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

Primary Purpose

Sickle Cell Anemia

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Hydroxyurea

About this trial

This is an interventional prevention trial for Sickle Cell Anemia focused on measuring Phase III, Sickle cell anemia, Conditional transcranial doppler velocities, Reduce risk of conversion to abnormally high transcranial doppler velocities, Pediatric patients

Eligibility Criteria

2 Years - 10 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

St. Jude Children's Research Hospital
Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO)
Tropical Medicine Research Institute, University of the West Indies (UWI)

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Standard Therapy: Observation

Hydroxyurea

Arm Description

Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

Full Information

NCT ID

NCT01531387

First Posted

February 6, 2012

Last Updated

January 13, 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

1. Study Identification

Unique Protocol Identification Number

NCT01531387

Brief Title

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

Acronym

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.

Study Type

Interventional

2. Study Status

Record Verification Date

January 2016

Overall Recruitment Status

Terminated

Why Stopped

inability to reach a satisfactory endpoint with respect to adequate recruitment

Study Start Date

May 2012 (undefined)

Primary Completion Date

January 2014 (Actual)

Study Completion Date

January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the 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

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sickle Cell Anemia

Keywords

Phase III, Sickle cell anemia, Conditional transcranial doppler velocities, Reduce risk of conversion to abnormally high transcranial doppler velocities, Pediatric patients

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

38 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Standard Therapy: Observation

Arm Type

No Intervention

Arm Description

Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations

Arm Title

Hydroxyurea

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Hydroxyurea

Other Intervention Name(s)

Hydroxycarbamide, Hydrea, Droxia

Intervention Description

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.

Primary Outcome Measure Information:

Title

Conversion to Abnormal Maximum TAMV

Description

Time Frame

30 months

Secondary Outcome Measure Information:

Title

Serial TCD Velocities

Description

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.

Time Frame

30 months

Title

Cumulative Incidence of Neurological Events

Description

Time Frame

30 months

Title

Cumulative Incidence of Non-Neurological Events

Description

Time Frame

30 months

Title

Quality of Life

Description

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.

Time Frame

30 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

2 Years

Maximum Age & Unit of Time

10 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Russell E. Ware, MD, PhD

Organizational Affiliation

Children's Hospital Medical Center, Cincinnati

Official's Role

Principal Investigator

Facility Information:

Facility Name

St. Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

Facility Name

Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HEMORIO)

City

Centro

State/Province

Rio de Janeiro

Country

Brazil

Facility Name

Tropical Medicine Research Institute, University of the West Indies (UWI)

City

Mona

State/Province

Kingston

Country

Jamaica

12. IPD Sharing Statement

Citations:

PubMed Identifier

26414435

Citation

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.

Results Reference

result

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

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