Sickle Cell Disease
Conditions
Keywords
Africa
Brief summary
REACH is a prospective, phase I/II open-label dose escalation trial of hydroxyurea for for pediatric patients with sickle cell anemia (SCA). 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 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 explore the pharmacokinetic and genetic basis for any observed inter-patient variability in the clinical or laboratory response to hydroxyurea. 5. To evaluate the economic cost of providing hydroxyurea therapy in the REACH study sites. 6. To investigate the effects of hydroxyurea dose escalation on laboratory and clinical parameters
Interventions
DRUGHydroxyurea
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.
Sponsors
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
After enrollment, a two-month screening phase was used to perform baseline evaluations including nutritional and infectious assessments, along with supplements and treatments as deemed necessary by local guidelines (e.g., penicillin, pneumococcal immunization, Vitamin A and albendazole/mebendazole treatment per WHO recommendations, malaria prophylaxis, and iron/folate supplementation)
Eligibility
Sex/Gender
ALL
Age
1 Years to 10 Years
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 height for age \>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 (temporary exclusion)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
Countries
Angola, Democratic Republic of the Congo, Kenya, Uganda
Contacts
PRINCIPAL_INVESTIGATORRussell Ware, MD, PhD
Children's Hospital Medical Center, Cincinnati
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyurea Hydroxyurea administered at 15-20 mg/kg/ day as a single daily dose. | 606 |
| Total | 606 |
Baseline characteristics
| Characteristic | Hydroxyurea |
|---|---|
| Age, Categorical <=18 years | 606 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 606 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 606 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Angola | 150 participants |
| Region of Enrollment Congo, The Democratic Republic of the | 156 participants |
| Region of Enrollment Kenya | 151 participants |
| Region of Enrollment Uganda | 149 participants |
| Sex: Female, Male Female | 296 Participants |
| Sex: Female, Male Male | 310 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 16 / 635 |
| other Total, other adverse events | 500 / 635 |
| serious Total, serious adverse events | 66 / 635 |
Outcome results
Primary
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.
Time frame: 3 months
Population: N= number of participants analyzed for toxicity during the first 3 months of trial therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hydroxyurea | Percentage of Participants With Dose Limiting Toxic Events | 5.1 percentage of participants |
Secondary
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.
Time frame: Assessed every 4 ± 1 weeks up to 204 months
Secondary
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
Time frame: Assessed every 4 ± 1 weeks up to 204 months