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.
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Single dose
Induced Blood Stage Malaria from infected erythrocytes.
Single dose
Single dose
Single dose
Single dose
Single dose
South Bank
Brisbane, Queensland, Australia
USC Clinical Trials, Morayfield
Brisbane, Queensland, Australia
Emax
Maximum effect of drug (maximum parasite killing rate). Emax used in the PK/PD model comes from the mean viable parasite elimination half-life of cohort 1 as estimated in the parasite viability report as Emax was not clearly observed in the cohort 2 parasitemia profiles.
Time frame: Day 8 (IMP dosing) until Day 27 (End of Study)
EC50
Half Maximal Effective Concentration PK/PD dataset contains the individual information from all arms including date and time of inoculum administration, MMV367 dose; MMV367 plasma PK concentrations; total parasitemia counts by 18S qPCR; gametocytemia counts by pfs25, pfMGET and pfSBP-1 if relevant; and typical covariates such as age, body weight, height, sex and race, to build the model and derive outcome results.
Time frame: Day 8 (IMP dosing) until Day 27 (End of Study)
MIC
MIC is defined as the concentration when drug killing equals the parasite growth, i.e., the time at which the minimum parasite concentration is observed. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan.
Time frame: Day 8 (IMP dosing) until Day 27 (End of Study)
MPC90
MPC90 is defined as the concentration at which the clearance effect is at 90% of the maximum. Calculated using the combined data from all doses/arms/groups in both period 1 and 2, as prespecified in section 10 of the Statistical Analysis Plan. PK/PD dataset contains the individual information from all arms including date and time of inoculum administration, MMV367 dose; MMV367 plasma PK concentrations; total parasitemia counts by 18S qPCR; gametocytemia counts by pfs25, pfMGET and pfSBP-1 if relevant; and typical covariates such as age, body weight, height, sex and race, to build the model and derive outcome results.
Time frame: Day 8 (IMP dosing) until Day 27 (End of Study)
Parasite Killing Achieved Within 48 Hours, PRR48
PRR48 is given as the reduction of values on log10 transformed scale. Only MMV\_MMV367\_22\_01 data was used. PRR48 provides an estimate of the efficacy of an anti-malarial treatment. It is the ratio of parasite density over a 48-hour period, estimated using the slope of the optimal fit of the log-linear relationship of parasitemia decay. Optimal fit is derived using geometric mean parasitemia data (i.e. 18S qPCR measuring all blood stage malaria parasites). The optimal fit of the log-linear parasitemia decay by time relationship is determined using left and right censoring to systematically remove potential lag and tail phases of parasitemia decay. PRR48 was calculated for each participant using daily PCR data. If the model fit was adequate (overall model p-value\<0.001), the slope and corresponding SE from the log-linear regression was used to calculate overall dose-specific PRR48. Participants without adequate model fits were excluded from all dose-specific PRR48 calculations.
Time frame: Day 8 (IMP dosing) until Day 27 (End of Study)
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