title: Novel Use of Hydroxyurea in an African Region With Malaria: Protocol for a Randomized Controlled Clinical Trial.
abstract: BACKGROUND
  Sickle cell anemia (SCA), one of most prevalent monogenic diseases worldwide, is caused by a glutamic acid to valine substitution on the beta globin protein of hemoglobin, which leads to hemolytic anemia. Hydroxyurea, the only disease-modifying therapy approved by the Food and Drug Administration for SCA, has proven to be a viable therapeutic option for SCA patients in resource-rich settings, given clinical improvements experienced while taking the medication and its once-daily oral dosing. Significant studies have demonstrated its safety and clinical efficacy among children and adults in developed countries. In Sub-Saharan Africa, however, the risk of malaria, hematologic toxicities, and safety of hydroxyurea in children with SCA living in malaria-endemic areas are unknown.
  
  
  OBJECTIVE
  Study objectives include determining the incidence of malaria in SCA patients taking hydroxyurea versus placebo; establishing the frequency of hematologic toxicities and adverse events (AEs) in children with SCA treated with hydroxyurea versus placebo; and defining the relationships between hydroxyurea treatment and fetal hemoglobin, soluble intracellular adhesion molecule-1, and nitric oxide levels, and between levels of these factors and risk of subsequent malaria.
  
  
  METHODS
  Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM, NCT01976416) is a prospective, randomized, placebo-controlled, double-blinded phase III trial to compare risk of malaria with oral hydroxyurea versus placebo. Children will be recruited from the Mulago Hospital Sickle Cell Clinic in Kampala, Uganda.
  
  
  RESULTS
  Two hundred Ugandan children aged between 1.00 and 3.99 years with confirmed SCA will be randomized into treatment groups by order of entry in the study, based on a predetermined blinded randomization list. The primary outcome of the trial is malaria incidence in the 2 study groups, defined as episodes of clinical malaria occurring over the 1-year randomized study treatment period.
  
  
  CONCLUSIONS
  NOHARM will be the first prospective randomized, placebo-controlled clinical trial investigating the use of hydroxyurea for children with SCA in a malaria-endemic region within Africa. The results of this trial have the potential to significantly advance understanding of how to safely and effectively use hydroxyurea in children with SCA in malaria-endemic areas.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01976416; https://clinicaltrials.gov/ct2/show/NCT01976416 (Archived by WebCite at http://www.webcitation.org/6hmoilZnp).
authors.affiliation: University of Minnesota, Minneapolis, MN, United States.
authors.forename: Juliana N
authors.identifier: http://orcid.org/0000-0002-4271-7910
authors.initials: JN
authors.lastname: Anyanwu
authors.forename: Olatundun
authors.identifier: http://orcid.org/0000-0003-2163-3918
authors.initials: O
authors.lastname: Williams
authors.forename: Casey L
authors.identifier: http://orcid.org/0000-0001-9727-4953
authors.initials: CL
authors.lastname: Sautter
authors.forename: Phillip
authors.identifier: http://orcid.org/0000-0001-6620-483X
authors.initials: P
authors.lastname: Kasirye
authors.forename: Heather
authors.identifier: http://orcid.org/0000-0002-4171-104X
authors.initials: H
authors.lastname: Hume
authors.forename: Robert O
authors.identifier: http://orcid.org/0000-0003-3240-2058
authors.initials: RO
authors.lastname: Opoka
authors.forename: Teresa
authors.identifier: http://orcid.org/0000-0002-4473-5821
authors.initials: T
authors.lastname: Latham
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0002-3244-551X
authors.initials: C
authors.lastname: Ndugwa
authors.forename: Russell E
authors.identifier: http://orcid.org/0000-0001-9582-0594
authors.initials: RE
authors.lastname: Ware
authors.forename: Chandy C
authors.identifier: http://orcid.org/0000-0002-1634-1411
authors.initials: CC
authors.lastname: John
keywords: hydroxyurea; malaria; sickle cell anemia