OZ439 PhIIa Study in Plasmodium Falciparum: Extended Observation

The Extended Observation Over a Period of 28 Days of the Effects of Single Doses of OZ439 on the Recrudescence of Plasmodium Falciparum Malaria - a PhIIa, Open Label Study in Adult Patients

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.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: OZ439

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10400
    • Faculty of Tropical Medicine,
  • Tak
    • Mae Ramat, Tak, Thailand, 63140
      • Mae Ramat District hospital
    • Mae Sot, Tak, Thailand, 63110
      • Shoklo Malaria Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OZ439 100mg; Single dose of 100mg of OZ439 administered as an oral suspension	Drug: OZ439; OZ439 is a novel synthetic trioxolane antimalarial agent
Experimental: OZ439 500mg; Single dose of 500mg of OZ439 administered as an oral suspension	Drug: OZ439; OZ439 is a novel synthetic trioxolane antimalarial agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC)	The estimated MIC and MPC were derived from the fitted parasitaemia concentration and PK/PD relationship.	up to 28 days

Collaborators and Investigators

• Sponsor: Medicines for Malaria Venture
• Investigators: Principal Investigator: Sasithon Pukrittayakamee, MD, Faculty of Tropical Medicine, Mahidol University, Bangkok; Principal Investigator: Francois Nosten, MD, Shoklo Malaria Research Unit, Faculty of Tropical medicine, Mahidol University

Publications and helpful links

General Publications

• Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FC, Chollet J, Dong Y, Dorn A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Santo Tomas J, Scheurer C, Scorneaux B, Tang Y, Urwyler H, Wittlin S, Charman WN. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004 Aug 19;430(7002):900-4. doi: 10.1038/nature02779.

Helpful Links

• Information about Medicines for Malaria Venture

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: October 22, 2012
• First Submitted That Met QC Criteria: October 22, 2012
• First Posted (Estimate): October 25, 2012

Study Record Updates

• Last Update Posted (Actual): April 14, 2017
• Last Update Submitted That Met QC Criteria: March 17, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: malaria; P. falciparum
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Artefenomel
• Other Study ID Numbers: MMV_OZ439_12_006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO