Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa

Study Overview
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Brief Summary
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Sickle cell anemia (SCA) is among the world's most common and devastating blood disorders, affecting more than 300,000 newborns per year. Most infants with SCA are born in the low-resource settings of sub- Saharan Africa, where an estimated 50-90% will die before 5 years of age due to lack of early diagnosis and appropriate care. Hydroxyurea is a safe and effective once-daily oral medication that has become the standard of care for the treatment of children with SCA in high-resource settings. There is now a growing body of evidence to support the safety and clinical benefits of hydroxyurea for the treatment of SCA in sub-Saharan Africa. The requirement for frequent laboratory monitoring, uncertainties about appropriate, most effective dosing, and the concern for hematologic laboratory toxicities, however, will continue to limit widespread hydroxyurea utilization and real-world effectiveness. The investigators have recently developed and prospectively evaluated an individualized, pharmacokinetics-guided hydroxyurea dosing strategy for children with SCA that has demonstrated optimal clinical and laboratory benefits with minimal toxicity. In this research study, the investigators aim to extend this precision medicine approach to Africa.

Detailed Description
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The Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa (PUSHUP) trial is a prospective, randomized clinical trial of hydroxyurea for 400 children with SCA in Luanda, Angola. The study will prospectively evaluate the safety and efficacy of hydroxyurea with limited laboratory monitoring and will bring precision medicine to children with SCA using several novel features including measurement of hydroxyurea using a battery-powered HPLC machine and individualized dose calculations using an automated computer-based algorithm. The objective of this study is to establish evidence-based guidelines for hydroxyurea in sub-Saharan Africa, including appropriate dosing and laboratory monitoring strategy with the goal of allowing for widespread use of hydroxyurea across sub-Saharan Africa, regardless of clinical or laboratory resources.

Official Title
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BrUOG 419 - Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa (PUSHUP)

Conditions
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Sickle Cell Anemia in Children, Sickle Cell Disease

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of sickle cell anemia (HbSS or HbS/B0-thalassemia) Age 6 months- 12 years of age at enrollment Parent or guardian willing and able to provide written or informed consent Weight ≥ 7.5 kg (temporary exclusion) Exclusion Criteria: Splenomegaly with evidence of hypersplenism as defined by platelet count <150,000, hemoglobin <5 g/dL or absolute neutrophil count <1.0 x10^9/L Hydroxyurea use within the past 6 months Blood transfusion within the past 6 months (temporary exclusion) Pregnancy Pre-existing severe hematologic toxicity, as defined by platelet count <80,000, hemoglobin <4 regardless of ANC; hemoglobin <6 AND ARC <100; hemoglobin <7 AND ARC <80 x10^9/L (temporary exclusion)

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Weight Based Starting Dose<br>25 mg/kg starting dose Hydroxyurea | Drug: Hydroxyurea<br>* Hydroxyurea has a narrow therapeutic window such that selection of the correct dose is essential to optimize benefits and avoid toxicity.<br>* Other names: Droxia;|
| Experimental: PK-guided starting dose<br>Individualized, PK-guided starting dose Hydroxyurea | Drug: Hydroxyurea<br>* Hydroxyurea has a narrow therapeutic window such that selection of the correct dose is essential to optimize benefits and avoid toxicity.<br>* Other names: Droxia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical, sickle cell adverse events (grade ≥ 3) as assessed by CTCAE v5.0 | These events will primarily include vaso-occlusive painful events, acute chest syndrome, stroke, acute splenic sequestration, and death. Data regarding adverse events, including severity grade and relatedness to SCA will be determined on site by the local investigator. All events will be centrally adjudicated by a blinded hematologist who is not a primary study investigator (Medical Safety Monitor) for inclusion in this endpoint. | From start of study treatment through first 12 months of treatment. | 
| Number of non-SCA related adverse events (grade ≥3), including death as assessed by CTCAE v5.0 | The clinical event rate with limited laboratory monitoring will be compared to the 3-months prior to hydroxyurea therapy. | From start of study treatment through treatment completion, approximately 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic response at 12 months | As measured by %HbF, proportion of participants in each arm with HbF ≥ 30%, hemoglobin, absolute reticulocyte count, absolute neutrophil count, platelet count, and mean corpuscular volume), hematologic laboratory toxicities (dose limiting toxicities defined a priori), hospitalizations, death, and all adverse events grade ≥ 3 (SCA and non-SCA related) as assessed by CTCAE v5.0. | From start of study treatment through first 12 months of treatment. |