Optimizing Hydroxyurea Therapy in Children With SCA In Malaria Endemic Areas
Condition: Sickle Cell Anemia; Sickle Cell Disease; Malaria
MeSH terms: Malaria; Anemia; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 3

Summary: 
      The Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM) study is the first
      placebo-controlled randomized clinical trial of hydroxyurea treatment in a malaria endemic
      region. NOHARM has now achieved full enrollment; all children have completed the blinded
      portion of the protocol and are in the open-label study treatment portion.

      This extension study of maximum tolerated dose (MTD), addresses the next critical set of
      questions about the optimal dosing and monitoring of hydroxyurea treatment for children with
      SCA in low-resource settings. By providing guidance about optimal hydroxyurea treatment, the
      NOHARM MTD Study will directly inform policies that can transform the health of African
      children living with SCA.
    

Detailed description: 
      All children enrolled in NOHARM received hydroxyurea treatment at a fixed daily dose of 20
      mg/kg/day. This dose was selected as a likely safe dose, but does not escalate hydroxyurea to
      MTD as is commonly done in the US. Without this information, we cannot know whether
      hydroxyurea treatment at the MTD would be feasible (since it requires closer monitoring to
      avoid hematological toxicities), safe (since adverse events may be greater with MTD, risk of
      malaria may be altered by MTD, and risk of infections as a result of neutropenia could also
      be greater with MTD) or beneficial (MTD is associated with higher hemoglobin and fetal
      hemoglobin concentration).

      In this extension MTD study of open-label hydroxyurea for children in NOHARM who complete the
      initial study, consented children will be randomized to either fixed-dose or MTD hydroxyurea
      treatment for a minimum of 24 months. If hydroxyurea treatment continues to prove safe and
      effective in this low-resource malaria endemic area, and an optimal dosing scheme is
      determined, then the long-term goal is for all study children to transition to hydroxyurea
      treatment provided through the Ugandan Ministry of Health. To provide for a smooth
      transition, we will continue all children at either MTD or fixed dose hydroxyurea until a
      common end date (November 2019), at which time all study participants will have received a
      minimum of 24 months of additional hydroxyurea (either MTD or fixed dose). Addmedica, the
      Paris-based pharmaceutical company that provides the current active drug and placebo for the
      NOHARM trial, has agreed to provide additional hydroxyurea for this MTD study at no cost to
      the study or the participants.

      The Specific Aims of the NOHARM MTD proposal include two initiatives for participants who are
      currently enrolled in NOHARM:

      Aim 1. To determine the safety and efficacy of maximum tolerated dose (MTD) vs. fixed dose
      (20 mg/kg/day) hydroxyurea treatment in children with SCA in a low-resource, malaria endemic
      setting. For safety, we will compare adverse events and severe adverse events, including
      hematologic toxicities. For efficacy, we will assess hemoglobin level, fetal hemoglobin
      percentage (% HbF), and incidence of vaso-occlusive events such as pain crisis and acute
      chest syndrome.

      Aim 2. To compare the clinical outcomes of MTD vs. fixed dose hydroxyurea treatment in
      children with SCA in a low-resource, malaria endemic setting. Clinical outcomes assessed will
      include growth and malaria incidence over a 24-month follow-up period, and differences in
      renal, splenic, and cerebrovascular function between study entry and 24-month follow-up.
    

Intervention name(s): Hydroxyurea
Intervention type(s): Drug
Intervention description(s): Administered once a day in tablet form (100mg or scored 1000mg) for 24 months
Other intervention name(s): Siklos; Hydroxycarbamide
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hydroxyurea