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

NCT02535767 | Completed Phase 1 DMC

• 1 other identifier: 14-14495
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria

Keywords

Primaquine

Outcome Measures

Primary Outcomes (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.

  Between day 0 and day 10.

Secondary Outcomes (12)

• To measure the occurrence of adverse events, graded by severity, at each primaquine dose among G6PD deficient men

  Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28

• 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

  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

  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

  Days 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 28

• To determine G6PD enzyme activity (semiquantitative testing, U/g Hb)

  Day 0

Study Arms (4)

A: 0.40 mg/kg PQ G6PDd

EXPERIMENTAL

0.40 mg/kg of primaquine (as a single dose) in G6PD-deficient individuals

Drug: Primaquine

B: PQ in G6PDd

EXPERIMENTAL

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

C: PQ in G6PDd

EXPERIMENTAL

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

D: PQ G6PDn

EXPERIMENTAL

A single dose of primaquine in G6PD-normal men, at the highest tolerable dose determined by the DSMB, from previous dose groups.

Drug: Primaquine

Interventions

Primaquine DRUG

A single low dose of primaquine will be crushed and dissolved in water, and administered in weight-based doses.

A: 0.40 mg/kg PQ G6PDd; B: PQ in G6PDd; C: PQ in G6PDd; D: PQ G6PDn

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Malaria Research and Training Center, Bamako, Mali: collaborator
• Radboud University Medical Center: collaborator
• University of Mississippi Medical Center: collaborator
• Bill and Melinda Gates Foundation: collaborator

Study Sites (1)

Malaria Research and Training Centre

Bamako, Mali

Location

Related Publications (2)

• Chotsiri P, Mahamar A, Diawara H, Fasinu PS, Diarra K, Sanogo K, Bousema T, Walker LA, Brown JM, Dicko A, Gosling R, Chen I, Tarning J. Population pharmacokinetics of primaquine and its metabolites in African males. Malar J. 2024 May 21;23(1):159. doi: 10.1186/s12936-024-04979-y.

  PMID: 38773528 DERIVED

• Chen I, Diawara H, Mahamar A, Sanogo K, Keita S, Kone D, Diarra K, Djimde M, Keita M, Brown J, Roh ME, Hwang J, Pett H, Murphy M, Niemi M, Greenhouse B, Bousema T, Gosling R, Dicko A. Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial. J Infect Dis. 2018 Mar 28;217(8):1298-1308. doi: 10.1093/infdis/jiy014.

  PMID: 29342267 DERIVED

MeSH Terms

Conditions

Malaria

Interventions

Primaquine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Roland Gosling, PhD, MS

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2015
• First Posted: August 31, 2015
• Study Start: August 1, 2015
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: February 6, 2017

Record last verified: 2017-02

Locations

MA (1)