Safety, Tolerability and Pharmacokinetic Profile of Ascending Oral Doses of MMV390048, Part A
Condition: Malaria
MeSH terms: Malaria
Intervention: MMV390048 40 mg; Placebo to match MMV390048 40 mg; MMV390048 80 mg; Placebo to match MMV390048 80 mg; MMV390048 120 mg; Placebo to match MMV390048 120 mg
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: malaria, single ascending dose,

Summary:

      This Phase I study will evaluate the safety, tolerability and pharmacokinetic properties of
      escalating single doses of reformulated MMV390048 when administered to healthy men and women
      of non-childbearing potential (WNCBP) under fasted conditions (Part A).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Completion of the written informed consent process.

          2. Men or WNCBP age 18 to 55 years, in good health as determined by past medical history,
             physical examination, vital signs, electrocardiogram, and laboratory tests at
             screening.

          3. Male subjects agree to use acceptable methods of contraception if the male subject's
             partner could become pregnant from the time of the first administration of study
             medication until 130 (90+40) days following administration of the investigational
             medicinal product. One of the following acceptable methods of contraception must be
             utilized:

               -  Condom and occlusive cap (diaphragm or cervical/vault caps)

               -  Surgical sterilization (vasectomy with documentation of azoospermia) and a
                  barrier method (condom or occlusive cap [diaphragm or cervical/vault caps].

               -  The subject's female partner uses oral contraceptives (combination
                  estrogen/progesterone pills), injectable progesterone or subdermal implants and a
                  barrier method (condom or occlusive cap [diaphragm or cervical/vault caps].

               -  The subject's female partner uses medically prescribed topically-applied
                  transdermal contraceptive patch and a barrier method (condom or occlusive cap
                  [diaphragm or cervical/vault caps].

               -  The subject's female partner has undergone documented tubal ligation (female
                  sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm
                  or cervical/vault caps].

               -  The subject's female partner has undergone documented placement of an
                  intrauterine device or intrauterine system. In addition, a barrier method (condom
                  or occlusive cap [diaphragm or cervical/vault caps].

               -  True abstinence: when this is in line with the preferred and usual lifestyle of
                  the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception. Abstinent subjects have to agree to use 1 of the above-mentioned
                  contraceptive methods, if they start sexual relationships during the study and
                  for up to 100 days after the last dose of study drug.

          4. Women subjects must be of non-childbearing potential (WNCBP) as per one of the
             following definitions:

               -  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 consistent with 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 subject medical history).

          5. Haematology, clinical chemistry and urinalysis results at screening that are within
             the local laboratory reference range or, if outside the range, not clinically
             significant as judged by the Investigator. More specifically, serum creatinine,
             hepatic transaminase enzymes (AST ALT), and total bilirubin (unless the subject has
             documented Gilbert syndrome) should not exceed the upper laboratory norm and
             haemoglobin must be equal to or higher than the lower limit of the normal range.

          6. Total body weight greater than 50 kg and a body mass index (BMI) within the range of
             18 to 32 kg/m2 (inclusive).

          7. Non-smoker or ex-smoker for more than 90 days prior to screening, or smoke no more
             than 5 cigarettes per day as determined by history. Must be able to abstain from
             smoking during the inpatient stay.

          8. Willing and able to comply with all scheduled visits, treatment plan, laboratory
             tests, and other study procedures.

          9. Agree to stay in contact with the study site for the duration of the study and up to 2
             weeks following the end of study visit, provide updated contact information as
             necessary, and have no current plans to move away from the study area for the duration
             of the study.

        Exclusion Criteria:

          1. Male subjects with a female partner(s) who is (are) pregnant or lactating from the
             time of the administration of study medication.

          2. Women of childbearing potential, defined as all women physiologically capable of
             becoming pregnant, including women whose career, lifestyle, or sexual orientation
             precludes intercourse with a male partner and women whose partners have been
             sterilized by vasectomy or other means.

          3. Evidence or history of clinically significant haematological, renal, endocrine,
             pulmonary, gastrointestinal (including gallbladder), cardiovascular (including a
             family history of long QT syndrome or sudden death), hepatic, psychiatric, neurologic,
             or allergic disease (including drug or food allergies, anaphylaxis or other severe
             allergic reactions but excluding untreated, asymptomatic, seasonal allergies at the
             time of dosing).

          4. History of malignancy of any organ system (other than localised basal cell carcinoma
             of the skin), treated or untreated, within the past five years, regardless of whether
             there is evidence of local recurrence or metastases.

          5. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the Investigator, would make the subject
             inappropriate for entry into this study.

          6. Any surgical or medical condition possibly affecting drug absorption (e.g.
             cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or
             excretion.

          7. Previous splenectomy.

          8. A history of photosensitivity.

          9. Subject positive for any of the following

               -  Anti-human immunodeficiency virus 1 or 2 antibodies (anti-HIV1 or anti-HIV2 Ab)
                  (ELISA)

               -  Hepatitis B surface antigen (HBsAg)

               -  Anti-hepatitis B core antibodies (anti-HBcAb)

               -  Anti-hepatitis C antibodies (anti-HCV)

         10. Resting vital signs (measured after 5 minutes in the supine position) at screening,
             pre-dose (Part A) or pre-inoculation (Part B) outside of the following study-specific
             normal ranges:

               -  tympanic body temperature < 38.0 °C

               -  90 < SBP < 140 mmHg

               -  50 < DBP < 90 mmHg

               -  40 < pulse rate < 100 bpm

         11. Symptomatic postural hypotension at screening, irrespective of the decrease in blood
             pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood
             pressure ≥20 mmHg 2 minutes after changing from a supine to standing position.

         12. A history of clinically significant ECG abnormalities, or any of the following ECG
             abnormalities at screening, pre-dose (Part A and B) or pre-inoculation (Part B):

               -  PR >210 ms

               -  QRS complex >120 ms

               -  QTcF >450 ms

               -  Second or third degree atrioventricular block

               -  Incomplete, complete or intermittent bundle branch block

               -  Abnormal T wave morphology

               -  Left ventricular hypertrophy with repolarisation abnormalities

               -  Right ventricular hypertrophy.

         13. Presence of acute infectious disease or fever (i.e. tympanic body temperature ≥38.5
             ºC) within five days prior to the first dose of study medication (Part A) or the
             inoculation administration (Part B).

         14. Use of prescription or non-prescription drugs, herbal and dietary supplements within
             14 days or 5 half-lives (whichever is the longer) prior to the first dose of study
             medication (Part A) or the inoculation administration (Part B). [As an exception,
             paracetamol may be used at doses of up to 1 g/day (Part A) or 2 g/day (Part B), or
             ibuprofen up to 1.2 g/day (Part B). Limited use of other non-prescription medications
             not believed to affect subject safety or the overall results of the study, may be
             permitted on a case-by-case basis following approval by the sponsor.]

         15. Recipient of any vaccination within 28 days prior to the first dose of study
             medication (Part A) or the inoculation administration (Part B).

         16. Urine drug screen at screening, pre-dose (Part A) or pre-inoculation (Part B) positive
             for any drug as listed in Section 9.2.4 unless there is an explanation acceptable to
             the medical Investigator (e.g. the subject has stated in advance that they consumed a
             prescription or over the counter product which contained the detected drug) and/or the
             subject has a negative urine drug screen on retest by the pathology laboratory.

         17. Ingestion of any poppy seeds within the 24 hours prior to the screening blood test.

         18. A positive alcohol breath test at screening, pre-dose (Part A) or pre-inoculation
             (Part B).

         19. History of regular alcohol consumption exceeding a weekly intake of more than 21 units
             for males and more than 14 units for females (one unit is equivalent to 8-10 g of
             ethanol, 285 ml of beer or lager, one glass [125 ml] of wine, or 25 ml of spirits)
             within 6 months of screening.

         20. History of drug habituation, or any prior intravenous usage of an illicit substance.

         21. Participation in any investigational product study within 12 weeks or five half-lives
             (whichever is longer) prior to the first dose of the study medication.

         22. Intake of grapefruit, grapefruit juice or grapefruit-related citrus fruits (e.g.
             Seville oranges, pomelos) within 28 days prior to the first dose of the study
             medication.

         23. Excessive consumption of beverages containing xanthine bases (e.g. more than 400 mg of
             caffeine per day, equivalent to approximately 4 cups of coffee).

         24. Pregnant or nursing (lactating) women.

         25. Participation in any research study involving blood sampling (more than 450 ml/ unit
             of blood), or blood donation to the Australian Red Cross Blood Service (ARCBS) or
             other blood bank during the 8 weeks prior to IMP administration (Part A) or
             inoculation (Part B).

         26. Blood donation (excluding plasma donation) of any volume, within 1 month prior to
             screening.

         27. Medical requirement for intravenous immunoglobulin or blood transfusions.

         28. Subject with poor peripheral venous access.

         29. Subject unwilling or unable to comply with the restrictions described in this
             protocol.

         30. Any subject who, in the judgment of the Investigator, is likely to be noncompliant
             during the study, or unable to cooperate because of a language problem or poor mental
             development.

         31. Any subject who is the Investigator or any sub-investigator, research assistant,
             pharmacist, study coordinator, or other staff thereof, directly involved in conducting
             the study.

         32. Recent (within the last three years) and/or recurrent history of autonomic dysfunction
             (e.g. recurrent episodes of fainting, palpitations, etc.).