Assessing a Risk Model for G6PD Deficiency

Developing a Methodology to Assess 8-aminoquinoline Associated Haemolytic Risk in Females Heterozygous for G6PD in Endemic Populations

A clinical study designed to develop and inform an individual risk of hemolysis model based on individual red blood cell G6PD levels. Volunteers who are eligible to treatment with primaquine as per national guidelines and with confirmed normal G6PD levels as per the fluorescent spot test will be exposed to treatment regimens of either primaquine alone for 14 days or 3 day chloroquine with concomitant primaquine for 14 days. The volunteers will be followed intensively during treatment and for 14 days after treatment for haematologic measures, G6PD quantification, and drug level assays.

Study Overview

• Status: Terminated
• Conditions: Malaria, Vivax; G6PD Deficiency
• Intervention / Treatment: Drug: primaquine; Drug: chloroquine + primaquine

Detailed Description

Open label, randomized trial with 72 total participants assigned to one of two treatment arms. Each arm will have 36 participants comprised of 12 males hemizygous for wildtype G6PD, 12 females homozygous for wildtype G6PD, and 12 females heterozygous for G6PD with a normal fluorescent spot test (FST) (G6PD genotype abnormal with G6PD activity ≥40% and ≤80% of normal). Arm 1a will receive primaquine for 14 days, and Arm 1b will receive chloroquine for 3 days and concomitant primaquine for 14 days. All participants will be healthy volunteers without severe G6PD deficiency who will be followed for two weeks after completing their study drug dosing. Pregnant women and those breastfeeding will be excluded. Venous blood samples will be taken at regular intervals for haematologic measures, G6PD quantification, and drug level assays. G6PD levels will be measured both by spectrophotometry to provide whole blood G6PD levels normalized for hemoglobin, as well by flow cytometry to to provide red blood cell G6PD distributions throughout the treatment and post treatment. Changes in the G6PD distributions will be modeled, incorporating other critical haematological indicators collected throughout the study too.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 4

Contacts and Locations

Study Locations

• Thailand
  • Mae Sot, Thailand
    • Shoklo Malaria Research Unit (SMRU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Previous G6PD test at Shoklo Malaria Research Unit (SMRU) clinic with one of following results: 1) G6PD homozygous wildtype females (G6PD genotype normal) 2) G6PD heterozygous females with a normal FST (G6PD genotype abnormal with G6PD activity ≥40% and ≤80% of normal ) 3) G6PD hemizygous wildtype males (G6PD genotype normal)
• Willing to participate and sign informed consent form
• Willing to allow donated samples to be used in future research
• Aged ≥18 years
• Ability (in the investigators' opinion) and willing to comply with all study requirements

Exclusion Criteria:

All participants:

• Malaria or other illness
• Recent history (within 20 days) of anti-malarial treatment
• History of allergy or adverse reaction to chloroquine or primaquine
• Blood transfusion in the past 3 months
• G6PD activity less than 40% normal activity or 3.00 IU/gHb by the quantitative G6PD spectrophotometric assay
• Haemoglobin ≤10 g/dL
• Presence of any condition which in the judgment of the investigator would place the subject at undue risk or interfere with the results of the study

Female participants only:

• Pregnancy at the time of screening
• Breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 1A: primaquine; Twelve males hemizygous for wildtype G6PD, 12 females homozygous for wildtype G6PD, and 12 females heterozygous for G6PD deficiency will be randomized to arm 1A. Participants in arm 1A will receive primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.	Drug: primaquine; Participants receive primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.
Other: 1B: chloroquine + primaquine; Twelve males hemizygous for wildtype G6PD, 12 females homozygous for wildtype G6PD, and 12 females heterozygous for G6PD deficiency will be randomized to arm 1B. Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.	Drug: chloroquine + primaquine; Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Haemoglobin	The change in haemoglobin from baseline on exposure to primaquine for P.vivax treatment over treatment course to hemoglobin level at day 28.	28 days after enrollment
Change in G6PD Concentration	The haemoglobin-related change in G6PD concentration, as determined by spectrometer, over treatment course. Change is determined from baseline to day 28	28 days after enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Significance of CYP2D6	relevance of Dextromethorphan assay results to risk of haemolysis models	28 days after enrollment
Association of Drug Levels	Association of chloroquine and primaquine drug levels at the time of sampling for haematological and G6PD profiles.	Days 1,2,3,5,7,9,11,14,17,21
Serious Adverse Events	frequency of serious adverse events in women heterozygous for G6PD	28 days after enrollment
Significance of Reticulocyte Count	relevance of reticulocyte count to risk of haemolysis models	Days 1,2,3,5,7,9,11,14,17,21
Significance of Urobilinogen Levels	relevance of urobilinogen tests to risk of haemolysis models	Days 1,2,3,5,7,9,11,14,17,21

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: Mahidol Oxford Tropical Medicine Research Unit
• Investigators: Principal Investigator: François Nosten, MD, PhD, Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2018
• Primary Completion (Actual): August 21, 2018
• Study Completion (Actual): October 21, 2018

Study Registration Dates

• First Submitted: October 27, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): November 12, 2021
• Last Update Submitted That Met QC Criteria: October 15, 2021
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Infections; Hematologic Diseases; Genetic Diseases, Inborn; Vector Borne Diseases; Anemia; Parasitic Diseases; Protozoan Infections; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Malaria; Malaria, Vivax; Glucosephosphate Dehydrogenase Deficiency; Anti-Infective Agents; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Chloroquine; Primaquine
• Other Study ID Numbers: 856370-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Individual participant data sharing plan will be completed by the time of completion of the study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No