Open Label Pharmacokinetic Study of OZ439 and Piperaquine on Administration of OZ439+TPGS Granules for Oral Suspension Alone or With Either Piperaquine Phosphate Tablets or Granules for Oral Solution in Healthy Volunteers
Condition: Malaria
MeSH terms: Malaria
Intervention: 1440mg PQP tablets; 960mg PQP tablets; 800mg OZ439 + TPGS; 960mg PQP granules
Intervention description: Piperaquine phosphate tablets (1440mg); Piperaquine phosphate tablets (960mg); OZ439 (800mg) + TPGS granules for oral suspension; Piperaquine phosphate granules for oral solution (960mg)
Intervention MeSH terms: Artefenomel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: open label; healthy volunteers; pharmacokinetic; parallel group

Summary:

      A healthy volunteer study to characterise the exposure of the two study medications,
      following administration of OZ439 + TPGS granules with piperaquine phosphate granules
      (intended for children) and with piperaquine phosphate tablets (intended for adults).
      Ideally, to confirm the exposure demonstrated in an earlier bioavailability study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  healthy, male or female, any race aged 18-55 years at screening

          -  body mass index of 18-30kg/m2 inclusive; and a total body weight >50kg and up to 100kg
             at screening

          -  Females must have negative pregnancy test at screening, be non-lactating and of
             non-childbearing potential confirmed by:

               -  natural (spontaneous) post-menopausal defined as amenorrheic for 12 months
                  without an alternative medical cause with a screening FSH level >25IU/L for post
                  menopause

               -  irreversible surgical sterilisation by bilateral oophorectomy or bilateral
                  salpingectomy but not tubal ligation (with or without hysterectomy) at least six
                  months ago

          -  Must agree to use acceptable methods of contraception Males must use acceptable
             methods of contraception if the male subject's partner could become pregnant from the
             time of the first administration of treatment or study medication until 3 months
             following administration of the last dose of study medication

        One of the following acceptable methods of contraception must be used:

          -  Condom & occlusive cap (diaphragm or cervical/vault caps) with spermicidal
             foam/gel/film/cream/suppository)

          -  Surgical sterilisation (vasectomy with documentation of azoospermia) and a barrier
             method (condom or occlusive cap [diaphragm or cervical/vault caps] used with
             spermicidal foam/gel/film/cream/suppository)

          -  Female partner uses oral contraceptives (combination oestrogen/progesterone pills),
             injectable progesterone or subdermal implants and a barrier method (as above)

          -  Female partner uses medically prescribed topically-applied transdermal contraceptive
             patch and a barrier method (as above)

          -  Female partner has had documented tubal ligation (sterilization). In addition, a
             barrier method (as above) must be used

          -  Female partner has had documented placement of an intrauterine device or system and
             the use of a barrier method (as above)

          -  True abstinence: when 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 must
             agree use one of the above-mentioned contraceptive methods, if sexual relationships
             start during the study or up to 90 days after the last dose of study drug

               -  Subjects should not donate egg and sperm from the time of administration of study
                  medication until 3 months after study medication

               -  Must be capable of understanding and complying with the requirements of the
                  protocol and must have signed the informed consent form prior to undergoing any
                  study-related procedures

        Exclusion Criteria:

          -  Male subjects with female partner(s) who is (are) pregnant or lactating from the time
             of the administration of study medication

          -  Has a clinically significant disease or any condition or disease that might affect
             drug absorption, distribution or excretion

          -  History of allergic reaction to artemisinin-based compounds, 4-aminoquinolines such as
             piperaquine or any other clinically relevant allergy to drugs or food

          -  Any 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

          -  History or current evidence of any clinically relevant cardiovascular, pulmonary,
             hepatic, renal, gastrointestinal (excluding appendectomy and cholecystectomy),
             haematological, endocrinological, immunological, metabolic, neurological, oncological,
             psychiatric, urological or other disease, or current infection

          -  History of post-antibiotic colitis

          -  Electrocardiogram abnormalities in the 12-lead Electrocardiogram (at screening) and/or
             24-hour Holter Electrocardiogram (at screening) which in the opinion of the
             Investigator is clinically relevant or will interfere with the ECG analysis

          -  History of clinically significant Electrocardiogram abnormalities, or any of the
             following abnormalities at screening or on admission:

               -  PR >200ms

               -  QRS complex >120ms

               -  QTcB or QTcF >450ms or shortened QTcB or QTcF less than 340ms for males and
                  females or family history of long QT syndrome or sudden death

               -  Any degree of heart block (such as first, second or third degree atrioventricular
                  block, incomplete, full or intermittent bundle branch block)

               -  Abnormal T wave morphology / prominent U waves

          -  Positive results in any of the serology tests for Hepatitis B Surface Antigen, anti
             Hepatitis core antibody, Hepatitis C antibodies, and HIV 1 and 2 antibodies

          -  Confirmed positive results from urine drug screen (amphetamines, benzodiazepines,
             cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol
             breath test at screening and admission

          -  History or clinical evidence of alcohol abuse, or any recreational drug abuse within
             the 2 years of screening

          -  Mentally handicapped

          -  Participation in a drug trial within 90 days of drug administration

          -  Use of ANY prescription or over the counter medications, within 3 weeks of study
             medication administration, or vitamins or herbal supplements within 2 weeks of
             administration of the study drug, unless prior approval is granted. Intermittent use
             of paracetamol at doses of up to 2g/day is permitted

          -  Use of moderate/strong inhibitors and/or inducers of CYP450 in 4 weeks of drug
             administration (or at least 5 half-lives of the compound whichever is the longer)

          -  Veins unsuitable for intravenous puncture or cannulation on either arm (veins
             difficult to locate, access or puncture, or veins with a tendency to rupture during or
             after puncture)

          -  Transaminases, bilirubin, serum potassium outside normal range at screening or
             admission

          -  Haemoglobin < lower limit of normal at screening or admission

          -  Donation of >500mL blood in 90 days prior to drug administration

          -  Must be non-smoker for at least three months before screening. "Tobacco use" includes
             smoking and the use of snuff and chewing tobacco, and other nicotine containing
             products. May not use any non-nicotine containing smoking cessation aids, e.g.
             varenicline, for at least three months before screening

          -  Any consumption of grapefruit, Seville oranges, wild grapes, black mulberries,
             pomegranates as fruit juice, marmalade or as a raw fruit within 7 days prior to dosing
             of study drug and throughout the study

          -  Any circumstances or conditions, which may affect full participation in the trial or
             compliance with the protocol

          -  Legal incapacity or limited legal capacity at screening

          -  Vegetarians, vegans or any dietary restrictions conflicting with the study
             standardised menus