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

Overview

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.

Interventions

• 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).

Primary outcome measures

• Prevalence of Elevated TCD [Time frame: Baseline]
• Change in Primary Stroke Risk [Time frame: Up to 12 Months at Month 12]

Secondary outcome measures (6)

• Laboratory and Clinical Correlates [Time frame: Up to 24 Months]
• Change in Hemoglobin Concentration [Time frame: 6 Months]
• Effect of Splenomegaly and Malaria Infections [Time frame: Up to 24 Months]
• Prevalence of Co-inherited G6PD and Alpha Thalassemia [Time frame: One time at Baseline]
• Hydroxyurea Area Under the Curve (AUC) [Time frame: One time at 24 Months (Study Exit)]
• Single Nucleotide Polymorphisms Associated with Change in Percent Hemoglobin F on Hydroxyurea [Time frame: One Time at 24 Months (Study Exit)]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Cincinnati Children's Hospital Medical Center — Cincinnati

Tanzania · 1 center

• Bugando Medical Centre — Mwanza

Publications

• Ambrose EE, Latham TS, Songoro P, Charles M, Lane AC, Stuber SE, Makubi AN, Ware RE, Smart LR. Hydroxyurea with dose escalation for primary stroke risk reduction in children with sickle cell anaemia in Tanzania (SPHERE): an open-label, phase 2 trial. Lancet Haematol. 2023 Apr;10(4):e261-e271. doi: 10.1016/S2352-3026(22)00405-7. Epub 2023 Mar 1. PMID 36870358

Identifiers

NCT: NCT03948867 · SPHERE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗