Phase 1b MMV367 PK/PD and Safety in Healthy Adult Volunteers Experimentally Infected With Blood Stage P. Falciparum

An Open Label Phase 1b Study to Characterise the Pharmacokinetic/Pharmacodynamic Relationship and Safety of MMV367 in Healthy Adult Participants Experimentally Infected With Blood Stage Plasmodium Falciparum

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.

Study Overview

• Status: Completed
• Conditions: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Parasitemia; Malaria,Falciparum; Anti-Infective Agents; Antimalarials
• Intervention / Treatment: Drug: MMV367; Other: P. falciparum IBSM infection

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).

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • South Bank
    • Brisbane, Queensland, Australia, 4506
      • USC Clinical Trials, Morayfield

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1 Healthy adults aged 18 to 55 years inclusive who will be contactable and available for the duration of the trial and up to two weeks following the EOS visit.

2. Total body weight greater than or equal to 50 kg, and a body mass index (BMI) within the range of 18 to 32 kg/m2 (inclusive). BMI is an estimate of body weight adjusted for height. It is calculated by dividing the weight in kilograms by the square of the height in metres.

3. Completion of the written informed consent process prior to undertaking any trial-related procedure. 4. Must be willing and able to communicate and participate in the whole trial. 5. Agreement to adhere to Lifestyle Considerations (Section 5.3) throughout the trial duration.

6. Must be able to provide contact details of a support person (responsible adult) who is aware of the participant's participation in the study and is available to provide assistance if required (for example with contacting the participant in the event that study staff are unable to, or with transporting the participant to and from the study site if required).

Vital signs and ECG parameters 7. Vital signs at screening (measured after 5 min in the supine position):

• Systolic blood pressure (SBP): 90-140 mmHg,
• Diastolic blood pressure (DBP): 40-90 mmHg,

• Heart rate (HR): 40-100 bpm. Note: Symptomatic postural hypotension will be assessed by measuring SBP and DPB in the standing position (see exclusion criterion 10).

  8. At Screening and pre-inoculation with the malaria challenge agent (Day 0), normal standard mean of triplicate 12-lead electrocardiogram (ECG) parameters after 5 minutes resting in supine position:

• QTcF: ≤450 msec (males) or ≤470 msec (females),
• QRS: 50-120 msec,
• PR interval: ≤ 210 msec,
• Normal ECG tracing unless the Principal Investigator or delegate considers an ECG tracing abnormality to be not clinically relevant.

Contraception 9. Women of childbearing potential (WOCBP) who anticipate being sexually active with a male during the trial must agree to use a highly effective method of birth control (see below) combined with a barrier contraceptive from the screening visit until 34 days after the last dose of MMV367 (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose of MMV367) and have a negative urine pregnancy test result prior to inoculation with the malaria challenge agent on Day 0.

• Highly effective birth control methods include: combined (oestrogen and progestogen containing) oral/intravaginal/transdermal/implantable hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual abstinence or same sex relationship.
• Female participants who are abstinent (from penile-vaginal intercourse) must agree to start a double method if they start a sexual relationship with a male during the study. Female participants must not be planning in vitro fertilisation within the required contraception period.

Women of non-childbearing potential (WONCBP) are defined as:

• Natural (spontaneous) post-menopausal defined as being amenorrhoeic for at least 12 months without an alternative medical cause with a screening follicle stimulating hormone level (FSH) >25 IU/L (or at the local laboratory levels for post-menopause).

• Premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months before screening (as determined by participant medical history).

  10. Males who have, or may have, female sexual partners of childbearing potential during the course of the study must agree to use a double method of contraception including condom plus diaphragm, or intrauterine device, or stable oral/transdermal/injectable/implantable hormonal contraceptive by the female partner, from the time of informed consent through to 94 days after MMV367 administration. This has been calculated based on 90 days (one cycle of spermatogenesis) plus 5 half-lives of the IMP (4 days). Abstinent males must agree to start a double method if they begin a sexual relationship with a female during the study and up to 94 days after the last dose of MMV367. Males that are surgically sterile, or who have undergone sterilisation and have had testing to confirm the success of the sterilisation, may also be included and will not be required to use above described methods of contraception.

Exclusion Criteria:

Medical history

1. Known hypersensitivity to artesunate or other artemisinin derivatives, lumefantrine, proguanil/atovaquone, primaquine, or 4-aminoquinolines.
2. Any history of anaphylaxis or other severe allergic reactions, or other food or drug allergy that the Investigator considers may impact on participant safety.
3. History of convulsion (including drug or vaccine-induced episodes). A medical history of febrile convulsion during childhood (< 5 years) is not an exclusion criterion.
4. Presence of current or suspected uncontrolled chronic diseases that may impact participant safety or interpretation of clinical trial results, such as (but not limited to) cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, hepatic or renal disease, epilepsy, or asthma.
5. History of malignancy of any organ system (other than localised basal or squamous cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within five years of screening, regardless of whether there is no evidence of local recurrence or metastases.
6. Individuals with history of schizophrenia, bipolar disorder psychoses, attempted or planned suicide, or any other severe (disabling) chronic psychiatric diagnosis including generalised anxiety disorder.
7. History of an episode of depression lasting more than 6 months that required pharmacological therapy and/or psychotherapy within the last 2 years.

8. A score of 20 or more on the Beck Depression Inventory-II (BDI-II) and/or a response of 1, 2 or 3 for item 9 of this inventory (related to suicidal ideation).

   - The BDI-II will be used as a validated tool for the assessment of depression at screening. Participants that meet criterion 8 will be referred to a general practitioner or medical specialist as appropriate. Participants with a BDI-II score of 17 to 19 may be enrolled at the discretion of the Investigator if they do not have a history of the psychiatric conditions mentioned in criterion 6 and their mental state is not considered to pose additional risk to the health of the participant during the trial or to the execution of the trial and interpretation of the data gathered.

9. History of splenectomy.
10. Symptomatic postural hypotension at screening (confirmed on two consecutive readings), irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease of SBP of ≥20 mmHg after 3 min standing and/or a decrease of DBP of ≥10 mmHg after 3 min standing. This 3 min standing period will commence after the volunteer has rested for 5 min in the supine position.

11. Cardiac/QT risk:

    • Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval.
    • History of symptomatic cardiac arrhythmias or of clinically relevant bradycardia.
12. Evidence of increased cardiovascular disease risk (defined as >10%, 5-year risk for those greater than 35 years of age, as determined by the Australian Absolute Cardiovascular Disease Risk Calculator [http://www.cvdcheck.org.au/]). Risk factors include sex, age, systolic blood pressure (mm/Hg), smoking status, total and HDL cholesterol (mmol/L), and reported diabetes status.

13. Presence of clinically significant infectious disease or fever (e.g., sublingual temperature ≥38°C) within the five days prior to inoculation.

    Prior medications and treatments

14. Any COVID-19 vaccine within 14 days of malaria inoculation, any other vaccination within 28 days of IMP dosing, and any vaccination planned during the study.
15. Use of prescription drugs (excluding contraceptives), investigational medical products, or nonprescription drugs or herbal supplements, that in the opinion of the investigator may potentially interfere with study interventions, within 14 days or five half-lives (whichever is longer) prior to inoculation. Requirements for concomitant medication use (from inoculation until the end of study) are specified in Section 6.5.
16. Individual who has ever received a blood transfusion. Malaria exposure
17. Any history of malaria or participation in a previous malaria challenge trial or malaria vaccine trial.

18. Must not have had malaria exposure that is considered by the Principal Investigator or their delegate to be significant. This includes but is not limited to: history of having travelled to or lived (>2 weeks) in a malaria-endemic region during the past 12 months or planned travel to a malariaendemic region during the course of the trial; history of having lived for >1 year in a malariaendemic region in the past 10 years; history of having ever lived in a malaria-endemic region for more than 10 years inclusive. For endemic regions see https://malariaatlas.org/explorer/#/, Bali is not considered a malaria-endemic region.

    Alcohol use and smoking

19. History or presence of alcohol abuse (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), or drug habituation, or any prior intravenous usage of an illicit substance.

20. Any individual who currently smokes cigarettes on a daily basis (including e-cigarettes, vaping, and other nicotine use).

    Blood donation

21. Blood product donation to any blood bank during the 8 weeks (whole blood) or 4 weeks (plasma and platelets) prior to admission in the clinical unit on Day 8.

22. Individual unwilling to defer blood donations for at least twelve months after the EOS visit.

    Laboratory results

23. Haematology, biochemistry or urinalysis results at screening or at the eligibility visit (Day -1 to Day -3) that are outside of the standard clinically acceptable laboratory ranges (Appendix 12.2) or are considered clinically significant by the Principal Investigator.
24. Positive result for: hepatitis B surface antigen (HBs Ag), anti-hepatitis B core antibodies (anti-HBc Ab), anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti-HIV2 Ab), COVID-19 by PCR at Screening or RAT on Day 0, red blood cell alloantibodies.
25. Positive urine drug test. Any drug listed in the urine drug screen unless there is an explanation acceptable to the Investigator (e.g., the participant has stated in advance that they consumed a prescription or over-the-counter product that contained the detected drug) and the participant has a negative urine drug screen on retest by the pathology laboratory.
26. G6PD deficiency (result below the lower limit of the laboratory reference range for quantitative G6PD test).
27. Positive alcohol breath test.

28. Positive serum pregnancy test at screening or eligibility visit, positive urine pregnancy test on Day 0.

    Other

29. Individual who, in the judgement of the Investigator, is likely to be non-compliant during the trial
30. Individual who is an Investigator, research assistant, pharmacist, trial coordinator, or other staff thereof, directly involved in conducting the trial.
31. Individual without good peripheral venous access.
32. Individual who is breastfeeding or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MMV367; IBSM challenge and MMV367	Drug: MMV367; Single dose; Other: P. falciparum IBSM infection; Induced Blood Stage Malaria

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Emax	Maximum effective concentration	Day 8 (IMP dosing) until Day 27 (End of Study)
EC50	Half Maximal Effective Concentration	Day 8 (IMP dosing) until Day 27 (End of Study)
Hill coefficient	Hill coefficient is the slope of the drug concentration-response curve (i.e. response in this study is the parasite killing).	Day 8 (IMP dosing) until Day 27 (End of Study)
Minimum Inhibitory Concentration (MIC)	MIC is defined as the concentration when parasite clearance by the drug equals the parasite growth, i.e., the time at which the minimum parasite concentration is observed.	Day 8 (IMP dosing) until Day 27 (End of Study)
Minimal Parasiticidal Concentration (MPC90)	MPC90 is defined as the concentration at which the clearance effect is at 90% of the maximum.	Day 8 (IMP dosing) until Day 27 (End of Study)
Parasite Reduction Rate in 48 h (log10PRR48)	PRR48 is defined as the parasite clearance achieved within 48 hours, usually given as the reduction of values on log10 transformed scale.	Day 8 (IMP dosing) until Day 27 (End of Study)

Collaborators and Investigators

• Sponsor: Medicines for Malaria Venture
• Collaborators: GlaxoSmithKline; ICON plc; QIMR Berghofer Medical Research Institute; Swiss BioQuant A.G., Switzerland; Southern Star Research Pty Ltd.; University of the Sunshine Coast; Queensland Paediatric Infectious Diseases (QPID) laboratory
• Investigators: Study Director: Benoit Bestgen, PhD, MMV

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: July 30, 2023
• First Submitted That Met QC Criteria: July 30, 2023
• First Posted (Actual): August 7, 2023

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Malaria; Malaria, Falciparum; Malaria Recrudescence; Parasitaemia
• Additional Relevant MeSH Terms: Disease Attributes; Shock; Sepsis; Inflammation; Infections; Communicable Diseases; Malaria; Malaria, Falciparum; Systemic Inflammatory Response Syndrome; Pathologic Processes; Parasitemia; Protozoan Infections; Parasitic Diseases; Vector Borne Diseases
• Other Study ID Numbers: MMV_MMV367_22_01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No