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Realizing Effectiveness Across Continents With Hydroxyurea (REACH) (REACH)

Primary Purpose

Sickle Cell Disease

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Hydroxyurea
Sponsored by
Children's Hospital Medical Center, Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease focused on measuring Africa

Eligibility Criteria

1 Year - 10 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria

  1. Pediatric patients with documented sickle cell anemia (typically HbSS supported by hemoglobin electrophoresis, complete blood count, and peripheral blood smear)
  2. Age range of 1.00-9.99 years, inclusive, at the time of enrollment
  3. Weight at least 10.0 kg at the time of enrollment
  4. Parent or guardian willing and able to provide written informed consent, with child's verbal assent as per local IRB/Ethics Board requirements
  5. Willingness to comply with all study-related treatments, evaluations, and follow-up

Exclusion Criteria

  1. Known medical condition making participation ill-advised, (e.g., acute or chronic infectious disease, HIV, or malignancy)
  2. Acute or chronic severe malnutrition determined by impaired growth parameters as defined by WHO (weight for length/height or weight-for-length/height >3 z-scores below the median WHO growth standards, as defined in Appendix I)

  3. Pre-existing severe hematological toxicity (temporary exclusions)

    1. Anemia: Hb <4.0 gm/dL
    2. Anemia: Hb <6.0 gm/dL with ARC <100 x 109/L
    3. Reticulocytopenia: ARC <80 x 109/L with Hb <7.0 gm/dL
    4. Thrombocytopenia: Platelets <80 x 109/L
    5. Neutropenia: ANC <1.0 x 109/L
  4. Blood transfusion within 60 days before enrollment (temporary exclusion)
  5. Hydroxyurea use within 6 months before enrollment

Sites / Locations

  • Hospital Pediátrico David Bernardino
  • Centre Hospitalier Monkole
  • KEMRI/Wellcome Trust Research
  • Ministry of Health Mbale Regional Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Hydroxyurea

Arm Description

After patient enrollment, a two-month pre-hydroxyurea evaluation phase will be used to perform baseline evaluations including nutritional and infectious assessments, and to provide supplements or treatments as deemed necessary. After the pre-hydroxyurea evaluation and supplementation phase, hydroxyurea dosing will be administered as a single daily dose, using capsules provided as a monthly supply in 200mg, 300mg, 400mg, or 500mg sizes.

Outcomes

Primary Outcome Measures

Percentage of Participants With Dose Limiting Toxic Events
An expected toxicity rate of 20% and acceptable toxicity rate of 30% were used for statistical calculations. After 53 participants at each site complete 3 months of therapy, if ≤ 15 participants have hematologic toxicity there is no early evidence against safety. If ≥ 15 of the initial participants experience toxicity, this is early evidence against safety. Future participants will begin at a lower dose of hydroxyurea (10 ± 2.5 mg/kg), with another 53 participants recruited of the same safety analysis. Upon final analysis of 133 participants at the same starting dose, safety for fixed-dose hydroxyurea can be concluded.

Secondary Outcome Measures

Efficacy of Hydroxyurea
The efficacy of hydroxyurea will be primarily assessed through fetal hemoglobin (HbF), comparing treatment with baseline values. Additional measures of laboratory efficacy will include changes in Hb, MCV, WBC, ANC, ARC, and bilirubin. Clinical events such as vaso-occlusive pain will be captured as secondary outcomes.
Medication Adherence and the Ability for Families to Adhere to Monthly Clinic Visits Are Important Feasibility Outcomes
Hydroxyurea treatment will be dispensed only 35 days at a time, requiring a clinic visit every 4 ± 1 weeks. Medication adherence and the ability for families to adhere to monthly clinic visits are important feasibility outcomes

Full Information

First Posted
October 4, 2013
Last Updated
January 17, 2023
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT01966731
Brief Title
Realizing Effectiveness Across Continents With Hydroxyurea (REACH)
Acronym
REACH
Official Title
Realizing Effectiveness Across Continents With Hydroxyurea (REACH): A Phase I/II Pilot Study Of Hydroxyurea For Children With Sickle Cell Anemia
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 2014 (undefined)
Primary Completion Date
July 1, 2018 (Actual)
Study Completion Date
August 2033 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
REACH is a prospective, phase I/II open-label dose escalation trial of hydroxyurea for children with confirmed SCA between 12 months 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
STUDY OBJECTIVES To assess the feasibility of conducting a prospective research study using hydroxyurea therapy for SCA in sub-Saharan Africa (including adherence to monthly clinic visits and laboratory assessments, and medication compliance) To monitor the safety of hydroxyurea therapy, specifically documenting hematological toxicities (cytopenias) and serious infections (bacterial and malarial) To evaluate the benefits of hydroxyurea therapy, using both laboratory (e.g., fetal hemoglobin, hemoglobin, white blood cell count) and clinical parameters (e.g., pain, hospitalization, growth) To investigate the effects of hydroxyurea dose escalation on laboratory and clinical parameters

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease
Keywords
Africa

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
635 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hydroxyurea
Arm Type
Experimental
Arm Description
After patient enrollment, a two-month pre-hydroxyurea evaluation phase will be used to perform baseline evaluations including nutritional and infectious assessments, and to provide supplements or treatments as deemed necessary. After the pre-hydroxyurea evaluation and supplementation phase, hydroxyurea dosing will be administered as a single daily dose, using capsules provided as a monthly supply in 200mg, 300mg, 400mg, or 500mg sizes.
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Other Intervention Name(s)
Hydrea, Droxia
Intervention Description
Hydroxyurea will begin at 15-20 mg/kg PO daily. Six months of treatment will be given at the fixed dose, followed by another six months with dose escalation (2.5-5.0 mg/kg increments every 8 weeks) as tolerated to 20-30 mg/kg/day or MTD. The dose escalation phase will continue through the 12-month evaluation, after which hydroxyurea will continue in maintenance phase until the common treatment termination date. The daily dose will be calculated using available capsule sizes and a goal of 15-20 (17.5 ± 2.5) mg/kg/day based on weight. After 6 months of treatment, hydroxyurea will be titrated according to myelosuppression, and will be increased to 20-30 mg/kg/day or the maximum tolerated dose (MTD). Hydroxyurea dose escalation will occur in 5.0 ± 2.5 mg/kg/day increments.
Primary Outcome Measure Information:
Title
Percentage of Participants With Dose Limiting Toxic Events
Description
An expected toxicity rate of 20% and acceptable toxicity rate of 30% were used for statistical calculations. After 53 participants at each site complete 3 months of therapy, if ≤ 15 participants have hematologic toxicity there is no early evidence against safety. If ≥ 15 of the initial participants experience toxicity, this is early evidence against safety. Future participants will begin at a lower dose of hydroxyurea (10 ± 2.5 mg/kg), with another 53 participants recruited of the same safety analysis. Upon final analysis of 133 participants at the same starting dose, safety for fixed-dose hydroxyurea can be concluded.
Time Frame
3 months
Secondary Outcome Measure Information:
Title
Efficacy of Hydroxyurea
Description
The efficacy of hydroxyurea will be primarily assessed through fetal hemoglobin (HbF), comparing treatment with baseline values. Additional measures of laboratory efficacy will include changes in Hb, MCV, WBC, ANC, ARC, and bilirubin. Clinical events such as vaso-occlusive pain will be captured as secondary outcomes.
Time Frame
Assessed every 4 ± 1 weeks up to 204 months
Title
Medication Adherence and the Ability for Families to Adhere to Monthly Clinic Visits Are Important Feasibility Outcomes
Description
Hydroxyurea treatment will be dispensed only 35 days at a time, requiring a clinic visit every 4 ± 1 weeks. Medication adherence and the ability for families to adhere to monthly clinic visits are important feasibility outcomes
Time Frame
Assessed every 4 ± 1 weeks up to 204 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
10 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Pediatric patients with documented sickle cell anemia (typically HbSS supported by hemoglobin electrophoresis, complete blood count, and peripheral blood smear) Age range of 1.00-9.99 years, inclusive, at the time of enrollment 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 weight-for-length/height >3 z-scores below the median WHO growth standards, as defined in Appendix I) Pre-existing severe hematological toxicity (temporary exclusions) Anemia: Hb <4.0 gm/dL Anemia: Hb <6.0 gm/dL with ARC <100 x 109/L Reticulocytopenia: ARC <80 x 109/L with Hb <7.0 gm/dL Thrombocytopenia: Platelets <80 x 109/L Neutropenia: ANC <1.0 x 109/L Blood transfusion within 60 days before enrollment (temporary exclusion) Hydroxyurea use within 6 months before enrollment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Russell Ware, MD, PhD
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Pediátrico David Bernardino
City
Luanda
Country
Angola
Facility Name
Centre Hospitalier Monkole
City
Kinshasa
Country
Congo, The Democratic Republic of the
Facility Name
KEMRI/Wellcome Trust Research
City
Kilifi
Country
Kenya
Facility Name
Ministry of Health Mbale Regional Hospital
City
Mbale
Country
Uganda

12. IPD Sharing Statement

Citations:
PubMed Identifier
30501550
Citation
Tshilolo L, Tomlinson G, Williams TN, Santos B, Olupot-Olupot P, Lane A, Aygun B, Stuber SE, Latham TS, McGann PT, Ware RE; REACH Investigators. Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2019 Jan 10;380(2):121-131. doi: 10.1056/NEJMoa1813598. Epub 2018 Dec 1.
Results Reference
derived
PubMed Identifier
29318647
Citation
McGann PT, Williams TN, Olupot-Olupot P, Tomlinson GA, Lane A, Luis Reis da Fonseca J, Kitenge R, Mochamah G, Wabwire H, Stuber S, Howard TA, McElhinney K, Aygun B, Latham T, Santos B, Tshilolo L, Ware RE; REACH Investigators. Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa. Am J Hematol. 2018 Aug;93(4):537-545. doi: 10.1002/ajh.25034. Epub 2018 Jan 27.
Results Reference
derived
PubMed Identifier
26275071
Citation
McGann PT, Tshilolo L, Santos B, Tomlinson GA, Stuber S, Latham T, Aygun B, Obaro SK, Olupot-Olupot P, Williams TN, Odame I, Ware RE; REACH Investigators. Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial. Pediatr Blood Cancer. 2016 Jan;63(1):98-104. doi: 10.1002/pbc.25705. Epub 2015 Aug 14.
Results Reference
derived

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Realizing Effectiveness Across Continents With Hydroxyurea (REACH)

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