Safety, Tolerability and Antimalarial Activity of Single Doses of OZ439 and PQP
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 1

Summary: 
      A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile,
      and antimalarial activity of single doses of coadministered artefenomel (OZ439) and
      piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in
      healthy adult volunteers.
    

Detailed description: 
      This is a single-centre, open-label, adaptive, study using the P. falciparum induced blood
      stage malaria (IBSM) inoculum as a model to characterise the pharmacodynamic (PD) activity of
      combined single dose administration of OZ439 and PQP.

      The study will be conducted in a maximum of three cohorts (up to 8 subjects per cohort) using
      up to 4 different doses of OZ439 and PQP in each cohort. Subjects will be malaria naïve
      healthy males or females, aged between 18-55 years old, who meet all of the inclusion
      criteria and none of the exclusion criteria.

      The first cohort will be composed of 4 groups of 2 subjects each. Subjects will be randomised
      into one of 4 dose groups and administered single oral doses of OZ439 and PQP in combination
      The combined dose of OZ439 and PQP will be different for each of the 4 groups in this cohort
      as shown in Table 1.

      Table 1 OZ439 and PQP Cohort 1 Dose Drug Dose group

      1A 1B 1C 1D OZ439 (mg) 200 200 400 400 PQP (mg) 480 640 480 640

      The data captured from this first cohort will be used to determine the relationship between
      OZ439 and PQP concentrations and parasitaemia levels. Based on safety and tolerability data
      up to Day 35 post-dose, and pharmacokinetic/pharmacodynamic (PK/PD) analysis outcomes (based
      on PD data up to Day 35 and PK data up to Day 28 post-dose) of the drugs given in
      combination, the dose(s) for the subsequent cohort will be determined. A similar analysis
      will be done at the end of cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to
      be tested in cohort 3. This will be decided by the funding sponsor and the Principal
      Investigator following review of the data by the Safety and Data Review Team (SDRT) and
      scientific evaluation.

      The doses used in all cohorts will not exceed the maximum acceptable doses predefined for
      this study (800 mg for OZ439 and 1440 mg for PQP) as determined in previous safety, pilot
      efficacy and phase 2 studies.

      Each subject will be inoculated on Day 0 with approximately 2,800 viable parasites of P.
      falciparum-infected human erythrocytes administered intravenously. Subjects will be followed
      up daily via phone call or text message on Days 1 to 3 post-inoculation to solicit any AEs.

      Subjects will then come to the clinical unit once daily from Day 4 until presence of asexual
      parasites is established by quantitative polymerase chain reaction (qPCR) targeting the 18S
      rRNA gene (referred to hereafter as malaria 18S qPCR). Once qPCR becomes positive and until
      OZ439 and PQP administration, subjects will come to the clinical unit twice-daily, separated
      by approximately 12 hours, for clinical evaluation and blood sampling.

      Subjects will be admitted to the clinical unit for single dose administration of OZ439 and
      PQP 8 days after malaria inoculation or at Investigators discretion (i.e. as per parasitaemia
      levels). Subjects will be followed up as inpatients for at least 72 hours to ensure tolerance
      of the investigational treatments and clinical response, then if clinically well on an
      outpatient basis for safety and clearance of malaria parasites via qPCR.

      After discharge from the clinical unit, subjects will be followed up regularly for safety
      assessments, PK sampling, clinical evaluation, and malaria qPCR blood sampling until 35 days
      after OZ439 and PQP administration. All subjects will receive a standard course of therapy
      with Riamet® (artemether-lumefantrine) 34 days after OZ439 and PQP administration, or earlier
      in the event of failure of clearance of parasitaemia or recrudescence of parasitaemia. The
      presence of gametocytes in subjects' blood will be determined by parasite lifecycle stage
      qRT-PCR or by the presence of stable low level parasitaemia. If gametocytes are present at
      the time of treatment with Riamet®, Primacin™ (primaquine) will also be administered as a
      single oral dose.

      AEs (AEs) will be monitored via telephone, within the clinical unit, and on outpatient review
      after malaria challenge inoculation and antimalarial study drugs administration. Blood
      samples for safety evaluation, malaria monitoring, and red blood cell antibodies will be
      drawn at screening and/or baseline and at nominated times after malaria challenge.
    

Intervention name(s): OZ439 + α-tocopherol polyethylene glycol 1000 succinate
Intervention type(s): Drug
Intervention description(s): Artefenomel (OZ439), is a novel trioxolane Piperaquine is a bis 4-aminoquinoline and was used mainly in China from the 1960's to the 1980's as an antimalarial monotherapy.
Other intervention name(s): Piperaquine phosphate (PQP),
Intervention MeSH terms: Tocopherols; Vitamin E; Tocotrienols; alpha-Tocopherol; Piperaquine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Based on safety and tolerability data up to Day 35 post-dose, and pharmacokinetic/pharmacodynamic (PK/PD) analysis outcomes (based on PD data up to Day 35 and PK data up to Day 28 post-dose) of the drugs given in combination, the dose(s) for the subsequent cohort will be determined. A similar analysis will be done at the end of cohort 2 combining cohorts 1 and 2 data to decide the dose(s) to be tested in cohort 3.
Masking: None (Open Label)
Primary purpose: Other