Healthy Volunteers, Malaria Falciparum, Malaria Vivax
Conditions
Keywords
Phase I, Safety and tolerability, Pharmacokinetic, synthetic peroxide, trioxolane, treatment of erythrocytic stages of malaria
Brief summary
OZ439 is a synthetic trioxolane that has potential value as a peroxide antimalarial agent. This was a Phase I, single-centre, multi-component, double-blind, randomised, placebo-controlled study in healthy male and female subjects. The study was conducted in 3 parts: * Part A investigated the safety, tolerability and pharmacokinetics (PK) of single oral escalating doses of OZ439. Up to 6 dose levels will be investigated to estimate dose proportionality. * Part B, the effect of food on a single oral dose of OZ439 was investigated in a 2-way crossover design. * Part C investigated the safety, tolerability and PK profile of multiple oral doses of OZ439. The starting oral dose was 50 mg and the maximum single dose to be administered did not exceed 1600 mg per subject. The maximum duration of dosing proposed was 3 days.
Interventions
DRUGOZ439 200mg aqueous dispersion
DRUGOZ439 50mg API capsules
DRUGOZ439 200mg API capsules
DRUGOZ439 400mg aqueous dispersion
DRUGOZ439 800mg aqueous dispersion
DRUGOZ439 100mg API capsules
OZ439 100mg (2x50mg API capsules)
DRUGOZ439 400mg API capsules
OZ439 400mg (2x200mg API capsules)
DRUGOZ439 1600mg aqueous dispersion
DRUGOZ439 800mg API capsules
OZ439 800mg (4x200 API capsules)
DRUGOZ439 1200mg API capsules
OZ439 1200mg (6x200mg API capsules)
DRUGPlacebo
Sponsors
Medicines for Malaria Venture
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male//female subjects between 18- 55 years of age (inclusive). 2. Body mass Index (BMI) between 18 - 30 kg/m2, inclusive; and a total body weight \>60 kg (132 lbs). 3. Healthy as determined by pre-study medical history, PE, 12 Lead ECG. 4. Females of childbearing potential must use 1 of birth control methods throughout study and for 30 days after last dose of study drug: 1. Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) 6 months minimum prior to first dose of study drug. 2. Intrauterine device (IUD) in place for at least 3 months prior to first dose of study drug. 3. Barrier methods (condom or diaphragm) with spermicide starting at least 14 days prior to first dose of study drug through 30 days after last dose of study drug. 4. Surgical sterilization of the partner(s) (vasectomy with zero sperm count for 6 months minimum prior to the first dose of study drug). 5. Hormonal contraceptives starting at least 3 months prior to first dose of study drug. In addition, subjects must agree to use a barrier method (condom or diaphragm) with spermicide at least 14 days prior to first dose of study drug through 30 days after the last dose of study drug. 5. Post-menopausal women with amenorrhea for at least 1 year will be eligible confirmed by FSH. 6. Male subjects must agree to use double barrier method of contraception, from time of first dose of study drug through 90 days after last dose of study drug and must also agree to not donate sperm for 90 days after last dose of study drug. Clinical laboratory tests within the reference ranges. 7. Able/willing to give written informed consent. 8. Willing/to adhere to lifestyle guideline restrictions outlined in protocol. 9. Willing and able to be confined to Clinical Research Unit as required by the protocol.
Exclusion criteria
1. Evidence/history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, current infection. 2. Evidence/history of clinically significant gastrointestinal (some exclusions exist) disease, current infection. 3. Any condition that affecting drug absorption, e.g., gastrectomy. 4. History of post-antibiotic colitis. 5. Breast feeding. 6. QTc greater than 450 msec for males and 470 msec for females as corrected by the Bazett formula. 7. History of drug or alcohol abuse within the past 2 years prior to Screening. 8. Tobacco users 9. Received investigational drug/ participated in another research study within 30 days of first dose of study drug in any part of study. 10. Use of prescription drugs within 14 days prior to the first dose of study drug in Period 1, or need for any antibiotic during study. 11. Received any non prescription meds, vitamins, herbal/dietary supplements within 7 days of administration of first dose of study drug in Period 1 (exceptions exist) 12. Consumed alcohol within 72 hours of Day -1 in any part of study, or have a positive alcohol screen at screening or each admission to Clinical Research Unit (CRU). 13. Consumed grapefruit juice or juices containing grapefruit or ate grapefruit within 7 days prior to first dose of study drug in any part of study. 14. Positive serum pregnancy test at the Screening Visit or on Day -1 prior to inclusion in any part of the study. 15. Positive test for HIV-1, HBsAg,HCV. 16. Positive urine drug screen at Screening or admission to CRU. 17. History of intolerance/ hypersensitivity to artemisinins. 18. Likelihood of requiring treatment during study period with drugs not permitted by protocol. 19. Subjects who have donated blood or experienced significant blood loss within 60 days of screening for study. 20. Subjects whose hemoglobin is \<12.5 g/dL for males/ \<11.5 g/dL for females. 21. Any concern by investigator regarding safe participation of the subject in study or for any other reason investigator considers subject inappropriate for participation in study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | From screening and at 10 (+/-2) days after last dose of study medication | Safety/Tolerability evaluation took into account the recorded AE profile, clinical laboratory safety tests, vital signs, 12 lead and continuous (Parts A and C) ECG monitoring, audiometry/Brainstem Auditory Evoked Potentials (BAEP) parameters (Parts A and C) including any additional tests required to evaluate any safety concerns. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OZ439 AUC0-∝ | Samples collected from Pre-dose up to 96h post dose | Area under the plasma concentration-time curve from zero to infinity (AUC0-∝). |
| OZ439 Cmax | Samples collected from Pre-dose up to 96h post dose | Maximum observed plasma drug concentration (Cmax). |
| OZ439 AUC0-t | Samples collected from Pre-dose up to 96h post dose | Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification (AUC0-t). |
| OZ439 t1/2 | Samples collected from Pre-dose up to 96h post dose | Apparent terminal half-life (t1/2) |
| OZ439 Rac | Samples collected from Pre-dose up to 96h post dose | Accumulation index is the ratio of drug exposure observed during a dosing interval at steady-state divided by drug exposure after a single first dose, as described by the following equations: Accumulation index (Rac) = AUC0-(Day 3)/ AUC0-(Day 1) |
| OZ439 Tmax | Samples collected from Pre-dose up to 96h post dose | Time to maximum observed plasma drug concentration of OZ439 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A - OZ439 Single Rising Dose Included 3 Cohorts, where subjects in cohorts 1 and 2 were randomized to a treatment sequence, receiving doses of OZ439 on four occasions and placebo on one occasion, and subjects in Cohort 3 were administered increasing doses of the oral dispersion. | 26 |
| Part B - OZ439 Food Effect Subjects were randomized to sequence groups, fasted/fed or fed/fasted while receiving a single dose of 800 mg OZ439. | 13 |
| Part C - OZ439 Multiple Rising Dose Subjects were assigned to individual dose cohorts (200, 400 and 800 mg OZ439) and placebo. | 24 |
| Total | 63 |
Baseline characteristics
| Characteristic | Part A - OZ439 Single Rising Dose | Part B - OZ439 Food Effect | Part C - OZ439 Multiple Rising Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 10.35 | 33.7 years STANDARD_DEVIATION 8.49 | 40.1 years STANDARD_DEVIATION 10.17 | 36.5 years STANDARD_DEVIATION 9.67 |
| Region of Enrollment United States | 26 participants | 13 participants | 24 participants | 63 participants |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Male | 21 Participants | 4 Participants | 15 Participants | 40 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 0 / 8 | 2 / 8 | 0 / 7 | 0 / 6 | 1 / 5 | 2 / 8 | 1 / 6 | 1 / 6 | 5 / 6 | 4 / 17 | 3 / 12 | 4 / 12 | 3 / 6 | 1 / 6 | 4 / 6 | 0 / 6 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 7 | 0 / 6 | 0 / 5 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 1 / 17 | 0 / 12 | 0 / 12 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Adverse Events
Safety/Tolerability evaluation took into account the recorded AE profile, clinical laboratory safety tests, vital signs, 12 lead and continuous (Parts A and C) ECG monitoring, audiometry/Brainstem Auditory Evoked Potentials (BAEP) parameters (Parts A and C) including any additional tests required to evaluate any safety concerns.
Time frame: From screening and at 10 (+/-2) days after last dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A - 50 mg Single Dose | Adverse Events | 1 participants |
| Part A - 100mg Single Dose | Adverse Events | 0 participants |
| Part A - 200mg Single Dose | Adverse Events | 2 participants |
| Part A - 400mg Single Dose | Adverse Events | 0 participants |
| Part A - 400mg Single Dose + Food | Adverse Events | 0 participants |
| Part A - 400mg AD Single Dose | Adverse Events | 1 participants |
| Part A - 800mg Single Dose | Adverse Events | 2 participants |
| Part A - 800mg AD Single Dose | Adverse Events | 1 participants |
| Part A - 1200mg Single Dose | Adverse Events | 1 participants |
| Part A - 1600mg AD Single Dose | Adverse Events | 5 participants |
| Part A - Placebo | Adverse Events | 4 participants |
| Part B - 800mg AD Single Dose Fed | Adverse Events | 3 participants |
| Part B - 800mg AD Single Dose Fast | Adverse Events | 4 participants |
| Part C - 200mg AD Multiple Dose | Adverse Events | 3 participants |
| Part C - 400mg AD Multiple Dose | Adverse Events | 1 participants |
| Part C - 800mg AD Multiple Dose | Adverse Events | 4 participants |
| Part C - Placebo | Adverse Events | 0 participants |
Secondary
OZ439 AUC0-∝
Area under the plasma concentration-time curve from zero to infinity (AUC0-∝).
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - 50 mg Single Dose | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part A - 100mg Single Dose | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part A - 200mg Single Dose | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part A - 400mg Single Dose | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part A - 400mg Single Dose + Food | OZ439 AUC0-∝ | 5540 ng.h/ml | Geometric Coefficient of Variation 71.3 |
| Part A - 400mg AD Single Dose | OZ439 AUC0-∝ | 4690 ng.h/ml | Geometric Coefficient of Variation 43.5 |
| Part A - 800mg Single Dose | OZ439 AUC0-∝ | 9790 ng.h/ml | Geometric Coefficient of Variation 56.7 |
| Part A - 800mg AD Single Dose | OZ439 AUC0-∝ | 9130 ng.h/ml | Geometric Coefficient of Variation 136.8 |
| Part A - 1200mg Single Dose | OZ439 AUC0-∝ | 18400 ng.h/ml | Geometric Coefficient of Variation 68 |
| Part A - 1600mg AD Single Dose | OZ439 AUC0-∝ | 23900 ng.h/ml | Geometric Coefficient of Variation 49 |
| Part A - Placebo | OZ439 AUC0-∝ | 8080 ng.h/ml | Geometric Coefficient of Variation 68.7 |
| Part B - 800mg AD Single Dose Fed | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part B - 800mg AD Single Dose Fast | OZ439 AUC0-∝ | NA ng.h/ml | — |
| Part C - 200mg AD Multiple Dose | OZ439 AUC0-∝ | NA ng.h/ml | — |
Secondary
OZ439 AUC0-t
Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification (AUC0-t).
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - 50 mg Single Dose | OZ439 AUC0-t | 102 ng.h/ml | Geometric Coefficient of Variation 133.7 |
| Part A - 100mg Single Dose | OZ439 AUC0-t | 249 ng.h/ml | Geometric Coefficient of Variation 145.4 |
| Part A - 200mg Single Dose | OZ439 AUC0-t | 890 ng.h/ml | Geometric Coefficient of Variation 89.1 |
| Part A - 400mg Single Dose | OZ439 AUC0-t | 1130 ng.h/ml | Geometric Coefficient of Variation 186.6 |
| Part A - 400mg Single Dose + Food | OZ439 AUC0-t | 5430 ng.h/ml | Geometric Coefficient of Variation 72 |
| Part A - 400mg AD Single Dose | OZ439 AUC0-t | 3010 ng.h/ml | Geometric Coefficient of Variation 115.7 |
| Part A - 800mg Single Dose | OZ439 AUC0-t | 9630 ng.h/ml | Geometric Coefficient of Variation 56.9 |
| Part A - 800mg AD Single Dose | OZ439 AUC0-t | 6530 ng.h/ml | Geometric Coefficient of Variation 172.4 |
| Part A - 1200mg Single Dose | OZ439 AUC0-t | 17500 ng.h/ml | Geometric Coefficient of Variation 70.1 |
| Part A - 1600mg AD Single Dose | OZ439 AUC0-t | 23100 ng.h/ml | Geometric Coefficient of Variation 48.9 |
| Part A - Placebo | OZ439 AUC0-t | 7590 ng.h/ml | Geometric Coefficient of Variation 64.7 |
| Part B - 800mg AD Single Dose Fed | OZ439 AUC0-t | 3060 ng.h/ml | Geometric Coefficient of Variation 60.1 |
| Part B - 800mg AD Single Dose Fast | OZ439 AUC0-t | 7990 ng.h/ml | Geometric Coefficient of Variation 57.5 |
| Part C - 200mg AD Multiple Dose | OZ439 AUC0-t | 13700 ng.h/ml | Geometric Coefficient of Variation 46 |
Secondary
OZ439 Cmax
Maximum observed plasma drug concentration (Cmax).
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - 50 mg Single Dose | OZ439 Cmax | 17.4 ng/ml | Geometric Coefficient of Variation 84.7 |
| Part A - 100mg Single Dose | OZ439 Cmax | 34.2 ng/ml | Geometric Coefficient of Variation 173.5 |
| Part A - 200mg Single Dose | OZ439 Cmax | 102 ng/ml | Geometric Coefficient of Variation 82.9 |
| Part A - 400mg Single Dose | OZ439 Cmax | 135 ng/ml | Geometric Coefficient of Variation 164.9 |
| Part A - 400mg Single Dose + Food | OZ439 Cmax | 566 ng/ml | Geometric Coefficient of Variation 53.9 |
| Part A - 400mg AD Single Dose | OZ439 Cmax | 315 ng/ml | Geometric Coefficient of Variation 121.8 |
| Part A - 800mg Single Dose | OZ439 Cmax | 917 ng/ml | Geometric Coefficient of Variation 35.6 |
| Part A - 800mg AD Single Dose | OZ439 Cmax | 701 ng/ml | Geometric Coefficient of Variation 154.7 |
| Part A - 1200mg Single Dose | OZ439 Cmax | 1340 ng/ml | Geometric Coefficient of Variation 44.5 |
| Part A - 1600mg AD Single Dose | OZ439 Cmax | 2220 ng/ml | Geometric Coefficient of Variation 52.6 |
| Part A - Placebo | OZ439 Cmax | 730 ng/ml | Geometric Coefficient of Variation 61.1 |
| Part B - 800mg AD Single Dose Fed | OZ439 Cmax | 342 ng/ml | Geometric Coefficient of Variation 52.5 |
| Part B - 800mg AD Single Dose Fast | OZ439 Cmax | 764 ng/ml | Geometric Coefficient of Variation 46.6 |
| Part C - 200mg AD Multiple Dose | OZ439 Cmax | 1390 ng/ml | Geometric Coefficient of Variation 51.7 |
Secondary
OZ439 Rac
Accumulation index is the ratio of drug exposure observed during a dosing interval at steady-state divided by drug exposure after a single first dose, as described by the following equations: Accumulation index (Rac) = AUC0-(Day 3)/ AUC0-(Day 1)
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population received multiple dosing only. This PK parameter is not applicable in a single dose setting.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - 50 mg Single Dose | OZ439 Rac | 1.16 ratio | Geometric Coefficient of Variation 18.7 |
| Part A - 100mg Single Dose | OZ439 Rac | 1.76 ratio | Geometric Coefficient of Variation 29.9 |
| Part A - 200mg Single Dose | OZ439 Rac | 1.43 ratio | Geometric Coefficient of Variation 26 |
Secondary
OZ439 t1/2
Apparent terminal half-life (t1/2)
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - 50 mg Single Dose | OZ439 t1/2 | NA hours | — |
| Part A - 100mg Single Dose | OZ439 t1/2 | NA hours | — |
| Part A - 200mg Single Dose | OZ439 t1/2 | NA hours | — |
| Part A - 400mg Single Dose | OZ439 t1/2 | NA hours | — |
| Part A - 400mg Single Dose + Food | OZ439 t1/2 | 31.2 hours | Geometric Coefficient of Variation 33.5 |
| Part A - 400mg AD Single Dose | OZ439 t1/2 | 27.9 hours | Geometric Coefficient of Variation 24.1 |
| Part A - 800mg Single Dose | OZ439 t1/2 | 25.2 hours | Geometric Coefficient of Variation 25.8 |
| Part A - 800mg AD Single Dose | OZ439 t1/2 | 31.6 hours | Geometric Coefficient of Variation 46.9 |
| Part A - 1200mg Single Dose | OZ439 t1/2 | 30.7 hours | Geometric Coefficient of Variation 41.9 |
| Part A - 1600mg AD Single Dose | OZ439 t1/2 | 31.7 hours | Geometric Coefficient of Variation 30.1 |
| Part A - Placebo | OZ439 t1/2 | 38.8 hours | Geometric Coefficient of Variation 50.2 |
| Part B - 800mg AD Single Dose Fed | OZ439 t1/2 | 41.7 hours | Geometric Coefficient of Variation 18.2 |
| Part B - 800mg AD Single Dose Fast | OZ439 t1/2 | 40.8 hours | Geometric Coefficient of Variation 31.4 |
| Part C - 200mg AD Multiple Dose | OZ439 t1/2 | 37.8 hours | Geometric Coefficient of Variation 28.6 |
Secondary
OZ439 Tmax
Time to maximum observed plasma drug concentration of OZ439
Time frame: Samples collected from Pre-dose up to 96h post dose
Population: Pharmacokinetics Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A - 50 mg Single Dose | OZ439 Tmax | 3 hours |
| Part A - 100mg Single Dose | OZ439 Tmax | 5 hours |
| Part A - 200mg Single Dose | OZ439 Tmax | 3.5 hours |
| Part A - 400mg Single Dose | OZ439 Tmax | 3 hours |
| Part A - 400mg Single Dose + Food | OZ439 Tmax | 3 hours |
| Part A - 400mg AD Single Dose | OZ439 Tmax | 3 hours |
| Part A - 800mg Single Dose | OZ439 Tmax | 3 hours |
| Part A - 800mg AD Single Dose | OZ439 Tmax | 3 hours |
| Part A - 1200mg Single Dose | OZ439 Tmax | 5 hours |
| Part A - 1600mg AD Single Dose | OZ439 Tmax | 5 hours |
| Part A - Placebo | OZ439 Tmax | 3 hours |
| Part B - 800mg AD Single Dose Fed | OZ439 Tmax | 3 hours |
| Part B - 800mg AD Single Dose Fast | OZ439 Tmax | 3 hours |
| Part C - 200mg AD Multiple Dose | OZ439 Tmax | 3 hours |