Tafenoquine Combinations for Improved Radical Cure Efficacy of Plasmodium Vivax

Background: There are several anti-malarials to kill P. vivax in the bloodstream and resolve the illness; however, the hallmark of P. vivax is its dormant liver-stage parasite (hypnozoite), which can reactivate months to years after the initial treatment, resulting in relapses of clinical disease. There are only two drugs that can clear hypnozoites, both of the 8-aminoquinoline (8-AQ) class: primaquine (PQ) and tafenoquine (TQ). The anti-hypnozoite mechanism(s) of action of these drugs are not entirely clear but presumably act by reactive oxygen species generated by redox cycling of the metabolites of PQ or TQ. In late 2020, a clinical trial in Indonesia (nicknamed INSPECTOR), testing TQ plus the blood stage drug, dihydroartemisinin-piperaquine (DHA-PPQ), reported 79% of participants experienced TQ drug failure which continued to have P. vivax relapses. This rate of relapse was almost the same as those participants who received no TQ (only DHA-PPQ). The dramatically lower efficacy was unexpected, the mechanisms behind these failures, unknown, and with TQ being one of the only two available medications to fully treat P. vivax infections, underscores the need to investigate the causes and find potential solutions. The best method to evaluate drug efficacy and the mechanisms underlying treatment failures is through a clinical trial. A Congressionally Directed Medical Research Program (CDMRP)-funded Clinical Trial Award project will conduct a clinical trial of tafenoquine in adults infected with P. vivax living in Thailand and fits the CDMRP Strategic Goal to develop and test more effective and shorter treatment regimens, including those that address treatment resistance. This study is supported by the U.S. DoD.

Study objective: The primary objective is to compare the rates of therapeutic efficacy of dihydroartemisinin-piperaquine or artemether-lumefantrine with tafenoquine to chloroquine plus tafenoquine in preventing recurrence of Plasmodium vivax over a 6-month period in adult subjects with uncomplicated P. vivax infection.

Study design: This clinical study designs a four arm, randomized, open-label clinical efficacy trial of adults with acute, uncomplicated mono-infection with P. vivax. At enrollment, participants will be randomized with ration 1:1:1:1.

• Arm 1: TQ 300 mg once + Chloroquine (CQ),weight-based dosing (following Thai National Treatment guidelines), for the 3-day course.
• Arm 2: TQ 300 mg once + Dihydroartemisinin-piperaquine (DHA-PPQ), weight-based dosing (following Thai National Treatment guidelines), for the 3-day course.
• Arm 3: TQ 300 mg once + Artemether-Lumefantrine (AL), weight-based dosing twice daily for the 3-day course.
• Arm 4: DHA-PPQ weight-based dosing (following Thai National Treatment guidelines), for the 3-day course. Then pause the treatment for one day and tafenoquine 300 mg will be given on the 4th day.

All study participants with P. vivax infection meeting inclusion/exclusion criteria will be enrolled, treated monitored for recurrence over 6 months to determine the rate of efficacy of the four groups. After 7 days inpatient, all participants will have outpatient clinic follow-up visits at Day 14, 21, 28, 60, 90, 120, 150 and 180. Arm 4 schedule will be different a bit depend on blood and urine collection schedule.

Study population: Adult subjects, aged 18 years or older, male or non-pregnant/non-lactating female who agreed not to be pregnant, who are diagnosed with uncomplicated P. vivax mono-infection.

Number of subjects: Up to 300 volunteers will be screened to meet the goal enrollment is 200 participants (50 in each arm) to meet the primary objective and endpoint of efficacy at 180 days.

Study location: Clinical study activities will take place in Tha Song Yang district, Tak province, in western Thailand, along the Thai-Myanmar border. Another site, Sop Moei District, Mae Hong Son province, may be added if enrollment is deemed insufficient to meet target goal of 200 enrolled cases within the sponsor's specified timeline.

Timeline: The clinical study itself is expected to run for approximately 5 years to enroll and complete study procedures for all subjects. Sample and data analysis would still be conducted after clinical study closure.

Inclusion criteria

• Participants who meet all of the following criteria may participate in the study:

• Thai or non-Thai, male or non-pregnant/non-lactating female, aged at least 18 years
• Willingness to participate in the study and provides signed written informed consent form
• Have P. vivax malaria mono-infection as determined by blood smear, with a parasitemia range of 100-400,000 parasites/microliter
• Have normal (non-deficient or >70% activity) G6PD phenotype as measured by quantitative spectrophotometry
• Agree to not seek outside medical care prior to contacting the WRAIR-AFRIMS study team if a fever develops during study participation (approximately 180 days), unless emergency medical care is required

Exclusion criteria

• Participants meeting any of the following criteria will be excluded from this study:

• Have an allergic reaction to any of the study drugs or components (AL,TQ, artemisinins, PPQ or CQ)
• History of anti-malarial drug use within the past 14 days (28 days for mefloquine or PPQ)
• On screening EKG, found to have a QTcF of greater than 450 milliseconds (ms) (470 ms for females)
• History of sudden cardiac death in an immediate family member, or personal history of known symptomatic coronary artery disease or arrhythmias
• Acute or chronic, clinically significant, pulmonary, cardiovascular, hepatic, neurologic, or renal functional abnormality, as determined by history, physical examination, and laboratory evaluation; specific tests for this criteria, and in the definition of severe malaria, include:

• Hemoglobin level of <7 g/dL
• Alanine aminotransferase (ALT/SGPT) and/or Aspartate transaminase (AST/SGOT) more than two times upper limit of normal or total bilirubin greater than 3 mg/dL
• Serum creatinine greater than 3 mg/dL
• History of or current psychotic disorders (schizophrenia or other type of psychosis with hallucinations/delusions)
• Have symptoms of severe malaria needing urgent treatment, such as impaired consciousness, shock, seizures, respiratory distress, unable to eat or drink, prostration (WHO guidelines for malaria, 2024) or other signs/symptoms of concern to the doctors
• Are a pregnant or lactating female, or female of childbearing age, up to 50 years of age or otherwise individually assessed for childbearing potential, who does not agree to use an acceptable form of contraception (e.g. pills or injectable) during this study and for 1 month after study completion
• Chronic use of medications that may cause drug interactions with tafenoquine (metformin) and/or drugs known to prolong the QTc interval.
• Any other significant finding that in the opinion of the study physician would increase the risk of having an adverse outcome from participating in this study