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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03948867
Recruitment Status : Active, not recruiting
First Posted : May 14, 2019
Last Update Posted : August 12, 2020
Sponsor:
Collaborators:
Bugando Medical Centre
The American Society of Hematology
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Tracking Information
First Submitted Date  ICMJE February 8, 2019
First Posted Date  ICMJE May 14, 2019
Last Update Posted Date August 12, 2020
Actual Study Start Date  ICMJE April 24, 2019
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 10, 2019)
  • Prevalence of Elevated TCD [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2019)
  • Laboratory and Clinical Correlates [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE)
Official Title  ICMJE Stroke Prevention With Hydroxyurea Enabled Through Research and Education (SPHERE): A Prospective Trial to Reduce Primary Stroke in Children With Sickle Cell Anaemia
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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 schedule
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Sickle Cell Anemia in Children
Intervention  ICMJE
  • 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.

  • 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).
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Hydroxyurea
    • Diagnostic Test: Elevated Arm TCD Examination
  • 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.
    Intervention: Diagnostic Test: Normal Arm TCD Examination
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 11, 2020)
202
Original Estimated Enrollment  ICMJE
 (submitted: May 10, 2019)
200
Estimated Study Completion Date  ICMJE March 31, 2022
Estimated Primary Completion Date March 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 16 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Tanzania,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03948867
Other Study ID Numbers  ICMJE SPHERE
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Hospital Medical Center, Cincinnati
Study Sponsor  ICMJE Children's Hospital Medical Center, Cincinnati
Collaborators  ICMJE
  • Bugando Medical Centre
  • The American Society of Hematology
Investigators  ICMJE Not Provided
PRS Account Children's Hospital Medical Center, Cincinnati
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP