Malaria, Sickle Cell Anemia, Sickle Cell Disease
Conditions
Keywords
Hydroxyurea
Brief summary
Multiple studies have shown that hydroxyurea has clinical efficacy in preventing acute painful episodes and reducing the need for blood transfusions in children with sickle cell anemia (SCA), but no study has been conducted in malaria endemic regions of sub-Saharan Africa, the areas with the most children with SCA. The primary goal of this study is to investigate the safety and efficacy of hydroxyurea for children with SCA in a malaria endemic region within sub-Saharan Africa.
Detailed description
The risk of malaria and hematologic toxicities from hydroxyurea in children with SCA living in malaria endemic regions is unknown. Some changes associated with hydroxyurea treatment (increased nitric oxide and HbF) would be expected to protect against malaria, but the data on hydroxyurea-related endothelial changes thought to be important in malaria pathogenesis (e.g. intracellular adhesion molecule (ICAM)-1, von Willebrand factor (VWF), tumor necrosis factor (TNF)-α) is unclear, with some studies suggesting that these factors might be increased with hydroxyurea and others suggesting no difference or a decrease. The specific aims of this study are as follows: 1. Determine the incidence of malaria in children with sickle cell anemia treated with hydroxyurea vs. placebo 2. Establish the frequency of hematologic toxicities and adverse events in children with sickle cell anemia treated with hydroxyurea vs. placebo 3. Define the relationship between hydroxyurea treatment and fetal hemoglobin (HbF), soluble ICAM-1 (sICAM-1) and nitric oxide (NO) levels, and between levels of these factors and risk of subsequent malaria. Two hundred children from the Mulago Hospital Sickle Cell Clinic (MHSCC) in Kampala, Uganda will be randomized to receive either hydroxyurea (100) or placebo (100) at a fixed dose of 20 ± 2.5 mg/kg/day. The primary study endpoints will be evaluated after twelve months of study treatment. After twelve months of study treatment, children will enter a follow-up phase during which they can receive an additional twelve months of open-label hydroxyurea treatment if they/their parents wish to do so after consultation with local physicians at the MHSCC. The working hypotheses of this research study are: 1. The incidence of malaria is not greater in children with SCA treated with hydroxyurea than those treated with placebo 2. Children with SCA treated with hydroxyurea will have more medication-related hematologic toxicities, such as neutropenia, but no increase in SCA-related adverse events (e.g. pain crises, hospitalizations, requirement for blood transfusion) compared to children treated with placebo 3. Hydroxyurea will increase HbF and plasma NO levels and decrease plasma sICAM-1 levels; HbF and plasma NO levels will inversely correlate, and plasma sICAM-1 levels will positively correlate, with subsequent malaria incidence
Interventions
DRUGHydroxyurea
DRUGPlacebo
Sponsors
Doris Duke Charitable Foundation
Makerere University
Mulago Hospital, Uganda
Children's Hospital Medical Center, Cincinnati
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 47 Months
Healthy volunteers
No
Inclusion criteria
* Pediatric subjects with documented sickle cell anemia (HbSS supported by hemoglobin electrophoresis or by peripheral blood smear showing sickled red blood cells) * Age range of 1.00-3.99 years, inclusive, at the time of enrollment * Weight at least 5.0 kg at the time of enrollment * Willingness to comply with all study-related treatments, evaluations, and follow up
Exclusion criteria
* Known chronic medical condition (e.g., HIV, malignancy, active clinical tuberculosis) * 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) * Pre-existing severe hematological toxicity: 1. Hb \<4.0 g/dL 2. Hb \<6.0 g/dL AND ARC \<100 x 10E9/L 3. Hb \<7.0 g/dL AND ARC \<80 x 10E9/L 4. Platelets \<80 x 10E9/L 5. ANC \<1.0 x 10E9/L * Alanine transaminase (ALT) or creatinine \>2 times the upper limit of normal for age * Blood transfusion within 30 days prior to enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Malaria Episodes | 12 months | Malaria is defined as the presence of P. falciparum or P. malariae on the peripheral smear of any child brought in for medical evaluation of fever. P. vivax, P. ovale and P. knowlesi are not known to be present in this region, but if a child is seen with suspected infection with any of these malaria parasites, this will also be recorded as a case of malaria. Incidence will be reported in the number of cases per 100 patient years. |
Countries
Uganda
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydroxyurea Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
Hydroxyurea | 104 |
| Placebo Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
Placebo | 103 |
| Total | 207 |
Baseline characteristics
| Characteristic | Placebo | Total | Hydroxyurea |
|---|---|---|---|
| Age, Customized Age 1.00-3.99 years | 103 Participants | 207 Participants | 104 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Uganda | 103 participants | 207 participants | 104 participants |
| Sex: Female, Male Female | 46 Participants | 95 Participants | 49 Participants |
| Sex: Female, Male Male | 57 Participants | 112 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 104 | 1 / 103 |
| other Total, other adverse events | 76 / 104 | 88 / 103 |
| serious Total, serious adverse events | 6 / 104 | 6 / 103 |
Outcome results
Primary
Number of Malaria Episodes
Malaria is defined as the presence of P. falciparum or P. malariae on the peripheral smear of any child brought in for medical evaluation of fever. P. vivax, P. ovale and P. knowlesi are not known to be present in this region, but if a child is seen with suspected infection with any of these malaria parasites, this will also be recorded as a case of malaria. Incidence will be reported in the number of cases per 100 patient years.
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hydroxyurea | Number of Malaria Episodes | 5 malaria episodes |
| Placebo | Number of Malaria Episodes | 7 malaria episodes |