Novel Use Of Hydroxyurea in an African Region With Malaria (NOHARM)

Indiana University

Status and phase: Completed; Phase 3

Conditions: Malaria; Sickle Cell Anemia; Sickle Cell Disease

Treatments: Drug: Hydroxyurea; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT01976416

2012139

Details and patient eligibility

About

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.

Full 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

Enrollment: 208 patients

Sex: All

Ages: 12 to 47 months old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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208 participants in 2 patient groups, including a placebo group

Hydroxyurea

Experimental group

Description:

Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months

Treatment:

Drug: Hydroxyurea

Placebo

Placebo Comparator group

Description:

Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months

Treatment:

Drug: Placebo