Determining a Tolerable Dose of Primaquine in G6PD-deficient Persons Without Malaria in Mali
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The purpose of this study is to determine the highest tolerable dose of primaquine within
      0.75 mg/kg. A tolerable dose is defined as one in which:

        -  Two or fewer participants (< 30%) experience hemolysis;

        -  No participant experiences a drug-related serious adverse event; and

        -  No participant requires a blood transfusion.
    

Detailed description: 
      Purpose: The purpose of this study is to determine the highest tolerable dose of primaquine
      within 0.75 mg/kg. A tolerable dose is defined as one in which:

        -  Two or fewer participants (< 30%) experience hemolysis;

        -  No participant experiences a drug-related serious adverse event; and

        -  No participant requires a blood transfusion.

      Design:

        -  This is an open-label, phase 2, dose-adjustment study.

        -  The initial primaquine dose will be 0.40 mg/kg. Subsequent dose groups will be selected
           depending on the occurrence of adverse events in the previous dose group. Once the
           highest tolerable dose in G6PD-deficient (G6PDd) individuals is established, a control
           group of G6PD normal malaria-free men will be enrolled and evaluated under the highest
           tolerable dose of primaquine.

      Study Population:

        -  Malian men aged 18-50 years without malaria infection.

        -  The majority of study participants will be G6PDd.

      Study Size: This study will enroll 7 participants per dose group. If all dose groups are
      tested, this study will enroll approximately 28 participants.

      Study visit and duration:

        -  Each participant will be followed for 28 days.

        -  Participants will be evaluated for hemolysis and adverse events on Days 1-10, 14, and 28
           following their assigned primaquine dose.

      Primary objective:

      To measure the change in hemoglobin among G6PD deficient west-African men following a single
      low-dose of primaquine not to exceed 0.75 mg/kg.

      Secondary objectives:

        1. To measure the occurrence of adverse events, graded by severity, at each primaquine dose
           among G6PD deficient men

        2. To measure the occurrence of markers of acute hemolytic anemia (AHA), at each primaquine
           dose among G6PD deficient men. AHA markers will include:

             -  Absolute and fractional change in hemoglobin on day 7 vs. baseline

             -  Urine color

             -  Reticulocyte count

             -  Bilirubin (both total and direct)

             -  Methemoglobin concentration

             -  Development of physical signs or symptoms of hemolytic anemia

        3. To compare the change in hemoglobin, frequency and severity of adverse events, and
           occurrence of markers of AHA between G6PD deficient and non-deficient participants
           receiving the highest tolerable primaquine dose

        4. To measure G6PD enzyme activity (semiquantitative testing, U / gHb)

        5. To measure the pharmacokinetics of primaquine, carboxyprimaquine, and other metabolites
           according to plasma concentrations.

        6. To genotype participant blood samples for cytochrome P450 2D6 (CYP2D6) single nucleotide
           polymorphisms (SNPs), to determine if potential hemolysis in G6PDd individuals is
           affected by CYP2D6 metabolizer status (e.g. weak metabolizers and/or intermediate
           metabolizers)
    

Intervention name(s): Primaquine
Intervention type(s): Drug
Intervention description(s): A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.
Intervention MeSH terms: Primaquine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Primaquine