A Study to Investigate the Safety, Tolerability and Pharmacokinetics of OZ439 in Healthy Male and Female Subjects

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Study To Investigate The Safety, Tolerability And Pharmacokinetic Profile Of OZ439 In Healthy Male and Female Subjects

Conditions
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Malaria Falciparum, Malaria Vivax, Healthy Volunteers

Intervention / Treatment
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* Drug: OZ439 50mg API capsules
* Drug: OZ439 200mg API capsules
* Drug: OZ439 400mg aqueous dispersion
* Drug: OZ439 800mg aqueous dispersion
* Drug: OZ439 100mg API capsules
* Drug: OZ439 400mg API capsules
* Drug: OZ439 1600mg aqueous dispersion
* Drug: OZ439 800mg API capsules
* Drug: OZ439 1200mg API capsules
* Drug: Placebo
* Drug: OZ439 200mg aqueous dispersion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male//female subjects between 18- 55 years of age (inclusive). Body mass Index (BMI) between 18 - 30 kg/m2, inclusive; and a total body weight >60 kg (132 lbs). Healthy as determined by pre-study medical history, PE, 12 Lead ECG. Females of childbearing potential must use 1 of birth control methods throughout study and for 30 days after last dose of study drug: Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) 6 months minimum prior to first dose of study drug. Intrauterine device (IUD) in place for at least 3 months prior to first dose of study drug. 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. Surgical sterilization of the partner(s) (vasectomy with zero sperm count for 6 months minimum prior to the first dose of study drug). 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. Post-menopausal women with amenorrhea for at least 1 year will be eligible confirmed by FSH. 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. Able/willing to give written informed consent. Willing/to adhere to lifestyle guideline restrictions outlined in protocol. Willing and able to be confined to Clinical Research Unit as required by the protocol. Exclusion Criteria: Evidence/history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, current infection. Evidence/history of clinically significant gastrointestinal (some exclusions exist) disease, current infection. Any condition that affecting drug absorption, e.g., gastrectomy. History of post-antibiotic colitis. Breast feeding. QTc greater than 450 msec for males and 470 msec for females as corrected by the Bazett formula. History of drug or alcohol abuse within the past 2 years prior to Screening. Tobacco users Received investigational drug/ participated in another research study within 30 days of first dose of study drug in any part of study. 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. 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) 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). 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. Positive serum pregnancy test at the Screening Visit or on Day -1 prior to inclusion in any part of the study. Positive test for HIV-1, HBsAg,HCV. Positive urine drug screen at Screening or admission to CRU. History of intolerance/ hypersensitivity to artemisinins. Likelihood of requiring treatment during study period with drugs not permitted by protocol. Subjects who have donated blood or experienced significant blood loss within 60 days of screening for study. Subjects whose hemoglobin is <12.5 g/dL for males/ <11.5 g/dL for females. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - 50 mg Single Dose<br>OZ439 Single doses of 50mg (capsules) | Drug: OZ439 50mg API capsules<br> <br> * Other names: OZ439;|
| Experimental: Part A - 100mg Single Dose<br>OZ439 Single doses of 100mg (capsules) | Drug: OZ439 100mg API capsules<br>* OZ439 100mg (2x50mg API capsules)<br>* Other names: OZ439;|
| Experimental: Part A - 200mg Single Dose<br>OZ439 Single doses of 200mg (capsules) | Drug: OZ439 200mg API capsules<br> <br> * Other names: OZ439;|
| Experimental: Part A - 400mg Single Dose<br>OZ439 Single doses of 400mg (capsules) | Drug: OZ439 400mg API capsules<br>* OZ439 400mg (2x200mg API capsules)<br>* Other names: OZ439;|
| Experimental: Part A - 400mg Single Dose + Food<br>OZ439 Single doses of 400mg (capsules) administered with food. | Drug: OZ439 400mg API capsules<br>* OZ439 400mg (2x200mg API capsules)<br>* Other names: OZ439;|
| Experimental: Part A - 400mg AD Single Dose<br>OZ439 Single doses of 400mg (aqueous dispersion) | Drug: OZ439 400mg aqueous dispersion<br> <br> |
| Experimental: Part A - 800mg Single Dose<br>OZ439 Single doses of 800mg (capsules) | Drug: OZ439 800mg API capsules<br>* OZ439 800mg (4x200 API capsules)<br>* Other names: OZ439;|
| Experimental: Part A - 800mg AD Single Dose<br>OZ439 Single doses of 800mg (aqueous dispersion) | Drug: OZ439 800mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Experimental: Part A - 1200mg Single Dose<br>OZ439 Single doses of 1200mg (capsules) | Drug: OZ439 1200mg API capsules<br>* OZ439 1200mg (6x200mg API capsules)<br>* Other names: OZ439;|
| Experimental: Part A - 1600mg AD Single Dose<br>OZ439 Single doses of 800mg (aqueous dispersion) | Drug: OZ439 1600mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Placebo Comparator: Part A - Placebo<br>Placebo control for Single rising Part A | Drug: Placebo<br> <br> |
| Experimental: Part B - 800mg AD Single Dose Fed<br>Single dose of OZ439 800mg aqueous dispersion administered under fed conditions | Drug: OZ439 800mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Experimental: Part B - 800mg AD Single Dose Fast<br>Single dose of OZ439 800mg aqueous dispersion administered under fast conditions | Drug: OZ439 800mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Experimental: Part C - 200mg AD Multiple Dose<br>200mg aqueous solution OZ439 or placebo once daily for 3 days fasted | Drug: OZ439 200mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Experimental: Part C - 400mg AD Multiple Dose<br>400mg aqueous solution OZ439 or placebo once daily for 3 days fasted | Drug: OZ439 400mg aqueous dispersion<br> <br> |
| Experimental: Part C - 800mg AD Multiple Dose<br>800mg aqueous solution OZ439 or placebo once daily for 3 days fasted | Drug: OZ439 800mg aqueous dispersion<br> <br> * Other names: OZ439;|
| Placebo Comparator: Part C - Placebo<br>Placebo control for Multiple rising Part C | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From screening and at 10 (+/-2) days after last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Samples collected from Pre-dose up to 96h post dose | 
| OZ439 AUC0-∝ | Area under the plasma concentration-time curve from zero to infinity (AUC0-∝). | Samples collected from Pre-dose up to 96h post dose | 
| OZ439 Cmax | Maximum observed plasma drug concentration (Cmax). | Samples collected from Pre-dose up to 96h post dose | 
| OZ439 Tmax | Time to maximum observed plasma drug concentration of OZ439 | Samples collected from Pre-dose up to 96h post dose | 
| OZ439 t1/2 | Apparent terminal half-life (t1/2) | Samples collected from Pre-dose up to 96h post dose | 
| 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) | Samples collected from Pre-dose up to 96h post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Safety and tolerability, Pharmacokinetic, synthetic peroxide, trioxolane, treatment of erythrocytic stages of malaria