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Assessing a Risk Model for G6PD Deficiency

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ClinicalTrials.gov Identifier: NCT03337152
Recruitment Status : Suspended (study met study halting rules)
First Posted : November 8, 2017
Last Update Posted : May 23, 2019
Sponsor:
Collaborator:
Mahidol Oxford Tropical Medicine Research Unit
Information provided by (Responsible Party):
PATH

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 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.
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
Estimated Primary Completion Date : December 7, 2019
Estimated Study Completion Date : December 31, 2019


Arm Intervention/treatment
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.

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.




Primary Outcome Measures :
  1. absolute haemoglobin drop [ Time Frame: 28 days after enrollment ]
    The absolute haemoglobin reduction from baseline on exposure to primaquine for P.vivax treatment over treatment course.

  2. change in intracellular G6PD concentration [ Time Frame: 28 days after enrollment ]
    The absolute reduction in haemoglobin-related change in intracellular G6PD concentration profiles over treatment course.


Secondary Outcome Measures :
  1. significance of CYP2D6 [ Time Frame: 28 days after enrollment ]
    relevance of Dextromethorphan assay results to risk of haemolysis models

  2. association of drug levels [ Time Frame: 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. adverse events [ Time Frame: 28 days after enrollment ]
    frequency of adverse events in in women heterozygous for G6PD

  4. significance of reticulocyte count [ Time Frame: 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 [ Time Frame: Days 1,2,3,5,7,9,11,14,17,21 ]
    relevance of urobilinogen tests to risk of haemolysis models



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03337152


Locations
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Thailand
Shoklo Malaria Research Unit (SMRU)
Mae Sot, Thailand
Sponsors and Collaborators
PATH
Mahidol Oxford Tropical Medicine Research Unit
Investigators
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Principal Investigator: François Nosten, MD, PhD Shoklo Malaria Research Unit (SMRU), Mahidol-Oxford Tropical Medicine Research Unit

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Responsible Party: PATH
ClinicalTrials.gov Identifier: NCT03337152     History of Changes
Other Study ID Numbers: 856370-2
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Individual participant data sharing plan will be completed by the time of completion of the study

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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:
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Malaria, Vivax
Glucosephosphate Dehydrogenase Deficiency
Malaria
Protozoan Infections
Parasitic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Genetic Diseases, Inborn
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases
Chloroquine
Chloroquine diphosphate
Primaquine
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides