Study To Investigate The Relative Bioavailability of OZ439 Formulations In Healthy Volunteers

Study Overview
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Brief Summary
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This study is designed to assess prototype formulations compared to the aqueous dispersion of Active Pharmaceutical Ingredient used in Phase I and Phase IIa studies to date. It is hoped that the bioavailability of OZ439 can be enhanced in the fasted state to be close to that observed when given after food. This will improve the utility of OZ439 in the field as well as decreasing the cost of treatment (by decreasing the dose of OZ439 required) which is very important for an antimalarial drug product destined for use in developing counties.

Detailed Description
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This study was a single centre, open-label, pharmacokinetic, randomized cross-over study in healthy male volunteers and post-menopausal women. This study was conducted over three different cohorts as follows: Cohort 1: Subjects received a single 800 mg (as free base) dose of five different treatment regimes (treatments A, B, C, D and E) on five occasions. Cohort 2: Subjects received a single 800 mg (as free base) dose of four different treatment regimes (treatments F, G, H and I) on four occasions. Cohort 3: Subjects received a single dose, 800mg (as free base) of prototype solution formulation 1 (treatment J) and 400mg (as free base) of prototype solution formulation 1 (treatment K) on two occasions. The treatments were administered under the fasted state.

Official Title
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A Phase I Study To Investigate The Relative Bioavailability of OZ439 Formulations In Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension
* Drug: OZ439 mesylate 400mg Prototype Solution Formula 1
* Drug: OZ439 mesylate 800mg Prototype Solution Formula 1
* Drug: OZ439 mesylate 800mg Prototype Solution Formula 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female volunteers between 18 and 55 years (inclusive). Post-menopausal women with amenorrhoea for at least 2 years are eligible confirmed by FSH level >/ = 25microlU/ml Body mass Index between 18 and 30 kg/m2, inclusive; and body weight > 50 kg. Healthy as determined by pre-study medical history, physical examination (including body temperature), 12 Lead ECG. Male volunteers must agree to use a double barrier method of contraception including abstinence, condom plus diaphragm or condom plus IUD or condom plus stable oral/transdermal/injectable hormonal contraceptive by female partner for at least 14 days prior to the time of the first dose of study drug through 90 days after the last dose of study drug and must also agree to not donate sperm for 90 days after the last dose of study drug. Vasectomy with zero sperm count for 6 months minimum prior to the first dose of study drug is an acceptable form of contraception Clinical laboratory tests at screening within the reference ranges or if outside the normal range not clinically significant. ALT, AST and total bilirubin must be within the normal range Able and willing to give written informed consent Willing and able to adhere to the lifestyle guideline requirements Willing and able to be confined to the Clinical Research Unit as required by the protocol Exclusion Criteria: Evidence of or history of clinically significant oncologic, pulmonary, hepatic, cardiovascular, hematologic, metabolic, neurological, immunologic, nephrologic, endocrine, psychiatric disease, or current infection Evidence of or history of clinically significant gastrointestinal (excluding appendectomy and cholecystectomy) disease or current infection. Any condition that could possibly affect drug absorption, e.g. gastrectomy, diarrhea History of post-antibiotic colitis Pregnancy or breastfeeding QTc greater than 450 msec for males and females as corrected by the Fredricia's formula or evidence or history of abnormal cardiac rhythm History of drug or alcohol abuse within the past 2 years prior to Screening Tobacco users (includes stopping smoking less than 90 days prior to screening. Tobacco use includes smoking and the use of snuff and chewing tobacco, and other nicotine containing products Received an investigational drug or participated in another research study within 30 days of the first dose of study drug in any part of the 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 the study Received any non prescription medications, vitamins, herbal supplements or dietary supplements within 7 days of the first dose of study drug in Period 1, unless prior approval is granted. Excluded from this list is intermittent use of acetaminophen at doses of up to 2 g/day Consumed alcohol within 72 hours of Day -1 in any part of the study, or have a positive alcohol screen at screening or each admission Consumed fruit juice or ate grapefruit within 7 days prior to the first dose of study drug in any part of the study Positive test for human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus Positive urine drug screen at Screening or admission History of intolerance or hypersensitivity to artemisinins Likelihood of requiring treatment during the study period with drugs not permitted by the study protocol Volunteers who have donated blood or experienced significant blood loss within 90 days of screening Hemoglobin < 13.5 g/dL for males and < 12.5 g/dL for females Any concern by the investigator regarding the safe participation of the volunteer or any reason the investigator considers the volunteer inappropriate for participation

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1 - Treatment A: OZ439 800mg PIB, fed<br>OZ439 800 mg (as free base) as powder in a bottle (PIB)for reconstitution in a suspension prior to administration. Administered 30 minutes after a standard fatty breakfast. | Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension<br>* OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration<br>* Other names: OZ439 PIB;|
| Experimental: Cohort 1 - Treatment D: OZ439 800 mg Prototype F1 fasted<br>OZ439 800 mg (as free base) as a prototype solution formulation 1. Administered fasted. | Drug: OZ439 mesylate 800mg Prototype Solution Formula 1<br>* OZ439 800 mg (as free base) as a prototype solution formulation 1<br>* Other names: OZ439 800mg Prototype 1;|
| Experimental: Cohort 2 - Treatement H: OZ439 800 mg Prototype F2 fasted<br>OZ439 800 mg (as free base) as a prototype solution formulation 2. Administered fasted. | Drug: OZ439 mesylate 800mg Prototype Solution Formula 2<br>* OZ439 800 mg (as free base) as a prototype solution formulation 2<br>* Other names: OZ439 800mg Prototype 2;|
| Experimental: Cohort 3 - Treatement K: OZ439 400mg Prototype F1 fasted<br>Best Prototype Solution - OZ439 400 mg as prototype solution formulation 1. Administered fasted. | Drug: OZ439 mesylate 400mg Prototype Solution Formula 1<br>* OZ439 400 mg (as free base) as a prototype solution formulation 1<br>* Other names: OZ439 400mg Prototype 1;|
| Experimental: Cohort 1 - Treatement B: OZ439 800mg PIB fasted<br>OZ439 800 mg (as free base) as powder in a bottle (PIB) for reconstitution in a suspension prior to oral administration. Administered fasted. | Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension<br>* OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration<br>* Other names: OZ439 PIB;|
| Experimental: Cohort 1 - Treatment C:OZ439 800mg PIB with milk<br>OZ439 800 mg (as free base) as powder in a bottle (PIB) for reconstitution in a suspension prior to oral administration. Administered following 200 mL milk. | Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension<br>* OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration<br>* Other names: OZ439 PIB;|
| Experimental: Cohort 3 - Treatment J: OZ439 800mg Prototype F1 fasted<br>Best Prototype Solution - OZ439 800 mg (as free base) as prototype solution formulation 1. Administered fasted. | Drug: OZ439 mesylate 800mg Prototype Solution Formula 1<br>* OZ439 800 mg (as free base) as a prototype solution formulation 1<br>* Other names: OZ439 800mg Prototype 1;|
| Experimental: Cohort 1 - Treatement E: OZ439 800mg Prototype F1 with milk<br>OZ439 800 mg (as free base) as a prototype solution formulation 1. Administered with milk. | Drug: OZ439 mesylate 800mg Prototype Solution Formula 1<br>* OZ439 800 mg (as free base) as a prototype solution formulation 1<br>* Other names: OZ439 800mg Prototype 1;|
| Experimental: Cohort 2 - Treatement F: OZ439 800 mg PIB fasted<br>OZ439 800 mg (as free base) as powder in a bottle (PIB) for reconstitution in a suspension prior to oral administration. Administered fasted. | Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension<br>* OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration<br>* Other names: OZ439 PIB;|
| Experimental: Cohort 2 - Treatement G: OZ439 800mg PIB with milk<br>OZ439 800 mg (as free base) as powder in a bottle (PIB) for reconstitution in a suspension prior to oral administration. Administered following 200 mL milk. | Drug: OZ439 mesylate 800mg Powder in Bottle for Oral Suspension<br>* OZ439 800 mg (as free base) as powder in a bottle for reconstitution in a suspension prior to oral administration<br>* Other names: OZ439 PIB;|
| Experimental: Cohort 2 - Treatement I: OZ349 800mg Prototype F2 with milk<br>OZ439 800 mg (as free base) as a prototype solution formulation 2. Administered with milk. | Drug: OZ439 mesylate 800mg Prototype Solution Formula 2<br>* OZ439 800 mg (as free base) as a prototype solution formulation 2<br>* Other names: OZ439 800mg Prototype 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Cmax | The maximum observed plasma drug concentrations (Cmax) | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | 
| OZ439 AUC0-∞ | Area under the plasma concentration-time curve from zero to infinity (AUC0-∞) | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | 
| OZ439 t1/2 | Apparent terminal half life (t1/2) | 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 168 hours post dosing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OZ439, Bioavailability, Food Effect