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

• 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: Indiana University
• 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: October 22, 2013
• First Posted Date: November 5, 2013
• Results First Submitted Date: February 2, 2018
• Results First Posted Date: October 1, 2018
• Last Update Posted Date: December 4, 2018
• Study Start Date: September 2014
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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 ]

• Current Secondary Outcome Measures: Not Provided

Original Secondary Outcome Measures (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: Novel Use Of Hydroxyurea in an African Region With Malaria
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Sickle Cell Anemia
• Sickle Cell Disease
• Malaria

Intervention

• Drug: Hydroxyurea
  Other Names:

  • Siklos
  • Hydroxycarbamide
• Drug: Placebo

Study Arms

• 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 *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 26, 2017): 208
• Original Estimated Enrollment (submitted: October 29, 2013): 200
• Actual Study Completion Date: November 2017
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 47 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Uganda

Administrative Information

• NCT Number: NCT01976416
• Other Study ID Numbers: 2012139
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Chandy John, Indiana University
• Original Responsible Party: University of Minnesota
• Current Study Sponsor: Indiana University
• Original Study Sponsor: University of Minnesota

Collaborators

• 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

• PRS Account: Indiana University
• Verification Date: November 2018