Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa (PUSHUP)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Sickle Cell Disease; Sickle Cell Anemia in Children
• Intervention / Treatment: Drug: Hydroxyurea

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: BrUOG; Phone Number: 401-863-3000; Email: BrUOG@brown.edu

Study Locations

• Angola
  • Luanda, Angola
    • Recruiting
    • Hospital Geral dos Cajueiros
    • Contact: Eugenia Alberto Mateus, MSN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health-Related Quality of Life Questionnaires	To evaluate the utility and validity of two established measures of health-related quality of life (HRQoL) for patients and families affected by SCA in Angola before and after hydroxyurea treatment. we will evaluate the Pediatric Quality of Life Sickle Cell Disease (PedsQL SCD) module for children ≥ 2 years of age and the PedsQL™ Family Impact Module for families of all enrolled participants. We will also utilize the International Sickle Cell World Assessment Survey (SWAY). These tools are available in the Portuguese language; for consistency and to account for the likely low literacy rate in the population, all surveys will be administered verbally to participants by study staff, recorded on paper or via tablet. We will compare results before and after hydroxyurea treatment. We will compare results to each other and to the published literature from other SCA populations.	From start of study treatment through treatment completion, approximately 24 months.

Collaborators and Investigators

• Sponsor: Brown University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Novartis
• Investigators: Principal Investigator: Patrick T McGann, MD, MS, Rhode Island Hospital and Hasbro Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2023
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 1, 2022
• First Submitted That Met QC Criteria: March 9, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea
• Other Study ID Numbers: BrUOG 419; U01HL157872 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes