Comparison of artesunate parasite clearance of Plasmodium falciparum K13 and 3D7 isolates in healthy subjects

This single-centre, open-label study will compare the response of the Plasmodium falciparum isolates Cam3.II^R539T (referred to as K13, artemisinin-resistant) and 3D7 (artemisinin-sensitive) to a single dose of the antimalarial drug artesunate in healthy subjects using the induced blood stage malaria model. The study will be conducted in up to 9 subjects per cohort, with up to 3 cohorts. Within each cohort, subjects will be randomised to receive either the K13 or 3D7 challenge agent, in a 2:1 ratio. Subjects randomised to receive the K13 challenge agent will be inoculated on Day 0 with approximately 2,800 viable P. falciparum K13 parasite-infected red blood cells (RBCs). Subjects randomised to receive the 3D7 challenge agent will be inoculated on Day 1 with approximately 2,800 viable P. falciparum 3D7 parasite-infected RBCs. On an outpatient basis, subjects will be monitored daily via phone and then will attend the clinical unit daily from 4 days post-inoculation – Day 4 for K13 subjects and Day 5 for 3D7 subjects – until positive for presence of malaria parasites by quantitative polymerase chain reaction (qPCR) targeting the 18S rRNA gene. Once qPCR positive, subjects will be monitored twice daily until artesunate treatment for parasitaemia, symptoms or signs of malaria, and adverse events. The threshold for commencement of artesunate treatment will be when all subjects reach a parasitaemia of greater than or equal to 5,000 parasites/mL. If the parasitaemia of any subject is greater than or equal to 5,000 parasites/mL, and is accompanied by a malaria clinical score greater than 6 before all subjects have reached the treatment threshold, then treatment of that subject will begin within a 24 hour period. Subjects may also receive artesunate treatment at any time based on parasitaemia and/or clinical symptoms at the Investigator’s discretion. Subjects will be admitted to the clinical unit (approximately Day 9), administered a single dose of approximately 2 mg/kg artesunate (as oral tablets), and confined for 72 hours to monitor for tolerability of therapy and to ensure adequate clinical response. Once clinically well, subjects will be followed up on an out-patient basis for monitoring of safety and parasite clearance. If artesunate does not clear parasitaemia, subjects will be administered piperaquine phosphate as a single dose of 960 mg (as oral tablets). All subjects will receive compulsory rescue treatment with atovaquone/proguanil hydrochloride on Day 26+/-3 or earlier at the Investigator’s discretion. A treatment course consists of 4 tablets of atovaquone 250 mg/proguanil hydrochloride 100 mg once daily, orally for 3 days. Subjects may also be treated with a single dose of 45 mg primaquine (as oral tablets) at the time of atovaquone/proguanil hydrochloride treatment, if gametocytaemia is suspected from parasite lifecycle stage reverse transcriptase qPCR or by the presence of stable low level parasitaemia, or at the Investigator’s discretion, to ensure complete clearance of gametocytes. Follow-up for safety assessments will be performed on Day 28+/-3 (End of Study).