Malaria, Vivax, G6PD Deficiency
Conditions
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.
Interventions
DRUGprimaquine
Participants receive primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.
Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg. Drug administration will be directly observed.
Sponsors
Mahidol Oxford Tropical Medicine Research Unit
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | 28 days after enrollment | frequency of serious adverse events in women heterozygous for G6PD |
| Significance of CYP2D6 | 28 days after enrollment | relevance of Dextromethorphan assay results to risk of haemolysis models |
| Significance of Urobilinogen Levels | Days 1,2,3,5,7,9,11,14,17,21 | relevance of urobilinogen tests to risk of haemolysis models |
| 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. |
Countries
Thailand
Participant flow
Pre-assignment details
6 participants were enrolled into the trial but had not been randomized at the time of the study halt. Those 6 participants were thus never assigned to a study group.
Participants by arm
| Arm | Count |
|---|---|
| 1A: Primaquine primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg. | 24 |
| 1B: Chloroquine + Primaquine chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg. | 24 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Stopped drug dosing due to study halt | 6 | 7 |
Baseline characteristics
| Characteristic | 1A: Primaquine | 1B: Chloroquine + Primaquine | Total |
|---|---|---|---|
| Age, Continuous | 33.5 years | 38.5 years | 36 years |
| G6PD Concentration | 7.66 IU/g Hb | 7.515 IU/g Hb | 7.58 IU/g Hb |
| G6PD Status Hemizygous Male | 8 Participants | 8 Participants | 16 Participants |
| G6PD Status Heterozygous Female | 5 Participants | 4 Participants | 9 Participants |
| G6PD Status Homozygous Female | 11 Participants | 12 Participants | 23 Participants |
| Hemoglobin | 13.2 g/dL | 12.65 g/dL | 12.9 g/dL |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Thailand | 24 participants | 24 participants | 48 participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 8 / 24 | 17 / 24 |
| serious Total, serious adverse events | 3 / 24 | 1 / 24 |
Outcome results
Primary
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
Time frame: 28 days after enrollment
Population: Among those with available data at baseline and at least one timepoint after study treatment began.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1A: Primaquine | Change in G6PD Concentration | -1.23 IU/g Hb |
| 1B: Chloroquine + Primaquine | Change in G6PD Concentration | -1.94 IU/g Hb |
Primary
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.
Time frame: 28 days after enrollment
Population: Among those with available data at baseline and at least one timepoint after study treatment began.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1A: Primaquine | Change in Haemoglobin | -1.1 g/dL |
| 1B: Chloroquine + Primaquine | Change in Haemoglobin | -1.05 g/dL |
Secondary
Association of Drug Levels
Association of chloroquine and primaquine drug levels at the time of sampling for haematological and G6PD profiles.
Time frame: Days 1,2,3,5,7,9,11,14,17,21
Population: This association was dependent on developing a model which requires completion of the study for an appropriate sample size. The incompletion of the study resulted in it not being possible to generate this model and therefore assess the association of drug levels with hematological and G6PD activity levels
Secondary
Serious Adverse Events
frequency of serious adverse events in women heterozygous for G6PD
Time frame: 28 days after enrollment
Population: All randomized women heterozygous for G6PD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1A: Primaquine | Serious Adverse Events | 3 Participants |
| 1B: Chloroquine + Primaquine | Serious Adverse Events | 1 Participants |
Secondary
Significance of CYP2D6
relevance of Dextromethorphan assay results to risk of haemolysis models
Time frame: 28 days after enrollment
Population: Analysis not possible due to the study termination as the planned risk model could not be developed without sufficient data. Relevance of CYP2D6 results in the model thus unable to be determined.
Secondary
Significance of Reticulocyte Count
relevance of reticulocyte count to risk of haemolysis models
Time frame: Days 1,2,3,5,7,9,11,14,17,21
Population: The relevance of reticulocyte count was dependent on developing a model which requires completion of the study for an appropriate sample size. The incompletion of the study resulted in it not being possible to generate this model and therefore assess the relevance of reticulocyte count on risk of hemolysis
Secondary
Significance of Urobilinogen Levels
relevance of urobilinogen tests to risk of haemolysis models
Time frame: Days 1,2,3,5,7,9,11,14,17,21
Population: The relevance of urobilinogen tests of was dependent on developing a model which requires completion of the study for an appropriate sample size. The incompletion of the study resulted in it not being possible to generate this model and therefore assess the relevance of urobilinogen tests on hemolytic risk models