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DHA-PPQ vs CHQ With Tafenoquine for P. Vivax Mono-infection (ACTQ)

Primary Purpose

Malaria, Malaria, Vivax, Plasmodium Vivax Malaria

Status
Recruiting
Phase
Phase 4
Locations
Thailand
Study Type
Interventional
Intervention
Dihydroartemisinin-piperaquine plus tafenoquine (450 mg adult dose)
Chloroquine plus Tafenoquine (450 mg adult dose)
Sponsored by
Shoklo Malaria Research Unit
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria focused on measuring artemisinin combination treatment, tafenoquine, Plasmodium vivax malaria, Malaria

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients with P. vivax mono-infection as diagnosed by Rapid Diagnostic Test Fever or history of fever in the previous 7 days Quantitative G6PD activity ≥70% of the population median i.e., ≥6.1U/gHb Age > 18 years, Weight >35 kg Ability to understand the study instructions and provide informed consent Willing to be followed for 4 months and likely to adhere to the study protocol. Exclusion Criteria: Coincident P. falciparum malaria or other infections Pregnancy Lactation Hb < 8 g/dL Quantitative G6PD activity <70% of the population median i.e., <6.1U/gHb Severe malaria (as per WHO guideline) History of allergic or haemolytic response to any of the study drugs

Sites / Locations

  • Shoklo Malaria Research Unit (SMRU)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Dihydroartemisinin-piperaquine plus tafenoquine (450 mg adult dose)

Chloroquine plus Tafenoquine (450 mg adult dose)

Arm Description

Dihydroartemisinin-Piperaquine will be purchased as Duo-Cotecxin® Beijing Holley-Cotec Pharmaceuticals Co., Ltd, China). One tablet contains 40 mg of dihydroartemisinin and 320 mg piperaquine (i.e. a 1:8 ratio). A weight-based regimen containing a total dose of approximately 7 mg/kg DHA and 55 mg/kg piperaquine given in 3 divided doses once daily. Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.

Chloroquine will be dosed as a 25 mg/kg base given in divided doses of 10 mg/kg orally on days 0 and 1, and in 5 mg/kg dose on day 2. Tablets will be obtained from Government Pharmaceutical Organization (GPO) in Bangkok, Thailand and supplied as 250 mg tablets (155.3 mg base). Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.

Outcomes

Primary Outcome Measures

Determine whether DHA-PPQ plus TQ is non-inferior to CQ plus TQ
Number of participants with relapse-free efficacy (measured by PCR)

Secondary Outcome Measures

Characterise the safety and tolerability of both regimens
Number of participants with drop in hemoglobin ≥2 g/dL and/or hematocrit by ≥10% from baseline Number of participants with Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
Characterise population pharmacokinetics of tafenoquine in both DHA-PPQ and CQ regimens
Area Under the Curve From Time-0 Extrapolated to Infinite Time (AUC0-infinite time) of Tafenoquine

Full Information

First Posted
January 9, 2023
Last Updated
October 13, 2023
Sponsor
Shoklo Malaria Research Unit
Collaborators
Mahidol Oxford Tropical Medicine Research Unit
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1. Study Identification

Unique Protocol Identification Number
NCT05788094
Brief Title
DHA-PPQ vs CHQ With Tafenoquine for P. Vivax Mono-infection
Acronym
ACTQ
Official Title
Does Artemisinin Combination Treatment Reduce the Radical Curative Efficacy of High Dose Tafenoquine for Plasmodium Vivax Malaria?
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 26, 2023 (Actual)
Primary Completion Date
February 28, 2025 (Anticipated)
Study Completion Date
August 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Shoklo Malaria Research Unit
Collaborators
Mahidol Oxford Tropical Medicine Research Unit

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In this area of Greater Mekong Subregion (GMS), vivax malaria is the most common kind of malaria. It can stay very long in the liver, and come out later to make another episode of illness. This can happen many times even without a mosquito bite. Only 8-aminoquinoline drugs can kill the liver forms of the malaria parasite. One of these drugs is called primaquine, and it has been used all over the world for a long time. There is now a new formulation of this 8-aminoquinoline drug called tafenoquine that can also treat the malaria in the liver. The main benefit of this drug is that it is a single dose, which makes much convenient for the patients as well as for the malaria control program than conventional 14 days of primaquine. Recent research suggests that ACT (Artemisinin Combination Therapy) may antagonise the efficacy of tafenoquine (Baird et al. 2020) . This could prevent the use of tafenoquine in areas with chloroquine resistant P. vivax parasites where national malaria programmes recommend ACTs for vivax malaria. Also, currently recommended tafenoquine dose is sub-optimal: 300 mg dose proved significantly inferior to low dose primaquine in a meta-analysis of the phase 3 studies when restricted to the Southeast Asian region (Llanos-Cuentas et al. 2019; Watson et al. 2022). A tafenoquine dose of 450mg is predicted to provide >90% of the maximal effect. The objective of this research is to find out whether 450 mg dose of tafenoquine can be combined effectively with ACT providing a short course treatment for P. vivax malaria.
Detailed Description
Plasmodium vivax malaria is a major cause of morbidity and is a significant contributor to mortality in tropical regions (Battle et al. 2019). Relapses are the major cause of illness and in higher transmission settings contribute to severe anaemia and death in young children as well as pregnancy loss. SE Asia has the highest proportion of the estimated global burden of P. vivax malaria burden 51.2% (7.2 million of 14.3 million) in 2017. In SE Asia over half of the patients treated for an acute P. vivax blood stage infection will develop at least one relapse (Betuela et al. 2012; Chu et al. 2018; Commons et al. 2019; Luxemburger et al. 1999; Poespoprodjo et al. 2009; Sutanto et al. 2013) if an anti-relapse drug is not given. The only widely available drug to prevent relapses (radical cure) currently is the 8-aminoquinoline primaquine. The doses of primaquine required to prevent relapses in Southeast Asia and the Western Pacific region are higher than elsewhere. P. vivax relapses more in these regions where with large populations over 80% of the global P. vivax burden occurs so it is likely that most of the world's relapses occur in East Asia and thus the benefits of effective radical cure are greatest in this area. Adherence to the currently recommended 14-day primaquine regimen is variable and this compromises widespread primaquine use and efficacy (Cheoymang et al. 2015; Grietens et al. 2010; Leslie et al. 2004; Maneeboonyang et al. 2011) . Recently a slowly eliminated 8-aminoquinoline, tafenoquine, has become available and has been registered in several countries. Tafenoquine can be given in a single dose (Lacerda et al. 2019; Llanos-Cuentas et al. 2014a; Llanos-Cuentas et al. 2019) which allows supervised dosing. However, tafenoquine is contraindicated in persons with G6PD activity below 70% as it may cause significant haemolysis in G6PD deficiency (including in female heterozygotes who may test as normal with current qualitative screens). Thus, quantitative G6PD deficiency testing is required to identify individuals with intermediate G6PD activity to ensure that female G6PD deficiency heterozygotes are not enrolled. Near patient quantitative G6PD tests (G6PD Biosensor) (Bancone et al. 2018; Pal et al. 2019; Zobrist et al. 2021) which provide a quantitative result will be used before tafenoquine is prescribed. The currently recommended tafenoquine dose is sub-optimal. The 300 mg dose proved significantly inferior to low dose primaquine in a meta-analysis of the phase 3 studies when restricted to the Southeast Asian region (Llanos-Cuentas et al. 2019; Watson et al. 2022). These data and an individual patient data meta-analysis of all (>1000) patients in the pre-registration studies (Watson et al. 2022) suggest that a 450mg adult dose of tafenoquine is needed in the Southeast Asian and Western Pacific regions (Figures 2-3). Doses up to 1200mg have proved safe and well tolerated in G6PD normal individuals. However a recent study suggests that ACTs may antagonize the curative efficacy of tafenoquine. If true this would complicate current treatment of both falciparum and vivax malaria with a single blood stage drug. The results from the INSPECTOR trial in Indonesian soldiers returning to non-endemic areas showed very low radical curative efficacy with tafenoquine in combination with DHA-PPQ (21%) - an efficacy which was similar to DHA-PPQ alone (11%) (Baird et al. 2020). This has prompted a product label update for Krintafel® (the branded form of tafenoquine in the USA) that tafenoquine should be combined only with chloroquine and not with other antimalarials such as artemisinin-based combination therapies (ACT)(CDC 2020). This now prevents the use of tafenoquine in areas with chloroquine resistant P. vivax parasites where national malaria programmes recommend ACTs for vivax malaria. As chloroquine resistance in P. vivax is increasing this poses a serious challenge to the potential use of this new radical cure antimalarial. However, this result is at variance with our earlier studies with the structurally and mechanistically similar primaquine, where radical curative efficacies were similar with DHA-PPQ and chloroquine combinations (Chu et al. 2019) . Whether DHA-PPQ can be combined effectively with tafenoquine needs to be resolved quickly to guide deployment. Tafenoquine could be particularly valuable in conflict-torn Myanmar where vivax malaria is now out of control and health services have broken down. This clinical trial and operational assessment will be performed within the established network of village health workers (VHW) in Eastern Myanmar. Scientific Rationale Tafenoquine, as a single dose regimen, has a tremendous advantage over the longer courses of primaquine needed for radical cure. Its use will be progressively restricted if it cannot be used in combination with ACTs. This trial will assess whether or not DHA-PPQ significantly reduces tafenoquine radical curative efficacy in comparison with chloroquine.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Malaria, Vivax, Plasmodium Vivax Malaria
Keywords
artemisinin combination treatment, tafenoquine, Plasmodium vivax malaria, Malaria

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Randomised open label non-inferiority trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
388 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dihydroartemisinin-piperaquine plus tafenoquine (450 mg adult dose)
Arm Type
Experimental
Arm Description
Dihydroartemisinin-Piperaquine will be purchased as Duo-Cotecxin® Beijing Holley-Cotec Pharmaceuticals Co., Ltd, China). One tablet contains 40 mg of dihydroartemisinin and 320 mg piperaquine (i.e. a 1:8 ratio). A weight-based regimen containing a total dose of approximately 7 mg/kg DHA and 55 mg/kg piperaquine given in 3 divided doses once daily. Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.
Arm Title
Chloroquine plus Tafenoquine (450 mg adult dose)
Arm Type
Experimental
Arm Description
Chloroquine will be dosed as a 25 mg/kg base given in divided doses of 10 mg/kg orally on days 0 and 1, and in 5 mg/kg dose on day 2. Tablets will be obtained from Government Pharmaceutical Organization (GPO) in Bangkok, Thailand and supplied as 250 mg tablets (155.3 mg base). Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.
Intervention Type
Drug
Intervention Name(s)
Dihydroartemisinin-piperaquine plus tafenoquine (450 mg adult dose)
Intervention Description
Dihydroartemisinin-Piperaquine will be purchased as Duo-Cotecxin® Beijing Holley-Cotec Pharmaceuticals Co., Ltd, China). One tablet contains 40 mg of dihydroartemisinin and 320 mg piperaquine (i.e. a 1:8 ratio). A weight-based regimen containing a total dose of approximately 7 mg/kg DHA and 55 mg/kg piperaquine given in 3 divided doses once daily. Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.
Intervention Type
Drug
Intervention Name(s)
Chloroquine plus Tafenoquine (450 mg adult dose)
Intervention Description
Chloroquine will be dosed as a 25 mg/kg base given in divided doses of 10 mg/kg orally on days 0 and 1, and in 5 mg/kg dose on day 2. Tablets will be obtained from Government Pharmaceutical Organization (GPO) in Bangkok, Thailand and supplied as 250 mg tablets (155.3 mg base). Tafenoquine KOZENIS® 150 mg film-coated tablets will be purchased from GSK (Glaxo Smith Kline Pharmaceutical industry), 450 mg (3 tablets) will be given.
Primary Outcome Measure Information:
Title
Determine whether DHA-PPQ plus TQ is non-inferior to CQ plus TQ
Description
Number of participants with relapse-free efficacy (measured by PCR)
Time Frame
Month-4
Secondary Outcome Measure Information:
Title
Characterise the safety and tolerability of both regimens
Description
Number of participants with drop in hemoglobin ≥2 g/dL and/or hematocrit by ≥10% from baseline Number of participants with Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
Time Frame
Day3, Day7, Month1, Month2, Month3, Month4
Title
Characterise population pharmacokinetics of tafenoquine in both DHA-PPQ and CQ regimens
Description
Area Under the Curve From Time-0 Extrapolated to Infinite Time (AUC0-infinite time) of Tafenoquine
Time Frame
Day3, Day7, Month1, Month2, Month3, Month4
Other Pre-specified Outcome Measures:
Title
Genotyping and probabilistic assessment to differentiate P. vivax relapse from reinfection
Description
Number of participants with relapse and reinfection in both regimen
Time Frame
Day3, Day7, Month1, Month2, Month3, Month4
Title
Evaluate the performance of village health workers as safe prescribers of tafenoquine radical cure
Description
Number of participants with correct dosing, adverse event recording including haemoglobin drops
Time Frame
Day3, Day7, Month1, Month2, Month3, Month4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with P. vivax mono-infection as diagnosed by Rapid Diagnostic Test Fever or history of fever in the previous 7 days Quantitative G6PD activity ≥70% of the population median i.e., ≥6.1U/gHb Age > 18 years, Weight >35 kg Ability to understand the study instructions and provide informed consent Willing to be followed for 4 months and likely to adhere to the study protocol. Exclusion Criteria: Coincident P. falciparum malaria or other infections Pregnancy Lactation Hb < 8 g/dL Quantitative G6PD activity <70% of the population median i.e., <6.1U/gHb Severe malaria (as per WHO guideline) History of allergic or haemolytic response to any of the study drugs
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Aung Pyae Phyo, DPhil
Phone
+66 927 127 091
Email
aungpyaephyo@tropmedres.ac
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Francois Nosten, Prof
Organizational Affiliation
Shoklo Malaria Research Unit
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shoklo Malaria Research Unit (SMRU)
City
Mae Sot
State/Province
Tak
ZIP/Postal Code
63110
Country
Thailand
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aung Pyae Phyo, DPhil
Email
aungpyaephyo@tropmedres.ac
First Name & Middle Initial & Last Name & Degree
Francois Nosten, MD
First Name & Middle Initial & Last Name & Degree
Aung Pyae Phyo, MD
First Name & Middle Initial & Last Name & Degree
Nicholas J White, FRS
First Name & Middle Initial & Last Name & Degree
James Watson, PhD
First Name & Middle Initial & Last Name & Degree
Mallika Imwong, PhD
First Name & Middle Initial & Last Name & Degree
Germana Bancone, PhD
First Name & Middle Initial & Last Name & Degree
Joel Tarning, PhD
First Name & Middle Initial & Last Name & Degree
Cindy S Chu, PhD
First Name & Middle Initial & Last Name & Degree
Aung Myint Thu, MSc
First Name & Middle Initial & Last Name & Degree
Khin Mg Lwin, MD

12. IPD Sharing Statement

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https://www.acreme.edu.au/evaluation-of-the-efficacy-and-safety-of-tafenoquine-co-administered-with-dihydroartemisinin-piperaquine-for-the-radical-cure-anti-relapse-of-plasmodium-vivax-malaria-in-indonesia-inspector-study/
Description
Baird, J Kevin, et al. (2020), 'Evaluation of the efficacy and safety of tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure (anti-relapse) of Plasmodium vivax malaria in Indonesia-INSPECTOR study', ASTMH Annual Meeting

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DHA-PPQ vs CHQ With Tafenoquine for P. Vivax Mono-infection

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