Escalating Monthly Doses of Tafenoquine in Healthy Volunteers

Safety, Tolerability and Pharmacokinetics of Tafenoquine After Weekly and Escalating Monthly Doses of Tafenoquine in Healthy Vietnamese Volunteers

In 2018, the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) approved tafenoquine for malaria prevention. The approved tafenoquine prophylactic regimen is 600 mg loading dose (200 mg daily for 3 days) prior to travel and a weekly 200 mg maintenance dose commencing 7 days after the last loading dose. This weekly tafenoquine regimen is more convenient with potentially improved compliance than daily doxycycline or atovaquone proguanil (Malarone), the other recommended prophylactic agents by the U.S. Centers for Disease Control and Prevention (CDC) for the prevention of malaria infections.

Current assumptions are that a systemic minimum inhibitory concentration (MIC) of tafenoquine in plasma is 80 ng/mL in nonimmune individuals is required to prevent symptomatic breakthroughs of malaria infections. Because of tafenoquine's lengthy blood elimination half-life of 2-3 weeks, a monthly regimen of 600 mg and 800 mg of tafenoquine in individuals weighing 60 kg and 80 kg, respectively, have pharmacokinetic (PK) profiles (i.e., drug concentration versus time curves) of achieving MIC values of at least 80 ng/mL in the majority of healthy individuals. The aim of this study is to determine whether the safety and tolerability profiles in healthy participants taking monthly doses of 600 mg or 800 mg tafenoquine are comparable in the same participants taking weekly 200 mg tafenoquine.

Study Hypothesis: The study hypothesis is that the frequency of tafenoquine-related safety (e.g. blood chemistries) and adverse events (AEs) in healthy participants who take a higher dose (600 mg and 800 mg) of tafenoquine monthly would be comparable to the frequency of treatment related safety and AEs in the same individuals who take weekly tafenoquine (200 mg).

This is an open-label study to evaluate the safety, tolerability and PK of tafenoquine after weekly and two monthly doses of tafenoquine in healthy participants. The study will be conducted in three parts with 200 participants invited to participate in the study.

• Part 1 consist of 200 participants to be administered a loading dose of 600 mg tafenoquine (200 mg daily for 3 days) followed by 200 mg weekly for two weeks.
• Part 2: The same participants from Part 1 will be administered a monthly dose of tafenoquine (600 mg total, given as 300 mg split over 2 days) for two consecutive months. This monthly dose of 600 mg tafenoquine is designated the "low" monthly tafenoquine dose.
• Part 3: The same participants from Parts 1 and 2 will be administered a monthly dose of tafenoquine (800 mg total, given as 400 mg split over 2 days) for two consecutive months. This monthly dose of 800 mg tafenoquine is designated the high monthly tafenoquine dose.

The 200 healthy participants will be divided into two cohorts (A and B) of 100 participants to fully cover the three tafenoquine regimens (i.e. weekly, low monthly and high monthly) in obtaining study information (e.g. AEs) and biospecimens for monitoring the safety, tolerability and PK of tafenoquine.

Tafenoquine: Arakoda™ tablets (each containing 100 mg of tafenoquine base) are dark pink, capsule shaped, debossed with "TQ100" on one side and plain on the other. Arakoda™ tablets are supplied in blister packs. Each blister pack contains 8 tablets. Monthly tafenoquine will be administered as 100 mg oral tafenoquine tablets (Arakoda™) identical to those marketed for weekly prophylaxis.

Objectives: Primary Objective: In a dose escalating study in the same healthy participants compare the frequency of treatment-related safety and adverse events (AEs) after weekly 200 mg tafenoquine and two monthly (600 mg and 800 mg) tafenoquine regimens.

Secondary Objectives:

• Characterize the PK profiles of tafenoquine after weekly 200 mg and two monthly (600 mg and 800 mg) tafenoquine regimens in the same healthy participants.
• Characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship between blood tafenoquine concentrations and safety and tolerability of the weekly 200 mg and two monthly (600 mg or 800 mg) tafenoquine regimens in the same healthy participants.
• Determine the association of tafenoquine and its metabolite 5,6, orthoquinone in red blood cells, the site of action of the drug's blood schizontocidal activity.
• Determine the ex vivo antimalarial activity of tafenoquine in participants' plasma samples after tafenoquine administration (weekly and monthly regimens) against Plasmodium falciparum strains with different levels of drug susceptibility.

Study Population: Two hundred healthy participants are planned to be enrolled in this study for Parts 1 to 3. It is planned to recruit 200 participants from 108 Military Central Hospital.

The healthy participants will be judged to be in good health based on medical history, physical examination, blood chemistries, urinalysis, serology, normal electrocardiogram (ECG), glucose-6-phosphate dehydrogenase (G6PD) normal, and free of infectious diseases, psychiatric concerns, allergies and other medical conditions that the Investigator deems may compromise the potential participant's safety and wellbeing.

Inclusion Criteria:

1. Male or female aged 18 to 55 years inclusive who will be contactable and available for the duration of the study.

2. Total body weight greater than or equal to 45 kg, and a body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive).

3. Vietnamese (Kinh people) or belonging to one of the other 53 ethnic groups in Vietnam.

4. G6PD enzyme activity levels of >70% of the site median value for normal G6PD using a quantitative G6PD test.

5. Certified as in good health as determined by a comprehensive clinical assessment (past medical history, complete physical examination, vital signs, ECG) and laboratory tests (biochemical, hematology and urinalysis results at screening that are within the local laboratory reference range).

6. Vital signs at screening and throughout the study (measured after five minutes in the supine position) within the following ranges:

   • Systolic blood pressure (SBP) - 90-140 mmHg.
   • Diastolic blood pressure (DBP) - 40-90 mmHg.
   • Heart rate (HR) 40-100 bpm.

7. ECG ranges at screening: Time from the start of the Q wave to the end of the T wave (QT) corrected (QTc) by Bazett's formula (QTcB)/QT interval corrected by Fridericia's formula (QTcF) ≤450 ms for male participants, QTcB/QTcF ≤470 ms for female participants, and Pulse Rate (PR) interval ≤210 ms.

8. A female participant of childbearing potential is eligible to enter the study if she is non-pregnant, non-lactating, has a negative pregnancy test at the screening visit and agrees to comply with one of the following contraceptive procedures during the study and for a period of 90 days after the last dose of tafenoquine.

   - Use of oral contraceptive, either combined or progestogen alone used in conjunction with a double barrier method.

   - Use of an intrauterine device with a documented failure rate of <1% per year.

   - Use of depo provera injection.

   - Double barrier method consisting of spermicide with either condom or diaphragm.

   - Male partner who is sterile prior to the female participant's entry into the study and is the sole sexual partner for the female.

   - Complete abstinence from intercourse for two weeks prior to tafenoquine administration, throughout the study and for a period of 90 days after the last dose of tafenoquine.

9. Women of non-childbearing potential who will not require contraception during the study are defined as: surgically sterile or post-menopausal.

10. Male participants who have, or may have, female sexual partner(s) during the course of the study must agree to one of the following acceptable double methods of contraception:

    - Condom plus diaphragm or condom plus insertable device, or condom plus stable oral/transdermal/injectable hormonal contraceptive by the female partner.

    - Surgical sterilization (vasectomy) and a barrier method (condom or occlusive cap).

11. Abstinent male participants must agree to start a double method of contraception if they begin sexual relationships with a female during the study.

12. Willing and able to comply with all scheduled visits, physical examination, AE questionnaire, laboratory tests, and other study procedures.

13. Willingness to complete an acceptability questionnaire after each tafenoquine regimen.

14. Completion of the written informed consent process prior to undertaking any study-related procedure.

Exclusion Criteria:

1. Female participants who are pregnant or breast feeding (lactating).

2. Resting vital signs (measured after 5 minutes) at screening outside of the following ranges:

   • Body temperature (i.e. tympanic body temperature >38.0°C).
   • 40 ≤ PR ≥ 100 bpm.
   • 90 ≤ SBP ≥ 140 mmHg.
   • 50 ≤ DBP ≥ 90 mmHg.

3. Presence of acute infectious disease or fever (i.e. tympanic body temperature >38.0°C) within 5 days prior to the first dose of study medication.

4. Cardiac/QT risk:

   - Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.

   • History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.
   • Electrolyte disturbances, particularly hypokalemia, hypocalcaemia, or hypomagnesaemia.
   • ECG abnormalities in the standard 12-lead ECG at screening which in the opinion of the PI/Co-PI is clinically relevant or will interfere with the ECG analyses.

5. Positive result for any of the following serology tests: hepatitis B surface antigen (HBs Ag), anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab).

6. Any recent (<6 weeks) or current systemic therapy with an antibiotic or drug with potential antimalarial activity (e.g. azithromycin, clindamycin, doxycycline, trimethoprim/sulfamethoxazole, hydroxychloroquine etc.) (only participants providing blood for ex vivo antimalarial studies of tafenoquine).

7. Participants are currently taking medications and chemicals that are commonly associated with the development of hemolytic anemia such as chloroquine, dapsone, fava beans, flutamide, methylthioninium chloride, nitrofurantoin, pegloticase, phenazopyridine, primaquine, rasburicase, and trimethoprim/sulfamethoxazole.

8. History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies or any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing. Participants with seasonal allergies/hay fever can be enrolled in the study.

9. Presence of current or suspected serious chronic diseases such as cardiac or autoimmune disease, insulin-dependent and non-insulin dependent diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic disease, acute or progressive renal disease, porphyria, psoriasis, rheumatoid arthritis, asthma (excluding childhood asthma, or mild asthma with preventative asthma medication required less than monthly), epilepsy, or obsessive-compulsive disorder.

10. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within five years of screening, regardless of whether there is evidence of local recurrence or metastases.

11. Participants with history of schizophrenia, bi-polar disease, psychoses, disorders requiring lithium, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis.

12. Participants who have received psychiatric medications within one year prior to screening, or who have been hospitalized within five years prior to screening for either a psychiatric illness or due to danger to self or others.

13. History of an episode of minor depression that required at least six months of pharmacological therapy and/or psychotherapy within the last five years; or any episode of major depression. The Beck Depression Inventory (BDI) will be used as an objective tool for the assessment of depression at screening.

4. History of recurrent headache (e.g. tension-type, cluster or migraine), recurrent nausea, and/or vomiting with a frequency of ≥2 episodes per month on average and severe enough to require medical therapy, during the six months preceding the screening visit.

15. Evidence of acute illness within the four weeks prior to screening that the PI/Co-investigator deems may compromise participant safety.

16. Significant inter-current disease of any type, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical examination, and/or laboratory studies including urinalysis.

17. Participant has a clinically significant disease or any condition or disease that might affect drug absorption, distribution or excretion (e.g. gastrectomy, diarrhea).

18. Use of prescription or non-prescription drugs, herbal and dietary supplements within 14 days or five blood elimination half-lives (whichever is the longer) prior to the first dose of tafenoquine. The exceptions are: Ibuprofen (preferred) may be used at doses of up to 1.2 g per day or paracetamol at doses of up to 4 g per day. Limited use of other non-prescription medications or dietary supplements not believed to affect participant safety or the overall results of the study may be permitted on a case-by-case basis following approval by the Sponsor in consultation with the PI or Co-investigator.

19. History of retinal abnormalities, diseases of the retina or macula of the eye, visual field defects, and hearing disorders like reduced hearing and tinnitus.

20. Any participant who, in the judgment of the PI or Co-investigator, is likely to be non-compliant during the study, or is unable to cooperate because of a language problem or poor mental development.

21. Any participant who is directly involved in conducting the study. 22. Any participant with poor peripheral venous access for blood sampling. 23. Known hypersensitivity reactions to primaquine, other 8-aminoquinolines, or any component of Arakoda™.