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

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01976416
First Posted: November 5, 2013
Last Update Posted: March 24, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Doris Duke Charitable Foundation
Makerere University
Mulago Hospital, Uganda
Children's Hospital Medical Center, Cincinnati
Information provided by (Responsible Party):
Chandy John, Indiana University
  Purpose

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 Intervention Phase
Sickle Cell Anemia Sickle Cell Disease Malaria Drug: Hydroxyurea Drug: Placebo Phase 3

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Chandy John, Indiana University:

Primary Outcome Measures:
  • Malaria incidence [ 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.


Secondary Outcome Measures:
  • Malaria incidence (using additional criteria) [ Time Frame: Over the 12 month randomized study treatment period ]

    To add specificity (at the cost of some sensitivity), the following definitions will be added to the primary definition of malaria:

    • P. falciparum parasitemia >1000 parasites/µL
    • Measured axillary temperature ≥37.5 degrees C
    • P. falciparum parasitemia >1000 parasites/µL and measured axillary temperature ≥37.5 degrees C
    • Malaria requiring hospital admission

  • Change in plasma concentration of vascular cellular adhesion molecule-1 (VCAM-1) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]
  • Change in plasma concentration of von Willebrand factor (VWF) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]
  • Change in plasma concentration of tumor necrosis factor-alpha (TNF-alpha) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]
  • Incidence of SCA-related adverse events [ Time Frame: 12 months ]

    SCA-related adverse events are defined as:

    • Pain event
    • Dactylitis
    • Acute chest syndrome
    • Splenic sequestration
    • Requirement of blood transfusion

  • Incidence of hematologic toxicities [ Time Frame: 12 months ]

    Hematologic toxicities are defined as:

    • Hemoglobin (Hb) <4.0g/dL
    • Hb <6.0g/dL AND absolute reticulocyte count (ARC) <100 x 10E9/L
    • Hb <7.0g/dL AND ARC <80 x 10E9/L
    • Platelets <80 x 10E9/L
    • Absolute neutrophil count (ANC) <1.0 x 10E9/L

  • Change in fetal hemoglobin (HbF) level [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]
  • Change in plasma concentration of soluble intracellular adhesion molecule-1 (sICAM-1) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]
  • Change in plasma concentration of nitric oxide (NO) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment initiation ]

Estimated Enrollment: 200
Study Start Date: September 2014
Estimated Study Completion Date: October 2017
Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Hydroxyurea
Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
Drug: Hydroxyurea
Other Names:
  • Siklos
  • Hydroxycarbamide
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
Drug: Placebo

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

Information from the National Library of Medicine

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Ages Eligible for Study:   12 Months to 47 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

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


Locations
Uganda
Mulago Hospital Sickle Cell Clinic
Kampala, Uganda
Sponsors and Collaborators
Indiana University
Doris Duke Charitable Foundation
Makerere University
Mulago Hospital, Uganda
Children's Hospital Medical Center, Cincinnati
Investigators
Principal Investigator: Chandy C. John, M.D. Indiana University
  More Information

Responsible Party: Chandy John, Professor of Pediatrics, Medicine, Microbiology and Immunology, Indiana University
ClinicalTrials.gov Identifier: NCT01976416     History of Changes
Other Study ID Numbers: 2012139
First Submitted: October 22, 2013
First Posted: November 5, 2013
Last Update Posted: March 24, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Chandy John, Indiana University:
Hydroxyurea

Additional relevant MeSH terms:
Malaria
Anemia, Sickle Cell
Protozoan Infections
Parasitic 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