Malaria
Conditions
Keywords
Malaria, Bioavailability, Formulation
Brief summary
This is a single-centre, 2-part, randomised, single-dose parallel group study in healthy male subjects and female subjects of non-childbearing potential.
Detailed description
Parts 1 and 2 will be randomised with 8 subjects receiving each regimen: Part 1: * Regimen A: Reference: 800 mg OZ439 + α-Tocopherol polyethylene glycol 1000 succinate (TPGS) granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets * Regimen B: Prototype 1: 800 mg OZ439 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets * Regimen C: Prototype 3: 800 mg OZ439 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets There will be an interim decision after Part 1 to determine the formulation prototypes and the oral suspension volume to be administered in Part 2. Part 2 * Regimen D: Reference: 800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets * Regimen E: Prototype 1 or 3: 800 mg OZ439 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets * Regimen F: Prototype 1 or 3: 800 mg OZ439 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets
Interventions
DRUGOZ439 + TPGS
DRUGOZ439 Prototype 1
DRUGOZ439 Prototype 3
DRUGPQP
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
* Healthy males, or healthy females of non-childbearing potential ie surgically sterilised or post-menopausal * Body mass index of 18.0 to 30.0 kg/m2 inclusive. Total body weight \>50 kg at screening. * Must agree to use an adequate method of contraception. * Normal laboratory tests as judged by the Investigator. * Must have QTcF ≤450 ms, QTcB ≤450 ms for male subjects, QTcF ≤470 ms, QTcB ≤470 ms for female subjects and PR interval ≤200 ms for screening and pre-dose ECG measurements.
Exclusion criteria
* Male subjects who have currently pregnant partners or who have partners planning to be pregnant. * Evidence or history of clinically significant disease, or current infection.3. * Clinically relevant abnormalities in the ECG. * 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. * History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia, heart rate ≤39 bpm. * Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. * History of any drug or alcohol abuse in the past 2 years prior to screening. * Receipt of an investigational drug or participation in another clinical research study within 90 days prior to drug administration. * 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. * Positive hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus results. * Clinically significant abnormal biochemistry, haematology or urinalysis. * Positive urine drug screen result. * History of intolerance or hypersensitivity to PQP or any 4-aminoquinoline, 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. * Presence or history of allergy requiring treatment; hayfever is allowed unless it is active. * Donation or loss of \>400 mL of blood within 90 days prior to drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 Cmax | Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose | OZ439 Maximum observed concentration |
| OZ439 AUC(0-168 h) | pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose | OZ439 Area under the plasma concentration (AUC) versus time curve |
| Piperaquine Cmax | Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose | Piperaquine Maximum observed concentration |
| Piperaquine AUC(0-168 h) | Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose | PQP Area under the plasma concentration versus time curve |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A: OZ439 + TPGS and PQP 800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL 800 mg OZ439 Prototype 1 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL 800 mg OZ439 Prototype 3 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Regimen D: OZ439 + TPGS and PQP 800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL 800 mg OZ439 Prototype 1 or 3 granules (120 mL oral suspension and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL 800 mg OZ439 Prototype 1 or 3 granules (120 mL oral suspension and 100 mL rinse volume ) and 960 mg (3 × 320 mg) PQP tablets | 8 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Regimen A: OZ439 + TPGS and PQP | Regimen B: OZ439 Prototype 1 and PQP - 110mL | Regimen C: OZ439 Prototype 3 and PQP - 110mL | Regimen D: OZ439 + TPGS and PQP | Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 8.9 | 34.5 years STANDARD_DEVIATION 12.7 | 34.9 years STANDARD_DEVIATION 9.8 | 32.0 years STANDARD_DEVIATION 12.9 | 31.3 years STANDARD_DEVIATION 12.9 | 30.1 years STANDARD_DEVIATION 7 | 32.1 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment United Kingdom | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 48 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 7 Participants | 8 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 4 / 8 | 3 / 8 | 6 / 8 | 5 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 8 | 1 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
OZ439 AUC(0-168 h)
OZ439 Area under the plasma concentration (AUC) versus time curve
Time frame: pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
Population: The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: OZ439 + TPGS and PQP | OZ439 AUC(0-168 h) | 15300 ng*h/mL | Geometric Coefficient of Variation 26.1 |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL | OZ439 AUC(0-168 h) | 7920 ng*h/mL | Geometric Coefficient of Variation 26.4 |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL | OZ439 AUC(0-168 h) | 5610 ng*h/mL | Geometric Coefficient of Variation 38.1 |
| Regimen D: OZ439 + TPGS and PQP | OZ439 AUC(0-168 h) | 14000 ng*h/mL | Geometric Coefficient of Variation 29.6 |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | OZ439 AUC(0-168 h) | 9550 ng*h/mL | Geometric Coefficient of Variation 57.5 |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | OZ439 AUC(0-168 h) | 7100 ng*h/mL | Geometric Coefficient of Variation 45.7 |
Primary
OZ439 Cmax
OZ439 Maximum observed concentration
Time frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose
Population: The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: OZ439 + TPGS and PQP | OZ439 Cmax | 1600 ng/mL | Geometric Coefficient of Variation 36.6 |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL | OZ439 Cmax | 824 ng/mL | Geometric Coefficient of Variation 38.3 |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL | OZ439 Cmax | 616 ng/mL | Geometric Coefficient of Variation 49.4 |
| Regimen D: OZ439 + TPGS and PQP | OZ439 Cmax | 1530 ng/mL | Geometric Coefficient of Variation 13.2 |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | OZ439 Cmax | 999 ng/mL | Geometric Coefficient of Variation 40.8 |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | OZ439 Cmax | 730 ng/mL | Geometric Coefficient of Variation 35.7 |
Primary
Piperaquine AUC(0-168 h)
PQP Area under the plasma concentration versus time curve
Time frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
Population: The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: OZ439 + TPGS and PQP | Piperaquine AUC(0-168 h) | 3740 ng*h/mL | Geometric Coefficient of Variation 61.2 |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL | Piperaquine AUC(0-168 h) | 1940 ng*h/mL | Geometric Coefficient of Variation 69.5 |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL | Piperaquine AUC(0-168 h) | 2980 ng*h/mL | Geometric Coefficient of Variation 47.6 |
| Regimen D: OZ439 + TPGS and PQP | Piperaquine AUC(0-168 h) | 2860 ng*h/mL | Geometric Coefficient of Variation 40.2 |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | Piperaquine AUC(0-168 h) | 2550 ng*h/mL | Geometric Coefficient of Variation 47.8 |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | Piperaquine AUC(0-168 h) | 2470 ng*h/mL | Geometric Coefficient of Variation 60.8 |
Primary
Piperaquine Cmax
Piperaquine Maximum observed concentration
Time frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours and Day36 post-dose
Population: The PK population was to include all valid profiles from subjects dosed with IMP. 45 subjects were included in the PK population. 3 subjects vomited approximately 1 to 2 h after dosing and were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: OZ439 + TPGS and PQP | Piperaquine Cmax | 183 ng/mL | Geometric Coefficient of Variation 124.9 |
| Regimen B: OZ439 Prototype 1 and PQP - 110mL | Piperaquine Cmax | 62.1 ng/mL | Geometric Coefficient of Variation 154.4 |
| Regimen C: OZ439 Prototype 3 and PQP - 110mL | Piperaquine Cmax | 100 ng/mL | Geometric Coefficient of Variation 80.7 |
| Regimen D: OZ439 + TPGS and PQP | Piperaquine Cmax | 119 ng/mL | Geometric Coefficient of Variation 52.1 |
| Regimen E: OZ439 Prototype 1 or 3 and PQP - 220mL | Piperaquine Cmax | 91.8 ng/mL | Geometric Coefficient of Variation 108.2 |
| Regimen F: OZ439 Prototype 1 or 3 and PQP - 220mL | Piperaquine Cmax | 95.7 ng/mL | Geometric Coefficient of Variation 81.5 |