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

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

This is a single-centre, 2-part, randomised, single-dose parallel group study in healthy male subjects and female subjects of non-childbearing potential.

Study Overview

• Status: Completed
• Conditions: Malaria
• Intervention / Treatment: Drug: OZ439 + TPGS; Drug: PQP; Drug: OZ439 Prototype 1; Drug: OZ439 Prototype 3

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

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG11 6JS
      • Quotient Clinical

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: OZ439 + TPGS; Other Names: 800 mg OZ439 + TPGS Reference Treatment; Drug: PQP; Other Names: PQP 960 mg tablets
Experimental: 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	Drug: PQP; Other Names: PQP 960 mg tablets; Drug: OZ439 Prototype 1; Other Names: OZ439 Granules Prototype 1 Granules Formulation
Experimental: 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	Drug: PQP; Other Names: PQP 960 mg tablets; Drug: OZ439 Prototype 3; Other Names: OZ439 Granules Prototype 3 Granules Formulation
Active Comparator: 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	Drug: OZ439 + TPGS; Other Names: 800 mg OZ439 + TPGS Reference Treatment; Drug: PQP; Other Names: PQP 960 mg tablets
Experimental: Regimen E: OZ439 Prototype 1 or 3 and PQP - XmL; 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: PQP; Other Names: PQP 960 mg tablets; Drug: OZ439 Prototype 1; Other Names: OZ439 Granules Prototype 1 Granules Formulation
Experimental: Regimen F: OZ439 Prototype 1 or 3 and PQP - XmL; 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: PQP; Other Names: PQP 960 mg tablets; Drug: OZ439 Prototype 3; Other Names: OZ439 Granules Prototype 3 Granules Formulation

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

Collaborators and Investigators

• Sponsor: Medicines for Malaria Venture
• Collaborators: Quotient Clinical
• Investigators: Study Director: Fiona Macintyre, PhD, Medicines for Malaria Ventire

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: March 5, 2015
• First Submitted That Met QC Criteria: March 12, 2015
• First Posted (Estimate): March 13, 2015

Study Record Updates

• Last Update Posted (Estimate): February 8, 2016
• Last Update Submitted That Met QC Criteria: January 13, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Malaria; Bioavailability; Formulation
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Artefenomel
• Other Study ID Numbers: MMV_OZ439_15_001