This is a single-centre, controlled, open label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the effectiveness of OZ439 as a gametocytocidal agent, as well as its treatment effects on gametocyte infectivity and development in vector mosquitoes. Previous clinical studies including one IBSM study have shown that in addition to effectively clearing replicating, asexual (pathogenic) life cycle stages of malaria, a single dose of piperaquine (480 mg) results in the production of gametocytes, as determined by gametocyte-specific transcript (pfs25) qPCR. The propensity of piperaquine to induce gametocytaemia will be employed in this study to assess the efficacy of OZ439 as a gametocytocidal and transmission blocking agent. Experimental mosquito feeding via both direct feeding on participants and artificial (indirect) membrane mosquito feeding will be performed. The study will be conducted in up to 3 cohorts where participants will be randomised into an experimental or a control group (n=2 per group) when peak gametocytemia occurs (approximately 15 days after administration of piperaquine). The groups will be of equal size with participants in the experimental group receiving OZ439 and participants in the control group receiving primaquine (positive control for OZ439, to be administered 15 mg as a single dose). The dose of OZ439 that will be investigated in the experimental group of the first cohort will be 500 mg administered as a single dose. Doses used in subsequent cohort(s) will be determined following a review of observed OZ439 safety, and pharmacodynamic drug effects as defined by gametocyte clearance kinetics and transmission blocking activity. The doses used in cohort 2 and 3 may be adjusted, but will not exceed the maximum acceptable dose predefined for this study (i.e. 1200 mg OZ439) as determined in previous safety and pilot efficacy studies. The dose will be determined by the funding sponsor and the principal investigator (PI) following Safety Review team (SRT) and scientific evaluation. Subsequent cohorts will not commence until at least after day 28 of the previous cohort and review by Safety Review Team. This interval will also allow cohorting of experimental infection of mosquitoes to optimise logistics and enable iterative improvements in the system if applicable.

Each participant in the cohort will be inoculated on Day 0 with \~2,800 viable parasites of Plasmodium falciparum-infected human erythrocytes (BSPC) administered intravenously. On an outpatient basis, participants will be monitored daily via phone call and then daily (AM) from day 4 (until PCR positive for presence of malaria parasites). Once PCR positive they will be monitored twice-daily morning (AM) and evening (PM) until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment as determined by qPCR results (approximately Study day 7), participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when PCR quantification of all participants is = 5,000 parasites/mL. If the PCR quantification of any participant is = 5,000 parasites/mL and is accompanied by a clinical symptom score \>5, before all participants have reached the treatment threshold (PCR quantification of = 1,000), then treatment of that participant will begin within a 24 h period. Participants will be followed up as inpatients for at least 48 h to ensure tolerance of the treatment and clinical response, then if clinically well on an outpatient basis for safety and clearance of malaria parasites via PCR.

Cohort1. Following initial piperaquine treatment, a repeat dose of piperaquine (960 mg) may be administered on an outpatient basis if recrudescent asexual parasitemia occurs (defined as 3 consecutively increasing parasite count over 1000 parasites/mL). Participants will also be evaluated for the presence of gametocytes in the blood, as determined by qPCR (amplification of pfs25 gametocyte-specific transcript). Assessment of OZ439 gametocytocidal properties and transmission studies will be undertaken when gametocytemia appears. Participants will be randomised into an experimental or a control group when peak gametocytemia occurs (approximately 15 days after administration of piperaquine i.e. about day 22 of the study). Participants in the experimental group (n=2 per dose cohort) will be administered OZ439 as a single 500 mg dose and participants in the control group (n=2) will receive primaquine 15 mg as a single dose. Blood will be collected (AM) from each participant in both groups for membrane feeding assays with An. stephensi vector mosquitoes. For direct feeding assays (DFA), participants will be escorted to the quarantine insectary facility at QIMR Berghofer Medical Research Institute and asked to allow vector mosquitoes to feed on the volar surface of their forearms, calves or thighs for a period of 10 ± 5 minutes. The experimental infection of mosquitoes by direct feeding on participants will be performed up to a maximum of three time points over a maximum interval of up to 10 days, approximately 15 days post-piperaquine treatment (1 direct feed prior to receiving OZ439 (active) or primaquine (control), and 2 feeds scheduled following OZ439 (active) or primaquine (control) treatment). Artificial (indirect) membrane feeding (IFA) may occur up to 10 times prior to curative anti-malarial treatment at the End of Study with Riamet® (artemether-lumefantrine)and primaquine (45 mg).

Cohort2 and 3. A similar study design and treatment procedure will be used for the two subsequent cohorts. Doses of OZ439 to be evaluated will be selected after analysis of the data from cohort1. Doses of OZ439 will not exceed 1200 mg.

Pre-emptive rescue treatment with Riamet® can commence whenever deemed necessary by the investigator. Participants can be administered the rescue Riamet® on site for initial dosing followed by monitoring, either in clinic, or by telephone for three days to ensure adherence to Riamet® therapy.

Participants will be treated with a single dose of primaquine (45 mg) as described in section 4.4.2 in this protocol concurrent with their Riamet® treatment to ensure clearance of any gametocytes present.

Adverse events will be monitored via telephone monitoring, within the clinical research unit, and on outpatient review after malaria challenge inoculation and anti-malarial study drugs administration. Blood samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be drawn at screening.