A Study to Investigate the Safety, Tolerability and Pharmacokinetics of OZ439 in Healthy Male and Female Subjects
Condition: Malaria Falciparum; Malaria Vivax; Healthy Volunteers
MeSH terms: Malaria; Malaria, Falciparum
Intervention: OZ439 50mg API capsules; OZ439 200mg API capsules; OZ439 400mg aqueous dispersion; OZ439 800mg aqueous dispersion; OZ439 100mg API capsules; OZ439 400mg API capsules; OZ439 1600mg aqueous dispersion; OZ439 800mg API capsules; OZ439 1200mg API capsules; Placebo; OZ439 200mg aqueous dispersion
Intervention description: OZ439 100mg (2x50mg API capsules); OZ439 400mg (2x200mg API capsules); OZ439 800mg (4x200 API capsules); OZ439 1200mg (6x200mg API capsules)
Intervention MeSH terms: Artefenomel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 63.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Phase I; Safety and tolerability; Pharmacokinetic; synthetic peroxide; trioxolane; treatment of erythrocytic stages of malaria

Summary:

      OZ439 is a synthetic trioxolane that has potential value as a peroxide antimalarial agent.

      This was a Phase I, single-centre, multi-component, double-blind, randomised,
      placebo-controlled study in healthy male and female subjects. The study was conducted in 3
      parts:

        -  Part A investigated the safety, tolerability and pharmacokinetics (PK) of single oral
           escalating doses of OZ439. Up to 6 dose levels will be investigated to estimate dose
           proportionality.

        -  Part B, the effect of food on a single oral dose of OZ439 was investigated in a 2-way
           crossover design.

        -  Part C investigated the safety, tolerability and PK profile of multiple oral doses of
           OZ439.

      The starting oral dose was 50 mg and the maximum single dose to be administered did not
      exceed 1600 mg per subject. The maximum duration of dosing proposed was 3 days.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male//female subjects between 18- 55 years of age (inclusive).

          2. Body mass Index (BMI) between 18 - 30 kg/m2, inclusive; and a total body weight >60 kg
             (132 lbs).

          3. Healthy as determined by pre-study medical history, PE, 12 Lead ECG.

          4. Females of childbearing potential must use 1 of birth control methods throughout study
             and for 30 days after last dose of study drug:

               1. Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral
                  oophorectomy) 6 months minimum prior to first dose of study drug.

               2. Intrauterine device (IUD) in place for at least 3 months prior to first dose of
                  study drug.

               3. Barrier methods (condom or diaphragm) with spermicide starting at least 14 days
                  prior to first dose of study drug through 30 days after last dose of study drug.

               4. Surgical sterilization of the partner(s) (vasectomy with zero sperm count for 6
                  months minimum prior to the first dose of study drug).

               5. Hormonal contraceptives starting at least 3 months prior to first dose of study
                  drug. In addition, subjects must agree to use a barrier method (condom or
                  diaphragm) with spermicide at least 14 days prior to first dose of study drug
                  through 30 days after the last dose of study drug.

          5. Post-menopausal women with amenorrhea for at least 1 year will be eligible confirmed
             by FSH.

          6. Male subjects must agree to use double barrier method of contraception, from time of
             first dose of study drug through 90 days after last dose of study drug and must also
             agree to not donate sperm for 90 days after last dose of study drug. Clinical
             laboratory tests within the reference ranges.

          7. Able/willing to give written informed consent.

          8. Willing/to adhere to lifestyle guideline restrictions outlined in protocol.

          9. Willing and able to be confined to Clinical Research Unit as required by the protocol.

        Exclusion Criteria:

          1. Evidence/history of clinically significant oncologic, pulmonary, hepatic,
             cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic,
             endocrine, psychiatric disease, current infection.

          2. Evidence/history of clinically significant gastrointestinal (some exclusions exist)
             disease, current infection.

          3. Any condition that affecting drug absorption, e.g., gastrectomy.

          4. History of post-antibiotic colitis.

          5. Breast feeding.

          6. QTc greater than 450 msec for males and 470 msec for females as corrected by the
             Bazett formula.

          7. History of drug or alcohol abuse within the past 2 years prior to Screening.

          8. Tobacco users

          9. Received investigational drug/ participated in another research study within 30 days
             of first dose of study drug in any part of study.

         10. Use of prescription drugs within 14 days prior to the first dose of study drug in
             Period 1, or need for any antibiotic during study.

         11. Received any non prescription meds, vitamins, herbal/dietary supplements within 7 days
             of administration of first dose of study drug in Period 1 (exceptions exist)

         12. Consumed alcohol within 72 hours of Day -1 in any part of study, or have a positive
             alcohol screen at screening or each admission to Clinical Research Unit (CRU).

         13. Consumed grapefruit juice or juices containing grapefruit or ate grapefruit within 7
             days prior to first dose of study drug in any part of study.

         14. Positive serum pregnancy test at the Screening Visit or on Day -1 prior to inclusion
             in any part of the study.

         15. Positive test for HIV-1, HBsAg,HCV.

         16. Positive urine drug screen at Screening or admission to CRU.

         17. History of intolerance/ hypersensitivity to artemisinins.

         18. Likelihood of requiring treatment during study period with drugs not permitted by
             protocol.

         19. Subjects who have donated blood or experienced significant blood loss within 60 days
             of screening for study.

         20. Subjects whose hemoglobin is <12.5 g/dL for males/ <11.5 g/dL for females.

         21. Any concern by investigator regarding safe participation of the subject in study or
             for any other reason investigator considers subject inappropriate for participation in
             study.