Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000589088
Ethics application status
Approved
Date submitted
20/07/2010
Date registered
21/07/2010
Date last updated
4/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A single arm, open label pilot study of low dose regular opioids with low dose regular benzodiazepines for the relief of refractory breathlessness.
Scientific title
A single arm, open label pilot study of low dose regular opioids with low dose regular benzodiazepines for the palliative relief of breathlessness for people with refractory dyspnoea.
Secondary ID [1] 252096 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory breathlessness 257650 0
Condition category
Condition code
Respiratory 257823 257823 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will take one dose of regular low dose oral sustained release morphine (10 mg) every morning and one dose of oral clonazepam (0.5 mg) every evening of each day of the intervention period. A total of four doses of oral clonazepam and five doses of low dose oral sustained release morphine will be administered to all participants.
This is a four day (96 hour) study. Participants will complete the study intervention in the morning of the 5th day when the exit assessments will be made. In order that participants may continue with ongoing treatment a 5th morphine dose is administered in the morning of the exit assessment.
Intervention code [1] 256721 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 258684 0
The primary outcome measure to inform the power calculations of a definitive study will be based on average breathlessness in the previous 12 hours (morning and evening) on the Visual Analogue Scale (VAS) score for breathlessness.
Timepoint [1] 258684 0
Day 5
Secondary outcome [1] 264703 0
Whether any perceived benefit is maintained over the study period given concerns about rapid tolerance to any of the beneficial effects of benzodiazepines using daily Visual Analogue scores for breathlessness, assessment of function using the dyspnoea exertion scale and a comparison of descriptors of breathless between baseline and exit.
Timepoint [1] 264703 0
Baseline, daily, and Day 5
Secondary outcome [2] 264704 0
Use of rescue medications such as apperients, other medications aimed at breathlessness control and oxygen. This will be recorded within the participant diary and the concurretn mediction sheet.
Timepoint [2] 264704 0
Day 5
Secondary outcome [3] 264705 0
Safety measures by National Cancer Institutes of Health Adverse Event Criteria daily, at exit and 4 week follow-up (weekly telephone call).
Timepoint [3] 264705 0
Daily, day 5, exit and weekly for four weeks
Secondary outcome [4] 264706 0
Global impression of change (5 point likert scale) and wish to continue to take the medication if available (Yes/no answer) using patient interview at exit.
Timepoint [4] 264706 0
Day 5

Eligibility
Key inclusion criteria
Adults (age>18)
Refractory dyspnoea where the underlying cause of the dyspnoea has been maximally treated.
A medical specialist must document that all identified reversible causes of the dyspnoea are being optimally managed
Breathlessness of a level 3 or higher on Modified Medical Research COuncil (MRC) dyspnoea scale
On stable medications over the prior week except “as needed” medications
Prognosis of at least 2 months in the opinion of the treating clinician
English-speaking and able to read questionnaires
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Allergic to clonazepam or to other benzodiazepines
Severe liver disease, key results greater than three times the upper limit of normal for the local laboratory
On regular opioid medications above the dose in the study (10 mg)
Anemia requiring transfusion
Confusion with a Folstein Mini-mental Status Exam <24/30.
Severely restricted performance status with Australian Modified Karnofsky Scale score of <50 at baseline
Uncontrolled nausea, vomiting and/or gastrointestinal obstruction.
Renal dysfunction with creatinine clearance calculated as less than 25 mls / minute.
Evidence of respiratory depression with resting respiratory rate less than 8 breaths per minute or a history of opioid induced respiratory depression.
Active respiratory or cardiac event in the previous week, not including upper respiratory tract infections.
Unable to give informed consent or complete diary entries.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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 to briefly explain the study. If the person is interested to learn more about the study, the Site Investigator will be available to explain the study further.
Obtaining consent for this study will be a process of information exchange between the site investigator, the potential participant and any other person the potential participant believes should be included in the discussion. The participant information sheet will be used as a basis for the discussion, which will cover all procedures, benefits, burdens and side effects expected of possible during the study. The participant will be given opportunity (in time and physical capacity) to consider the study and formulate questions. Any questions will be addressed and answered fully.
All baseline assessments will be undertaken before the first study dose. The first dose of regular low dose sustained release morphine (10 mg) will be taken on the morning of day 1 and the first dose of clonazepam (0.5 mg) will be started on the evening of day 1. Both will be taken at 24 hourly intervals.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
None
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This is a pilot study
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
20/08/2010
Actual
Date of last participant enrolment
Anticipated
17/02/2012
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
10
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 2144 0
Modbury Hospital - Modbury
Recruitment hospital [2] 2145 0
Repatriation Hospital - Daw Park
Recruitment hospital [3] 2146 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 7823 0
5092 - Modbury
Recruitment postcode(s) [2] 7824 0
5041 - Daw Park
Recruitment postcode(s) [3] 7825 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 257198 0
Charities/Societies/Foundations
Name [1] 257198 0
Foundation Daw Park
Country [1] 257198 0
Australia
Primary sponsor type
University
Name
Flinders University
Address
Flinders Drive
Bedford Park
South Australia 5042
Country
Australia
Secondary sponsor category [1] 256453 0
None
Name [1] 256453 0
Address [1] 256453 0
Country [1] 256453 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 259227 0
Central Northern Adelaide Health Service, Ethics of Human Research Committee
Ethics committee address [1] 259227 0
The Queen Elizabeth Hospital
28 Woodville Road
Woodville South, SA 5011
Ethics committee country [1] 259227 0
Australia
Date submitted for ethics approval [1] 259227 0
03/05/2010
Approval date [1] 259227 0
08/06/2010
Ethics approval number [1] 259227 0
EC00190
Ethics committee name [2] 290635 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [2] 290635 0
Flinders Medical Centre
Bedford Park
SA 5042
Ethics committee country [2] 290635 0
Australia
Date submitted for ethics approval [2] 290635 0
29/08/2011
Approval date [2] 290635 0
13/09/2012
Ethics approval number [2] 290635 0
EC00188

Summary
Brief summary
Breathlessness at rest or on minimal exertion (speaking, bathing, dressing) continues to be a major clinical problem for many people with advanced progressive illnesses such as cancer, end-stage cardiac failure or chronic obstructive pulmonary disease even when they are receiving the best treatment for that underlying disease. Although there are some interventions that may offer benefit (oxygen therapy (when oxygen levels in the blood are low), sustained release low dose morphine) for this refractory breathlessness, other therapeutic options need to be explored.

Benzodiazepines are widely used as sedatives to help with sleep, to reduce anxiety and to decrease the risk of seizures in people who have, or are at risk of epilepsy. These medications are also widely used around the world to treat breathlessness, however there have been no adequately powered studies that have explored net symptomatic benefit (symptom relief, side effects, maintenance of any benefit) for refractory breathlessness. Each benzodiazepine has slightly different properties in the level of sedation, ability to reduce anxiety and duration of effect.

Two key questions need to be answered in order to establish the place of benzodiazepines in the management of refractory background dyspnoea: is there a net symptomatic benefit from benzodiazepines and, if so, is that benefit maintained over time? The latter question is important given the rapid tolerance to benzodiazepines when used as sedatives.

Given the ability to dose once daily, the well defined pharmacokinetic and pharmacodynamics (including in children) and the range of formulations/routes of administration available, clonazepam has been chosen for this study. The proposed dose is unlikely to cause significant sedation and is at the lower end of the dosing range for its major long term clinical use in epilepsy.

Aim: The primary aim of this pilot study is to refine protocol design including recruitment and retention to the study, establish levels of symptomatic response and variance in that response for power calculations for a definitive trial, and establish whether that benefit is maintained at two weeks.
Trial website
Trial related presentations / publications
Allcroft P, Margitanovic V, Greene A, Agar MR, Clark K, Abernethy AP, Currow DC. The role of benzodiazepines in breathlessness: a single site, open label pilot of sustained release morphine together with clonazepam. Journal of Palliative Medicine, July 2013; 16(7): 741-744
Public notes

Contacts
Principal investigator
Name 31335 0
Prof David Currow
Address 31335 0
Flinders University
700 Goodwood Road
Daw Park SA 5041
Country 31335 0
Australia
Phone 31335 0
+61 8 8275 1732
Fax 31335 0
Email 31335 0
[email protected]
Contact person for public queries
Name 14582 0
Ms Belinda Fazekas
Address 14582 0
Palliative Care Clinical Studies Collaborative
700 Goodwood Road
Daw Park
South Australia
5041
Country 14582 0
Australia
Phone 14582 0
+61 8 8275 1396
Fax 14582 0
Email 14582 0
[email protected]
Contact person for scientific queries
Name 5510 0
Prof Professor David Currow
Address 5510 0
Department of Palliative and Supportive Services
Flinders University
C/- Health Sciences Building
Repatriation General Hospital
Daws Road
Daw Park SA 5041
Country 5510 0
Australia
Phone 5510 0
+61 8 7221 8235
Fax 5510 0
Email 5510 0
[email protected]

No information has been provided regarding IPD availability


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No Supporting Document Provided



Results publications and other study-related documents

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