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Trial registered on ANZCTR


Registration number
ACTRN12621000752864
Ethics application status
Approved
Date submitted
12/05/2021
Date registered
15/06/2021
Date last updated
1/07/2021
Date data sharing statement initially provided
15/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of morphine on breathlessness and sleep in chronic obstructive pulmonary disease: A randomised, double-blind, placebo controlled cross-over study
Scientific title
The effects of morphine on breathlessness and sleep in chronic obstructive pulmonary disease: A randomised, double-blind, placebo controlled cross-over study
Secondary ID [1] 304190 0
N/A
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
chronic obstructive pulmonary disease 321905 0
Condition category
Condition code
Respiratory 319633 319633 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The primary aim of this randomised double-blind placebo-controlled cross-over study of sustained-release oral morphine 20mg daily for 3 days in a row versus placebo (oral, daily for 3 days in a row) is to determine the effect of morphine on sleep quality, as measured by sleep efficiency, in community-dwelling people with chronic obstructive pulmonary disease (COPD). Sleep efficiency will be determined by the percentage of time spent sleeping whilst in bed during an overnight sleep study in the Adelaide Institute for Sleep Health laboratory. Twenty-two participants will be recruited from Flinders Medical Centre (FMC) respiratory clinics, the nurse-led home outreach program, or the South Adelaide Local Health Network (SALHN) pulmonary rehabilitation and airway clearance programs. Secondary aims include subjective (questionnaire) assessments of sleep quality, subjective and objective assessments of breathlessness, blood tests to assess individuals’ morphine concentration and genetic polymorphisms, and alertness as measured by 30 minute driving simulator performance in the morning after the overnight in-lab sleep study. Participants will attend the sleep lab on the night following the third dose of study medication on both the placebo and morphine weeks. There will be a minimum four-day washout period after the first overnight sleep study before the second study drug period (either morphine or placebo) commences. In addition to morphine concentration testing, we will request drug tablet return at the end of the study to further monitor adherence.
Intervention code [1] 320548 0
Treatment: Drugs
Comparator / control treatment
The control will be placebo oral capsules to be taken daily for three days in a row. The capsules will be identical to the active drug. As this study is a cross-over design, all participants will receive both the active drug and placebo (with a minimum four day washout period). The placebo capsules will be filled with maize starch and pregelatinised maize starch.
Control group
Placebo

Outcomes
Primary outcome [1] 327496 0
Sleep efficiency (% of total possible sleep time spent asleep) during overnight in-lab polysomnography.
Timepoint [1] 327496 0
Night three of the study, measured during the overnight in-lab sleep study
Secondary outcome [1] 395390 0
Apnea-hypopnea index (AHI)
Timepoint [1] 395390 0
Night 3
Secondary outcome [2] 395391 0
Transcutaneous carbon dioxide level using a TcCO2 monitor.
Timepoint [2] 395391 0
Night 3
Secondary outcome [3] 395392 0
Breathlessness level via Breathlessless Now score, and modified BORG scale during external resistive load magnitude testing.
Timepoint [3] 395392 0
Night 3 and morning 4
Secondary outcome [4] 395393 0
Blood morphine concentration
Timepoint [4] 395393 0
Night 3 and morning 4
Secondary outcome [5] 395394 0
Opioid metabolism genotype via PCR.
Timepoint [5] 395394 0
Night 3
Secondary outcome [6] 395395 0
COPD assessment test (CAT)
Timepoint [6] 395395 0
Baseline and Morning 4
Secondary outcome [7] 395396 0
Hospital Anxiety and Depression (HAD) questionnaire
Timepoint [7] 395396 0
Baseline and Morning 4
Secondary outcome [8] 395397 0
Driving simulator performance to assess alertness.
Timepoint [8] 395397 0
Morning 4
Secondary outcome [9] 395398 0
Subjective sleepiness assessed via the Karolinska sleepiness scale.
Timepoint [9] 395398 0
Morning 4

Eligibility
Key inclusion criteria
- Aged 18 years and older
- Chronic Obstructive Pulmonary Disease (COPD)
- Chronic breathlessness syndrome (as defined as a modified Medical Research Council breathlessness score of 2 or more)
- Optimal pharmacological treatment based on Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) 2021 Report
- An Australia-modified Karnofsky Performance Status (AKPS) scale score greater than or equal to 40
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Concurrent use of opioids, benzodiazepines, or monoamine-oxidase inhibitors, or within 7 days of such therapy
- Body mass index >40kg/m2
- Prior diagnosis of severe obstructive sleep apnea (apnea-hypopnea index more than 30 events/hr)
- Uncontrolled nausea, vomiting, or gastrointestinal obstruction
- Calculated creatinine clearance <25mL/min
- Two or more hepatic enzyme greater than or equal to 3 times the upper limit of normal
- International normalised ratio >1.2 in the absence of warfarin
- Unresolved cardiac or respiratory event in the past 7 days (excluding upper respiratory tract infections)
- Anaemia for which a blood transfusion was indicated for breathlessness in the past 12 months
- Pregnant, or childbearing potential not using contraception
- Breastfeeding
- Waiting list for lung transplantation
- Change in COPD medications in the past 7 days (except "as needed" medications)
- Use of home non-invasive ventilation (NIV)
- History of endotracheal intubation for respiratory failure
- History of severe COPD exacerbation requiring acute NIV
- History of opioid-related respiratory failure
- History of opioid dependence (as per the International Classification of Diseases and Health Problems (ICD-10) definition)
- Any condition that in the investigator’s opinion would present an unreasonable risk to the participant, or which would interfere with their participation in the study or confound study interpretation

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)
Yes: via numbered medication containers supplied by the study pharmacist (Optima Ovest).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization list will be generated using block randomization in blocks of 4 by the study pharmacy (Optima Ovest Pharmacy). No person who has any knowledge of the randomization sequence will be involved in recruiting patients or measuring outcomes. All data collection will be undertaken without involvement of any person who is aware of the order of drug allocation.
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 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Data will be analysed using paired sample t-tests, or equivalent non-parametric tests, to evaluate placebo versus morphine differences.
Inter-individual differences in morphine-related changes in breathlessness and sleep disordered breathing will be explored using a regression model that includes opioid pharmacokinetics, genetic polymorphisms, baseline questionnaire responses, lung function results, and sleep variables derived from sleep study data.

Recruitment
Recruitment status
Recruiting
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)
SA
Recruitment hospital [1] 19439 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 19440 0
Noarlunga Health Service - Noarlunga Centre
Recruitment postcode(s) [1] 34021 0
5042 - Bedford Park
Recruitment postcode(s) [2] 34022 0
5168 - Noarlunga Centre

Funding & Sponsors
Funding source category [1] 308568 0
Government body
Name [1] 308568 0
National Health and Medical Research Council (NHMRC)
Address [1] 308568 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 308568 0
Australia
Primary sponsor type
Other
Name
Adelaide Institute for Sleep Health, Flinders University
Address
5 Laffer Drive, Bedford Park, South Australia 5042
Country
Australia
Secondary sponsor category [1] 309420 0
None
Name [1] 309420 0
Address [1] 309420 0
Country [1] 309420 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308510 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 308510 0
Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042
Ethics committee country [1] 308510 0
Australia
Date submitted for ethics approval [1] 308510 0
01/05/2021
Approval date [1] 308510 0
15/06/2021
Ethics approval number [1] 308510 0
2021/HRE00178

Summary
Brief summary
The purpose of this study is to determine the effects of sustained-release oral morphine (20mg) on sleep efficiency, breathlessness, and daytime alertness in breathless people with chronic obstructive pulmonary disease. We hypothesize that low dose morphine will improve sleep efficiency.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110954 0
Prof Danny Eckert
Address 110954 0
Adelaide Institute for Sleep Health
5 Laffer Drive, Bedford Park, South Australia 5042
Country 110954 0
Australia
Phone 110954 0
+61 8 7421 9780
Fax 110954 0
Email 110954 0
danny.eckert@flinders.edu.au
Contact person for public queries
Name 110955 0
Dr Thomas Altree
Address 110955 0
Adelaide Institute for Sleep Health
5 Laffer Drive, Bedford Park, South Australia 5042
Country 110955 0
Australia
Phone 110955 0
+61 8 8201 2299
Fax 110955 0
Email 110955 0
thomas.altree@flinders.edu.au
Contact person for scientific queries
Name 110956 0
Dr Thomas Altree
Address 110956 0
Adelaide Institute for Sleep Health
5 Laffer Drive, Bedford Park, South Australia 5042
Country 110956 0
Australia
Phone 110956 0
+61 8 8201 2299
Fax 110956 0
Email 110956 0
thomas.altree@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual sleep and physiological data will only be made available if participant identity can be assured to remain anonymous in accordance with ethical approval at the commencement of this study.
When will data be available (start and end dates)?
After publication (no end date determined)
Available to whom?
Anyone who has access to the publication.
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Individual data will be provided within the publication. Requests for access to data may be granted subject to approval from the Principal Investigator (Prof Danny Eckert, danny.eckert@flinders.edu.au) and pending approval from a human research ethics committee.
What supporting documents are/will be available?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 11657 0
Ethical approval
Citation [1] 11657 0
Link [1] 11657 0
Email [1] 11657 0
thomas.altree@flinders.edu.au
Other [1] 11657 0
Summary results
No Results