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Trial registered on ANZCTR


Registration number
ACTRN12620000812998
Ethics application status
Approved
Date submitted
23/06/2020
Date registered
13/08/2020
Date last updated
13/08/2020
Date data sharing statement initially provided
13/08/2020
Date results information initially provided
13/08/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Comparative assessment of the absorption of a generic formulation of 5/2.5 mg s 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet against the innovator 5/2.5 mg s 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet administered 12 hours apart conducted under fasting conditions and at steady state in healthy volunteers.
Scientific title
A multiple dose, randomized, open-label, pharmacokinetic study of a generic formulation of 5/2.5 mg s 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet in a 2 way crossover comparison against the innovator 5/2.5 mg s 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet administered 12 hours apart conducted under fasting conditions and at steady state in healthy volunteers.
Secondary ID [1] 301021 0
None
Universal Trial Number (UTN)
U1111-1235-0907
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
5/2.5 mg s 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone belongs to a class of medicines called opioid analgesics and is prescribed for the relief of severe pain. 317063 0
Condition category
Condition code
Anaesthesiology 315228 315228 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Multiple dose, crossover study design whereby each participant receives the test formulation of 5/2.5 mg 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet on two occasions 12-hours apart, for 2.5 days and the innovator formulation of 5/2.5 mg 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet 12-hours apart, for 2.5 days on two occasions with each dosing period separated by a 14 day washout period. The intervention for this trial is the test tablet formulation.

On study days 1-3 subjects will receive 5 doses 12 hours apart of one formulation (either the test or innovator) and on study days 15-17 they will receive 5 doses 12 hours apart of the other formulation (either the innovator or test). Subjects will be instructed to swallow the medication whole and delegated staff will examine every subject by performing a mouth/hand check to ensure that the medication has been taken as directed.

No water is allowed for 1 hour prior to each dosing until 1 hour after dosing (except for water consumed with the dose).

Participants are required to fast for at least 4 hours prior to the first four dose administration in each period and at least 8 hours prior to the fifth (last) dose administration in each period.

Participants will be confined at the Zenith Clinical Site from at least 1 hour before dosing on Day 1 until after the 12-hour post-dose blood draw on Day 3 for dosing and observation of adverse events, vital sign & pulse oximetry monitoring and the provision of blood samples.

Bathroom visits will be supervised to ensure no unauthorised water or food intake and for personal safety. Participants will be confined at the Clinical Site for 1 hour prior to dosing to ensure compliance can be monitored until 12 hours after receiving the final dose (61 hours in each study period).

Standard meals will be consumed at the Clinical Site with no additional food intake allowed. Alcohol breath testing and urine DOA testing will be performed upon each participant reporting to the Clinical Site prior to dosing.

Pre and post study laboratory tests will be completed to assess the health of participants along with HIV, Hepatitis and drugs of abuse testing.
Intervention code [1] 317335 0
Treatment: Drugs
Comparator / control treatment
Multiple dose, crossover study design whereby each participant receives 5 doses of the test formulation (1 x 5/2.5 mg) on one occasion and the innovator formulation of 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone (1 x 5/2.5 mg) on one occasion with each dosing period separated by a 14 day washout. The comparator/control for this trial is the innovator tablet formulation.
Control group
Active

Outcomes
Primary outcome [1] 323484 0
To evaluate the pharmacokinetics (as summarised by Cmax(ss), AUC(ss), Ctau(ss) and DF(ss)) of the test formulation relative to that of the reference formulation. All plasma samples will be assayed for 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines.
Timepoint [1] 323484 0
Pre-dose before each dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10 and 12 hours post dosing on day 3 and 17
Secondary outcome [1] 382042 0
Time to maximum peak concentration (Tmax). Tmax will be the time where the maximum concentration occurred in the sample points. All plasma samples will be assayed for 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxne tablet using a fully validated LC/MS/MS method.
Timepoint [1] 382042 0
Pre-dose before each dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10 and 12 hours post dosing on day 3 and 17
Secondary outcome [2] 384750 0
Adverse Events monitored.
Timepoint [2] 384750 0
Each subject will be asked how they feel prior to dosing and at 1, 2, 4, 8 and 12 hours post dosing each morning dose administration and again at 0, 1, 2, 4, and 12 hours post dosing at the evening dose administration on days 1, 2, 15 and 16 and then prior to dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10 and 12 hours post dosing on day 3 and 17
Secondary outcome [3] 384751 0
Vital sign monitoring will comprise temperature, heart rate, respiration rate and blood pressure.
Timepoint [3] 384751 0
Prior to dosing and at 1, 2, 4, 8 and 12 hours post dosing each morning dose administration and again at 0, 1, 2, 4, and 12 hours post dosing at the evening dose administration.
Secondary outcome [4] 384752 0
Pulse oximetry measurements
Timepoint [4] 384752 0
Prior to dosing and at 1, 2, 4 and 8 hours post dosing
Secondary outcome [5] 384753 0
Average steady-state plasma drug concentration (Cav). Cav will be the average concentration at steady state. All plasma samples will be assayed for 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxne tablet using a fully validated LC/MS/MS method.
Timepoint [5] 384753 0
Pre-dose before each dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10 and 12 hours post dosing on day 3 and 17

Eligibility
Key inclusion criteria
Healthy males and non-pregnant females
Aged between 18 and 55 years
Non-smoker
BMI greater than or equal to 18.5 and less than 32 inclusive
Normal, healthy individuals as determined by medical history, physical examination, ECG, blood pressure and laboratory tests
Drug free as determined by urine drug testing
Able to comply with the study restrictions
Able to provide written informed consent
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Clinically significant medical conditions
History of conditions that might interfere with the absorption, distribution, metabolism or excretion of the drug
History of alcohol or drug abuse or dependency
Participation in a drug study within 30 days of the start of the study
Sensitivitie to the study drug or excipients
Individuals for whom the Clinical Investigator believes, for any reason, that participation would not be an acceptable risk

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All formulations will be labeled as Formulation A and B. The identification of each treatment will only be known to the Managing Director and Section Head - Trials and Regulatory Affairs or their delegate.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each participant will be identified by a 3 digit screening number and a 2 digit subject number. The screening number will be issued once the participant has given written consent to participate in the study and the two digit study number (randomisation number) after acceptance into the study. Randomization will be performed using a randomisation table created by computer software (i.e. computerized sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 22494 0
New Zealand
State/province [1] 22494 0
Otago

Funding & Sponsors
Funding source category [1] 305465 0
Commercial sector/Industry
Name [1] 305465 0
AU Pharma Pty Ltd
Address [1] 305465 0
Unit 3, 57 Avalon Parade
Avalon Beach 2107
NSW
Country [1] 305465 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zenith Technology Corporation Limited
Address
PO Box 1777
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 305863 0
None
Name [1] 305863 0
Address [1] 305863 0
Country [1] 305863 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305780 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 305780 0
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington 6145
Ethics committee country [1] 305780 0
New Zealand
Date submitted for ethics approval [1] 305780 0
25/06/2019
Approval date [1] 305780 0
08/08/2019
Ethics approval number [1] 305780 0
19/STH/126

Summary
Brief summary
The objective of this study is to evaluate the bioequivalence of the test (new) formulation
5/2.5 mg 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet
relative to that of the reference formulation following oral administration of multiple doses of 5/2.5 mg 4,5a-epoxy14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride/naloxone tablet in healthy subjects under fasting conditions and at steady state.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101574 0
Dr Noelyn Hung
Address 101574 0
Zenith Technology Corp Ltd
PO Box 1777,
Dunedin 9054
Country 101574 0
New Zealand
Phone 101574 0
+64 3 477 9669
Fax 101574 0
+64 3 477 9605
Email 101574 0
noelyn.hung@otago.ac.nz
Contact person for public queries
Name 101575 0
Mrs Linda Folland
Address 101575 0
Zenith Technology Corp Ltd
PO Box 1777,
Dunedin 9054
Country 101575 0
New Zealand
Phone 101575 0
+64 3 477 9669
Fax 101575 0
+64 3 477 9605
Email 101575 0
linda.folland@zenithtechnology.co.nz
Contact person for scientific queries
Name 101576 0
Dr Tak Hung
Address 101576 0
Zenith Technology Corp Ltd
PO Box 1777,
Dunedin 9054
Country 101576 0
New Zealand
Phone 101576 0
+64 3 477 9669
Fax 101576 0
+64 3 477 9605
Email 101576 0
tak.hung@zenithtechnology.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
All data will be compiled into a final report that is the property of the sponsor company. All participant data will be provided in summary format and result of the study only will be reported
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary