Experimental Falciparum Transmission to Anopheles
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Administration of the malaria inoculum; Piperaquine Phosphate 480 mg
Intervention type(s): Biological; Drug
Intervention description(s): 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.; When PCR quantification of all participants is ≥ 5,000 parasites/mL, participants will receive a single dose of 480 mg Piperaquine Phosphate
Intervention MeSH terms: Piperaquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Induced blood stage malaria; Transmission; Standard membrane feeding assay