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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Anemia
• Intervention / Treatment: Drug: Hydroxyurea

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro
    • Centro, Rio de Janeiro, Brazil
      • Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO)
• Jamaica
  • Kingston
    • Mona, Kingston, Jamaica
      • Tropical Medicine Research Institute, University of the West Indies (UWI)
• United States
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard Therapy: Observation; 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; 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; 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.; Other Names: Hydrea; Hydroxycarbamide; Droxia

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); St. Jude Children's Research Hospital; Tropical Medicine Research Institute; Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti

Publications and helpful links

General Publications

• Hankins JS, McCarville MB, Rankine-Mullings A, Reid ME, Lobo CL, Moura PG, Ali S, Soares DP, Aldred K, Jay DW, Aygun B, Bennett J, Kang G, Goldsmith JC, Smeltzer MP, Boyett JM, Ware RE. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial. Am J Hematol. 2015 Dec;90(12):1099-105. doi: 10.1002/ajh.24198. Epub 2015 Nov 17.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: February 6, 2012
• First Submitted That Met QC Criteria: February 10, 2012
• First Posted (Estimate): February 13, 2012

Study Record Updates

• Last Update Posted (Estimate): February 8, 2016
• Last Update Submitted That Met QC Criteria: January 13, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Phase III; Pediatric patients; Sickle cell anemia; Conditional transcranial doppler velocities; Reduce risk of conversion to abnormally high transcranial doppler velocities
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: H-29205 SCATE; R01HL098239 (U.S. NIH Grant/Contract)