Novel Use Of Hydroxyurea in an African Region With Malaria (NOHARM)
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| ClinicalTrials.gov Identifier: NCT01976416 |
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Recruitment Status :
Completed
First Posted : November 5, 2013
Results First Posted : October 1, 2018
Last Update Posted : December 4, 2018
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Sickle Cell Anemia Sickle Cell Disease Malaria | Drug: Hydroxyurea Drug: Placebo | Phase 3 |
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:
- Determine the incidence of malaria in children with sickle cell anemia treated with hydroxyurea vs. placebo
- Establish the frequency of hematologic toxicities and adverse events in children with sickle cell anemia treated with hydroxyurea vs. placebo
- 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:
- The incidence of malaria is not greater in children with SCA treated with hydroxyurea than those treated with placebo
- 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
- 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 Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 208 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | Novel Use Of Hydroxyurea in an African Region With Malaria |
| Study Start Date : | September 2014 |
| Actual Primary Completion Date : | October 2016 |
| Actual Study Completion Date : | November 2017 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Hydroxyurea
Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
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Drug: Hydroxyurea
Other Names:
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Placebo Comparator: Placebo
Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
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Drug: Placebo |
- Number of Malaria Episodes [ Time Frame: 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.
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| Ages Eligible for Study: | 12 Months to 47 Months (Child) |
| Sexes Eligible for Study: | All |
| Accepts 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)
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Pre-existing severe hematological toxicity:
- Hb <4.0 g/dL
- Hb <6.0 g/dL AND ARC <100 x 10E9/L
- Hb <7.0 g/dL AND ARC <80 x 10E9/L
- Platelets <80 x 10E9/L
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01976416
| Uganda | |
| Mulago Hospital Sickle Cell Clinic | |
| Kampala, Uganda | |
| Principal Investigator: | Chandy C. John, M.D. | Indiana University |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Chandy John, Professor of Pediatrics, Medicine, Microbiology and Immunology, Indiana University |
| ClinicalTrials.gov Identifier: | NCT01976416 |
| Other Study ID Numbers: |
2012139 |
| First Posted: | November 5, 2013 Key Record Dates |
| Results First Posted: | October 1, 2018 |
| Last Update Posted: | December 4, 2018 |
| Last Verified: | November 2018 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
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Hydroxyurea |
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Malaria Anemia, Sickle Cell Protozoan Infections Parasitic Diseases Infections Vector Borne Diseases Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia |
Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn Hydroxyurea Antineoplastic Agents Antisickling Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Nucleic Acid Synthesis Inhibitors |