Realizing Effectiveness Across Continents With Hydroxyurea (REACH)

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01966731
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 635
• Locations: 4
• Arm: 1
• Duration (Months): 230
• Patients Per Site: 158.8
• Patients Per Site Per Month: 0.7

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease	Drug: Hydroxyurea	Phase 1/Phase 2

Detailed Description

STUDY OBJECTIVES

1. 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)

2. To monitor the safety of hydroxyurea therapy, specifically documenting hematological toxicities (cytopenias) and serious infections (bacterial and malarial)

3. 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)

4. To investigate the effects of hydroxyurea dose escalation on laboratory and clinical parameters

Study Design

• Study Type: Interventional
• Actual Enrollment: 635 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Realizing Effectiveness Across Continents With Hydroxyurea (REACH): A Phase I/II Pilot Study Of Hydroxyurea For Children With Sickle Cell Anemia
• Study Start Date: Jun 1, 2014
• Actual Primary Completion Date: Jul 1, 2018
• Anticipated Study Completion Date: Aug 1, 2033

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hydroxyurea 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.

Drug: Hydroxyurea; 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.; Other Names: Hydrea Droxia

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Dose Limiting Toxic Events [3 months]

   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

1. Efficacy of Hydroxyurea [Assessed every 4 ± 1 weeks up to 204 months]

   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.

2. Medication Adherence and the Ability for Families to Adhere to Monthly Clinic Visits Are Important Feasibility Outcomes [Assessed every 4 ± 1 weeks up to 204 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 10 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

4. Anemia: Hb <4.0 gm/dL

5. Anemia: Hb <6.0 gm/dL with ARC <100 x 109/L

6. Reticulocytopenia: ARC <80 x 109/L with Hb <7.0 gm/dL

7. Thrombocytopenia: Platelets <80 x 109/L

8. Neutropenia: ANC <1.0 x 109/L

9. Blood transfusion within 60 days before enrollment (temporary exclusion)

10. Hydroxyurea use within 6 months before enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Pediátrico David Bernardino	Luanda		Angola
2	Centre Hospitalier Monkole	Kinshasa		Congo, The Democratic Republic of the
3	KEMRI/Wellcome Trust Research	Kilifi		Kenya
4	Ministry of Health Mbale Regional Hospital	Mbale		Uganda

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Russell Ware, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

• Study Protocol - Aug 24, 2017
• Statistical Analysis Plan - Feb 8, 2018

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01966731
• Other Study ID Numbers: 2013-4221
• First Posted: Oct 22, 2013
• Last Update Posted: Dec 15, 2021
• Last Verified: Dec 1, 2021

• Keywords provided by Children's Hospital Medical Center, Cincinnati: Africa
• Additional relevant MeSH terms: Anemia, Sickle Cell; Hydroxyurea

Study Results

Participant Flow

Arm/Group Title	Hydroxyurea
Arm/Group Description	Hydroxyurea dosing was administered as a single daily dose, in 200mg, 300mg, 400mg, or 500mg sizes
Period Title: Overall Study
STARTED	635
Initiated Hydroxyurea	606
Completed 3 Months of Treatment	600
Completed Study	0
COMPLETED	0
NOT COMPLETED	635

Baseline Characteristics

Arm/Group Title	Hydroxyurea
Arm/Group Description	Hydroxyurea administered at 15-20 mg/kg/ day as a single daily dose.
Overall Participants	606
Age (Count of Participants)
<=18 years	606 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	296 48.8%
Male	310 51.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	606 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	606 100%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Angola	150 24.8%
Congo, The Democratic Republic of the	156 25.7%
Uganda	149 24.6%
Kenya	151 24.9%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

N= number of participants analyzed for toxicity during the first 3 months of trial therapy

Arm/Group Title	Hydroxyurea
Arm/Group Description	Hydroxyurea dosing was administered as a single daily dose, in 200mg, 300mg, 400mg, or 500mg sizes
Measure Participants	532
Number (95% Confidence Interval) [percentage of participants]	5.1 0.8%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	67 months
Arm/Group Title	Hydroxyurea
Arm/Group Description	Hydroxyurea administered at 15-20 mg/kg/ day as a single daily dose.
All Cause Mortality
	Hydroxyurea
	Affected / at Risk (%)	# Events
Total	16/635 (2.5%)
Serious Adverse Events
	Hydroxyurea
	Affected / at Risk (%)	# Events
Total	66/635 (10.4%)
Blood and lymphatic system disorders
Anemia	7/635 (1.1%)	7
Splenic sequestration	8/635 (1.3%)	9
Vaso-occlusive pain	8/635 (1.3%)	8
General disorders
Death NOS	2/635 (0.3%)	2
Fever NOS	2/635 (0.3%)	2
Infections and infestations
Bone infection	3/635 (0.5%)	3
Infection unidentified	2/635 (0.3%)	2
Malaria	12/635 (1.9%)	12
Sepsis	12/635 (1.9%)	12
Injury, poisoning and procedural complications
Fracture	1/635 (0.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/635 (0.2%)	1
Nervous system disorders
Stroke	10/635 (1.6%)	10
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome	8/635 (1.3%)	8
Other (Not Including Serious) Adverse Events
	Hydroxyurea
	Affected / at Risk (%)	# Events
Total	500/635 (78.7%)
Blood and lymphatic system disorders
Vaso-occlusive pain	353/635 (55.6%)	755
General disorders
Fever NOS	175/635 (27.6%)	258
Infections and infestations
Infection unidentified	72/635 (11.3%)	97
Malaria	216/635 (34%)	376
Sepsis	37/635 (5.8%)	41
Skin Infection	114/635 (18%)	184
Upper respiratory infection	218/635 (34.3%)	414
Reticulocyte count decreased	63/635 (9.9%)	75
Investigations
Aspartate aminotransferred	37/635 (5.8%)	39
Blood bilirubin increased	44/635 (6.9%)	52
Hemoglobin decreased	239/635 (37.6%)	451
Neutrophil count decreased	41/635 (6.5%)	49
Platelet count decreased	68/635 (10.7%)	106
Respiratory, thoracic and mediastinal disorders
Acute chest pain	59/635 (9.3%)	75

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.