Pyronaridine in Healthy Adult Participants Infected With Blood Stage Malaria
Condition: Malaria,Falciparum; Malaria; Malaria Recrudescence; Parasitemia; Protozoan Infections; Parasitic Disease
MeSH terms: Malaria; Malaria, Falciparum; Parasitemia; Parasitic Diseases; Protozoan Infections; Recurrence
Study type: Interventional
Phase: Phase 1

Summary: 
      This is an open-label, adaptive study that will utilise the P. falciparum induced blood stage
      malaria (IBSM) model to characterise the pharmacokinetic/pharmacodynamic (PK/PD) profile of
      pyronaridine. Up to 18 healthy, malaria naïve adult participants are planned to be enrolled
      into this study, in cohorts of up to six participants each. Following a screening period of
      up to 28 days, cohorts of up to 6 healthy participants will be enrolled. Each participant
      will be inoculated intravenously on Day 0 with P. falciparum infected erythrocytes.
      Participants will be followed up daily on Days 1 to 3, and will attend the clinical unit once
      on Days 4, 5, 6 and 7 for clinical evaluation and blood sampling. Participants will be
      admitted to the clinical trial unit on Day 8 for a single oral dose of pyronaridine.

      Different doses of pyronaridine will be administered across and within cohorts. Participants
      will be randomised to a dose group on the day of dosing. The highest dose of pyronaridine
      administered will be no more than 720 mg; the lowest dose administered will be no less than
      180 mg.

      Each subsequent cohort will be composed of up to 3 dose groups. The Safety Data Review Team
      (SDRT) will review all available safety and tolerability data from the previous cohort/s
      prior to inoculation of the next cohort.

      Participants will be confined in the clinical unit for at least 96 h (Days 8 - 12) to monitor
      the safety and tolerability of pyronaridine dosing. Upon discharge from the clinical unit
      participants will be monitored on an outpatient basis up to Day 50±2. Participants will
      receive compulsory antimalarial rescue treatment with Riamet® (artemether/lumefantrine) on
      Day 47±2 or earlier.
    

Detailed description: 
      This is an open-label, adaptive study that will utilise the P. falciparum induced blood stage
      malaria (IBSM) model to characterise the pharmacokinetic/pharmacodynamic (PK/PD) profile of
      pyronaridine.

      Up to 18 healthy, malaria naïve adult participants are planned to be enrolled into this
      study, in cohorts of up to six participants each. Following a screening period of up to 28
      days, cohorts of up to 6 healthy participants will be enrolled. Each participant will be
      inoculated intravenously on Day 0 with approximately 2,800 viable P. falciparum infected
      erythrocytes. Participants will be followed up daily via phone call or text message on Days 1
      to 3 post-inoculation to solicit any adverse events. Participants will attend the clinical
      unit once on Days 4, 5, 6 and 7 for clinical evaluation and blood sampling to monitor the
      progression of parasitaemia, using quantitative polymerase chain reaction (qPCR) targeting
      the gene encoding 18S rRNA (referred to hereafter as malaria 18S qPCR). Participants will
      have a nasopharyngeal aspirate (NPA) for SARS-CoV-2 on Day 6 am in the event that there is
      community transmission in South East Queensland of SARS-CoV-2. Participants will also have
      blood collected on Day 7 am to monitor haematology and biochemistry. Participants will be
      admitted to the clinical trial unit on Day 8 for dosing with the investigational medicinal
      product (IMP; pyronaridine) when parasitaemia for the majority of participants is expected to
      be above 5,000 parasites/mL. Pyronaridine will be administered as a single oral dose.
      Different doses of pyronaridine will be administered across and within cohorts in order to
      effectively characterise the PK/PD relationship. Each cohort will comprise up to three dose
      groups, with participants randomised to a dose group on the day of dosing. The highest dose
      of pyronaridine administered will be no more than 720 mg; the lowest dose administered will
      be no less than 180 mg. The proposed dosing regimen for the Cohort 1, assuming six
      participants are enrolled, is as below. If less than six participants are enrolled the Safety
      Data Review Team (SDRT) will meet between Day 0 and Day 8, to decide on the dose/s to be
      administered.

      Dose group

      1A (n=2) 360 mg

      1B (n=2) 540 mg

      1C (n=2) 720 mg

      Each subsequent cohort will be composed of up to 3 dose groups. If more than one dose is
      tested in a given cohort, subjects will be randomised after inoculation day (Day 0) but prior
      to Day 8. The dose/s administered to Cohort 2 and Cohort 3 will be selected based on PK/PD
      and safety data from the preceding cohort/s. The SDRT will review all available safety and
      tolerability data and PK/PD analysis outcomes from the previous cohort/s prior to inoculation
      of the next cohort. The study will conclude when sufficient data have been obtained to define
      the PK/PD parameters for pyronaridine (the primary endpoint).

      A maximum sample size of 18 participants administered pyronaridine is expected to be
      sufficient to achieve the primary endpoint.

      Participants will be confined in the clinical unit for at least 96 h (Days 8 - 12) to monitor
      the safety and tolerability of pyronaridine dosing and to ensure adequate clinical response
      against P. falciparum. During confinement, regular safety assessments will be performed and
      blood will be collected to monitor parasite clearance and pyronaridine concentration. If
      participants are clinically well at the end of the confinement period, they will be
      discharged and monitored on an outpatient basis up to Day 50±2.

      Participants will receive compulsory antimalarial rescue treatment with Riamet®
      (artemether/lumefantrine) on Day 47±2 or earlier.
    

Intervention name(s): Pyronaridine; P. falciparum IBSM infection
Intervention type(s): Drug; Biological
Intervention description(s): Single dose; Induced Blood Stage Malaria
Intervention MeSH terms: Pyronaridine
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Different doses of pyronaridine will be administered across and within cohorts in order to effectively characterise the PK/PD relationship. Each cohort will comprise up to three dose groups, with participants randomised to a dose group on the day of dosing. The highest dose of pyronaridine administered will be no more than 720 mg; the lowest dose administered will be no less than 180 mg. The proposed dosing regimen for the Cohort 1, assuming six participants are enrolled, is as below. If less than six participants are enrolled the Safety Data Review Team (SDRT) will meet between Day 0 and Day 8, to decide on the dose/s to be administered.
Masking: None (Open Label)
Primary purpose: Other
Keywords: Malaria; Malaria,Falciparum; Malaria Recrudescence; Parasitaemia; Pyronaridine