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Trial registered on ANZCTR


Registration number
ACTRN12621001252808
Ethics application status
Approved
Date submitted
10/08/2021
Date registered
16/09/2021
Date last updated
16/09/2021
Date data sharing statement initially provided
16/09/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Comparative assessment of the absorption of a generic formulation of 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid against the innovator 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid conducted under fasting conditions in healthy male and female volunteers.
Scientific title
A single dose, blinded, balanced, randomised, three-treatment, three-period, six-sequence, three-way crossover study to compare the efficacy and pharmacokinetics of 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid with 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid and placebo oral liquid in healthy male and female subjects under fasting conditions.
Secondary ID [1] 304901 0
None
Universal Trial Number (UTN)
U1111-1268-0144
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid is used to provide temporary relief for persistent unproductive and dry coughs 323034 0
Condition category
Condition code
Anaesthesiology 320606 320606 0 0
Pain management
Inflammatory and Immune System 320607 320607 0 0
Other inflammatory or immune system disorders
Respiratory 320926 320926 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single dose, three-treatment, three-period, six-sequence, crossover design whereby each participant receives the test formulation of 3 x 10 mL of 9.5 mg/5mL 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid on one occasion and the innovator formulation of 3 x 10 mL of 9.5 mg/5mL 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid on one occasion and the placebo of 3 x 10 mL oral placebo liquid on one occasion with each dose separated by a one week washout period. The intervention for this trial is the test formulation of 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid.

No water is allowed for 1 hour prior to dosing until 1 hour after dosing.

Participants are required not to eat for 10 hours prior to dosing and for approximately 4 hours after receiving each dose. Following this period of fasting standard meals will be consumed at the Clinical Site with no additional food intake allowed.

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 10 hours prior to dosing to ensure compliance and will be monitored for 24 hours post-dosing.

Alcohol breath testing will be performed upon each participant reporting to the Clinical Site 10 hours prior to dosing.

Pre and post study laboratory tests will be completed to assess the health of participants.

Each dose will be taken orally. Medication must be swallowed and a mouth check will be conducted to ensure the medication has been taken as directed.
Intervention code [1] 321297 0
Treatment: Drugs
Comparator / control treatment
Single dose, three-treatment, three-period, six-sequence, crossover design whereby each participant receives the test formulation of 3 x 10 mL of 9.5 mg/5mL 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid on one occasion and the innovator formulations of 3 x 10 mL of 9.5 mg/5mL 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid on one occasion and the placebo of 3 x 10 mL oral placebo liquid administered with each dose separated by a one week washout period. The comparator/control for this trial is the placebo oral liquid which contains sucrose, sorbitol solution, strawberry flavoring and water. This will be identical in appearance to the test and reference product containing no active ingredients.
Control group
Placebo

Outcomes
Primary outcome [1] 328436 0
To evaluate the pharmacokinetic profile of 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid (as summarised by Cmax and AUC) for the formulation. All plasma samples will be assayed for 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid using a fully validated LC/MS/MS method. Validation will be conducted to comply with EU and FDA guidelines.
Timepoint [1] 328436 0
0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 16, 20, 24, 28 and 32 hours post dosing
Primary outcome [2] 328437 0
To compare the efficacy of 4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol hydrogen tartrate oral liquid on cough threshold using an inhaled citric acid cough model for the formulations compared to placebo.
Timepoint [2] 328437 0
-2 prior to dosing and 1.5 - 3 hours post dosing

The exact time of the citric acid challenge will be determined based on the timing of the pre-dose test and cough response of each participant and machine availability. As indicated in previous research, post-dose testing should occur within 1.5-3 hours. This study will be conducted in smaller groups to allow flexibility with the cough challenge and to ensure all post-dose tests are completed within the prescribed timeframe
Secondary outcome [1] 399006 0
Time to maximum peak concentration (Tmax) will be determined by plasma sample analysis. Tmax will be the time where the maximum concentration occurred in the sample points.
Timepoint [1] 399006 0
0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 16, 20, 24, 28 and 32 hours post dosing

Eligibility
Key inclusion criteria
Healthy males and non-pregnant female volunteers.
Aged between 18 and 50
Non-smoker
BMI between 18 and 32
Absence of any cough or cold within 2 weeks prior to dosing.
Normal spirometry measurements (FEV1).
Cough response reached in the Citric Acid Provocation test at screening and pre-dose.
Normal, healthy individuals as determined by medical history, physical examination, ECG, blood pressure and laboratory tests.
Able to provide written informed consent.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Concomitant drug therapy of any kind
Any clinically significant medical conditions
Sensitive to the study drug
History of any conditions that might interfere with the absorption, distribution, metabolism or excretion of the drug
No cough response reached at any concentration of the citric acid test during screening.
History of bronchial asthma, chronic obstructive pulmonary disease (COPD).
History of recent head injuries, constipation, hypothyroidism or sleep apnoea
Females who are pregnant and/or breastfeeding
Smoker (anyone who has smoked in the last 6 months)
History of alcohol or drug abuse or dependency
Participation in a drug study within 60 days of the start of the study or donated blood within the 60 days preceding the study
Participants 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 labelled as Formulation A, B and C. The identification of each treatment will only be known to the Managing Director and the Section Head - Trials and Regulatory Affairs.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each participant will be given 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 subject number (randomisation number) after acceptance into the study. Sequence generation will be by using a simple randomisation using a randomisation table created by computer software (i.e. computerised 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
Bio-equivalence
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Sponsor Company withdrew the study.
Date of first participant enrolment
Anticipated
4/09/2021
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment outside Australia
Country [1] 24014 0
New Zealand
State/province [1] 24014 0
Otago

Funding & Sponsors
Funding source category [1] 309274 0
Commercial sector/Industry
Name [1] 309274 0
Aspen Pharmacare Australia
Country [1] 309274 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Zenith Technology Corporation Limited
Address
156 Frederick Street
Dunedin 9016
Country
New Zealand
Secondary sponsor category [1] 310245 0
None
Name [1] 310245 0
Address [1] 310245 0
Country [1] 310245 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309112 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 309112 0
Ethics committee country [1] 309112 0
New Zealand
Date submitted for ethics approval [1] 309112 0
10/06/2021
Approval date [1] 309112 0
06/07/2021
Ethics approval number [1] 309112 0
21/CEN/166

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113018 0
Dr Noelyn Hung
Address 113018 0
Zenith Technology Corporation Limited
156 Frederick Street (PO Box 1777)
Dunedin 9016
Country 113018 0
New Zealand
Phone 113018 0
+64 21 482 148
Fax 113018 0
+64 3 477 9605
Email 113018 0
noelyn.hung@otago.ac.nz
Contact person for public queries
Name 113019 0
Linda Folland
Address 113019 0
Zenith Technology Corporation Limited
156 Frederick Street (PO Box 1777)
Dunedin 9016
Country 113019 0
New Zealand
Phone 113019 0
+64 3 477 9669
Fax 113019 0
+64 3 477 9605
Email 113019 0
linda.folland@zenithtechnology.co.nz
Contact person for scientific queries
Name 113020 0
Tak Hung
Address 113020 0
Zenith Technology Corporation Limited
156 Frederick Street (PO Box 1777)
Dunedin 9016
Country 113020 0
New Zealand
Phone 113020 0
+64 3 477 9669
Fax 113020 0
+64 3 477 9605
Email 113020 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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.