Malaria
Conditions
Keywords
Malaria, Bio-availability
Brief summary
A single dose study to investigate how different formulations of OZ439 co-administered with PQP tablest are processed by the body when taken without food
Interventions
DRUG800mg OZ439 prototype formulation 1
DRUG800mg OZ439 prototype formulation 2
DRUG800mg OZ439 prototype formulation 3
DRUG960mg PQP
Sponsors
Quotient Clinical
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males, or healthy females of non-childbearing potential ie surgically sterilised or post-menopausal (amenorrhoea for at least 1 year and confirmed by a follicle stimulating hormone result of ≥25 IU/mL 2. Age 18 to 55 years of age 3. Body mass index of 18.0 to 30.0 kg/m2 inclusive. Total body weight \>50 kg at screening 4. Willing and able to communicate and participate in the whole study 5. Must provide written informed consent 6. Must agree to use an adequate method of contraception 7. Must have liver function tests and haemoglobin within the laboratory reference range at screening and Day -1 8. Must have heart trace measurements within the defined healthy limits at screening, Day -1 and pre-dose
Exclusion criteria
1. Male subjects who have currently pregnant partners 2. Evidence or history of clinically significant oncological, pulmonary, chronic respiratory, hepatic, cardiovascular, haematological, metabolic, neurological, immunological, nephrological, endocrine or psychiatric disease, or current infection 3. Clinically relevant abnormalities in the heart trace including any degree of heart block, including asymptomatic bundle branch block 4. Family history of sudden death or of congenital prolongation of the QTc interval or known congenital prolongation of the QTc interval or any clinical condition known to prolong the QTc interval 5. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia 6. Electrolyte disturbances, particularly hypokalemia, hypocalcaemia or hypomagnesaemia. 7. Any condition that could possibly affect drug absorption, such as gastrectomy or diarrhoea 8. History of post-antibiotic colitis 9. History of any drug or alcohol abuse in the past 2 years prior to screening 10. Subjects who have a breath carbon monoxide reading of greater than 10 ppm at screening will be excluded. Subjects who are tobacco users (including smokers and users of snuff, chewing tobacco and other nicotine or nicotine-containing products) must have stopped use within 90 days before screening. 11. Receipt of an investigational drug or participation in another clinical research study within 90 days prior to drug administration. 12. Subjects who are study site employees, or immediate family members of a study site or sponsor employee. 13. Subjects who have previously been enrolled in this study 14. Use of ANY prescription or non-prescription medications, vitamins, herbal supplements or dietary supplements, including protein supplements, within 14 days prior to the first dose of study drug and throughout the study, unless prior approval is granted by both the investigator and the sponsor. An exception will be made for intermittent use of paracetamol and hormone replacement therapy. Paracetamol at doses of, at most, 2 g per day or no more than 3 consecutive days or 6 non consecutive days, are allowed until 24 hours before dosing with study drug. Longer exclusion periods apply for: 1. amiodarone and hydroxychloroquine (210 days) 2. monoclonal antibodies/ immunoglobulins/ other therapeutic proteins and experimental drugs for which the half-life is not known to the investigator (120 days) 3. experimental drugs for which half-life is known to the investigator (5 half lives plus 14 days) 4. chloroquine, piperaquine phosphate and flunarizine (100 days) 5. fluoxetine (75 days) 6. benzodiazepines (for midazolam, lorazepam and triazolam, the exclusion period is 14 days), chlorpromazine, mephenytoin, nortryptyline, phenobarbital, primidone, phenprocoumone and cytochrome P450 3A4 inducers not already mentioned, including but not restricted to, rifampin, carbamazepine, oxcarbazepine, phenytoin and St John's Wort (35 days) 15. Positive hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus results 16. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator 17. Positive urine drug screen result at screening or admission to the clinical unit 18. History of intolerance or hypersensitivity to piperaquine or any 4-aminoquinolone, or ascertained or presumptive hypersensitivity to the active principle and/or formulation ingredients; history of anaphylaxis to drugs or allergic reactions in general, that the investigator considers may affect the outcome of the study 19. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients 20. Presence or history of allergy requiring treatment; hayfever is allowed unless it is active 21. Donation or loss of \>400 mL of blood within 90 days prior to drug administration 22. Regular alcohol consumption in males \>21 units per week and females \>14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) 23. Subjects who do not have suitable veins for multiple blood samples as assessed by the investigator at screening 24. Failure to satisfy the investigator of fitness to participate for any other reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 AUC(0-168h) | Up to 168 hours post-dose | OZ439 Area under the plasma concentration (AUC) versus time curve |
| OZ439 Cmax | Up to 168 hours post-dose | OZ439 Maximum observed concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Piperaquine (PQ) AUC(0-168h) | Up to 168h post-dose | PQ Area under the plasma concentration versus time curve |
| PQ Cmax | Up to 168h post-dose | PQ Maximum observed concentration |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment A: OZ439 Prototype 1 800mg OZ439 prototype formulation 1 and 960mg PQP single doses under fasted conditions | 7 |
| Treatment B: OZ439 Prototype 2 800mg OZ439 prototype formulation 2 and 960mg PQP single doses under fasted conditions | 8 |
| Treatment C: OZ439 Prototype 3 800mg OZ439 prototype formulation 3 and 960mg PQP single doses under fasted conditions | 7 |
| Total | 22 |
Baseline characteristics
| Characteristic | Treatment A: OZ439 Prototype 1 | Treatment B: OZ439 Prototype 2 | Treatment C: OZ439 Prototype 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 28 years STANDARD_DEVIATION 8.2 | 44.9 years STANDARD_DEVIATION 11.3 | 35.7 years STANDARD_DEVIATION 4.1 | 36.6 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment United Kingdom | 7 participants | 8 participants | 7 participants | 22 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 7 Participants | 20 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 | 2 / 7 | 7 / 8 | 2 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 8 | 0 / 7 |
Outcome results
Primary
OZ439 AUC(0-168h)
OZ439 Area under the plasma concentration (AUC) versus time curve
Time frame: Up to 168 hours post-dose
Population: All subjects who received at least one dose of study drug and had sufficient plasma concentration data for pharmacokinetics (PK) parameter estimation
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: OZ439 Prototype 1 | OZ439 AUC(0-168h) | 8780 ng*h/mL | Geometric Coefficient of Variation 43.7 |
| Treatment B: OZ439 Prototype 2 | OZ439 AUC(0-168h) | 10300 ng*h/mL | Geometric Coefficient of Variation 23.7 |
| Treatment C: OZ439 Prototype 3 | OZ439 AUC(0-168h) | 9460 ng*h/mL | Geometric Coefficient of Variation 43 |
Primary
OZ439 Cmax
OZ439 Maximum observed concentration
Time frame: Up to 168 hours post-dose
Population: All subjects who received at least one dose of study drug and had sufficient plasma concentration data for PK parameter estimation
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: OZ439 Prototype 1 | OZ439 Cmax | 877 ng/mL | Geometric Coefficient of Variation 41.3 |
| Treatment B: OZ439 Prototype 2 | OZ439 Cmax | 995 ng/mL | Geometric Coefficient of Variation 32.2 |
| Treatment C: OZ439 Prototype 3 | OZ439 Cmax | 924 ng/mL | Geometric Coefficient of Variation 50.5 |
Secondary
Piperaquine (PQ) AUC(0-168h)
PQ Area under the plasma concentration versus time curve
Time frame: Up to 168h post-dose
Population: All subjects who received at least one dose of study drug and had sufficient plasma concentration data for PK parameter estimation
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: OZ439 Prototype 1 | Piperaquine (PQ) AUC(0-168h) | 3730 ng*h/mL | Geometric Coefficient of Variation 41.3 |
| Treatment B: OZ439 Prototype 2 | Piperaquine (PQ) AUC(0-168h) | 2810 ng*h/mL | Geometric Coefficient of Variation 21.8 |
| Treatment C: OZ439 Prototype 3 | Piperaquine (PQ) AUC(0-168h) | 3300 ng*h/mL | Geometric Coefficient of Variation 50.7 |
Secondary
PQ Cmax
PQ Maximum observed concentration
Time frame: Up to 168h post-dose
Population: All subjects who received at least one dose of study drug and had sufficient plasma concentration data for PK parameter estimation
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: OZ439 Prototype 1 | PQ Cmax | 99.8 ng/mL | Geometric Coefficient of Variation 90.1 |
| Treatment B: OZ439 Prototype 2 | PQ Cmax | 89.5 ng/mL | Geometric Coefficient of Variation 54.1 |
| Treatment C: OZ439 Prototype 3 | PQ Cmax | 91.2 ng/mL | Geometric Coefficient of Variation 130.8 |