Clinical trial NCT02431637
Conditions: Malaria
Keywords: Induced blood stage malaria Transmission Standard membrane feeding assay
Sponsor: Medicines for Malaria Venture
Start date: 2015-04-01; Completion date: 2016-09-01
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-centre, open-label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the infectivity of sexual life cycle stages of the malaria parasite (gametocytes) to mosquito vectors. Previous clinical studies have shown that treatment of participants with the antimalarial drug piperaquine, in addition to effectively clearing asexual (pathogenic) stages of the malaria life cycle, induces the production of gametocytes in the blood. The propensity of piperaquine to induce gametocytemia will be employed in this study to assess gametocyte infectivity to Anopheles mosquitoes. For this purpose, experimental mosquito feeding directly on participants and artificial membrane mosquito feeding will be performed. The study will be conducted in 3 cohorts (n=2 per cohort). 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.

Detailed description:
This is a single-centre, open-label study using P. falciparum-induced blood stage malaria (IBSM) infection to assess the infectivity of sexual life cycle stages of the malaria parasite (gametocytes) to mosquito vectors. Previous clinical studies have shown that treatment of participants with the antimalarial drug piperaquine, in addition to effectively clearing asexual (pathogenic) stages of the malaria life cycle, induces the production of gametocytes in the blood. The propensity of piperaquine to induce gametocytemia will be employed in this study to assess gametocyte infectivity to Anopheles mosquitoes. For this purpose, experimental mosquito feeding directly on participants and artificial membrane mosquito feeding will be performed. The study will be conducted in 3 cohorts (n=2 per cohort). 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 day 6-8), 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 = 10,000 parasites/mL and is accompanied by a clinical symptom score \>8 occurs in any participant before all participants have reached the treatment threshold (PCR quantification of = 5,000), then treatment of that participant will begin within a 24 h period. Participants will be followed up as inpatients for at least 48 hours 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.

Following treatment with piperaquine, transmission studies will be undertaken when gametocytemia appears. Blood will be collected (AM) from each participant for membrane feeding assays with An. Stephensi. For membrane feeding studies, blood will be kept at 38C (to prevent premature exflagellation) for up to 35 minutes until dispensed into membrane feeders. For direct feeding studies, participants will be escorted to the quarantine insectary facility at QIMR Berghofer and will also be asked to allow vector mosquitoes to feed on the volar surface of their forearms or thighs for a period of 10 ± 5 minutes (direct feeding assay). The experimental infection of mosquitoes by direct feeding on participants will be performed up to 3 times, and by artificial (indirect) membrane feeding up to 10 times prior to curative antimalarial treatment at the End Of Study with Riamet® (artemether-lumefantrine) and primaquine (45 mg).

A repeat dose of piperaquine 960 mg may be administered on an outpatient basis if recrudescent asexual parasitemia occurs as defined by consecutively increasing parasite count over 1000 parasites/mL. Preemptive 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 and/or baseline and at nominated times after malaria challenge.

Arms: arm 1: Volunteers will receive a dose of 480 mg piperaquine phosphate (PQP) approx. 7 days after a challenge with P. falciparum infected red blood cells. The effects of PQP on gametocyte carriage (assessed by PCR) and infectivity to mosquitos after direct and indirect feeding on blood from volunteers will be assessed.
Interventions: intervention 1: Administration of the malaria inoculum intervention 2: Piperaquine Phosphate 480 mg
Intervention descriptions: intervention 1: 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. The threshold for commencement of treatment will be when PCR quantification of all participants is ≥ 5,000 parasites/mL. intervention 2: When PCR quantification of all participants is ≥ 5,000 parasites/mL, participants will receive a single dose of 480 mg Piperaquine Phosphate

Protocol documents: