Bioavailability Study of Oral OZ439 Prototype Granule Formulations Administered With Piperaquine Phosphate (PQP) Tablets

Study Overview
=================
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

Official Title
-----------------
A Phase I Bioavailability Study of Selected Oral Prototype Granule Formulations of OZ439 in Healthy Subjects, to Evaluate the Pharmacokinetics of OZ439 When Co-Administered With Piperaquine Phosphate Tablets in the Fasted State

Conditions
-----------------
Malaria

Intervention / Treatment
-----------------
* Drug: OZ439 + TPGS
* Drug: OZ439 Prototype 1
* Drug: OZ439 Prototype 3
* Drug: PQP


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regimen A: OZ439 + TPGS and PQP<br>800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 + TPGS<br> <br> * Other names: 800 mg OZ439 + TPGS Reference Treatment;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|
| Experimental: Regimen B: OZ439 Prototype 1 and PQP - 110mL<br>800 mg OZ439 Prototype 1 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 Prototype 1<br> <br> * Other names: OZ439 Granules Prototype 1 Granules Formulation;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|
| Experimental: Regimen C: OZ439 Prototype 3 and PQP - 110mL<br>800 mg OZ439 Prototype 3 granules (oral suspension 60 mL volume and 50 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 Prototype 3<br> <br> * Other names: OZ439 Granules Prototype 3 Granules Formulation;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|
| Active Comparator: Regimen D: OZ439 + TPGS and PQP<br>800 mg OZ439 + TPGS granules (oral suspension 240 mL volume and 100 mL rinse volume) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 + TPGS<br> <br> * Other names: 800 mg OZ439 + TPGS Reference Treatment;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|
| Experimental: Regimen E: OZ439 Prototype 1 or 3 and PQP - XmL<br>800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 Prototype 1<br> <br> * Other names: OZ439 Granules Prototype 1 Granules Formulation;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|
| Experimental: Regimen F: OZ439 Prototype 1 or 3 and PQP - XmL<br>800 mg OZ439 Prototype 1 or 3 granules (oral suspension and rinse volume to be determined) and 960 mg (3 × 320 mg) PQP tablets | Drug: OZ439 Prototype 3<br> <br> * Other names: OZ439 Granules Prototype 3 Granules Formulation;Drug: PQP<br> <br> * Other names: PQP 960 mg tablets;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OZ439 Cmax | OZ439 Maximum observed concentration | Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose | 
| OZ439 AUC(0-168 h) | OZ439 Area under the plasma concentration (AUC) versus time curve | pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96 and 168 hours post-dose | 
| Piperaquine Cmax | Piperaquine Maximum observed concentration | 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 AUC(0-168 h) | PQP Area under the plasma concentration versus time curve | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Malaria, Bioavailability, Formulation