Operational Feasibility of Appropriate Plasmodium Vivax Radical Cure After G6PD Testing in Thailand

Study Overview
=================
Brief Summary
-----------------
The purpose of this prospective, observational study is to assess the operational feasibility of appropriate radical cure treatment for P. vivax malaria with tafenoquine or primaquine, in patients 16 year and older, after G6PD testing in Thailand. The study will be implemented in a phased manner, in the provinces of Yala and Mae Hong Son. The first phase will be at higher level health facilities (hospitals). An interim analysis will be conducted after 40 patients are enrolled in the study in order to decide whether the study could be extended to lower level HFs. If approved by the Independent Study Oversight Committee, the study will be implemented in lower level HFs (malaria clinics).Higher level HFs will continue to include patients in the study during this 2nd phase.Written informed consent / assent is required from all patients /guardians in the case of minors.

Detailed Description
-----------------
This is a prospective, observational, multi-center, longitudinal study to be conducted in Yala province and Mae Hong Son province in patients with P. vivax malaria. Since 2020, quantitative G6PD testing has been available for routine use prior to providing PQ radical therapy at district hospitals and malaria clinics in the study provinces, in line with the national guidelines. Before study start, the relevant staff at all participating sites will be re-trained on the quantitative G6PD test procedure and the radical cure treatment algorithm by the Division of Vector Borne Diseases (DVBD). Standard operating procedures (SOP) for identification of patients with suspected AHA and guidance for initial management and transfer to a referral hospital will be provided. G6PD tests and TQ will be supplied to Health Facilities (HFs) by the DVBD using the usual supply route for drugs and diagnostics. PQ and other anti-malarial drugs are already available in Thailand. Within the study period, investigators will prospectively enroll all patients meeting the selection criteria. Each patient will have to sign an Informed Consent Form (ICF) indicating their consent for participation in the study by being considered for treatment with TQ provided that they have the appropriate G6PD enzyme activity (or treated with PQ, according to the current practice, otherwise) and permitting investigators to use their unidentified data for analysis purposes. Assent from patients <18 years of age, and the parent's or legal guardian's written informed consent must be obtained. This study will not change the patient/physician relationship, nor influence the investigator's drug prescription or therapeutic management of the patient other than what is specified regarding the algorithm for radical cure treatment of P. vivax malaria with TQ and PQ. As part of local practice in Yala province and Mae Hong Son province, patients treated for P. vivax infection are asked to return for a follow-up visit on Day 5 (+/- 1 day). This is in addition to the national policy of the first scheduled follow-up visit on Day 14 (+2/- 1 day) for vivax malaria patients. Patient data will be collected by the investigators on each patient visit. Any suspected case of AHA will be transferred to Yala Referral Hospital, the regional hospital with one board-certified haematologist or to the Mae Hong Son Provincial Hospital. Both hospitals have full services of blood transfusion, renal dialysis, and other life-saving procedures, for further investigation and treatment. As some patients may not return for the follow-up visits and might develop drug-induced AHA, the study staff at the referral hospitals will regularly screen hospital admission records for malaria patients participating in the study presenting signs of AHA, diagnosed with renal failure, and/or receiving blood transfusion. The study will be conducted in 2 phases: 1st phase (for about 3 months): the study will be implemented in higher level HFs (hospitals). An interim analysis will be conducted after 40 patients (≥16 years old) with P. vivax are enrolled in the study in order to decide whether the study could be extended to lower level HFs. The decision will be made by an Independent Study Oversight Committee (ISOC). 2nd phase (approximately 2 months): if approved by the ISOC, the study will be implemented in lower level HFs (malaria clinics). Higher level HFs will continue to include patients in the study during this 2nd phase. Final results will be reviewed by the ISOC. It is anticipated that it will take a total of about 11-12 months to complete data collection at the target hospitals and malaria clinics.

Official Title
-----------------
Operational Feasibility of Appropriate Plasmodium Vivax Radical Cure With Tafenoquine or Primaquine After Quantitative G6PD Testing in Thailand

Conditions
-----------------
G6PD Deficiency, Malaria, Vivax

Intervention / Treatment
-----------------
* Drug: Tafenoquine
* Drug: Primaquine
* Drug: Primaquine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Thai patient aged ≥16 years at enrolment Diagnosed with a mono-species, uncomplicated P. vivax malaria that is parasitologically confirmed through standardized Giemsa microscopy. Weighs >35 kg Haemoglobin level must be >7gm% Less than 24h away from emergency care Exclusion Criteria: Participating in a clinical trial Diabetic patients who are (1) being treated with metformin (because of possible increase in the risk of lactic acidosis due to metformin when administered in combination with tafenoquine) (2) G6PD-deficient and being treated with sulfonylureas e.g. Glucotrol, Glynase, Metaglip and Micronase (because of the increased risk of haemolysis in this population). Pregnant/lactating women, women with suspected pregnancy.1 Cases of severe/ complicated malaria

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tafenoquine (TQ)<br>Patients aged ≥16 years, G6PD activity ≥ 6.1 U/gHb, not pregnant or breastfeeding, will receive single-dose TQ in addition to chloroquine, the standard blood schizonticidal drug. | Drug: Tafenoquine<br>* Tafenoquine 300 mg (2x150 mg tablets)<br>* Other names: Kozenis;|
| Daily primaquine (PQ) for 14 days<br>Patients aged ≥16 years, G6PD activity ≥ 4.1 U/gHb, not pregnant or breastfeeding, will receive 14-day PQ in addition to chloroquine, the standard blood schizonticidal drug. | Drug: Primaquine<br>* Daily primaquine adjusted by weight (0.25 mg/kg/day for 14 days)<br>|
| Weekly primaquine (PQ) for 8 weeks<br>Patients aged ≥16 years, G6PD activity ≤ 4.0 U/gHb, not pregnant or breastfeeding, will receive 14-day PQ in addition to chloroquine, the standard blood schizonticidal drug. | Drug: Primaquine<br>* Weekly primaquine adjusted by weight (0.75mg/kg/week for 8 weeks)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Appropriate use of TQ based on G6PD activity | Percentage of P. vivax patients aged ≥16 years treated or not with TQ in accordance with the appropriate level of G6PD enzyme activity | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Appropriate use of PQ based on G6PD activity | Percentage of P. vivax patients aged ≥16 years treated or not with daily PQ in accordance with the appropriate level of G6PD enzyme activity | 8 months | 
| Appropriate application of treatment algorithm | Percentage of P. vivax patients who receive TQ or PQ based on the correct application of the treatment algorithm | 8 months | 
| Reported drug-induced AHA. | Frequency of reported drug-induced AHA. | 8 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tafenoquine, Primaquine, G6PD testing, Operational study, Thailand