A Dose-escalation Study to Investigate Safety and Toleration of OZ439
Condition: Malaria
MeSH terms: Malaria
Intervention: OZ439
Intervention description: OZ439 x mg once daily for 3 days with milk
Intervention MeSH terms: Artefenomel
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: malaria; dose escalation; safety; tolerability; maximum tolerated dose

Summary:

      A randomised, placebo-controlled, dose-escalation study to investigate safety and toleration
      of OZ439 OD for 3 days to healthy male and female volunteers. The study aims:

        -  To determine the safety and tolerability of ascending doses of OZ439 OD for three days.

        -  To assess pharmacokinetic parameters of ascending doses of OZ439 given OD.

        -  To identify the maximum tolerated dose of OZ439 administered.
    

Eligibility criteria:

        Inclusions:

          1. healthy males or females of any race aged 18 - 55 years

          2. BMI of 18 - 30 kg/m2 inclusive at screening

          3. Agree to use acceptable methods of contraception if of childbearing potential

          4. Capable of understanding and complying with the requirements of the protocol and must
             have signed the informed consent form

          5. Females are either of child bearing potential or are confirmed as post-menopausal.
             Post-menopausal is defined as being amenorrheic for 12 months without an alternative
             medical cause with a screening FSH level ≥ 25.8 IU/L

        Exclusions:

          1. Male subjects with female partner(s) who is (are) pregnant or lactating from the time
             of the first administration of study medication

          2. Clinically significant disease or any condition or disease that might affect drug
             absorption, distribution or excretion

          3. History of allergic reactions to artemisinin-based compounds or any other clinically
             relevant allergy to drugs or food

          4. Clinically relevant history of both soya and cow's milk intolerance/allergy

          5. Clinically significant abnormal laboratory, vital signs or other safety findings as
             determined by medical history, physical examination or other evaluations conducted at
             screening or on admission

          6. Electrocardiogram (ECG) abnormalities in the standard 12-lead ECG (at screening)
             and/or 24-hour 5 lead Holter ECG (at screening)

          7. Any abnormalities in rhythm, conduction or morphology of resting ECG that may
             interfere with the interpretation of QTc interval changes

          8. Prolonged QTcF >450 ms or shortened QTcF <340 ms, or family history of Long QT
             Syndrome

          9. History or current evidence of any clinically relevant cardiovascular, pulmonary,
             hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic,
             neurological, psychiatric, or other disease

         10. Positive results in any of the serology tests for Hepatitis B Surface Antigen (HbsAg),
             anti Hepatitis core antibody (anti HBc Ig G [and anti HBc IgM if IgG is positive],
             Hepatitis C antibodies (anti HCV), and HIV 1 and 2 antibodies (anti HIV 1/2)

         11. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
             cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol
             breath test at screening and on admission

         12. History or clinical evidence of alcohol or drug abuse. Alcohol abuse is defined as
             regular weekly intake of more than 21 units for males and 14 units for females; drug
             abuse is defined as compulsive, repetitive and/or chronic use of drugs or other
             substances with or without problems related to their use and/or where stopping or a
             reduction in dose will lead to withdrawal symptoms

         13. Is pregnant or lactating (female subjects who are of childbearing potential must have
             negative pregnancy tests at screening and admission)

         14. Mentally handicapped

         15. Participation in a drug trial within 90 days prior to first drug administration

         16. Use of any medication (incl. over-the-counter (OTC) medication) within 2 weeks prior
             to drug administration (Day 1) or within less than 10 times the elimination half-life
             of the respective drug, or anticipated concomitant medication during the treatment
             periods, (whichever is longer), including herbal, traditional and alternative
             medications. Excluding oral contraceptives (combination oestrogen/progesterone pills),
             injectable progesterone or subdermal implants. Limited amounts (4g/day for 2 days) of
             paracetamol will be permitted for the treatment of AEs

         17. Treatment with herbal supplements during the 7 days prior to drug administration, or
             use of vitamins during 48 hours prior to drug administration

         18. Is not permitted to use strong inhibitors and/or inducers of CYP450 within 21 days
             prior to the planned first drug administration

         19. Subjects have veins unsuitable for intravenous puncture or cannulation on either arm
             (e.g. veins that are difficult to locate, access or puncture veins with a tendency to
             rupture during or after puncture)

         20. Blood ALT, AST and bilirubin should be in the normal range at screening and on
             admission

         21. Donation of more than 500 mL of blood within 90 days prior to drug administration

         22. Subjects must be non-smokers for at least three months prior to first drug
             administration

         23. Any circumstances or conditions, which, in the opinion of the PI, may affect full
             participation in the trial or compliance with the protocol

         24. Legal incapacity or limited legal capacity at screening

         25. Subjects who are vegetarians, vegans or have any dietary restrictions conflicting with
             the study standardised menus