Effectiveness of OZ439 as a Gametocytocidal and Transmission Blocking Agent
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): OZ439; Primaquine
Intervention type(s): Drug; Drug
Other intervention name(s): Artefonomel
Intervention MeSH terms: Primaquine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Induced blood stage malaria; Transmission; Mosquito feeding; OZ439; Primaquine; Piperaquine; Artefonomel