Back to resultsStroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE)
Primary Purpose
Sickle Cell Anemia in Children
Status
Enrolling by invitation
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Hydroxyurea
Elevated Arm TCD Examination
Normal Arm TCD Examination
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Anemia in Children focused on measuring Sickle Celll Anemia, Transcranial Doppler, Tanzania, Hydroxyurea, Stroke
Eligibility Criteria
Inclusion Criteria:
- Willingness to sign informed consent
- Willingness to follow all study procedures
- Available for study visits for the duration of the study and no plans to move away from study center.
- Confirmed diagnosis of Sickle Cell Anemia (SCA) by haemoglobin electrophoresis.
- Able to take oral medication and follow hydroxyurea treatment schedule.
Exclusion Criteria:
There are no permanent exclusion criteria for participants to enroll in the screening TCD portion of SPHERE. Temporary, time-limited exclusion criteria for the screening TCD portion include the following:
- Febrile illness within the past two weeks. (Temporary Exclusion)
- Hospitalized within the past two weeks. (Temporary Exclusion)
- Transfusion within the past two weeks. (Temporary Exclusion)
Patients who enroll in the screening portion, have a conditional or abnormal TCD, and are eligible to start hydroxyurea will be excluded from receiving study treatment if they meet any of the following criteria:
- Abnormal pre-enrolment laboratory values (Temporary Exclusion)
- Known medical condition making participation ill-advised.
- Known allergic reactions to components of hydroxyurea.
- Previous history of stroke.
- Currently pregnant or lactating.
Sites / Locations
- Cincinnati Children's Hospital Medical Center
- Bugando Medical Centre
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Elevated Initial Screening TCD
Normal Initial Screening TCD
Arm Description
Those who have an elevated initial screening TCD (either conditional or abnormal TAMV) and will be a treatment cohort that receives open-label hydroxyurea therapy as per the dosing and administration schedule.
Those who are found to have a normal TCD at enrolment are a part of the observation/control cohort and will undergo repeat TCD every 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the study participant will be reassigned to the elevated initial screening TCD arm and can begin study treatment (hydroxyurea), but will not be included in the primary endpoint analysis.
Outcomes
Primary Outcome Measures
Prevalence of Elevated TCD
Determine the prevalence of elevated (conditional or abnormal) transcranial Doppler (TCD) velocities in a cross-sectional analysis of children with Sickle Cell Anemia (SCA) living in Tanzania
Change in Primary Stroke Risk
Transcranial Doppler ultrasound (TCD) will be used to measure the change in the TAMV of arterial blood flow in the 4 major intracranial arteries bilaterally from study enrollment to 12 months after study enrollment.
Secondary Outcome Measures
Laboratory and Clinical Correlates
Identify laboratory and clinical correlates of elevated TCD velocities such as age, haemoglobin concentration, foetal haemoglobin, oxygen saturation, splenomegaly, history of acute chest syndrome, and previous malaria infection
Change in Hemoglobin Concentration
For those receiving hydroxyurea, the change in hemoglobin between baseline hemoglobin and follow up hemoglobin when a participant has reached maximum tolerated dose of hydroxyurea.
Effect of Splenomegaly and Malaria Infections
Incidence of splenomegaly and malaria infection with rapid or laboratory malaria testing will be performed for any child presenting with fever. Incidence will be reported in the number of cases per 100 patient years. Abdominal ultrasound with splenic volume will be performed annually for all study participants. Quantify the degree of hypersplenism or autoinfarction and any association with malaria complications of SCA will be analyzed.
Prevalence of Co-inherited G6PD and Alpha Thalassemia
DNA will be collected at baseline to determine the prevalence of co-inherited hematologic diseases such as G6PD and alpha thalassemia.
Hydroxyurea Area Under the Curve (AUC)
For those receiving hydroxyurea, the AUC will be assessed after the patient has reached MTD.
Single Nucleotide Polymorphisms Associated with Change in Percent Hemoglobin F on Hydroxyurea
For those receiving hydroxyurea, we will identify single nucleotide polymorphisms that are associated with a greater change in hemoglobin F percent in response to hydroyxurea therapy.
Full Information
NCT ID
NCT03948867
First Posted
February 8, 2019
Last Updated
July 27, 2023
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Bugando Medical Centre, The American Society of Hematology
1. Study Identification
Unique Protocol Identification Number
NCT03948867
Brief Title
Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE)
Official Title
Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE): A Prospective Trial to Reduce Primary Stroke in Children With Sickle Cell Anaemia
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
April 24, 2019 (Actual)
Primary Completion Date
March 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Bugando Medical Centre, The American Society of Hematology
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study will 1) Evaluate the prevalence of elevated (conditional or abnormal) transcranial Doppler (TCD) velocities in a cross-sectional analysis of children with Sickle Cell Anemia (SCA) living in Tanzania; 2) Obtain longitudinal data on TCD velocities in this population; and 3) Measure the effects of hydroxyurea therapy on TCD velocities and associated primary stroke risk.
Detailed Description
Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) is a single-center prospective phase 2 pilot study. It will enroll a convenience sample of children with SCA, obtain cross-sectional baseline data at enrolment, and follow them as a prospective cohort for a period of 24 months. The cohort will be divided into two arms based on the initial screening TCD result: 1) those who have a normal (less than 170 cm/sec time averaged mean velocity (TAMV)) initial screening TCD and will be an observation/control cohort; and 2) those who have an elevated initial screening TCD (either conditional (170-199 cm/sec) or abnormal (greater than or equal to 200 cm/sec) TAMV) and will be a treatment cohort that receives open-label hydroxyurea therapy as per the dosing and administration schedule. Those who are found to have a normal TCD at enrolment and are part of the observation/control cohort will undergo repeat TCD 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the study participant can begin study treatment, but will not be included in the primary endpoint analysis. The primary hypothesis is after 12 months of hydroxyurea therapy, children with conditional TCD velocities will achieve a mean decrease of >15cm/sec from their baseline TCD TAMV.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia in Children
Keywords
Sickle Celll Anemia, Transcranial Doppler, Tanzania, Hydroxyurea, Stroke
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
The cohort will be divided into two arms based on the initial screening TCD result: 1) those who have a normal initial screening TCD and will be an observation/control cohort; and 2) those who have an elevated initial screening TCD (either conditional or abnormal TAMV) and will be a treatment cohort that receives open-label hydroxyurea therapy as per the dosing and administration schedule
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
202 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Elevated Initial Screening TCD
Arm Type
Experimental
Arm Description
Those who have an elevated initial screening TCD (either conditional or abnormal TAMV) and will be a treatment cohort that receives open-label hydroxyurea therapy as per the dosing and administration schedule.
Arm Title
Normal Initial Screening TCD
Arm Type
Experimental
Arm Description
Those who are found to have a normal TCD at enrolment are a part of the observation/control cohort and will undergo repeat TCD every 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the study participant will be reassigned to the elevated initial screening TCD arm and can begin study treatment (hydroxyurea), but will not be included in the primary endpoint analysis.
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Intervention Description
Hydroxyurea treatment will be provided to reduce stroke risk. Hydroxyurea treatment will be started at a fixed dose of 20.0 ± 5.0 mg/kg/day, followed by escalation to maximum tolerated dose (MTD).
Intervention Type
Diagnostic Test
Intervention Name(s)
Elevated Arm TCD Examination
Intervention Description
TCD examination on children with SCA between ages 2 and 16 years of age will be completed to evaluate their risk of stroke.
For children with elevated velocities at initial screening or at 1 Year who receive hydroxyurea therapy, TCD examinations will occur every 6 ± 2 months.
Intervention Type
Diagnostic Test
Intervention Name(s)
Normal Arm TCD Examination
Intervention Description
TCD examination on children with SCA between ages 2 and 16 years of age will be completed to evaluate their risk of stroke. TCD examination for all participants will occur at initial screening, at Year 1 (12 ± 3 months), and Year 2 (24 ± 3 months). Children with normal TCD velocities at initial screening will undergo repeat TCD 12 months after enrolment. If the TCD at 12 months has changed to an elevated velocity (conditional or abnormal), the child can begin study treatment (Hydroxyurea).
Primary Outcome Measure Information:
Title
Prevalence of Elevated TCD
Description
Determine the prevalence of elevated (conditional or abnormal) transcranial Doppler (TCD) velocities in a cross-sectional analysis of children with Sickle Cell Anemia (SCA) living in Tanzania
Time Frame
Baseline
Title
Change in Primary Stroke Risk
Description
Transcranial Doppler ultrasound (TCD) will be used to measure the change in the TAMV of arterial blood flow in the 4 major intracranial arteries bilaterally from study enrollment to 12 months after study enrollment.
Time Frame
Up to 12 Months at Month 12
Secondary Outcome Measure Information:
Title
Laboratory and Clinical Correlates
Description
Identify laboratory and clinical correlates of elevated TCD velocities such as age, haemoglobin concentration, foetal haemoglobin, oxygen saturation, splenomegaly, history of acute chest syndrome, and previous malaria infection
Time Frame
Up to 24 Months
Title
Change in Hemoglobin Concentration
Description
For those receiving hydroxyurea, the change in hemoglobin between baseline hemoglobin and follow up hemoglobin when a participant has reached maximum tolerated dose of hydroxyurea.
Time Frame
6 Months
Title
Effect of Splenomegaly and Malaria Infections
Description
Incidence of splenomegaly and malaria infection with rapid or laboratory malaria testing will be performed for any child presenting with fever. Incidence will be reported in the number of cases per 100 patient years. Abdominal ultrasound with splenic volume will be performed annually for all study participants. Quantify the degree of hypersplenism or autoinfarction and any association with malaria complications of SCA will be analyzed.
Time Frame
Up to 24 Months
Title
Prevalence of Co-inherited G6PD and Alpha Thalassemia
Description
DNA will be collected at baseline to determine the prevalence of co-inherited hematologic diseases such as G6PD and alpha thalassemia.
Time Frame
One time at Baseline
Title
Hydroxyurea Area Under the Curve (AUC)
Description
For those receiving hydroxyurea, the AUC will be assessed after the patient has reached MTD.
Time Frame
One time at 24 Months (Study Exit)
Title
Single Nucleotide Polymorphisms Associated with Change in Percent Hemoglobin F on Hydroxyurea
Description
For those receiving hydroxyurea, we will identify single nucleotide polymorphisms that are associated with a greater change in hemoglobin F percent in response to hydroyxurea therapy.
Time Frame
One Time at 24 Months (Study Exit)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Willingness to sign informed consent
Willingness to follow all study procedures
Available for study visits for the duration of the study and no plans to move away from study center.
Confirmed diagnosis of Sickle Cell Anemia (SCA) by haemoglobin electrophoresis.
Able to take oral medication and follow hydroxyurea treatment schedule.
Exclusion Criteria:
There are no permanent exclusion criteria for participants to enroll in the screening TCD portion of SPHERE. Temporary, time-limited exclusion criteria for the screening TCD portion include the following:
Febrile illness within the past two weeks. (Temporary Exclusion)
Hospitalized within the past two weeks. (Temporary Exclusion)
Transfusion within the past two weeks. (Temporary Exclusion)
Patients who enroll in the screening portion, have a conditional or abnormal TCD, and are eligible to start hydroxyurea will be excluded from receiving study treatment if they meet any of the following criteria:
Abnormal pre-enrolment laboratory values (Temporary Exclusion)
Known medical condition making participation ill-advised.
Known allergic reactions to components of hydroxyurea.
Previous history of stroke.
Currently pregnant or lactating.
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Bugando Medical Centre
City
Mwanza
Country
Tanzania
12. IPD Sharing Statement
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Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE)
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