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

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01531387
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), St. Jude Children's Research Hospital (Other), Tropical Medicine Research Institute (Other), Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (Other)
• Enrollment: 38
• Locations: 3
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia	Drug: Hydroxyurea	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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 Start Date: May 1, 2012
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

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: Hydroxycarbamide Hydrea Droxia

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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

1. 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.

2. Current participation in other therapeutic clinical trials

3. Serum creatinine more than twice the upper limit for age OR ≥ 1.0 mg/dL

4. Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised

5. Pregnancy (for post-menarchal females only)

6. Erythrocyte transfusion within the past 2 months

7. Previous stem cell transplant or other myelosuppressive therapy

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01531387
• Other Study ID Numbers: H-29205 SCATE; R01HL098239
• First Posted: Feb 13, 2012
• Last Update Posted: Feb 8, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Children's Hospital Medical Center, Cincinnati: Phase III; Sickle cell anemia; Conditional transcranial doppler velocities; Reduce risk of conversion to abnormally high transcranial doppler velocities; Pediatric patients
• Additional relevant MeSH terms: Anemia; Anemia, Sickle Cell; Hydroxyurea

Study Results

Participant Flow

Pre-assignment Detail	22 participants were randomized (e.g., a total of 38 participants enrolled, but only 22 participants were randomized to treatment)

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Period Title: Overall Study
STARTED	11	11
COMPLETED	0	0
NOT COMPLETED	11	11

Baseline Characteristics

Arm/Group Title	Standard Therapy: Observation	Hydroxyurea	Total
Arm/Group 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. 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.	Total of all reporting groups
Overall Participants	11	11	22
Age (Count of Participants)
<=18 years	11 100%	11 100%	22 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	6.3 (1.5)	6 (2.4)	6.15 (1.95)
Sex: Female, Male (Count of Participants)
Female	7 63.6%	7 63.6%	14 63.6%
Male	4 36.4%	4 36.4%	8 36.4%
Region of Enrollment (participants) [Number]
Jamaica	7 63.6%	6 54.5%	13 59.1%
Brazil	2 18.2%	3 27.3%	5 22.7%
United States	2 18.2%	2 18.2%	4 18.2%

Outcome Measures

1. Primary Outcome

Title	Conversion to Abnormal Maximum TAMV
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

No participants reached 30 months of treatment prior to study termination; therefore, the primary outcome measure was not analyzed.

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Measure Participants	0	0

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants reached 30 months of treatment prior to study termination; therefore, the secondary outcome measures were not analyzed.

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Measure Participants	0	0

3. Secondary Outcome

Title	Cumulative Incidence of Neurological Events
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

No participants reached 30 months of treatment prior to study termination; therefore, the secondary outcome measures were not analyzed.

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Measure Participants	0	0

4. Secondary Outcome

Title	Cumulative Incidence of Non-Neurological Events
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

No participants reached 30 months of treatment prior to study termination; therefore, the secondary outcome measures were not analyzed.

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Measure Participants	0	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

No participants reached 30 months of treatment prior to study termination; therefore, the secondary outcome measures were not analyzed.

Arm/Group Title	Hydroxyurea	Standard Therapy: Observation
Arm/Group Description	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. 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.	Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
Measure Participants	0	0

Adverse Events

Time Frame	May 2012 - Jan 2014 = 20 months
Adverse Event Reporting Description	AEs below grade 2 were not recorded for the SCATE trial
Arm/Group Title	Hydroxyurea		Standard Therapy: Observation
Arm/Group Description	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. 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.		Half of the subjects will be randomized to clinical observation only, which includes monthly visits with clinical evaluations, laboratory tests, and TCD endpoint examinations
All Cause Mortality
	Hydroxyurea		Standard Therapy: Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Hydroxyurea		Standard Therapy: Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/11 (54.5%)		11/11 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/11 (9.1%)	11	3/11 (27.3%)	11
General disorders
Fever	1/11 (9.1%)	11	0/11 (0%)	0
Acute Chest Syndrome	0/11 (0%)	0	1/11 (9.1%)	11
Acute Splenic Sequestration	1/11 (9.1%)	11	1/11 (9.1%)	11
Vaso-occlusive Event	0/11 (0%)	0	1/11 (9.1%)	11
AST	1/11 (9.1%)	11	0/11 (0%)	0
Hepatobiliary disorders
Hepatobiliary Disorder	2/11 (18.2%)	11	0/11 (0%)	0
Infections and infestations
Infections and Infestations	1/11 (9.1%)	11	0/11 (0%)	0
Lung Infection	0/11 (0%)	0	1/11 (9.1%)	11
Lymph gland infection	0/11 (0%)	0	1/11 (9.1%)	11
Renal and urinary disorders
Hematuria	0/11 (0%)	0	1/11 (9.1%)	11
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/11 (0%)	0	1/11 (9.1%)	11
Vascular disorders
Hypertension	0/11 (0%)	0	1/11 (9.1%)	11
Other (Not Including Serious) Adverse Events
	Hydroxyurea		Standard Therapy: Observation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/11 (63.6%)		7/11 (63.6%)
Blood and lymphatic system disorders
Acute Chest Syndrome	0/11 (0%)	0	1/11 (9.1%)	1
Acute Stlenic sequestration	1/11 (9.1%)	1	1/11 (9.1%)	1
Vaso-occlusive Event	2/11 (18.2%)	2	3/11 (27.3%)	4
ANC	1/11 (9.1%)	1	0/11 (0%)	0
ARC	1/11 (9.1%)	1	1/11 (9.1%)	1
AST	1/11 (9.1%)	1	0/11 (0%)	0
Hemoglobin	1/11 (9.1%)	1	2/11 (18.2%)	3
Bilirubin	2/11 (18.2%)	2	0/11 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/11 (9.1%)	1	0/11 (0%)	0
Gastritis	0/11 (0%)	0	1/11 (9.1%)	1
Vomiting	1/11 (9.1%)	1	0/11 (0%)	0
General disorders
Fever	2/11 (18.2%)	2	2/11 (18.2%)	2
Flu Like Symptoms	1/11 (9.1%)	1	1/11 (9.1%)	1
Non Cardiac Chest Pain	1/11 (9.1%)	1	0/11 (0%)	0
Pain	0/11 (0%)	0	1/11 (9.1%)	1
Hepatobiliary disorders
Hepatobiliary Disorders	1/11 (9.1%)	1	0/11 (0%)	0
Infections and infestations
Infections and Infestations	1/11 (9.1%)	1	1/11 (9.1%)	1
Lung infections	0/11 (0%)	0	1/11 (9.1%)	1
Lymph Glad Infection	0/11 (0%)	0	1/11 (9.1%)	1
Tooth Infection	1/11 (9.1%)	1	0/11 (0%)	0
Upper Respiratory Infection	2/11 (18.2%)	2	1/11 (9.1%)	1
Metabolism and nutrition disorders
Metabolism and Nutrition Disorders	1/11 (9.1%)	1	0/11 (0%)	0
Nervous system disorders
Dizziness	1/11 (9.1%)	1	0/11 (0%)	0
Headache	1/11 (9.1%)	1	1/11 (9.1%)	1
Renal and urinary disorders
Hematuria	0/11 (0%)	0	1/11 (9.1%)	1
Proteinuria	0/11 (0%)	0	1/11 (9.1%)	1
Respiratory, thoracic and mediastinal disorders
Allergic Rhinitis	1/11 (9.1%)	3	1/11 (9.1%)	1
Bronchospasm	1/11 (9.1%)	1	1/11 (9.1%)	1
Cough	1/11 (9.1%)	3	2/11 (18.2%)	2
Dysnea	1/11 (9.1%)	1	0/11 (0%)	0
Wheezing	0/11 (0%)	0	1/11 (9.1%)	1
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue dissorder other	1/11 (9.1%)	1	1/11 (9.1%)	1
Vascular disorders
hypertension	0/11 (0%)	0	1/11 (9.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.