Assessing a Risk Model for G6PD Deficiency

Phase 4

Terminated

Brief Summary: 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: 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.

Recruitment & Eligibility

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:

Arm && Interventions

Group	Intervention	Description
1A: primaquine	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.
1B: chloroquine + primaquine	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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