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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Sparing Conversion to Abnormal TCD Elevation (SCATE) - a Phase III Clinical Trial to Compare Standard Care (Observation) With Alternative Therapy (Hydroxyurea) for Reducing the Risk of Converting to an Abnormal TCD Velocity in Children With Sickle Cell Anemia and Conditional Pre-treatment TCD Velocities.

Conditions
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Sickle Cell Anemia

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard Therapy: Observation<br>Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations | |
| Experimental: Hydroxyurea<br>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. | Drug: Hydroxyurea<br>* Hydroxyurea will be administered once daily, in either capsule form (300mg, 400mg, or 500mg) or as a liquid formulation (100mg/ml). Dosing will commence at 20 mg/kg/day. Dose escalation will occur in 5 mg/kg/day increments, adjusting every 8 weeks unless hematological toxicity occurs.<br>* Other names: Droxia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conversion to Abnormal Maximum TAMV | 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. | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serial TCD Velocities | 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. | 30 months | 
| Cumulative Incidence of Neurological Events | 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. | 30 months | 
| Cumulative Incidence of Non-Neurological Events | 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. | 30 months | 
| Quality of Life | 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. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase III, Sickle cell anemia, Conditional transcranial doppler velocities, Reduce risk of conversion to abnormally high transcranial doppler velocities, Pediatric patients