A Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetic Profile of a Single Doses of MMV533.

NCT04323306 | Completed Phase 1 Results DMC

• 1 other identifier: MMV-MMV533_19_01
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

Phase 1, single -centre study in 2 parts. The study designs for each part are well established for first-in-human studies and are appropriate to assess safety, tolerability and preliminary pharmacokinetics.

Conditions

Malaria

Keywords

Safety; Tolerability

Outcome Measures

Primary Outcomes (10)

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Assessment of adverse events (AEs) /treatment-emergent adverse events (TEAEs) (treatment phase for Part 1 and 2 defined as from IMP administration up to and including EOS).

  Safety data will be evaluated from baseline until 28 days after IMP/placebo administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Haematology: change from baseline

  Change from baseline to 28 days post dose in Part 1 of the study and 21 days post dose in Part 2, Food effect study

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Biochemistry: number of participants with elevated Total Bile Acids considered as Clinically significant abnormalities

  24 hours to 648 hours post dose

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Urinalysis: parameters assessed: bilirubin, glucose, ketones, leucocytes, nitrite, blood, protein, urobilinogen, pH. Number of participants with clinically significant findings.

  Part 1: 28 days post IMP administration and for Part 2: 21 days post IMP administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Vital signs: respiratory rate supine and standing. Change from baseline.

  Part 1 is 28 days post IMP and for Part 2, 21 days post IMP administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Vital signs: heart rate supine and standing. Change from baseline.

  Part 1 is 28 days post IMP and for Part 2, 21 days post IMP administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Measurements of 12-lead triplicate ECG: QTcB and QTcF interval prolongations.

  Part 1: 28 days post IMP whereas for Part 2: 21 days post IMP administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Biochemistry: number of participants with Low Hemoglobin considered as Clinically significant abnormality

  24 hours to 648 hours post dose

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Vital signs: blood pressures, supine and standing. Change from baseline.

  Part 1 is 28 days post IMP and for Part 2, 21 days post IMP administration

• The Tolerability and Safety of Ascending Single Oral Doses of MMV533

  Vital signs: body temperature. Change from baseline.

  Part 1 is 28 days post IMP and for Part 2, 21 days post IMP administration

Study Arms (8)

Cohort 1 SAD

ACTIVE COMPARATOR

5 mg MMV533 with single ascending dose

Drug: MMV688533

Cohort 2 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined after SRC review of previous cohort.

Drug: MMV688533

Cohort 3 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined after SRC review of previous cohort.

Drug: MMV688533

Cohort 4 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined after SRC review of previous cohort.

Drug: MMV688533

Cohort 5 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined after SRC review of previous cohort.

Drug: MMV688533

Cohort 6 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined after SRC review of previous cohort.

Drug: MMV688533

Cohort 7 SAD

ACTIVE COMPARATOR

Single ascending dose to be determined determine after SRT review of previous cohort. Dose will not exceed 400 mg.

Drug: MMV688533

Part 2: Food Effect

ACTIVE COMPARATOR

Open label, 2-period cross-over, randomized, pilot 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 MMV533 determined to be safe in Part 1.

Drug: MMV688533

Interventions

MMV688533 DRUG

Investigational medicinal product

Cohort 1 SAD; Cohort 2 SAD; Cohort 3 SAD; Cohort 4 SAD; Cohort 5 SAD; Cohort 6 SAD; Cohort 7 SAD; Part 2: Food Effect

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Females of non-childbearing potential:
• 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)
• Women of childbearing potential that have or may have male sexual partners during the course of the study must agree to the use of a double method of contraception of a highly effective method of birth control combined with a barrier contraceptive (condom) when appropriate from screening visit to until 60 days after the last dose of IMP (covering a full menstrual cycle of 30 days starting after 5 half-lives of last dose of IMP. This duration is based on the predicted half-life of IMP, and may be amended once the actual half-life is calculated during this study). Note: Highly effective birth control methods include: combined (oestrogen and progestogen containing) oral/intravaginal/transdermal hormonal contraception associated with inhibition of ovulation, progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or sexual abstinence or same sex relationship.
• Male participants who have, or may have female sexual partners during the course of the study must agree to use a double method of contraception including condom plus diaphragm, or condom plus stable insertable (implant or IUD), injectable, transdermal or combination oral contraceptive by the female partner, from the time of informed consent through to 90 days after the last dose of the IMP (covering a full spermatogenesis cycle of 60 days starting after 5 half-lives of last dose of IMP. This duration is based on the predicted half-life of IMP, and may be amended once the actual half-life is calculated during this study).
• Abstinent male participants must agree to start a double method if they begin a sexual relationship with a female during the trial, and through to 90 days after the last dose of the IMP. Male participants with female partners that are surgically sterile or post-menopausal (defined as being amenorrhoeic for at least 12 months without an alternative medical cause), or male participants 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. Male participants must also agree not to donate sperm up to 3 months after dosing with the IMP.
• Total body weight greater than or equal to 50 kg, and body mass index (BMI) between 18 and 32 kg/m2 inclusive.
• Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination).
• Normal vital signs after 5 minutes resting in supine position:
• Systolic blood pressure (SBP) - 90-140 mmHg,
• Diastolic blood pressure (DBP) - 40-90 mmHg,
• Heart rate (HR) 40-100 bpm.
• Standard 12-lead electrocardiogram (ECG) parameters after 10 minutes resting in supine position in the following ranges for both males and females: QT ≤ 500 msec, QTcF ≤450 msec, QTcB ≤450 msec, and PR interval ≤210 msec; and normal ECG tracing unless the Principal Investigator or delegate considers an ECG tracing abnormality to be not clinically significant.
• Having given written informed consent prior to undertaking any study-related procedure.
• Available for the duration of the study and for 2 weeks following the End of Study visit.

You may not qualify if:

• Haematology, biochemistry or urinalysis results that are abnormal/outside of laboratory normal reference ranges AND are either:
• considered clinically significant by the Principal Investigator or delegate; OR
• considered not clinically significant by the Principal Investigator or delegate BUT ARE ALSO outside of the Sponsor-approved clinically acceptable laboratory ranges in Appendix 1 of the protocol.
• NOTE: Participants are not excluded if abnormal/out of laboratory normal reference range results are considered not clinically significant by the Principal Investigator or delegate AND are within the ranges specified in Appendix 1 of the protocol of .
• Positive serum pregnancy test at screening, positive urine pregnancy test upon admission or at other timepoints as specified by schedule of assessments.
• Male participants with a female partner(s) who is (are) pregnant or lactating from the time of the administration of study medication.
• Any history or presence of clinically relevant cardiovascular, broncho-pulmonary, gastrointestinal, hepatic/ gallbladder\*/ bile duct, renal, metabolic, haematological, neurological, musculoskeletal/rheumatologic, systemic, ocular, gynaecologic (if female), or infectious disease, or signs of acute illness. \*including medical history of asymptomatic gallbladder stones.
• Any gastrointestinal surgery or any condition or disease that could affect drug absorption, distribution or excretion (eg, gastrectomy, cholecystectomy, diarrhoea).
• Severe recurring headaches (cluster or migrainous headaches) requiring prescription medication/s. History of recurrent nausea and/or vomiting (for vomiting only: more than twice a month).
• Participation in any research study involving blood sampling (more than 450 mL/unit of blood) or blood donation during the 8 weeks prior to IMP administration (Parts 1 and 2).
• Any documented evidence of current or past cardiovascular disease including cardiac arrhythmias or family history of congenital long QT syndrome, Brugada syndrome, or unexplained sudden cardiac death. 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 in systolic blood pressure ≥20 mmHg within 2-3 min when changing from supine to standing position.
• History or presence of diagnosed (by an allergist/immunologist) or treated (by a physician) food or known drug allergies, or any history of anaphylaxis or other severe allergic reactions including face, mouth, or throat swelling or any difficulty breathing. Participants with seasonal allergies/hay fever or allergy to animals or house dust mite that are untreated and asymptomatic at the time of dosing can be enrolled in the trial.
• History of substance use disorder(s) within 5 years of screening, including alcohol consumption of more than 40g/4 units/4 standard drinks per day or any prior intravenous use of an illicit substance.
• Smoked \>1 pack of cigarettes per day for \>10 years, or who currently (within 14 days prior to IMP administration (Parts 1 and 2) smokes \>5 cigarettes per day.
• Any medication (including herbal such as St John´s Wort, vitamin supplements and over the counter \[OTC\]) within 5 half-lives prior to IMP administration (Parts 1 and 2), except occasional intakes (for acute pain) of ibuprofen at doses up to 1.8g/day, paracetamol at doses up to 4g/day, acetylsalicylic acid (300 to 650 mg orally every 4 to 6 hours as needed Maximum dose: 4g in 24 hours), diclofenac (diclofenac potassium liquid-filled capsules: 25mg orally 4 times a day; diclofenac free acid capsules: 18 or 35 mg orally 3 times a day; diclofenac potassium immediate-release tablets: 50mg orally 3 times a day \[initial dose of 100mg orally followed by 50mg oral doses acceptable if required for better relief\]) and contraceptives.

Sponsors & Collaborators

• Medicines for Malaria Venture: lead
• Nucleus Network Ltd: collaborator
• Southern Star Research: collaborator

Study Sites (1)

Nucleus Network Corporate

Melbourne, Victoria, 3004, Australia

Location

Related Publications (1)

• Bestgen B, Jones S, Thathy V, Kuemmerle A, Barcelo C, Haouala A, Gossen D, Marx MW, Di Resta I, Szramowska M, Webster RA, Llewellyn S, Ritacco DA, Yeo T, Leroy D, Barber BE, Fidock DA, Griffin P, Lickliter J, Chalon S. Safety, tolerability, pharmacokinetics, and antimalarial activity of MMV533: a phase 1a first-in-human, randomised, ascending dose and food effect study, and a phase 1b Plasmodium falciparum volunteer infection study. Lancet Infect Dis. 2025 May;25(5):507-518. doi: 10.1016/S1473-3099(24)00664-9. Epub 2024 Dec 18.

  PMID: 39708824 DERIVED

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Limitations and Caveats

No limitations or caveats to report.

Results Point of Contact

• Title: Benoit Bestgen
• Organization: MMV

bestgenb@mmv.org

+41 79 765 18 68

Study Officials

• Jason Lickliter, MD

  Nucleus Network Corporate

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Quadruple for part 1. Double-blind, randomized, placebo-controlled, sequential ascending single dose study Open label for part 2.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Part 1: 8 participants per cohort for 7-8 cohorts (56-64 participants total). Single ascending dose commencing at 5 mg with maximum 400 mg as determined by Safety Review Committee (SRC). Part 2: Open label, 2-period cross-over, randomized, pilot 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 MMV533

Study Record Dates

• First Submitted: March 12, 2020
• First Posted: March 26, 2020
• Study Start: August 12, 2020
• Primary Completion: September 27, 2022
• Study Completion: September 27, 2022
• Last Updated: October 17, 2024
• Results First Posted: October 17, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)