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Trial registered on ANZCTR

Registration number

ACTRN12615000121561

Ethics application status

Approved

Date submitted

12/01/2015

Date registered

10/02/2015

Date last updated

12/04/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Effect of opioids on outcomes of pulmonary rehabilitation

Scientific title

A randomised, double-blind, multi-site, parallel arm, fixed dose, placebo-controlled trial of the effects of morphine on exercise capacity and other outcomes of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD)

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Chronic obstructive pulmonary disease

Condition category

Condition code

Respiratory

Chronic obstructive pulmonary disease

Physical Medicine / Rehabilitation

Physiotherapy

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Blinded oral sustained release morphine 20mg in the morning and two capsules of blinded laxative (100mg docusate sodium and 26.6mg sennosoides in total) per 24 hours, during 8 weeks of pulmonary rehabilitation. Pulmonary rehabilitation is prescribed as per standard care.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Identically looking Placebo capsule and two capsules of placebo laxative, during 8 weeks of pulmonary rehabilitation. Pulmonary rehabilitation is prescribed as per standard care.

Control group

Placebo

Outcomes

Primary outcome [1]

Change in exercise capacity, measured as the difference in mean distance between two standardized six minute walk tests (6MWTs) at week one and at week eight, respectively, of pulmonary rehabilitation by group.

Timepoint [1]

Week eight of pulmonary rehabilitation

Secondary outcome [1]

Change in daily activity measured by accelerometer between week one and week eight by group.

Timepoint [1]

Week eight of pulmonary rehabilitation.

Secondary outcome [2]

Change in dyspnoea scores for current, usual, best and worst dyspnoea in the previous day measured on the 100mm visual analogue scale (VAS) in the 7 day diary by group.

Timepoint [2]

Average of last three days of week eight of pulmonary rehabilitation compared to the first 3 days of week one.

Secondary outcome [3]

Dyspnoea-related exertional limitation using the mMRC dypsnoea scale in the 7 day diary.

Timepoint [3]

Week eight compared to week one of pulmonary rehabilitation by group.

Secondary outcome [4]

Self-reported symptoms using 100mm VAS and/or Likert scales in patient diaries.

Timepoint [4]

Diary seven days at week one and week eight and for 24h each week of pulmonary rehabilitation.

Secondary outcome [5]

Exertional breathlessness measured on the modified Borg scale at each 6MWT

Timepoint [5]

Week eight compared to week one of pulmonary rehabilitation.

Secondary outcome [6]

Health related quality of life measured on the CRQ-SAS, 5D-ED-5L and CAT questionnaires.

Timepoint [6]

Week eight compared to week one of pulmonary rehabilitation.

Secondary outcome [7]

Sleepiness measured on the Epworth Sleepiness Scale, LSEQ, and the KSS and sleep quality on the PSQI.

Timepoint [7]

Week eight compared to week one of pulmonary rehabilitation.

Secondary outcome [8]

Sleepiness measured on the Epworth Sleepiness Scale, and sleep quality on the PSQI questionnaire.

Timepoint [8]

Week four of pulmonary rehabilitation.

Secondary outcome [9]

The ability perceived by the participant to move around and to undertake their affairs to the level they desire using LifeSpace and a categorical scale designed for this study.

Timepoint [9]

Week eight of pulmonary rehabilitation.

Secondary outcome [10]

Adherence rate to pulmonary rehabilitation sessions according to self-report and log books of the pulmonary rehabilitation program.

Timepoint [10]

Week eight of pulmonary rehabilitation.

Secondary outcome [11]

Blinded patient preference for continuing to take the medication if available using a questionnaire designed specifically for this study.

Timepoint [11]

Week eight of pulmonary rehabilitation.

Secondary outcome [12]

Performance status measured using the Australia-modified Karnofsky Performance Status Scale (participant and clinician rated).

Timepoint [12]

Weekly contacts during the eight weeks of pulmonary rehabilitation.

Secondary outcome [13]

Respiratory rate using manual counting and capnography.

Timepoint [13]

Week eight and week one of pulmonary rehabilitation.

Secondary outcome [14]

Medication compliance measured by counting the capsules remaining at the end of each week.

Timepoint [14]

Weekly contacts throughout eight weeks of pulmonary rehabilitation.

Secondary outcome [15]

Self-reported adverse effects, such as constipation, nausea, vomiting, and confusion, and ‘as needed’ medication using diary.

Timepoint [15]

Seven days at weeks one and eight, and 24 hours each week during pulmonary rehabilitation.

Secondary outcome [16]

Adverse events using the NCI’s Common Toxicity Criteria 3.0 comparing active to placebo treatment arms.

Timepoint [16]

At each study contact throughout eight weeks of pulmonary rehabilitation and four weeks of subsequent follow-up.

Secondary outcome [17]

Vital signs (basic medical examination).

Timepoint [17]

Weekly contacts throughout eight weeks of pulmonary rehabilitation.

Secondary outcome [18]

Differences in rates of withdrawal from the study between intervention arms.

Timepoint [18]

After eight weeks of pulmonary rehabilitation, at study end.

Secondary outcome [19]

Blood test for pharmacogenomics studies, including of opioid receptors and factors involved in the opioid system and metabolism, to better understand any difference between responders and non-responders.

Timepoint [19]

At the start of week one of pulmonary rehabilitation.

Secondary outcome [20]

Blood sample for pharmacokinetics studies, including blood concentration of opioids and opioid metabolites.

Timepoint [20]

At the start of week one and end of week eight of pulmonary rehabilitation.

Secondary outcome [21]

Health care utilization from patient self reports and linkage to patient medical records: number of inpatient admissions and type (DRG) and days spent in hospital during intervention and in the four weeks after study end; Number of presentations to the emergency department; general practitioner visits; concomitant medications; patient preferences for where prefer to be receiving care given current health state; medication compliance; number of specialty care service visits.

Timepoint [21]

Weekly Contacts throughout the eight weeks of pulmonary rehabilitation and four weeks after study end.

Secondary outcome [22]

Oxygen saturation using a pulse oximeter.

Timepoint [22]

Week eight and week one of pulmonary rehabilitation.

Secondary outcome [23]

End-tidal carbon dioxide (CO2) using a non-invasive detector.

Timepoint [23]

Week eight and week one of pulmonary rehabilitation.

Eligibility

Key inclusion criteria

* Eligible for pulmonary rehabilitation as judged by the treating physician and the investigator
* COPD verified by a post-bronchodilator FEV1/FVC<0.7 on a previous spirometry
* Age 18 years or more
* English speaking and able to read study questionnaires (5th grade level)
* On stable medications for breathlessness over the prior week except routine “as needed” medications
* Participant is capable of giving informed written consent, completing assessments, and complying with the study procedures
* Breathlessness of a level 3 or 4 on the mMRC dyspnoea scale

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

* Unstable cardiac or vascular disease within the previous four weeks.
* Severely restricted performance status with AKPS score < 50 at baseline.
* Anaemia with hemoglobin <10.0g/dL as measured within one month of baseline evaluation for which transfusion would be indicated in the view of the treating physician.
* History of chronic alcoholism or drug misuse problem.
* On regular or ‘as needed’ (PRN) opioid medications, including codeine preparations at or above a dose equivalent to 20mg of morphine sulphate per 24 hours.
* Renal dysfunction with creatinine clearance calculated <20 mls/minute using the MDRD formula. (Severe renal impairment – AMH)
* Hepatic impairment with serum alkaline phosphatase, total bilirubin, ALT or AST > four times the upper limit of normal for the local laboratory.
* Documented central hypoventilation syndrome.
* Evidence of respiratory depression with resting respiratory rate < 8.
* Participation in the current study at any time, or in a clinical study of a new chemical entity within the month prior to study entry
* History of adverse reactions to morphine or constituents in the placebo.
* Pregnant or breastfeeding.
* Unable to achieve two baseline 6MWTs of at least 200m each

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)

At each site, participants will be sequentially allocated a unique identifying number (ID) on referral to the study. This ID number will be used for all subsequent study documentation for that participant.
On notification of a participant, the pharmacist at each site will consult the strata table according to the strata determined by the mMRC dyspnoea scale and will allocate the next code available according to the supplied strata table and dispense the active or inactive medicine and laxative for four weeks use. The participant ID, allocation code, dates of request, preparation, and dispensing will be recorded in a log maintained by the pharmacist.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation schedules have been developed by an organisation not involved in this study. Treatment for each participant will be allocated according to a block randomisation schedule, held by the Central Registry Clinical trials Pharmacist, in a 1:1 ratio for each treatment arm, stratified for mMRC score (3 or 4) at baseline. Block randomisation will ensure even allocation to each code.

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

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Primary outcome

The primary analysis is a regression analysis with the mean distance on two 6MWTs at follow up as the dependent variable, and treatment group and mean 6MWT distance (of two measurements) at week one as the independent variables, and clustering over site to account for the possibility of correlated readings. The efficacy of the intervention will be assessed using the group term. Homoscedasticity, normality and independence of residuals at each level will be examined for possible model violation. A two-sided p-value at the 0.05 level will be deemed to be statistically significant.

The primary analysis will be conducted on an intention to treat basis. Missing data will be imputed using multiple imputation with 20 resamples drawn.

Secondary outcomes

These analyses will also involve pairwise comparisons of daily activity, severity and characteristics of dyspnoea, performance status (AKPS) and quality of life between the placebo and the morphine group.

Random effects mixed modeling, adjusting for prognostic factors, and clustering over site to account for the possibility of correlated readings and local differences between pulmonary rehabilitation programs will be used to examine the association between continuous secondary outcomes and the intervention. Differences between groups will be assessed using a time-by-group interaction term. For those models not meeting model assumptions, the Wilcoxon rank sum test will be used to assess differences.

Generalized estimating equations will be used in similar fashion to assess the effect of the intervention on binary secondary outcomes.

Severity of adverse events between the placebo and the morphine group will be examined using Mann-Whitney U tests. Those events scored only as present/absent will be compared by chi square tests.

Sample size calculation

Based on a assumed baseline mean 6MWT of 389m with a standard deviation of change of approximately 179m in each group, a correlation of 0.8 between repeated 6MWTs at the same time point, and a correlation of 0.5 between baseline and follow-up measures of 6MWT, a sample size of 104 participants per group provides 80% power to detect a minimally clinically meaningful increase (MCID) in 6MWT of 55m between groups, assuming a two tailed p-value (risk of false negative result) of 5%. Given a likely drop-out rate of 20% of participants during follow-up, approximately 260 participants will need to enter the study to ensure adequate power for the primary endpoint.

Recruitment

Recruitment status

Stopped early

Data analysis

Data collected is being analysed

Reason for early stopping/withdrawal

Participant recruitment difficulties

Date of first participant enrolment

Anticipated

19/02/2015

Actual

18/05/2015

Date of last participant enrolment

Anticipated

31/12/2016

Actual

22/09/2017

Date of last data collection

Anticipated

Actual

30/10/2017

Sample size

Target

260

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

John Hunter Hospital Royal Newcastle Centre - New Lambton

Recruitment hospital [2]

Westmead Hospital - Westmead

Recruitment hospital [3]

Flinders Medical Centre - Bedford Park

Recruitment hospital [4]

Repatriation General Hospital - Daw Park

Recruitment hospital [5]

Noarlunga Health Service - Noarlunga Centre

Recruitment postcode(s) [1]

2145 - Westmead

Recruitment postcode(s) [2]

5042 - Bedford Park

Recruitment postcode(s) [3]

5041 - Daw Park

Recruitment postcode(s) [4]

5168 - Noarlunga Centre

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Commonwealth Department of Health

Address [1]

PO Box 9848
Canberra ACT, 2601

Country [1]

Australia

Primary sponsor type

University

Name

Flinders University

Address

Flinders Drive
Bedford Park,
SA 5042

Country

Australia

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

Palliative Care Clinical Studies Collaborative (PaCCSC)

Address [1]

Flinders University
School of Medicine
Department of Palliative and Supportive Services
Daw House Hospice
700 Goodwood Road
Daw Park SA 5041

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Human Research Ethics Committee

Ethics committee address [1]

Locked Bag 1
New Lambton NSW 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

17/12/2014

Ethics approval number [1]

14/10/15/3.01

Summary

Brief summary

Background

Impaired exercise capacity and activity due to chronic obstructive pulmonary disease (COPD) is a major threat to the health of the individual and impacts on the community at large. About 330 million people have COPD worldwide and 235,000 people have moderate or severe disease in Australia alone. These people often suffer from disabling symptoms and reduced physical capacity for many years despite best medical management. 

Pulmonary rehabilitation is first-line treatment in people with symptomatic COPD with a strong evidence base for improved functional status, better exercise tolerance and better longer term outcomes. 

Recent laboratory data show that regular, low dose opioids (such as morphine) may decrease exertional breathlessness without impairing exercise capacity. Regular, low dose sustained release morphine is a potential new approach to improve further the established outcomes of pulmonary rehabilitation in COPD. Such an intervention has not been tested in a randomised clinical trial.  

It is important to establish that the overall net effect is positive and that benefits outweigh any harms encountered.  A particular concern for many clinicians is the theoretical risk that opioids may cause respiratory depression. In steady state, at the relatively low regular doses proposed, there are no data to support this concern, but this study will specifically monitor this issue through careful collection of non-invasive measures of respiratory function, including end-tidal carbon dioxide, regularly throughout the study.


Study design

This is a phase III, multi-site, randomised, double-blind, parallel arm, fixed dose, placebo controlled trial of sustained release morphine (20 mg every 24 hours) or placebo during  eight weeks of pulmonary rehabilitation for COPD. Randomisation will be stratified according to the mMRC score. During the study period, therapy for constipation is also given to participants with active therapy and identical appearing laxative placebo is given in the placebo arm. Data on 260 people will be required in order to complete the study with adequate power for the primary endpoint.


Study population 

Suitable people with spirometry-verified COPD and  breathlessness (between grade three and four on the mMRC scale), who are eligible for pulmonary rehabilitation and  are able to give informed consent, will be recruited to participate in the study, provided  they have no contraindication for opioid use.


Objectives 

During eight weeks of pulmonary rehabilitation, the primary objective is to compare the efficacy for improving exercise capacity measured using the six minute walking test (6MWT) of sustained release morphine compared with placebo. Secondary objectives include effect on daily activity measured using an accelerometer, safety, breathlessness, quality of life (QOL), health care resource utilization, clinical and pharmacogenomic predictors of which individuals will achieve the greatest benefit from morphine, and to establish any blinded participant treatment preference.


Treatment schedule

Every day, participants will take three capsules (one Kapanol 20mg or placebo in the morning, and two capsules of docusate with senna or placebo). This will occur without titration and participants will continue the allocated treatment during eight weeks of pulmonary rehabilitation.  ‘As needed’ open label docusate with senna will also be provided to all study participants.

Assessments

Week 1: demographic and clinical data, blood sample, 6MWT, daily activity (accelerometer for seven days), severity and characteristics of dyspnoea, twice daily diary, adverse events, quality of life, and blinded treatment preference. Outcome measures are repeated at the end of week eight of pulmonary rehabilitation. For 24 hours each week throughout the study: daily diary and adverse events. 
 
Definition of response: A response will be defined as an increase of 55m or more on the 6MWT.

Primary endpoint: Change between week one and week eight of pulmonary rehabilitation in distance on a standardized 6MWT. 

Analysis: Longitudinal repeated measures mixed models with unstructured covariance matrices, two-sample t tests, and multivariable regression models will be used.

Economic analysis: 

This will estimate incremental costs, effects and net benefit of oral sustained release morphine relative to placebo in addition to pulmonary rehabilitation from participant level data collected over eight weeks of follow up  (survival to eight weeks or death, whichever is shorter) for:
 * resource use including bed days spent in hospital for inpatient admissions (index admission and readmissions);
 * professional community support utilised at home if discharged from hospital or enrolled at home, including general practitioner and specialty care service visits, 
 * concomitant medication use; and
 * effects including days of survival with response, toxicity, adverse events, health related quality of life, and compliance.
Bootstrapping of patient costs and effects data will be used to model decision making uncertainty related to the net benefit of oral sustained release morphine relative to placebo.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof David Currow

Address

Flinders University Flinders Centre for Clinical Change, Flinders University Institute of Palliative and Supportive Care Research Flinders Drive Bedford Park SA 5042

Country

Australia

Phone

+61 8 7221 8235

Fax

david.currow@health.sa.gov.au

Contact person for public queries

Name

David Currow

Address

Flinders University Flinders Centre for Clinical Change, Flinders University Institute of Palliative and Supportive Care Research Flinders Drive Bedford Park SA 5042

Country

Australia

Phone

+61 8 7221 8235

Fax

david.currow@health.sa.gov.au

Contact person for scientific queries

Name

David Currow

Address

Flinders University Flinders Centre for Clinical Change, Flinders University Institute of Palliative and Supportive Care Research Flinders Drive Bedford Park SA 5042

Country

Australia

Phone

+61 8 7221 8235

Fax

david.currow@health.sa.gov.au

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	A Randomized, Double-Blind, Multisite, Pilot, Placebo-Controlled Trial of Regular, Low-Dose Morphine on Outcomes of Pulmonary Rehabilitation in COPD.	2019	https://dx.doi.org/10.1016/j.jpainsymman.2019.07.026

N.B. These documents automatically identified may not have been verified by the study sponsor.

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