Assessing a Risk Model for G6PD Deficiency

• Sponsor: PATH (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03337152
• Collaborator: Mahidol Oxford Tropical Medicine Research Unit (Other)
• Enrollment: 54
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.5
• Patients Per Site Per Month: 9.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Malaria, Vivax; G6PD Deficiency	Drug: primaquine; Drug: chloroquine + primaquine	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• 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.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)
• Primary Purpose: Treatment
• Official Title: Developing a Methodology to Assess 8-aminoquinoline Associated Haemolytic Risk in Females Heterozygous for G6PD in Endemic Populations
• Actual Study Start Date: May 7, 2018
• Actual Primary Completion Date: Aug 21, 2018
• Actual Study Completion Date: Oct 21, 2018

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. Significance of CYP2D6 [28 days after enrollment]

   relevance of Dextromethorphan assay results to risk of haemolysis models

2. 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.

3. Serious Adverse Events [28 days after enrollment]

   frequency of serious adverse events in women heterozygous for G6PD

4. Significance of Reticulocyte Count [Days 1,2,3,5,7,9,11,14,17,21]

   relevance of reticulocyte count to risk of haemolysis models

5. Significance of Urobilinogen Levels [Days 1,2,3,5,7,9,11,14,17,21]

   relevance of urobilinogen tests to risk of haemolysis models

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Shoklo Malaria Research Unit (SMRU)	Mae Sot		Thailand

Sponsors and Collaborators

• PATH
• 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 Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 16, 2018

More Information

Publications

None provided.

• Responsible Party: PATH
• ClinicalTrials.gov Identifier: NCT03337152
• Other Study ID Numbers: 856370-2
• First Posted: Nov 8, 2017
• Last Update Posted: Nov 12, 2021
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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
• Additional relevant MeSH terms: Malaria, Vivax; Glucosephosphate Dehydrogenase Deficiency; Chloroquine; Primaquine

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Period Title: Overall Study
STARTED	24	24
COMPLETED	13	13
NOT COMPLETED	11	11

Baseline Characteristics

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine	Total
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.	Total of all reporting groups
Overall Participants	24	24	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	33.5	38.5	36
Sex: Female, Male (Count of Participants)
Female	16 66.7%	16 66.7%	32 66.7%
Male	8 33.3%	8 33.3%	16 33.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Thailand	24 100%	24 100%	48 100%
G6PD Status (Count of Participants)
Heterozygous Female	5 20.8%	4 16.7%	9 18.8%
Homozygous Female	11 45.8%	12 50%	23 47.9%
Hemizygous Male	8 33.3%	8 33.3%	16 33.3%
Hemoglobin (g/dL) [Median (Full Range) ]
Median (Full Range) [g/dL]	13.2	12.65	12.9
G6PD Concentration (IU/g Hb) [Median (Full Range) ]
Median (Full Range) [IU/g Hb]	7.66	7.515	7.58

Outcome Measures

1. Primary Outcome

Title	Change in Haemoglobin
Description	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

Outcome Measure Data

Analysis Population Description

Among those with available data at baseline and at least one timepoint after study treatment began.

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	24	24
Median (Full Range) [g/dL]	-1.1	-1.05

2. Primary Outcome

Title	Change in G6PD Concentration
Description	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

Outcome Measure Data

Analysis Population Description

Among those with available data at baseline and at least one timepoint after study treatment began.

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	24	24
Median (Full Range) [IU/g Hb]	-1.23	-1.94

3. Secondary Outcome

Title	Significance of CYP2D6
Description	relevance of Dextromethorphan assay results to risk of haemolysis models
Time Frame	28 days after enrollment

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	0	0

4. Secondary Outcome

Title	Association of Drug Levels
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	0	0

5. Secondary Outcome

Title	Serious Adverse Events
Description	frequency of serious adverse events in women heterozygous for G6PD
Time Frame	28 days after enrollment

Outcome Measure Data

Analysis Population Description

All randomized women heterozygous for G6PD.

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	Primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	Chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	5	4
Count of Participants [Participants]	3 12.5%	1 4.2%

6. Secondary Outcome

Title	Significance of Reticulocyte Count
Description	relevance of reticulocyte count to risk of haemolysis models
Time Frame	Days 1,2,3,5,7,9,11,14,17,21

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	0	0

7. Secondary Outcome

Title	Significance of Urobilinogen Levels
Description	relevance of urobilinogen tests to risk of haemolysis models
Time Frame	Days 1,2,3,5,7,9,11,14,17,21

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	1A: Primaquine	1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.	chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
Measure Participants	0	0

Adverse Events

Time Frame	28 days after enrollment
Arm/Group Title	1A: Primaquine		1B: Chloroquine + Primaquine
Arm/Group Description	primaquine: Participants receive primaquine for 14 days at 0.5 mg/Kg.		chloroquine + primaquine: Participants will receive chloroquine for 3 days concomitant with primaquine for 14 days at 0.5 mg/Kg.
All Cause Mortality
	1A: Primaquine		1B: Chloroquine + Primaquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)
Serious Adverse Events
	1A: Primaquine		1B: Chloroquine + Primaquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		1/24 (4.2%)
Blood and lymphatic system disorders
Hemolysis	3/24 (12.5%)	3	1/24 (4.2%)	1
Other (Not Including Serious) Adverse Events
	1A: Primaquine		1B: Chloroquine + Primaquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/24 (33.3%)		17/24 (70.8%)
Blood and lymphatic system disorders
Anemia	3/24 (12.5%)	3	0/24 (0%)	0
Methemoglobinemia	1/24 (4.2%)	1	1/24 (4.2%)	1
Hematuria	0/24 (0%)	0	1/24 (4.2%)	1
Hemolysis	0/24 (0%)	0	2/24 (8.3%)	2
Eye disorders
Blurred vision	1/24 (4.2%)	1	6/24 (25%)	6
Conjunctivitis	0/24 (0%)	0	1/24 (4.2%)	1
Gastrointestinal disorders
Decreased appetite	2/24 (8.3%)	2	5/24 (20.8%)	6
Gastritis	1/24 (4.2%)	1	0/24 (0%)	0
Diarrhea	0/24 (0%)	0	3/24 (12.5%)	3
Nausea	0/24 (0%)	0	2/24 (8.3%)	2
General disorders
Difficulty sleeping	2/24 (8.3%)	2	5/24 (20.8%)	5
Dizziness	1/24 (4.2%)	1	11/24 (45.8%)	12
Fatigue	2/24 (8.3%)	2	4/24 (16.7%)	4
Headache	4/24 (16.7%)	4	3/24 (12.5%)	3
Pain	0/24 (0%)	0	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Wound	1/24 (4.2%)	1	1/24 (4.2%)	1
Metabolism and nutrition disorders
Vitamin B1 deficiency	0/24 (0%)	0	1/24 (4.2%)	1
Psychiatric disorders
Depression	0/24 (0%)	0	1/24 (4.2%)	1
Renal and urinary disorders
Glucosuria	1/24 (4.2%)	1	0/24 (0%)	0
Elevated liver function test	0/24 (0%)	0	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Common cold	2/24 (8.3%)	3	2/24 (8.3%)	2
Pharyngitis	1/24 (4.2%)	1	0/24 (0%)	0
Viral infection	1/24 (4.2%)	2	0/24 (0%)	0

Limitations/Caveats

The study met study halting rules and was terminated early. As a result, the full sample size was not enrolled and a complete data set was not available. Thus, the objectives of assessing and developing a G6PD risk model could not be met.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.