clinical trials
Serum creatinine more than twice the upper limit for age OR ≥ 1.0 mg/dL
Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised
Pregnancy (for post-menarchal females only)
Erythrocyte transfusion within the past 2 months
Previous stem cell transplant or other myelosuppressive therapy

Arm && Interventions

Group	Intervention	Description
Hydroxyurea	Hydroxyurea	Half of the subjects will be randomized to hydroxyurea, taken as capsules (300 mg, 400 mg, or 500 mg), or as a liquid formulation (100 mg/mL). Hydroxyurea will be administered once daily by mouth. Subjects will be monitored monthly with clinical evaluations, laboratory tests, and TCD endpoint examinations.

Primary Outcome Measures

Name	Time	Method
Conversion to Abnormal Maximum TAMV	30 months	The primary endpoint of the SCATE trial is the cumulative incidence of conversion to abnormal maximum TAMV (time-averaged mean velocity) measured by transcranial doppler (TCD) ultrasonography. Subjects must have conditional velocities at baseline, defined as 170 - 199 cm/sec, which indicate moderate stroke risk. Abnormal velocities are defined as ≥ 200 cm/sec, which indicate high stroke risk. The number of conversions from conditional velocities to abnormal velocities in each treatment arm will be compared as the primary outcome.

Secondary Outcome Measures

Name	Time	Method
Cumulative Incidence of Neurological Events	30 months	The cumulative incidence of neurological events as a secondary endpoint, which include both stroke and non-stroke neurological events, will be determined over the treatment period for both standard and alternative arms.
Cumulative Incidence of Non-Neurological Events	30 months	The cumulative incidence of non-neurological sickle cell-related events, including vaso-occlusion and splenic sequestration, will be estimated over the treatment period for both standard and alternative arms.
Quality of Life	30 months	Standard Quality of Life measure will be taken during specific time points, as well as one newly-developed Sickle Cell Disease Quality of Life measure.
Serial TCD Velocities	30 months	This secondary outcome measure will be the highest TAMV obtained in specific arteries. Serial TCD velocities are measured throughout the SCATE trial and will be compared to the baseline value.

Locations (3): Tropical Medicine Research Institute, University of the West Indies (UWI)
🇯🇲
Mona, Kingston, Jamaica
Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO)
🇧🇷
Centro, Rio de Janeiro, Brazil
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States