Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE)

Sponsor

Children's Hospital Medical Center, Cincinnati (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03948867

Collaborator

Bugando Medical Centre (Other), The American Society of Hematology (Other)

202

Enrollment

Locations

Arms

35.2

Anticipated Duration (Months)

101

Patients Per Site

2.9

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia in Children	Drug: Hydroxyurea Diagnostic Test: Elevated Arm TCD Examination Diagnostic Test: Normal Arm TCD Examination	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

202 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention 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 scheduleThe 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)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Apr 24, 2019

Anticipated Primary Completion Date :

Mar 31, 2022

Anticipated Study Completion Date :

Mar 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Elevated Initial Screening TCD 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.	Drug: Hydroxyurea 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). Diagnostic Test: Elevated Arm TCD Examination 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.
Experimental: Normal Initial Screening TCD 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.	Diagnostic Test: Normal Arm TCD Examination 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).

Arm

Intervention/Treatment

Experimental: Elevated Initial Screening TCD

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.

Drug: Hydroxyurea

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).

Diagnostic Test: Elevated Arm TCD Examination

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.

Experimental: Normal Initial Screening TCD

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.

Diagnostic Test: Normal Arm TCD Examination

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).

Outcome Measures

Primary Outcome Measures

Prevalence of Elevated TCD [Baseline]
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 [Up to 12 Months at Month 12]
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 [Up to 24 Months]
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 [6 Months]
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 [Up to 24 Months]
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 [One time at Baseline]
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) [One time at 24 Months (Study Exit)]
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 [One Time at 24 Months (Study Exit)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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: