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

• ClinicalTrials.gov Identifier: NCT01531387
• Recruitment Status: Terminated
• First Posted: February 13, 2012
• Results First Posted: December 9, 2015
• Last Update Posted: February 8, 2016
• 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
• Information provided by (Responsible Party): Children's Hospital Medical Center, Cincinnati

Tracking Information

• First Submitted Date: February 6, 2012
• First Posted Date: February 13, 2012
• Results First Submitted Date: June 19, 2015
• Results First Posted Date: December 9, 2015
• Last Update Posted Date: February 8, 2016
• Study Start Date: May 2012
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2012)

Conversion to Abnormal Maximum TAMV [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2012)

• Serial TCD Velocities [ Time Frame: 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.
• Cumulative Incidence of Neurological Events [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sparing Conversion to Abnormal TCD (Transcranial Doppler) Elevation (SCATE)
• Official Title: 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.
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Sickle Cell Anemia

Intervention

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:

• Hydroxycarbamide
• Hydrea
• Droxia

Study Arms

• 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.
  Intervention: Drug: Hydroxyurea

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 13, 2016): 38
• Original Estimated Enrollment (submitted: February 10, 2012): 115
• Actual Study Completion Date: January 2014
• Actual Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 10 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Jamaica, United States

Administrative Information

• NCT Number: NCT01531387
• Other Study ID Numbers: H-29205 SCATE; R01HL098239 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Children's Hospital Medical Center, Cincinnati
• Study 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

Investigators

• Principal Investigator: Russell E. Ware, MD, PhD; Children's Hospital Medical Center, Cincinnati

• PRS Account: Children's Hospital Medical Center, Cincinnati
• Verification Date: January 2016