Novel Use Of Hydroxyurea in an African Region With Malaria

Phase 3

Completed

• Conditions: Sickle Cell Anemia; Sickle Cell Disease; Malaria
• Interventions: Drug: Hydroxyurea; Drug: Placebo

• Registration Number: NCT01976416
• Lead Sponsor: Indiana University

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

Study Timeline

• Study First Submitted: 2013-10-22
• Study First Submitted QC: 2013-10-29
• Study First Posted: 2013-11-05
• Study Start: 2014-09
• Primary Completion: 2016-10
• Study Completion: 2017-11
• Results First Submitted: 2018-02-02
• Results First Submitted QC: 2018-02-02
• Results First Posted: 2018-10-01
• Status Verified: 2018-11
• Last Update Submitted: 2018-11-07
• Last Update Posted: 2018-12-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 208

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (1)

Mulago Hospital Sickle Cell Clinic; 🇺🇬 Kampala, Uganda