OZ439 PhIIa Study in Plasmodium Falciparum: Extended Observation
Condition: Malaria
MeSH terms: Malaria
Intervention: OZ439
Intervention description: OZ439 is a novel synthetic trioxolane antimalarial agent
Intervention MeSH terms: Artefenomel
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: P. falciparum; malaria

Summary:

      This study aims to investigate the concentration dependent effects of OZ439 on the clearance
      of P. falciparum parasites in patients, specifically the determination of an in-vivo minimum
      inhibitory concentration (MIC) of OZ439. Characterisation of PK-PD
      (Pharmacokinetic-Pharmacodynamic) relationships is essential for rational evidence based
      dosing. The adaptive investigation of a range of doses will provide the best chance of
      accurate PK-PD characterisation, allowing the observation of Plasmodium falciparum growth
      dynamics and the subsequent identification of MIC and MPC (minimum parasiticidal
      concentration). Additionally the tolerability and pharmacokinetics of OZ439 will be
      confirmed. The PK/PD relationship between OZ439 exposure and subsequent effects on
      parasitaemia will be investigated.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Male or female patients between the age of 18 and 60 years, inclusive

          2. Body weight between 45 kg and 90 kg inclusive

          3. Presence of mono-infection of P. falciparum confirmed by:

               1. Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic
                  temperature ≥ 38°C, or history of fever in the previous 24 hours (history of
                  fever must be documented) and,

               2. Microscopically confirmed parasite infection: 1,000 to 75,000 asexual parasite
                  count/µL blood.

          4. Written informed consent, in accordance with local practice, provided by patient. If
             the patient is unable to write, witnessed consent is permitted according to local
             ethical considerations

          5. Ability to swallow oral medication

          6. Ability and willingness to participate and access the health facility

          7. Agree to hospitalization for at least 72h until parasites have fallen below the level
             of polymerase chain reaction (PCR) detection and have no signs or symptoms of malaria;
             and then to return once daily to the study centre for blood sampling for quantitative
             polymerase chain reaction (qPCR), and rehospitalisation when qPCR levels are
             detectable.

        Exclusion Criteria:

          1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral
             treatment according to the World Health Organization Criteria 2010

          2. Mixed Plasmodium infection

          3. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion
             in the study or inability to tolerate oral treatment, or severe diarrhoea defined as 3
             or more watery stools per day

          4. Presence of other serious or chronic clinical condition requiring hospitalization

          5. Severe malnutrition (defined as the weight-for-height being below -3 standard
             deviation or less than 70% of median of the NCHS/WHO normalized reference values)

          6. Known history or evidence of clinically significant disorders such as cardiovascular
             (including arrhythmia, QTc interval greater than or equal to 450 msec), respiratory
             (including active tuberculosis), history of jaundice, hepatic, renal,
             gastrointestinal, immunological (including active HIV-AIDS), neurological (including
             auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or
             other abnormality (including head trauma)

          7. Known history of hypersensitivity, allergic or adverse reactions to artemisinin
             containing compounds or mefloquine

          8. Known active Hepatitis A Immunoglobulin M (IgM) (HAV-IgM), Hepatitis B surface antigen
             (HBsAg) or Hepatitis C antibody (HCV Ab)

          9. Have received any antimalarial treatment in the preceding 14 days, as determined by
             history and screening test

         10. Have received antibacterial with known antimalarial activity in the preceding 14 days

         11. Have received an investigational drug within the past 4 weeks

         12. Liver function tests (Aspartate Aminotransferase(ASAT)/Alanine Aminotransferase (ALAT)
             levels) > 2x upper limit of normal (ULN) if Total Bilirubin normal or >1.5xULN if
             Total bilirubin between >1 and >1.5xULN

         13. Hemoglobin (Hb) level =< 8g/dl

         14. Total Bilirubin > 1.5XULN

         15. Serum creatinine levels more than 2 times the upper limit of normal range (>2xULN).

         16. Female patients must be neither pregnant as demonstrated by a negative serum pregnancy
             test at screening and urinary pregnancy test pre-dose (the result of the pre-dose
             assessment must be confirmed negative prior to dosing) nor lactating, and must be
             willing to take measures not to become pregnant during the study period and safety
             follow-up period.