Clinical Trial: Determining a Tolerable Dose of Primaquine in G6PD-deficient Persons Without Malaria in Mali

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Determining a Tolerable Dose of Primaquine in G6PD-deficient Persons Without Malaria in Mali

Brief 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 Summary:

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 pr
    Sponsor: University of California, San Francisco

    Current Primary Outcome: Primary outcome: the change in hemoglobin concentration from baseline levels following a single low-dose of primaquine not to exceed 0.75 mg/kg. [ Time Frame: Between day 0 and day 10. ]

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • To measure the occurrence of adverse events, graded by severity, at each primaquine dose among G6PD deficient men [ Time Frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28 ]

      Severity:

      1. = mild
      2. = moderate
      3. = severe
      4. = life threatening
    • To measure the occurrence of absolute and fractional change in hemoglobin concentration (g/dL) on day 7 vs. baseline at each primaquine dose among G6PD deficient men, in comparison with G6PD normal men [ Time Frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28 ]
    • To measure the occurrence of reticulocytosis (by microscopic quantification of reticulocytes stained with brilliant cresyl blue / 1,000 RBCs) on each day of followup, at each primaquine dose, among G6PD deficient men, in comparison with G6PD normal men [ Time Frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28 ]
    • To monitor methemoglobin levels (%) on each day of followup, at each primaquine dose among G6PD deficient men, in comparison with G6PD normal men [ Time Frame: Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28 ]
      Use of a Masimo Rad-57 pulse oximeter that measures methemoglobin levels non-invasively, based on absorption of light through the fingertip.
    • To determine G6PD enzyme activity (semiquantitative testing, U/g Hb) [ Time Frame: Day 0 ]
      Semiquantitative testing will be performed on frozen blood samples to determine G6PD activity on day of enrolment
    • Area Under Curve (AUC) for primaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of primaquine at all sampled timepoints
    • Maximal concentration (Cmax) for primaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of primaquine at all sampled timepoints
    • Area Under Curve (AUC) for carboxyprimaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of carboxyprimaquine
    • Maximal concentration (Cmax) for carboxyprimaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of carboxyprimaquine
    • Area Under Curve (AUC) for select minor metabolites of primaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of metabolites of primaquine, exact metabolites to be determined by ongoing in vivo studies (including 5-hydroxyprimaquine)
    • Maximal concentration (Cmax) for select minor metabolites of primaquine [ Time Frame: Hours 1, 2, 4, 6, 8, and 24 after primaquine administration ]
      Pharmacokinetic analysis of plasma concentration of metabolites of primaquine, exact metabolites to be determined by ongoing in vivo studies (including 5-hydroxyprimaquine)
    • Cytochrome P450 (CYP) 2D6 genotyping [ Time Frame: Day 0 ]
      To determine whether a correlation between CYP 2D6 metabolism (weak metabolizer, intermediate metabolizer, normal metabolizer, ultrarapid metabolizer) and hemolysis exists.


    Original Secondary Outcome: Same as current

    Information By: University of California, San Francisco

    Dates:
    Date Received: August 7, 2015
    Date Started: August 2015
    Date Completion:
    Last Updated: February 2, 2017
    Last Verified: February 2017