Novel Use Of Hydroxyurea in an African Region With Malaria
Condition: Sickle Cell Anemia; Sickle Cell Disease; Malaria
MeSH terms: Malaria; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 3

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
    

Intervention name(s): Hydroxyurea; Placebo
Intervention type(s): Drug; Drug
Other intervention name(s): Siklos; Hydroxycarbamide
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hydroxyurea