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

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ClinicalTrials.gov Identifier: NCT03948867
Recruitment Status : Recruiting
First Posted : May 14, 2019
Last Update Posted : May 14, 2019
Sponsor:
Collaborators:
Bugando Medical Centre
The American Society of Hematology
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 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 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 : April 24, 2019
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia
Drug Information available for: 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).




Primary Outcome Measures :
  1. 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

  2. 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03948867


Contacts
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Contact: Emmanuela E Ambrose, MD, MMed +255(0) 789 733 833 emmanuelaambrose@gmail.com

Locations
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United States, Ohio
Cincinnati Children's Hospital Medical Center Active, not recruiting
Cincinnati, Ohio, United States, 45229
Tanzania
Bugando Medical Centre Recruiting
Mwanza, Tanzania
Contact: Emmanuela E Ambrose, MD, MMed    +255(0) 789 733 833    emmanuelaambrose@gmail.com   
Principal Investigator: Emmanuela Ambrose, MD, MMed         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Bugando Medical Centre
The American Society of Hematology

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03948867     History of Changes
Other Study ID Numbers: SPHERE
First Posted: May 14, 2019    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: May 2019

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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
Keywords provided by Children's Hospital Medical Center, Cincinnati:
Sickle Celll Anemia
Transcranial Doppler
Tanzania
Hydroxyurea
Stroke
Additional relevant MeSH terms:
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Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Antisickling Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors