Malaria
Conditions
Keywords
P. falciparum, malaria
Brief 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.
Interventions
DRUGOZ439
OZ439 is a novel synthetic trioxolane antimalarial agent
Sponsors
Medicines for Malaria Venture
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC) | up to 28 days | The estimated MIC and MPC were derived from the fitted parasitaemia concentration and PK/PD relationship. |
Countries
Thailand
Participant flow
Recruitment details
Patients were recruited and followed up over 28 days in four clinics in Thailand from April 2013 to April 2015.
Participants by arm
| Arm | Count |
|---|---|
| OZ439 100mg Single dose of 100mg of OZ439 administered as an oral suspension | 8 |
| OZ439 500mg Single dose of 500mg of OZ439 administered as an oral suspension | 17 |
| Total | 25 |
Baseline characteristics
| Characteristic | OZ439 500mg | Total | OZ439 100mg |
|---|---|---|---|
| Age, Continuous | 34 years STANDARD_DEVIATION 10.49 | 35 years STANDARD_DEVIATION 10.98 | 37 years STANDARD_DEVIATION 12.44 |
| Race/Ethnicity, Customized Asian | 17 Participants | 25 Participants | 8 Participants |
| Region of Enrollment Thailand | 17 participants | 25 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 14 Participants | 21 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 8 | 10 / 17 |
| serious Total, serious adverse events | 0 / 8 | 0 / 17 |
Outcome results
Primary
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.
Time frame: up to 28 days
Population: Model predicted MIC and MPC
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| OZ439 100mg | Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC) | Model predicted MIC | 2.4 ng/Ml | Standard Deviation 3.5 |
| OZ439 100mg | Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC) | Model predicted MPC | 77 ng/Ml | Standard Deviation 128 |
| OZ439 500mg | Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC) | Model predicted MIC | 4.1 ng/Ml | Standard Deviation 5 |
| OZ439 500mg | Minimum Inhibitory Concentration (MIC) and Minimum Parasiticidal Concentration (MPC) | Model predicted MPC | 319 ng/Ml | Standard Deviation 877 |