Clinical trial NCT01976416: Novel Use Of Hydroxyurea in an African Region With Malaria
Official title: Novel Use Of Hydroxyurea in an African Region With Malaria
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sickle Cell Anemia
Sickle Cell Disease
Malaria
Keywords: Hydroxyurea
Lead sponsor: Indiana University
Sponsor class: OTHER
Collaborators: name: Doris Duke Charitable Foundation
name: Makerere University
name: Mulago Hospital, Uganda
name: Children's Hospital Medical Center, Cincinnati
First posted: 2013-11-05
Enrollment: 208
Sex: ALL
Minimum age (years): 12
Maximum age (years): 47
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Number of Malaria Episodes
timeFrame: 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Mulago Hospital Sickle Cell Clinic
Study officials:
affiliation: Indiana University
name: Chandy C. John, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Opoka RO, Ndugwa CM, Latham TS, Lane A, Hume HA, Kasirye P, Hodges JS, Ware RE, John CC. Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood. 2017 Dec 14;130(24):2585-2593. doi: 10.1182/blood-2017-06-788935. Epub 2017 Oct 19.
citation: Carman AS, Sautter C, Anyanwu JN, Ssemata AS, Opoka RO, Ware RE, Rujumba J, John CC. Perceived benefits and risks of participation in a clinical trial for Ugandan children with sickle cell anemia. Pediatr Blood Cancer. 2020 Feb;67(2):e27830. doi: 10.1002/pbc.27830. Epub 2019 May 28.
citation: Anyanwu JN, Williams O, Sautter CL, Kasirye P, Hume H, Opoka RO, Latham T, Ndugwa C, Ware RE, John CC. Novel Use of Hydroxyurea in an African Region With Malaria: Protocol for a Randomized Controlled Clinical Trial. JMIR Res Protoc. 2016 Jun 23;5(2):e110. doi: 10.2196/resprot.5599.