Realizing Effectiveness Across Continents With Hydroxyurea

Study Overview
=================
Brief Summary
-----------------
REACH is a prospective, phase I/II open-label dose escalation trial of hydroxyurea for children with confirmed SCA between 3 and 10 years of age. The short-term goal is to obtain critical pilot data regarding the feasibility, safety, and benefit of hydroxyurea for children with SCA in multiple distinct research settings in Africa. Based on that information, the longer-term goal is to make hydroxyurea more widely available for children with SCA in Africa, particularly those identified with SCA through expanded newborn screening programs.

Detailed Description
-----------------
REACH is a prospective, phase I/II open-label dose escalation trial of hydroxyurea for children with confirmed SCA between 3 and 10 years of age. The short-term goal is to obtain critical pilot data regarding the feasibility, safety, and benefit of hydroxyurea for children with SCA in multiple distinct research settings in Africa. Based on that information, the longer-term goal is to make hydroxyurea more widely available for children with SCA in Africa, particularly those identified with SCA through expanded newborn screening programs. In the REACH prospective trial, the Original Cohort will receive long-term treatment while for the New Cohort, treatment will continue at least 4 years using PK-guided dosing after an initial 3-month screening period.

Official Title
-----------------
Realizing Effectiveness Across Continents With Hydroxyurea: A Phase I/II Prospective Trial of Hydroxyurea for Children With Sickle Cell Anemia

Conditions
-----------------
Sickle Cell Disease, Children

Intervention / Treatment
-----------------
* Drug: Hydroxyurea
* Drug: Hydroxyurea


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Pediatric patients with documented sickle cell anemia (typically HbSS supported by hemoglobin electrophoresis, complete blood count, and peripheral blood smear) In the Original Cohort, age range of 1.00-9.99 years, inclusive, at the time of enrollment (now age 5.5 - 17.5 years); age range 3.0-10.0 years for the New Cohort Weight at least 10.0 kg at the time of enrollment Parent or guardian willing and able to provide written informed consent, with child's verbal assent as per local IRB/Ethics Board requirements Willingness to comply with all study-related treatments, evaluations, and follow-up Exclusion Criteria Known medical condition making participation ill-advised (e.g., acute or chronic infectious disease, HIV, or malignancy) Acute or chronic severe malnutrition determined by impaired growth parameters as defined by WHO (weight for length/height or height for age >3 z-scores below the median WHO growth standards. Pre-existing severe hematological toxicity (temporary exclusions) Anemia: Hb <4.0 g/dL Anemia: Hb <6.0 g/dL with ARC <100 x 109/L Reticulocytopenia: ARC <80 x 109/L with Hb <7.0 g/dL Thrombocytopenia: Platelets <80 x 109/L Neutropenia: ANC <1.0 x 109/L Blood transfusion within 60 days before enrollment (temporary exclusion) In the Original Cohort, hydroxyurea use within 6 months before enrollment (temporary exclusion). In the New Cohort, the children should be hydroxyurea naïve, without any prior treatment exposure.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years
Maximum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The original cohort will continue treatment per planned protocol schedule of evaluations, and a new cohort will join with consent, a 3-month screening period, and treatment per planned protocol schedule of evaluations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Original Cohort<br>The original REACH cohort continuing study treatment per the protocol schedule of evaluations. | Drug: Hydroxyurea<br>* Hydroxyurea, approximately 20-30 mg/kg/day, with modifications for toxicity or for mild marrow suppression<br>|
| Experimental: New Cohort<br>Newly enrolled REACH participants consent, 3 months screening, and treatment per the protocol schedule of evaluations | Drug: Hydroxyurea<br>* Hydroxyurea 15-35 mg/kg/day based on PK-guided dosing, with modifications for toxicity for mild marrow suppression<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of long-term Hydroxyurea treatment at MTD | The efficacy of hydroxyurea will be primarily assessed through fetal hemoglobin (HbF), comparing treatment with baseline values. | Assessed every 6 ± 1 months up to 204 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of malaria incidents while on hydroxyurea at MTD. | Clinical malaria infections to identify associations of risk or protection comparing treated and untreated incidents. | Assessed every 4 ± 1 weeks, then every 3 ± 1months up to 204 months | 
| Success of PK-guided dosing of hydroxyurea | Fetal Hemoglobin changes from hydroxyurea at MTD | Assessed every 6 ± 1 months up to 204 months |