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Determining a Tolerable Dose of Primaquine in G6PD-deficient Persons Without Malaria in Mali (PQSAFETY)

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ClinicalTrials.gov Identifier: NCT02535767
Recruitment Status : Completed
First Posted : August 31, 2015
Last Update Posted : February 6, 2017
Sponsor:
Collaborators:
Malaria Research and Training Center, Bamako, Mali
Radboud University
University of Mississippi Medical Center
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
University of California, San Francisco

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.

Condition or disease Intervention/treatment Phase
Malaria Drug: Primaquine Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Determining a Tolerable Dose of Primaquine in G6PD-deficient Persons Without Malaria in Mali
Study Start Date : August 2015
Actual Primary Completion Date : January 2016
Actual Study Completion Date : January 2016


Arm Intervention/treatment
Experimental: A: 0.40 mg/kg PQ G6PDd
0.40 mg/kg of primaquine (as a single dose) in G6PD-deficient individuals
Drug: Primaquine
A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.

Experimental: B: PQ in G6PDd
A single dose of primaquine in G6PD-deficient men, exact dose to be decided by DSMB based on findings in previous dose group. The minimum change in dose from the last study dose is 0.05 mg/kg, and the maximum change is 0.20 mg/kg of primaquine). Dose is not to exceed 0.75 mg/kg primaquine.
Drug: Primaquine
A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.

Experimental: C: PQ in G6PDd
A single dose of primaquine in G6PD-deficient men, exact dose to be decided by DSMB based on findings in previous dose group. The minimum change in dose from the last study dose is 0.05 mg/kg, and the maximum change is 0.20 mg/kg of primaquine). Dose is not to exceed 0.75 mg/kg primaquine.
Drug: Primaquine
A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.

Experimental: D: PQ G6PDn
A single dose of primaquine in G6PD-normal men, at the highest tolerable dose determined by the DSMB, from previous dose groups.
Drug: Primaquine
A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.




Primary Outcome Measures :
  1. 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. ]

Secondary Outcome Measures :
  1. 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

  2. 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 ]
  3. 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 ]
  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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)

  11. 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)

  12. 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.



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Males ages 18- 50 (inclusive)
  • Ability to swallow oral medication
  • Informed consent
  • Willing and able to participate in the study for 28 days

For the G6PDd participants:

  • G6PDd defined by Carestart 3 rapid diagnostic test or
  • The OSMMR2000 G6PD qualitative test

For the G6PDn participants:

  • G6PDn defined by Carestart 3 rapid diagnostic test or
  • The OSMMR2000 G6PD qualitative test

Exclusion Criteria:

  • Moderate to severe anemia (Hb < 10 g/dL)
  • Malaria infection by blood smear
  • Individuals with known positive HIV test
  • Individuals with known positive hepatitis B test.
  • Known allergy to study drugs
  • Current use of medication (for tuberculosis, HIV, or any drugs that have hemolytic potential in G6PDd individuals including sulphonamides, dapsone, nitrofurantoin, nalidixic acid, ciprofloxacin, methylene blue, toluidine blue, phenazopyridine, and co-trimoxazole)
  • The individual is unwilling to abstain from the ingestion of grapefruit-containing products from 72 hours prior to the start of dosing until the study is complete
  • Use of antimalarials within 2 weeks before contact with the study team as reported by the patient
  • History of blood transfusion or a bleed of > 500 mLs within the last 3 months, as reported by the patient
  • Reported history of high alcohol intake (> 14 units per week, each unit is equivalent to 10 g of alcohol (1 glass of wine or 1 bottle of beer or one shot of distilled spirits), within 6 months of study as reported by the patient
  • Reported use of illicit drugs (marijuana, heroin, cocaine, methamphetamine) or dependence within 6 months of study, as reported by the patient
  • Participants who vomit within 1 hour after administration of primaquine (will be removed from the analysis and will not count towards the total sample size, though they will be followed as any other enrolled individual)
  • Already enrolled in this study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02535767


Locations
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Mali
Malaria Research and Training Centre
Bamako, Mali
Sponsors and Collaborators
University of California, San Francisco
Malaria Research and Training Center, Bamako, Mali
Radboud University
University of Mississippi Medical Center
Bill and Melinda Gates Foundation
Investigators
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Principal Investigator: Roland Gosling, PhD, MS University of California, San Francisco

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT02535767     History of Changes
Other Study ID Numbers: 14-14495
First Posted: August 31, 2015    Key Record Dates
Last Update Posted: February 6, 2017
Last Verified: February 2017

Keywords provided by University of California, San Francisco:
Primaquine

Additional relevant MeSH terms:
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Malaria
Protozoan Infections
Parasitic Diseases
Primaquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents