ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Refractory breathlessness

Condition category

Condition code

Respiratory

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]

Treatment: Drugs

Comparator / control treatment

None

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Day 5

Secondary outcome [1]

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]

Baseline, daily, and Day 5

Secondary outcome [2]

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]

Day 5

Secondary outcome [3]

Safety measures by National Cancer Institutes of Health Adverse Event Criteria daily, at exit and 4 week follow-up (weekly telephone call).

Timepoint [3]

Daily, day 5, exit and weekly for four weeks

Secondary outcome [4]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Modbury Hospital - Modbury

Recruitment hospital [2]

Repatriation Hospital - Daw Park

Recruitment hospital [3]

Flinders Medical Centre - Bedford Park

Recruitment postcode(s) [1]

5092 - Modbury

Recruitment postcode(s) [2]

5041 - Daw Park

Recruitment postcode(s) [3]

5042 - Bedford Park

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Foundation Daw Park

Address [1]

Daws Road
Daw Park
South Australia 5041

Country [1]

Australia

Primary sponsor type

University

Name

Flinders University

Address

Flinders Drive
Bedford Park
South Australia 5042

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Northern Adelaide Health Service, Ethics of Human Research Committee

Ethics committee address [1]

The Queen Elizabeth Hospital
28 Woodville Road
Woodville South, SA 5011

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/05/2010

Approval date [1]

08/06/2010

Ethics approval number [1]

EC00190

Ethics committee name [2]

Southern Adelaide Clinical Human Research Ethics Committee

Ethics committee address [2]

Flinders Medical Centre
Bedford Park
SA 5042

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

29/08/2011

Approval date [2]

13/09/2012

Ethics approval number [2]

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

Prof David Currow

Address

Flinders University
700 Goodwood Road
Daw Park SA 5041

Country

Australia

Phone

+61 8 8275 1732

Fax

david.currow@flinders.edu.au

Contact person for public queries

Name

Belinda Fazekas

Address

Palliative Care Clinical Studies Collaborative
700 Goodwood Road
Daw Park
South Australia
5041

Country

Australia

Phone

+61 8 8275 1396

Fax

belinda.fazekas@health.sa.gov.au

Contact person for scientific queries

Name

Professor David Currow

Address

Department of Palliative and Supportive Services
Flinders University
C/- Health Sciences Building
Repatriation General Hospital
Daws Road
Daw Park SA 5041

Country

Australia

Phone

+61 8 7221 8235

Fax

david.currow@flinders.edu.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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No additional documents have been identified.

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