Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12609000806268
Ethics application status
Approved
Date submitted
2/09/2009
Date registered
16/09/2009
Date last updated
4/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised double-blind multi-site parallel arm controlled trial to assess relief of refractory breathlessness comparing fixed doses of morphine and placebo.
Scientific title
A randomised double-blind multi-site parallel arm controlled trial to assess relief of breathlessness comparing fixed doses of morphine and placebo in people with refractory breathlessness.
Secondary ID [1] 251928 0
008/08
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory breathlessness. 243620 0
Condition category
Condition code
Respiratory 239917 239917 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase III, multi-centre, randomised double-blind parallel arm controlled fixed dose trial studying treatment approaches for the relief of breathlessness in people with refractory dyspnoea. Participants will be randomised to identical-appearing sustained release morphine (20 mg every 24 hours (every morning), or placebo for one week. The intervention period will run for 7 days. At all times, all participants will have the ability to take up to eight doses of 2.5mg of immediate release oral morphine solution on an ‘as needed’ basis in any twenty four hour period.

Participants in the active arm will also take oral blinded docusate (50 milligram (mg)) with senna (8mg) (2 tablets orally each morning), and participants in the placebo arm, will take identical placebo (2 tablets orally each morning). In addition, participants will have access to open label oral docusate (50mg) with senna (8mg) to treat constipation if required.

People will be randomonly allocated to one of the 2 study arms
Arm 1 One week of sustained release morphine orally 20mg (on waking) or,
Arm 2 One week of identical looking oral placebo each day (on waking)
Intervention code [1] 241208 0
Treatment: Drugs
Comparator / control treatment
Identical blinded placebo opaque capsule filled with cornstarch
Control group
Placebo

Outcomes
Primary outcome [1] 240698 0
Change in the current sensation (intensity and unpleasantness) of breathlessness, measured using 100mm visual analogue dyspnoea scales and comparing outcomes by an average of morning and evening scores over the last three days of the study. A 15% improvement in breathlessness from baseline is considered a clinically meaningful improvement.
Timepoint [1] 240698 0
Average of morning and evening dyspnoea scores over last three days of the study.
Secondary outcome [1] 257346 0
Breathlessness
Comparative dyspnoea scores for current, usual, best and worst dyspnoea in the previous day measured on the 100mm visual analogue scale in the daily diary
Dyspnoea-related exertional limitation using the Medical Research Council (MRC) dypsnoea scale and the Dypsnoea Exertion Scale (DES) in the daily diary
Timepoint [1] 257346 0
Day 7
Secondary outcome [2] 257347 0
Side effects and safety
Daily assessments of pain, constipation, sedation, nausea, vomiting, appetite, confusion, agitation, depressed mood, sleep quality, well being and global Quality of Life (QOL) using 100mm visual analogue scales
Extensive assessment of adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Timepoint [2] 257347 0
Day 7
Secondary outcome [3] 257348 0
Medication compliance
Medication compliance measured by counting the capsules remaining at the end of the study
Timepoint [3] 257348 0
Day 7
Secondary outcome [4] 257349 0
Performance status measured using the Australia-modified Karnofsky Performance Status Scale (clinician rated) at baseline and the end of the study intervention
Timepoint [4] 257349 0
Baseline and Day 7
Secondary outcome [5] 257350 0
Changes in physiological parameters - end-tidal carbon dioxide (using a portable End Tidal carbon dioxide monitor), changes in pulse oximetry (using a finger applied pulse oximeter), changes in resting respiratory rate (counting respiratory rate).
Timepoint [5] 257350 0
Day 7
Secondary outcome [6] 257351 0
Pharmacogenomics studies to better understand any difference between responders and non-responders using blood analysis.
Timepoint [6] 257351 0
Day 7
Secondary outcome [7] 257352 0
Health service utilisation and long term outcomes:
Number of inpatient admissions and days spent in hospital by level of dependency (low, medium, high) level
Emergency department presentations
Home care palliative care team visits
General practitioner visits
Concomitant medications
Caregiver impact (Caregiver Quality of Life-Cancer scale - CQOLC)
Participant preference for where they prefer to be cared for given their current health state
Timepoint [7] 257352 0
Day 35

Eligibility
Key inclusion criteria
Adults (age >18)
Refractory dyspnoea where the underlying cause of the dyspnoea has been maximally treated. Refractory dyspnoea does not have a minimum duration and can have been present for any period of time. A medical specialist must document that all identified reversible causes of the dyspnoea are being optimally managed.
Breathlessness of a level 2 or higher on the modified MRC dyspnoea scale
On stable medications over the prior week except routine “as needed” medications
Prognosis of at least 2 months in the opinion of the treating clinician
English-speaking and able to read study questionnaires (5th grade level)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
On regular opioid medications, including codeine preparations at or above the dose being studied in the previous 7 days.
Anemia for which transfusion is not indicated within one month of baseline evaluation.
Severely restricted performance status with Australian Karnofsky Performance score of <40 at baseline
Uncontrolled nausea, vomiting and/or gastrointestinal obstruction.
Renal dysfunction with creatinine clearance calculated as less than 25 mls/minute.
Medical history of severe hepatic impairment defined as ‘3 times upper limit of normal for 2 or more hepatic enzymes', or clotting via International Normalisation Ratio (INR) >1.2 – not treated with warfarin.
Evidence of respiratory depression with resting respiratory rate <8.
Active respiratory or cardiac event in the previous week, not including upper respiratory tract infections. Illness must have resolved completely prior to baseline evaluation, as judged by a doctor involved in the care of the person.
Documented previous respiratory failure induced by any opiate medication.
Unable to give informed consent or complete diary entries.
Pregnant or breastfeeding

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 centre, 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. The procedures outlined in the Allocation of ID number Standard Operating Procedure are to be followed.

All people with breathlessness will be referred to the study. The study nurse will ask the consultant in charge for permission to approach potentially eligible participants. This referral will be recorded within both the Case Report Form and the participant’s clinical file.

On notification of a participant, the pharmacist at each site will consult the strata table according to the strata determined by the diagnosis of underlying dyspnoea, and will allocate the next code available according to the supplied strata table and dispense the active or inactive medicine delivered in a labeled bottle. The participant ID, allocation code, dates of request, preparation, and dispensing will be recorded in a log maintained by the pharmacist and supplied to the central registry on each randomisation.

All capsules will be prepared in a central manufacturing pharmacy, where the medication will be encased in an opaque capsule in order to have all study medications and the placebo looking identical. Each daily dose for each participant will be contained within a tamper proof bottle which will contain the 7 day supply of the study medication. A second tamper proof bottle will contain either 2 docusate with senna tablets (if on active arm) or placebo (if on the inactive arm). Each bottle will be numbered according to the pre-determined allocation code and labeled as:

008/08 study – Study medication – 1 capsule every 24 hours consisting of morphine Slow Release (SR) 20mg: placebo. Take one capsule as prescribed until finished.

All bottles for each site will be supplied to the site clinical trial pharmacist according to the randomisation schedule with a log of the bottle number. On randomisation of a participant, the site pharmacist will obtain the bottle corresponding to the randomisation number, and record the participant details in a log against the bottle number.

Treatment allocation will not be disclosed to participant, study staff, treating clinicians or investigators. The code will only be broken in cases of extreme clinical emergency. Such situations only include where knowledge of the code will have consequences for clinical decision making.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Strata tables will be developed for each site using random number tables, generated at an independent centre (central registry). Treatment for each participant will be allocated according to a block randomisation schedule held by the central registry. This is described in more detail within the Palliative Care Clinical Studies Collaborative (PaCCSC) Randomisation Standard Operating Procedure. Block randomisation will ensure even allocation to each code. The central registry will supply strata tables to each site pharmacy. Stratification will be according to baseline dominant cause of dyspnoea (chronic obstructive pulmonary disease, cancer, end-stage cardiac failure, mixed etiology and other). Stratification will ensure adequate distribution across study arms for each diagnosis.
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
None
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/10/2009
Actual
5/02/2010
Date of last participant enrolment
Anticipated
Actual
22/07/2015
Date of last data collection
Anticipated
Actual
27/08/2015
Sample size
Target
236
Accrual to date
Final
238
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 3190 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [2] 3191 0
Concord Repatriation Hospital - Concord
Recruitment hospital [3] 3192 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 2042 0
4101
Recruitment postcode(s) [2] 2043 0
3002
Recruitment postcode(s) [3] 2044 0
3084
Recruitment postcode(s) [4] 2045 0
6101
Recruitment postcode(s) [5] 2046 0
2310
Recruitment postcode(s) [6] 2047 0
2164
Recruitment postcode(s) [7] 2111 0
5041
Recruitment postcode(s) [8] 2112 0
2010
Recruitment postcode(s) [9] 7594 0
2217 - Kogarah
Recruitment postcode(s) [10] 7595 0
3065 - Fitzroy
Recruitment postcode(s) [11] 7596 0
3215 - North Geelong
Recruitment postcode(s) [12] 7597 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [13] 7598 0
4032 - Chermside
Recruitment postcode(s) [14] 8971 0
5112 - Elizabeth Vale
Recruitment postcode(s) [15] 8972 0
2139 - Concord Repatriation Hospital
Recruitment postcode(s) [16] 8973 0
2298 - Waratah

Funding & Sponsors
Funding source category [1] 237568 0
Government body
Name [1] 237568 0
Commonwealth Department of Health and Ageing
Country [1] 237568 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Flinders Drive
Bedford Park
SA 5042
Country
Australia
Secondary sponsor category [1] 237043 0
Government body
Name [1] 237043 0
Commonwealth Department of Health and Ageing
Address [1] 237043 0
GPO Box 9848
Canberra
ACT 2601
Country [1] 237043 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 243696 0
Southern Adelaide Clinical Research Ethics Committee
Ethics committee address [1] 243696 0
Southern Adelaide Clinical HREC The Flats G5 Flinders Drive c/- Flinders Medical Centre BEDFORD PARK SA 5042
Ethics committee country [1] 243696 0
Australia
Date submitted for ethics approval [1] 243696 0
18/02/2009
Approval date [1] 243696 0
27/04/2009
Ethics approval number [1] 243696 0
EC00188
Ethics committee name [2] 259125 0
Austin Health Human Research Ethics Committee
Ethics committee address [2] 259125 0
145 Studley Road, Heidelberg, Vic 3084
Ethics committee country [2] 259125 0
Australia
Date submitted for ethics approval [2] 259125 0
27/10/2009
Approval date [2] 259125 0
10/03/2010
Ethics approval number [2] 259125 0
EC00204
Ethics committee name [3] 259126 0
Hunter New England Human Research Ethics Committee
Ethics committee address [3] 259126 0
Locked Bag 1, New Lamberton, NSW 2305
Ethics committee country [3] 259126 0
Australia
Date submitted for ethics approval [3] 259126 0
01/09/2009
Approval date [3] 259126 0
30/10/2009
Ethics approval number [3] 259126 0
EC00403
Ethics committee name [4] 290246 0
Mater Health Services Human Research Ethics Committee
Ethics committee address [4] 290246 0
HREC Office Room 270 Level 2 Aubigny Place Raymond Terrace SOUTH BRISBANE QLD 4101
Ethics committee country [4] 290246 0
Australia
Date submitted for ethics approval [4] 290246 0
Approval date [4] 290246 0
26/10/2011
Ethics approval number [4] 290246 0
EC00332
Ethics committee name [5] 290247 0
The Prince Charles Hospital HREC
Ethics committee address [5] 290247 0
Building 12 The Prince Charles Hospital Rode Road Lower Ground Floor, Administration Building CHERMSIDE QLD 4032
Ethics committee country [5] 290247 0
Australia
Date submitted for ethics approval [5] 290247 0
25/08/2011
Approval date [5] 290247 0
25/10/2011
Ethics approval number [5] 290247 0
EC00168
Ethics committee name [6] 290248 0
St Vincent's Hospital (Melbourne) HREC D
Ethics committee address [6] 290248 0
Research Governance Unit St Vincent's Hospital 41 Victoria Parade FITZROY VIC 3065
Ethics committee country [6] 290248 0
Australia
Date submitted for ethics approval [6] 290248 0
Approval date [6] 290248 0
04/05/2011
Ethics approval number [6] 290248 0
EC00343
Ethics committee name [7] 290249 0
Barwon Health Human Research Ethics Committee
Ethics committee address [7] 290249 0
Human Research Ethics Committee Office for Research Barwon Health PO Box 281 GEELONG VIC 3220
Ethics committee country [7] 290249 0
Date submitted for ethics approval [7] 290249 0
10/07/2010
Approval date [7] 290249 0
07/10/2010
Ethics approval number [7] 290249 0
EC00208
Ethics committee name [8] 290250 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [8] 290250 0
Melbourne Health, Office for Research Level 6 East, Main Building Royal Melbourne Hospital 300-336 Grattan Street PARKVILLE VIC 3050
Ethics committee country [8] 290250 0
Australia
Date submitted for ethics approval [8] 290250 0
Approval date [8] 290250 0
22/06/2011
Ethics approval number [8] 290250 0
EC00243

Summary
Brief summary
Breathlessness continues to be a major clinical problem for many people with advanced progressive illnesses such as chronic obstructive pulmonary disease, end-stage cardiac failure, and cancer, even when they are receiving the best treatment for their underlying disease. There are phase II/III data and one meta-analysis which support the use of morphine in this setting, but further good phase III data are needed in order to that this is a well tolerated and effective intervention suitable for a broad range of people with refractory breathlessness. It is also important to establish that the overall net benefit outweighs any toxicity encountered. Further, a particular concern to 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 address this question through careful collection of non-invasive measures of respiratory function regularly throughout the study including end-tidal carbon dioxide at the beginning and the end of the study.

Objectives: Among participants with refractory breathlessness: 1) To compare the efficacy for relieving the sensation of dyspnoea, level of function, safety and quality of life (QOL) of opioids (sustained release morphine) with placebo; 2) To identify clinical and pharmacogenomic parameters that predict which individuals will achieve the greatest benefit from the intervention and establish any blinded participant preference. Secondary objectives focus of the impact of the intervention on improving quality of life, adverse effects, function, use of breakthrough opioids and clinical predictors of benefit.

Study design: This is a phase III, multi-site, randomised double-blind parallel arm fixed dose controlled trial studying treatment approaches for the palliative relief of breathlessness in participants with refractory dyspnoea. Participants will be randomised to fixed dose identical-appearing sustained release morphine (20 mg every 24 hours), or placebo for one week. The intervention period will run for 7 days; participants will receive study interventions at target doses and blinded therapy for constipation with each active arm together with identical appearing placebo for constipation for the placebo arm.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30109 0
Prof David Currow
Address 30109 0
Professor, Palliative & Supportive Services Flinders University 700 Goodwood Road Daw Park SA 5041
Country 30109 0
Australia
Phone 30109 0
+61 8 7221 8235
Fax 30109 0
Email 30109 0
[email protected]
Contact person for public queries
Name 13356 0
Prof David Currow
Address 13356 0
Professor, Palliative & Supportive Services
Flinders University
700 Goodwood Road
Daw Park SA 5041
Country 13356 0
Australia
Phone 13356 0
+61 8 7221 8235
Fax 13356 0
Email 13356 0
[email protected]
Contact person for scientific queries
Name 4284 0
Prof David Currow
Address 4284 0
Professor, Palliative & Supportive Services
Flinders University
700 Goodwood Road
Daw Park SA 5041
Country 4284 0
Australia
Phone 4284 0
+61 8 7221 8235
Fax 4284 0
Email 4284 0
[email protected]

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

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseControlled-Release Oxycodone vs. Placebo in the Treatment of Chronic Breathlessness-A Multisite Randomized Placebo Controlled Trial.2020https://dx.doi.org/10.1016/j.jpainsymman.2019.10.017
EmbaseRegular, sustained-release morphine for chronic breathlessness: A multicentre, double-blind, randomised, placebo-controlled trial.2020https://dx.doi.org/10.1136/thoraxjnl-2019-213681
EmbaseMinimal clinically important differences in average, best, worst and current intensity and unpleasantness of chronic breathlessness.2020https://dx.doi.org/10.1183/13993003.02202-2019
N.B. These documents automatically identified may not have been verified by the study sponsor.