Phase 1b MMV367 PK/PD and Safety in Healthy Adult Volunteers Experimentally Infected With Blood Stage P. Falciparum
Condition: Infections; Vector Borne Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Malaria; Malaria,Falciparum; Parasitemia; Parasitic Diseases; Protozoan Infections; Antimalarials; Anti-Infective Agents
MeSH terms: Infections; Communicable Diseases; Malaria; Malaria, Falciparum; Parasitemia; Parasitic Diseases; Vector Borne Diseases; Protozoan Infections; Inflammation; Systemic Inflammatory Response Syndrome; Pathologic Processes
Study type: Interventional
Phase: Phase 1

Summary: 
      This is an open-label, adaptive study using the P. falciparum induced blood stage malaria
      (IBSM) model to characterise the pharmacokinetic/pharmacodynamic (PK/PD) profile and safety
      of MMV367 (the IMP). Up to 18 participants will be enrolled in cohorts of up to 6
      participants each. The study will proceed as follows for all participants:

        -  Screening period of up to 28 days to recruit healthy adult participants.

        -  Day 0: Intravenous inoculation with approximately 2,800 viable P. falciparum-infected
           red blood cells.

        -  Days 1-3: Daily follow up via phone call or text message.

        -  Days 4-7: Daily site visits for clinical evaluation and blood sampling to monitor
           malaria parasite numbers via quantitative polymerase chain reaction (qPCR).

        -  Day 7 PM: Start of confinement within the clinical trial unit.

        -  Day 8: Administration of a single oral dose of the IMP (MMV367). Different doses of
           MMV367 will be administered across and within cohorts in order to effectively
           characterise the PK/PD relationship.

        -  Days 8-11: Regular clinical evaluation and blood sampling while confined to monitor
           malaria parasite numbers and measure MMV367 plasma concentration.

        -  Day 11 AM: End of confinement within clinical trial unit.

        -  Days 12-23: Outpatient follow-up for clinical evaluation and blood sampling.

        -  Day 24: Initiation of compulsory definitive antimalarial treatment with Riamet®
           (artemether/lumefantrine) and/or other registered antimalarials if required. Treatment
           will be initiated earlier than Day 24 in the event of:

        -  Insufficient parasite clearance following IMP dosing

        -  Parasite regrowth following IMP dosing Characterising the
           pharmacokinetic/pharmacodynamic relationship of MMV367

        -  Participant discontinuation/withdrawal,

        -  Investigator's discretion in the interest of participant safety.

        -  Day 27: End of study visit for final clinical evaluation and to ensure complete
           clearance of malaria parasites.
    

Detailed description: 
      This is an open-label, adaptive study using the P. falciparum induced blood stage malaria
      (IBSM) model to characterise the pharmacokinetic/pharmacodynamic (PK/PD) profile and safety
      of MMV367 (the IMP). Up to 18 participants will be enrolled in cohorts of up to 6
      participants each. The study will proceed as follows for all participants:

        -  Screening period of up to 28 days to recruit healthy adult participants.

        -  Day 0: Intravenous inoculation with approximately 2,800 viable P. falciparum-infected
           erythrocytes.

        -  Days 1-3: Daily follow up via phone call or text message.

        -  Days 4-7: Daily site visits for clinical evaluation and blood sampling to monitor
           malaria parasitaemia via quantitative polymerase chain reaction (qPCR).

        -  Day 7 PM: Start of confinement within the clinical trial unit.

        -  Day 8: Administration of a single oral dose of the IMP (MMV367). Different doses of
           MMV367 will be administered across and within cohorts in order to effectively
           characterise the PK/PD relationship.

        -  Days 8-11: Regular clinical evaluation and blood sampling while confined to monitor
           malaria parasitaemia and measure MMV367 plasma concentration.

        -  Day 11 AM: End of confinement within clinical trial unit.

        -  Days 12-23: Outpatient follow-up for clinical evaluation and blood sampling.

        -  Day 24: Initiation of compulsory definitive antimalarial treatment with Riamet®
           (artemether/lumefantrine) and/or other registered antimalarials if required. Treatment
           will be initiated earlier than Day 24 in the event of:

        -  Insufficient parasite clearance following IMP dosing (parasitaemia not reduced ≥10-fold
           by Day 10 compared with peak parasitaemia on Day 8).

        -  Parasite regrowth following IMP dosing (initial parasite clearance is followed by
           asexual parasite regrowth above 5000 parasites/mL).

      Characterising the pharmacokinetic/pharmacodynamic relationship of MMV367

        -  Participant discontinuation/withdrawal,

        -  Investigator's discretion in the interest of participant safety.

        -  Day 27: End of study visit for final clinical evaluation and to ensure complete
           clearance of malaria parasitaemia (at least one negative qPCR result required).
    

Intervention name(s): MMV367; P. falciparum IBSM infection
Intervention type(s): Drug; Other
Intervention description(s): Single dose; Induced Blood Stage Malaria
Intervention model: Sequential Assignment
Intervention model description: MMV367 will be administered as a single oral dose, with different doses to be tested across and within cohorts. The highest dose of MMV367 administered in this study will be no more than 1500 mg, to determine the maximum parasite killing rate of MMV367. Doses to be tested in Cohort 1 will be 20mg, 90mg and 1500mg. Parasite regrowth following initial parasite clearance is required to effectively characterise PK/PD parameters such as the half maximum effective concentration of MMV367.The Safety Data Review Team will review all safety, PK, and PD data. Doses to be tested in Cohort 2 will be informed by the results obtained in Cohort 1, and will be selected to refine the PK/PD parameter estimates. The SDRT will meet following the completion of Cohort 2 to review all safety, PK, and PD data. If the SDRT deems sufficient data has been obtained to achieve the primary endpoint, a third cohort of participants will not be enrolled.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malaria; Parasitaemia; Malaria Recrudescence; Malaria, Falciparum