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

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.
 
ClinicalTrials.gov Identifier: NCT01976416
Recruitment Status : Completed
First Posted : November 5, 2013
Results First Posted : October 1, 2018
Last Update Posted : December 4, 2018
Sponsor:
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

Tracking Information
First Submitted Date  ICMJE October 22, 2013
First Posted Date  ICMJE November 5, 2013
Results First Submitted Date  ICMJE February 2, 2018
Results First Posted Date  ICMJE October 1, 2018
Last Update Posted Date December 4, 2018
Study Start Date  ICMJE September 2014
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 7, 2018)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 29, 2013)
  • 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.
  • 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: Over the 12 month randomized study treatment period ]
    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 intiation ]
  • 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 intiation ]
  • Change in plasma concentration of nitric oxide (NO) [ Time Frame: At study treatment initiation then at 2, 4 and 12 months after study treatment intiation ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2013)
  • 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 intiation ]
  • 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 intiation ]
  • 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 intiation ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Novel Use Of Hydroxyurea in an African Region With Malaria
Official Title  ICMJE Novel Use Of Hydroxyurea in an African Region With Malaria
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Anemia
  • Sickle Cell Disease
  • Malaria
Intervention  ICMJE
  • Drug: Hydroxyurea
    Other Names:
    • Siklos
    • Hydroxycarbamide
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Hydroxyurea
    Fixed dose 20 ± 2.5 mg/kg/day, administered once a day in tablet form (100mg or scored 1000mg) for twelve months
    Intervention: Drug: Hydroxyurea
  • 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
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 26, 2017)
208
Original Estimated Enrollment  ICMJE
 (submitted: October 29, 2013)
200
Actual Study Completion Date  ICMJE November 2017
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 47 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Uganda
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01976416
Other Study ID Numbers  ICMJE 2012139
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Chandy John, Indiana University
Study Sponsor  ICMJE Indiana University
Collaborators  ICMJE
  • Doris Duke Charitable Foundation
  • Makerere University
  • Mulago Hospital, Uganda
  • Children's Hospital Medical Center, Cincinnati
Investigators  ICMJE
Principal Investigator: Chandy C. John, M.D. Indiana University
PRS Account Indiana University
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP