Malaria
Conditions
Keywords
Malaria, PK, OZ439, Mefloquine, Healthy Volunteers
Brief summary
OZ439 is a novel, synthetic trioxolane medicine which is related to artemisinin, but has the advantage of a longer elimination half-life so is being developed to be administered together with a potential partner drug e.g. mefloquine as a single dose cure for uncomplicated malaria. The study findings will be used to inform the dose and design of future studies. The aim of the study is to establish the safety, tolerability and pharmacokinetics of co-administered OZ439 and MQ at a range of doses up to the maximum tolerated dose, in healthy volunteers.
Interventions
DRUGOZ439 100mg
OZ439 100mg oral suspension, single dose
DRUGOZ439 400mg
OZ439 400mg oral suspension, single dose
DRUGMQ 250 mg, single dose
Mefloquine 250 mg tablet, single dose
DRUGMQ 750mg, single dose
Mefloquine 750mg oral tablet, single dose
DRUGPlacebo
Sponsors
University of Cape Town
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and non-childbearing potential female volunteers of between 18 and 55 years of age * Female volunteers must have a negative serum pregnancy test at screening * Females must be of non-childbearing potential * Male volunteers and their partner(s) must agree to use a double barrier method of contraception for at least 14 days prior to first dose of study drug through 90 days after the last dose. * Body mass Index between 18 and 30kg/m2, inclusive; and a total body weight \>50 kg * Laboratory tests at screening within normal ranges or not clinically significant as judged by the Investigator.
Exclusion criteria
* Received an investigational drug or participated in another research study within 30 days of the first dose of study drug or at any time through the study * Evidence of current or history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, gastrointestinal, haematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, or clinically significant current infection. * Any condition that could possibly affect drug absorption, such as gastrectomy, diarrhea and lactose intolerance * Use of any medications, vitamins, herbal supplements, dietary supplements or vaccinations within 14 days of the first dose of study drug or at any time through the study, unless prior approval is granted. This includes any drugs that are substrates, inhibitors or inducers of CYP3A4. Intermittent use of acetaminophen at doses of up to 2g/day is permitted * History of drug or alcohol abuse within 2 years of Screening * History of alcohol consumption within 24 hours of any study visit * Tobacco users * Consumption of fruit juices within 7 days prior to dosing * Participation in unaccustomed strenuous exercise within 7 days prior to * Positive urine drug screen * Positive test for HIV-1, HBsAg or HCV * Known hypersensitivity to MQ or artemisinins * QTcF greater than 450msec
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 AUC0-t | Up to 42 days post-dose | Area under the plasma concentration versus time curve (AUC) of OZ439 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Cmax | Up to 42 days post-dose | Peak Plasma Concentration (Cmax) of OZ439 |
| MQ AUC0-t | Up to 42 days post-dose | Area under the plasma concentration versus time curve (AUC) of MQ |
| MQ Cmax | Up to 42 days post-dose | Peak Plasma Concentration (Cmax) of MQ |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Period 1: OZ439 100mg single dose oral suspension
Period 2: Single dose OZ439 100mg oral suspension in combination with single dose MQ 250mg tablet | 8 |
| Cohort 2 Period 1: OZ439 400mg single dose oral suspension
Period 2: Single dose OZ439 400mg oral suspension in combination with single dose MQ 750mg tablets | 10 |
| Placebo Placebo | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 1 | 0 |
| Period 2 | Lost to Follow-up | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 29.1 years STANDARD_DEVIATION 10.3 | 30.6 years STANDARD_DEVIATION 9.42 | 26 years STANDARD_DEVIATION 4.45 | 28.6 years STANDARD_DEVIATION 8.06 |
| Region of Enrollment South Africa | 8 participants | 10 participants | 6 participants | 24 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 6 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 9 / 10 | 5 / 6 |
| serious Total, serious adverse events | 1 / 8 | 0 / 10 | 0 / 6 |
Outcome results
Primary
OZ439 AUC0-t
Area under the plasma concentration versus time curve (AUC) of OZ439
Time frame: Up to 42 days post-dose
Population: Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 100mg Single Dose | OZ439 AUC0-t | 1060 ng*h/mL | Geometric Coefficient of Variation 32 |
| OZ439 100mg Plus MQ 250mg Single Doses | OZ439 AUC0-t | 1060 ng*h/mL | Geometric Coefficient of Variation 32 |
| OZ439 400mg Single Dose | OZ439 AUC0-t | 8100 ng*h/mL | Geometric Coefficient of Variation 30 |
| OZ439 400mg Plus MQ 750mg Single Doses | OZ439 AUC0-t | 7300 ng*h/mL | Geometric Coefficient of Variation 30 |
Secondary
MQ AUC0-t
Area under the plasma concentration versus time curve (AUC) of MQ
Time frame: Up to 42 days post-dose
Population: Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 100mg Single Dose | MQ AUC0-t | 167 ng*h/mL | Geometric Coefficient of Variation 18 |
| OZ439 100mg Plus MQ 250mg Single Doses | MQ AUC0-t | 421 ng*h/mL | Geometric Coefficient of Variation 30 |
Secondary
MQ Cmax
Peak Plasma Concentration (Cmax) of MQ
Time frame: Up to 42 days post-dose
Population: Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 100mg Single Dose | MQ Cmax | 0.602 ng/mL | Geometric Coefficient of Variation 27 |
| OZ439 100mg Plus MQ 250mg Single Doses | MQ Cmax | 1.34 ng/mL | Geometric Coefficient of Variation 36 |
Secondary
OZ439 Cmax
Peak Plasma Concentration (Cmax) of OZ439
Time frame: Up to 42 days post-dose
Population: Only the subjects who completed all treatments in their respective cohort (per-protocol set) were included in the PK population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| OZ439 100mg Single Dose | OZ439 Cmax | 157 ng/mL | Geometric Coefficient of Variation 24 |
| OZ439 100mg Plus MQ 250mg Single Doses | OZ439 Cmax | 147 ng/mL | Geometric Coefficient of Variation 33 |
| OZ439 400mg Single Dose | OZ439 Cmax | 821 ng/mL | Geometric Coefficient of Variation 21 |
| OZ439 400mg Plus MQ 750mg Single Doses | OZ439 Cmax | 745 ng/mL | Geometric Coefficient of Variation 26 |