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:
- = mild
- = moderate
- = severe
- = 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
- 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 ]