First-in-Human Study to Assess the Safety, Tolerability and Pharmacokinetics of MMV367

Study Overview
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Brief Summary
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This three-part, first-in-human, healthy volunteer study aims to assess the safety and tolerability of the test medicine as well as how it is taken up by the body when given as single and multiple doses. The effect of food on the test medicine will also be investigated. In Part 1, up to 40 volunteers will be split into up to 5 groups and will receive single oral doses of the test medicine or dummy medicine (placebo), at different dose levels. In Part 2, up to 8 volunteers will receive one oral dose of the test medicine in the fed state and one oral dose in the fasted state. In Part 3, up to 24 volunteers will be split into up to 3 groups and will receive single oral daily doses of the test medicine or placebo for 3 consecutive days. Volunteers' blood and urine will be taken throughout the study for analysis of the test medicine and for their safety. In Part 1 and Part 3, volunteers will be discharged from the clinical unit 4 days after the final dose of the test medicine and will return to the clinical unit on two occasions for safety assessments to be performed. In Part 2, volunteers will be discharged from the clinical unit 4 days after the final dose of the test medicine and will return to the clinical unit on a single occasion for safety assessments to be performed. Volunteers are expected to be involved in this study for approximately 6 weeks for all study parts, from screening to the final return visit.

Detailed Description
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Part 1 will be a double-blinded, randomised, placebo-controlled, single ascending dose (SAD) study, which will comprise up to 5 fasted cohorts (Cohorts 1A to 1E; Cohort 1E will be optional), with 8 participants in each cohort. Participants will be randomly assigned to receive a single oral dose of either active IMP (investigational medicinal product) (6 participants) or placebo (2 participants) to assess its safety, tolerability and PK (pharmacokinetic) profile. Each participant will take part in one cohort. Cohort A dose is 100mg. Doses for cohorts B to E will be determined following a blinded interim review of the safety, tolerability and PK data after each cohort, prior to the dose decision for subsequent cohorts. Part 2 will be an open-label, randomised, balanced two-period crossover, food effect evaluation. It is planned to enrol 8 participants. In Period 1, participants will be randomised to 1 of 2 treatment sequences. If a participant is randomised to receive MMV367 in the fasted state in Period 1, they will receive MMV367 in the fed state in Period 2 and vice versa. The dose administered in Part 2 will be determined once predicted human therapeutic concentrations of MMV367 and a safe exposure window has been established in Part 1. Part 3 will be a double-blinded, randomised, placebo-controlled, multiple-dose study. A total of 8 participants per cohort (A-C) will receive once-daily doses of MMV367 (6 participants) or placebo (2 participants) for 3 days, in the fasted state, to assess safety, tolerability and PK profile of multiple dosing. Cohorts 3B and 3C are optional and may proceed after a review of the safety and PK data. The dose(s) administered in Part 3 will be determined after review of the data from Part 1. Parts 1 and 3 will follow a sentinel dosing design. For each of the three parts, participants will be screened within 28 days prior to first admission to the clinical unit on the morning of Day -1. Part 1: In each cohort, participants will be dosed on Day 1 and will remain resident in the clinical unit until discharge on Day 5. They will attend the clinical unit for a return visit on Day 7 and again on Day 15 for end of study assessments. Part 2: Participants will be dosed on Day 1 (Period 1 dose) and on Day 8 (Period 2 dose) and will remain resident in the clinical unit until discharge on Day 12. They will attend the clinical unit on Day 14 for end of study assessments. Based on emerging PK data from Part 1, the washout period between the Period 1 and Period 2 doses may be extended. Part 3: Participants will receive a single dose on Days 1, 2 and 3 and will remain resident in the clinical unit until discharge on Day 7. They will attend the clinical unit for a return visit on Day 9 and again on Day 17 for end of study assessments. For all parts, blood samples will be collected at regular intervals for PK analysis and safety from Day 1 to discharge from the study.

Official Title
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A First-in-Human, Single-Centre, Single Ascending Dose, Multiple Dose and Pilot Food Effect Study to Assess the Safety, Tolerability and Pharmacokinetics of MMV367 in Healthy Participants

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Drug: MMV367
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must provide written informed consent Must be willing and able to communicate and participate in the whole study Demographics and Contraception Aged 18 to 55 years inclusive at the time of signing informed consent Must agree to adhere to the contraception requirements defined in Section 9.4 Baseline characteristics Healthy males or non-pregnant, non-lactating healthy females. Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening Weight ≥50 kg at screening Exclusion Criteria: Medical/Surgical History and Mental Health Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator Blood pressure (supine) at screening or admission outside the range of 90 to 140 mmHg systolic or 50 to 90 mmHg diastolic; and pulse rate outside the range of 45 to 100 bpm, unless deemed not clinically significant by the investigator A decrease of SBP ≥20 mmHg after 3 min standing and/or a decrease of DBP ≥10 mmHg after 3 min standing, at screening History or presence of known structural cardiac abnormalities, family history of long QT syndrome, cardiac syncope or recurrent, idiopathic syncope, exercise related clinically significant cardiac events. Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QT interval changes Presence of sinus node dysfunction, clinically significant PR interval prolongation (>210 msec), intermittent second- or third-degree atrioventricular block, complete bundle branch block, sustained cardiac arrhythmias including (but not limited to) atrial fibrillation or supraventricular tachycardia; any symptomatic arrhythmia with the exception of isolated extra systoles, abnormal T wave morphology which may impact on the QT/QTc assessment, or QTcF >450 msec. Participants with borderline abnormalities may be included if the deviations do not pose a safety risk, and if agreed between the sponsor's medical monitor and the investigator Participants with a history of cholecystectomy or gall stones Participants with conditions that affect their ability to smell or taste (Part 1 only) including, but not limited to mouth ulcers, gum disease, nasal surgery and smell and/or taste disorders (e.g. dysosmia, dysgeusia, respiratory and/or sinus infection or cold) Physical Examination Participants who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening Diagnostic assessments Evidence of current SARS-CoV-2 infection Clinically significant abnormal clinical chemistry, haematology, coagulation or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1 of protocol). Participants with Gilbert's Syndrome are not allowed. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) 1 and 2 antibody results Females who are pregnant or lactating (all female participants must have a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test at admission) Prior Study Participation Participants who have received any IMP in a clinical research study within the 90 days prior to Day 1, or less than 5 elimination half-lives prior to Day 1, whichever is longer Participants who have previously been administered IMP in this study. Participants who have taken part in Part 1 are not permitted to take part in Parts 2 and 3 and participants who have taken part in Part 2 are not permitted to take part in Part 3 Donation of blood or plasma within the previous 3 months or loss of greater than 400 mL of blood Prior and Concomitant Medication Participants who are taking, or have taken, any prescribed or over-the-counter drug or herbal remedies (other than up to 4 g of paracetamol per day, hormonal contraception or HRT) in the 14 days before first IMP administration (see Section 11.4) Participants who have received a COVID-19 vaccine within 7 days before first IMP administration Lifestyle Characteristics History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type) A confirmed positive alcohol breath test at screening or admission Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in Appendix 1) Participant with a vegan or vegetarian diet (Part 2 only) Other Male participants with pregnant or lactating partners A score of 20 or more on the Beck Depression Inventory (BDI-II), and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation) [7]. Note, individuals with a BDI-II score of 17-19 may be enrolled, at the discretion of the investigator, if they do not have a medical history of psychiatric conditions and their mental state is not considered to pose additional risk to the health of the individual or to the execution of the trial and interpretation of the data Participants who are, or are immediate family members of, a study site or sponsor employee Failure to satisfy the investigator of fitness to participate for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Single Ascending Dose Cohort A<br>100 mg MMV367 or placebo, oral solution, fasted, | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 1 Single Ascending Dose Cohort B<br>Single ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 1 Single Ascending Dose Cohort C<br>Single ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 1 Single Ascending Dose Cohort D<br>Single ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 1 Single Ascending Dose Cohort E (optional)<br>Single ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 2 Food Effect<br>Open label, 2-period cross-over, randomized, food effect study to provide preliminary information on the effect of a high-fat meal on the pharmacokinetics of a single-dose oral administration of MMV367 determined to be safe in Part 1. | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 3 Multiple Dose Cohort A<br>Double-blinded, randomised, placebo-controlled, multiple-dose study. Intervention: MMV367 or placebo, oral solution, fasted. Once daily for 3 days. | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 3 Multiple Dose Cohort B (optional)<br>Multiple ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted. Once daily for 3 days. | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|
| Experimental: Part 3 Multiple Dose Cohort C (optional)<br>Multiple ascending dose to be determined after SAC review of previous cohort. Intervention: MMV367 or placebo, oral solution, fasted. Once daily for 3 days. | Drug: MMV367<br>* Single dose dispersed in sterile water.<br>Drug: Placebo<br>* Single dose dispersed in sterile water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total. | 
| Physical examination findings | In the targeted (symptom driven) physical examination, a physician will assess the participant; if the participant reports feeling unwell or has ongoing AEs, then the physician will examine the appropriate body system(s) if required. | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for blood pressure in mmHg: supine |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for electrocardiograms (ECGs): RR |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for laboratory safety tests (haematology, biochemistry and urinalysis) | Any lab values that move out of the normal range will be noted and assessed for clinical significance. | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2, and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for respiratory rate |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2,and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for heart rate: supine |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2, and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for heart rate: orthostatic |  | Screening/day-28 to Day 7 in Part 1 and Day 9 in part 3. Up to a maximum of 5 weeks in total | 
| Change from baseline for blood pressure in mmHg: orthostatic |  | Screening/day-28 to Day 7 in Part 1 and Day 9 in part 3. Up to a maximum of 5 weeks in total | 
| Change from baseline for electrocardiograms (ECGs): QTcF |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 
| Change from baseline for electrocardiograms (ECGs): QTcB |  | Screening/day-28 to EoS visit (Day 15 in Part 1, Day 14 in part 2 and Day 17 in part 3). Up to a maximum of 6.5 weeks in total | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, Healthy Volunteers