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Trial registered on ANZCTR


Registration number
ACTRN12614001152617
Ethics application status
Approved
Date submitted
15/10/2014
Date registered
31/10/2014
Date last updated
22/06/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study to determine how the bodies of healthy study participants handle axelopran and oxycodone given as a combined tablet compared with given as separate tablets.
Scientific title
An Open-label, Randomized, Single-dose, 4-way Crossover Study to Assess the Relative Bioavailability of Axelopran and Oxycodone Administered as a Fixed-Dose Combination and as Individual Components to Healthy Subjects with a Naltrexone Block Under Fasting Conditions
Secondary ID [1] 285358 0
Nil
Universal Trial Number (UTN)
U1111-1161-9023
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Opioid induced constipation 293086 0
Condition category
Condition code
Oral and Gastrointestinal 293362 293362 0 0
Normal oral and gastrointestinal development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The interventional product, axelopran 10mg, will be co-formulated with an oxycodone 20mg tablet and administered orally under fasting conditions. Both products will also be administered together but as separate tablets, and also as individual doses, so that study participants will each receive each of the 4 treatment options, separated by a week between dosing. In each Period, subjects will also receive co-treatment with naltrexone 50 mg orally (a single 50 mg dose 15 and 3 hours before and 9 and 21 hours after dosing with Study Treatment).
Intervention code [1] 290274 0
Treatment: Drugs
Comparator / control treatment
No comparator will be utilised for this study. The axelopran will be given alone and with the oxycodone in order to assess how the body handles these drugs in combination and separately. Naltrexone will be co-administered to each study participant in order to block the peripheral and central effects of opiate administration.
Control group
Active

Outcomes
Primary outcome [1] 293189 0
The primary outcome is to determine the relative bioavailability of axelopran and oxycodone (by assessment of plasma concentrations) after oral administration as a fixed-dose combination compared to the individual components when administered together to healthy subjects under fasting conditions
Timepoint [1] 293189 0
Measurements to be taken up to 72 hours following each dose administration. Blood samples for plasma PK analysis of axelopran and oxycodone will be collected at pre-dose and at approximately 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours postdose.
Secondary outcome [1] 310555 0
To determine the relative bioavailability of axelopran and oxycodone when administered as individual, single ingredient drug products relative to when co-administered either as the individual components or as a fixed-dose combination
Timepoint [1] 310555 0
To be assessed up to 72 hours following each dose. Blood samples for plasma PK analysis of axelopran and oxycodone will be collected at pre-dose and at approximately 0.25, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours postdose.
Secondary outcome [2] 310556 0
To assess the safety of single doses of axelopran and oxycodone administered (through evaluation of vital signs (including blood pressure, temperature, respiratory rate and oxygen saturation), physical examination, electrocardiography, adverse events, and laboratory safety tests) as a fixed-dose combination, co-administered as individual components, and administered as separate treatments to healthy subjects under fasting conditions. The study will monitor for all adverse events, including events that might be related to axelopran or the opioid. Any adverse event (either new or an exacerbation of a pre-existing condition) with an onset date after study drug administration will be recorded as an adverse event. The definition of an adverse event is defined as any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. In addition to the vital sign and laboratory assessments listed above, trial subjects will be assessed by site staff and questioned on how they are feeling and any adverse signs or symptoms will be recorded as adverse events.
Timepoint [2] 310556 0
For Safety assessment, blood pressure and temperature will be measured within 30 minutes predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48 and 72 hours after dosing in each period. Heart rate and respiratory rate will be measured within 30 minutes predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 24, 48 and 72 hours after dosing in each period. Continuous SaO2 will be measured beginning predose through 8 hours after dosing, and then checked at 12 and 24 hours (and as medically indicated). ECGs (12-lead) will be collected in triplicate within 5 minutes at Screening, on admission to the clinical research unit on Day -1, within 60 minutes prior to study drug dose, and at 4 hours post dose on Day 1 and prior to discharge on Day 4 of each Period. Physical examinations will be assessed on Day -1 and Day 4 of each Period. Adverse events will be assessed at least daily and recorded when reported or observed.

Eligibility
Key inclusion criteria
- healthy weight, BMI, medical history and on physical exam
- females must not be pregnant and males and females must practice approved contraception during the study
- screening lab assessments must have normal healthy results
- able to comply with study requirements and give informed consent
Minimum age
18 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- history or evidence of severe allergic, or other disease as determined by the investigator to be of clinical significance
- history of chronic obstructive pulmonary disease, asthma or reactive airway disease
- history of, or current hypersensitivity to drugs
- any condition which may affect drug absorption
- recent participation in a trial of an investigational drug (or medical device) within 60 days (or 5 half-lives of the investigational drug, whichever is longer) prior to screening.
- Unwilling to abstain from caffeine products or alcohol or strenuous exercise beginning 24 hours prior to admission on Day -1 until the final PK sample is collected for each period.
- Consumption of grapefruit or grapefruit juice within 14 days prior to admission on Day -1.
- Consumption of other fruit juices within 24 hours prior to admission to the unit on Day -1 of any period.
- history of alcoholism or drug abuse
- history of tobacco use within previous 6 months
- Use of prescription or over-the-counter medications including herbals within 7 days (or14 days if the drug is a potent inducer or inhibitor of cytochrome P450 isoenzyme 3A4 or permeability glycoprotein 1, or five half-lives (whichever is longer) prior to Day -1 or requires continuous use during study participation, with the exception of routine vitamins or minerals, paracetamol (up to 1000 mg/day) if required, ibuprofen (up to 400 mg/day) if required, or ondansetron IV (up to 8 mg /day) if required.
- Blood donors within 8 weeks prior to screening
-abnormal ECG or family history of congenital long QT syndrome or family history of sudden death

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)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Bio-availability
Statistical methods / analysis
A sample size of 28 subjects will afford approximately 80% power to provide a 90% confidence interval for the ratios AUC and Cmax to be within the interval of 0.8 - 1.25 (oxycodone vs the fixed dose combination of oxycodone and axelopran).

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 in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 8728 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 289996 0
Commercial sector/Industry
Name [1] 289996 0
Theravance Biopharma R&D, Inc.
Address [1] 289996 0
c/o Theravance Biopharma US, Inc.
901 Gateway Boulevard
South San Francisco, California 94080
Country [1] 289996 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Theravance Biopharma R&D, Inc.
Address
c/o Theravance Biopharma US, Inc.
901 Gateway Boulevard
South San Francisco, California 94080
Country
United States of America
Secondary sponsor category [1] 288681 0
Commercial sector/Industry
Name [1] 288681 0
CPR Pharma Services (acting as local sponsor in Australia only)
Address [1] 288681 0
28 Dalgleish St
Thebarton SA 5031
Country [1] 288681 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291705 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 291705 0
The Alfred Hospital
55 Commercial Road
Melbourne 3004
Ethics committee country [1] 291705 0
Australia
Date submitted for ethics approval [1] 291705 0
02/09/2014
Approval date [1] 291705 0
29/09/2014
Ethics approval number [1] 291705 0

Summary
Brief summary
The purpose of this study is to determine the pharmacokinetics (how the body absorbs the drug), safety, and tolerability of oxycodone and axelopran when given together and separately.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 51506 0
Dr Jason Lickliter
Address 51506 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct
89 Commercial Road,
Victoria 3004
Country 51506 0
Australia
Phone 51506 0
+61 3 9076 8960
Fax 51506 0
Email 51506 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 51507 0
Mr Jeffery Wong
Address 51507 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct
89 Commercial Road,
Victoria 3004
Country 51507 0
Australia
Phone 51507 0
+61 3 9076 8909
Fax 51507 0
Email 51507 0
j.wong@nucleusnetwork.com.au
Contact person for scientific queries
Name 51508 0
Mr Wayne Yates
Address 51508 0
Theravance Biopharma
901 Gateway Boulevard
South San Francisco,
California 94080
Country 51508 0
United States of America
Phone 51508 0
+1 650 808 4118
Fax 51508 0
Email 51508 0
wyates@theravance.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary