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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT05979207




Registration number
NCT05979207
Ethics application status
Date submitted
30/07/2023
Date registered
7/08/2023
Date last updated
16/01/2024

Titles & IDs
Public title
Phase 1b MMV367 PK/PD and Safety in Healthy Adult Volunteers Experimentally Infected With Blood Stage P. Falciparum
Scientific title
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
Secondary ID [1] 0 0
MMV_MMV367_22_01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infections 0 0
Vector Borne Diseases 0 0
Systemic Inflammatory Response Syndrome 0 0
Inflammation 0 0
Pathologic Processes 0 0
Malaria 0 0
Malaria,Falciparum 0 0
Parasitemia 0 0
Parasitic Diseases 0 0
Protozoan Infections 0 0
Antimalarials 0 0
Anti-Infective Agents 0 0
Condition category
Condition code
Infection 0 0 0 0
Studies of infection and infectious agents
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Sexually transmitted infections
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders
Blood 0 0 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - MMV367
Other interventions - P. falciparum IBSM infection

Experimental: MMV367 - IBSM challenge and MMV367


Treatment: Drugs: MMV367
Single dose

Other interventions: P. falciparum IBSM infection
Induced Blood Stage Malaria
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Emax
Timepoint [1] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)
Primary outcome [2] 0 0
EC50
Timepoint [2] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)
Primary outcome [3] 0 0
Hill coefficient
Timepoint [3] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)
Primary outcome [4] 0 0
Minimum Inhibitory Concentration (MIC)
Timepoint [4] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)
Primary outcome [5] 0 0
Minimal Parasiticidal Concentration (MPC90)
Timepoint [5] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)
Primary outcome [6] 0 0
Parasite Reduction Rate in 48 h (log10PRR48)
Timepoint [6] 0 0
Day 8 (IMP dosing) until Day 27 (End of Study)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/08/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
30/10/2023
Sample size
Target
Accrual to date
Final
18
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
South Bank - Brisbane
Recruitment hospital [2] 0 0
USC Clinical Trials, Morayfield - Brisbane
Recruitment postcode(s) [1] 0 0
4101 - Brisbane
Recruitment postcode(s) [2] 0 0
4506 - Brisbane

Funding & Sponsors
Primary sponsor type
Other
Name
Medicines for Malaria Venture
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
GlaxoSmithKline
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/industry
Name [2] 0 0
Southern Star Research Pty Ltd.
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/industry
Name [3] 0 0
ICON plc
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
University of the Sunshine Coast
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
QIMR Berghofer Medical Research Institute
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Queensland Paediatric Infectious Diseases (QPID) laboratory
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Swiss BioQuant A.G., Switzerland
Address [7] 0 0
Country [7] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/study/NCT05979207
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Benoit Bestgen, PhD
Address 0 0
MMV
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT05979207