Assessing a Risk Model for G6PD Deficiency

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Malaria, Vivax, G6PD Deficiency

Intervention / Treatment
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* Drug: primaquine
* Drug: chloroquine + primaquine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized into one of two arms. 1a will receive primaquine for 14 days, and Arm 1b will receive chloroquine for 3 days and concomitant primaquine for 14 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1A: primaquine<br>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<br>* Participants receive primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.<br>|
| Other: 1B: chloroquine + primaquine<br>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<br>* Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.<br>|

What is the study measuring?
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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 |