Condition category
Respiratory
Date applied
31/01/2019
Date assigned
25/02/2019
Last edited
25/02/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Chronic breathlessness affects most people with advanced lung cancer, lung fibrosis, chronic obstructive pulmonary disease (COPD), emphysema, and heart failure. People are often disabled by this long-term breathlessness despite best treatments of the underlying condition(s). Chronic breathlessness is frightening for patients and their families. It reduces quality of life, limits how people manage at home with everyday functions (bathing, dressing, preparing food) and at work, increases the number of emergency hospital visits and admissions, and shortens life (although some people may live with chronic breathlessness for many years). Studies of a few days of regular, low doses of ”long-acting” morphine show that this can help reduce chronic breathlessness safely, particularly for people with COPD - but we don't know if it keeps working when used for longer periods, or if it does any harm in the longer term. At present, some doctors will prescribe morphine for breathlessness and others won’t.
We will test if regular, low dose morphine capsules regularly twice a day are better than placebo (dummy) ones for chronic breathlessness and whether morphine improves daily activity in 158 people. We will also see any effect on the need to go to accident and emergency, call an ambulance, phone a GP after hours, or go into hospital. We will cost this care and, if it works, find the best ways to provide long-acting morphine to people who need it and would safely benefit from it.

Who can participate?
Men and women with breathlessness due to heart or lung disease or cancer that persists despite best treatment of their underlying disease.

What does the study involve?
People with fully treated disease still causing chronic breathlessness participating in the study will be chosen at random to have either morphine or a placebo capsule twice a day for two months. After a week, the dose will be increased if breathlessness isn’t improving and they don’t want to stop because of side-effects. At the end, participants can try morphine as part of their usual care if they want, while being followed up by the study team. We will judge success on how participants’ worst daily breathlessness feels. We will also measure how much activity they actually do (daily step count using a small monitor worn on the wrist), quality of life, how well the person sleeps, possible side-effects, overall ability to function, use of healthcare services and - as the study includes people with serious illness - survival. Family members will also be able to help by completing questionnaires telling us about caring for someone with breathlessness. Alongside the study, we will ask clinicians and study participants about issues which would help or hinder patients to have routine access to regular, low dose morphine for breathlessness if the study shows it is the better treatment.
Participants will be required to attend the research clinic 2 times over 2 months. Other assessments can be done by phone or the research nurse can visit at home. Participants will complete the study questionnaires and measures when needed (the research nurse will help) and continue with any treatment the usual medical team advises. The activity monitor will be worn for 7 days before the study starts and again during the last 7 days of the first month.

What are the possible benefits and risks of participating?
Although this study may not directly benefit participants, it may improve future treatment of breathlessness. Morphine has been used in medical practice for many years. We therefore know what side-effects might occur. Most patients cope very well with the low doses of morphine that we intend to use. We will check regularly about the known side effects that people can get. These include nausea or feeling sick, constipation or sleepiness. In some people concentration may be affected until they get used to the steady dose after a few days. Therefore participants will be advised to observe the usual warnings about operating machinery or driving during the first week of taking the medicine. After this time they should carefully consider whether concentration is affected before driving - if in doubt, they should not drive. If side effects persist which may affect driving, participants would need to inform the DVLA if they wished to continue with study medication. As with any other change in medication, participants should inform their motor insurance company to ensure cover is valid. Although people may worry about becoming addicted to morphine, we rarely see this in people who take it for health reasons. However, if the body has become accustomed to morphine over time, then it may take a few days to readjust when morphine is stopped. This is not expected to be an issue with this study but all participants will receive a phone call in the few days after the end of the study to check all is well.

Where is the study run from?
The study is run by the Edinburgh Clinical Trials Unit on behalf of the Sponsor (Hull University Teaching Hospitals NHS Trust) and Chief Investigator (Prof. Miriam Johnson, University of Hull). About 14 centres in the United Kingdom will be involved with each centre recruiting about 1-2 participants per month.

When is study starting and how long is it expected to run for?
The study will start recruitment from December 2019. Recruitment will be open for up to two years.

Who is funding the study?
National Institute for Health Research, Health Technology Assessment, UK.

Who is the main contact?
Professor Miriam Johnson
miriam.johnson@hyms.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Miriam Johnson

ORCID ID

http://orcid.org/0000-0001-6204-9158

Contact details

HYMS
Allam Medical Building
The University of Hull
Hull
HU6 7RX
United Kingdom
01482 463309
miriam.johnson@hyms.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

1.0

Study information

Scientific title

A parallel group, double-blind, randomised, placebo-controlled trial comparing the effectiveness and cost effectiveness of low dose oral modified release morphine versus placebo on patient-reported worst breathlessness in people with chronic breathlessness.

Acronym

MABEL

Study hypothesis

The null hypothesis is that there is no difference in the relief of chronic breathlessness in people with heart or lung disease or cancer provided by morphine or placebo.

Ethics approval

To be submitted

Study design

Two-month parallel randomised double-blind placebo-controlled trial.

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Chronic breathlessness due to heart disease or lung disease or cancer

Intervention

Randomised patients will receive either modified release morphine 5mg capsules twice daily with docusate laxative 100mg capsules twice daily (intervention arm 1) or placebo “5mg” morphine capsules twice daily and placebo docusate laxative capsules twice daily (intervention arm 2). To maintain blinding active drug and placebo capsules and their packaging will look the same.
The dose may be increased to 10mg twice daily if the participant does not achieve an improvement (reduction) from baseline in the primary outcome measures (worst breathlessness over the past 24 hours – 0 to 10 numerical rating scale(NRS)) and the participant had acceptable side-effects (see definition of acceptable side-effects below). The decision to dose escalate will be made if the NRS measure has not improved by at least one point at the day 7 assessment. The dose increase will start on day 15 to allow time for the prescription to be issued, dispensed and new dose to be supplied to the participant in a manner which ensures continuous drug supply. Whilst awaiting the new dose, the participant will continue on 5mg twice daily.

Dose titration applies only if the participant has acceptable side-effects

The morphine preparation is MST Continus, encapsulated for blinding purposes.

Each participant will take the study medication for two months.

Acceptable side-effects in this trial are defined as:
1. No side-effects (all CTCAE grades 0)
OR
2. i) Gastro-intestinal effects acceptable (nausea, vomiting, constipation CTCAE grades ≤ 2) AND neuro-cognitive effects acceptable (cognition, memory, hallucinations CTCAE grade 0 AND no vivid dreams; grade 1 symptoms acceptable if present at the same grade at baseline);
ii) AND there is ongoing side-effect management and monitoring;
iii) AND both clinician and participant are happy to continue or increase IMP as appropriate

Intervention type

Drug

Phase

Phase III

Drug names

Modified release morphine

Primary outcome measure

The amount of breathlessness at its most over the previous 24 hours (worst breathlessness) measured at day 28 using a 0 – 10 numerical rating scale (NRS) where 0 = no breathlessness and 10 = the most imaginable breathlessness).

Secondary outcome measures

All measured at baseline, and day 2, 4, 7, 14, 28, 56
1. Distress due to breathlessness using 0 to 10 NRS distress/past 24 hours
2. Assessment of related symptoms using 0-10 NRS (pain) and quality of sleep (Epworth Sleepiness Scale); sleepiness using the Karolinska Sleepiness Scale (KSS)
3. Assessment of physical activity (daily steps Actigraphy monitor); performance status (Australia modified Karnofsky Performance Status (AKPS) and cognitive function (St Louis University Mental Status (SLUMS)
4. Quality of life (SF-12)
5. Health economic assessment (EQ5D; EQVAS; ICECAP; service utilisation);
6. Harms, including survival
7. Carer burden (Zarit 6; VOICES survey for those bereaved during the study time course
8. Opioid withdrawal: Subjective opioid withdrawal scale (SOWS)

Overall trial start date

01/03/2019

Overall trial end date

31/07/2022

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Ambulant people with chronic breathlessness due to cardiac, respiratory disease or cancer*. Chronic breathlessness is defined as those with persistent disabling breathlessness despite optimum treatment** of their underlying disease in the opinion of the identified clinician.
2. Breathlessness severity defined as modified Medical Research Council (mMRC) breathlessness scale grade 3 or 4 (i.e. stops for breath after walking about 100 yards or after a few minutes on level ground, or is too breathless to leave the house or is breathless when dressing). A pooled data study shows that people with worse baseline breathlessness are more likely to respond to opioids. A phase 3 trial in people with COPD showed that those with mMRC grade 3 or 4 were more likely to respond to opioids. This approach also concurs with clinical recommendations.
3. Male or female aged ≥ 18 years old
4. Management of the underlying condition unchanged for the previous 1 week. This, and criterion 5, excludes the very unstable patient who is unlikely to complete the 8 week RCT phase.
5. Australia-modified Karnofsky Performance Scale (AKPS) ≥40. This, with criterion 4, is to identify patients most likely to complete the 2 months RCT phase.
6. Estimated Glomerular Filtration Rate (eGFR) of 25 ml/min or more, unless the primary diagnosis is heart failure (≥ 30 ml/min). Renal clearance of eGFR ≥25 ml/min is adequate for the study doses of morphine, however, in heart failure patients are more likely to have fluctuations in renal function for which the higher level will allow.
7. If female and of child-bearing potential, must agree to use adequate contraception when taking IMP and for 7 days following cessation
8. Able to complete questionnaires and trial assessments
9. Willing to stop wearing any personal activity meter during the actigraphy attachment period.
10. Able to provide written informed consent

* People with cancer may be included only if they are opioid naïve (as defined in the exclusion criteria) as there are insufficient data to guide dosing of opioids for breathlessness in people already taking opioids for pain.
Eligible cardio-respiratory diseases: chronic obstructive pulmonary disease (COPD); interstitial lung diseases (ILD); chronic heart failure (New York Heart Association (NYHA) class III or IV) [HFPEF or HFNEF]
**Optimum tolerated treatment is defined according to condition:
The assessment of whether the participant is receiving optimal treatment for their underlying disease is to be made by the identifying clinician and should be based on the following guidance (unless specific contra-indications):
1. For COPD or ILD***
2. For COPD or ILD***
2.1 On optimal immunosuppression for Connective Tissue Disease (CTD) ILD
2.2 On anti-fibrotic drug therapy (Pirfenidone or Nintedanib) for IPF if suitable.
2.3 On oxygen therapy (long term or ambulatory) if they fulfill guideline criteria 61
2.4 On appropriate treatment for pulmonary hypertension, if applicable
3. For heart failure (left ventricular dysfunction only):
3.1 Reached target dose (or be on maximally tolerated dose, or be intolerant) of an inhibitor of the renin-angiotensin system (including ARNIs) shown to improve prognosis;
AND
3.2 Reached target dose (or be on maximally tolerated dose, or be intolerant) of a beta adrenoceptor antagonist shown to improve prognosis;
AND
3.3 Reached target dose (or be on maximally tolerated dose, or be intolerant) of an aldosterone antagonist.
*** Based on NICE Idiopathic Pulmonary Fibrosis (IPF) / pirfenidone/ nintedanib guidelines, British Thoracic Society ILD guidelines (includes CTD assoc ILD), American Thoracic Society (ATS) / European Respiratory Society (ERS) guideline IPF.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

158

Participant exclusion criteria

1. Unable to provide informed consent
2. Unable to complete baseline study questionnaires even with the assistance of the study nurse
3. Presence of co-existing malignant disease, only if this would affect the study in the investigators’ opinion
4. Used opioid medications > 5 mg morphine-equivalents daily for > 7 out of last 14 days
5. Morphine or docusate allergies or hypersensitivity to any of the tablet constituents as assessed by a clinician
6. Central hypoventilation syndrome (e.g. Ondine’s curse post stroke)
7. Involved in another medicinal trial (CTIMP) within the past four weeks
8. Pregnant or lactating.
9. Respiratory depression, head injury, paralytic ileus, 'acute abdomen', acute hepatic disease
10. Concurrent administration of monoamine oxidase inhibitors or are within two weeks of discontinuation of their use
11. Within first 24 hours post-operation

Recruitment start date

01/12/2019

Recruitment end date

30/09/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Hull and York Medical School
University of Hull
Hull
HU6 7RX
United Kingdom

Sponsor information

Organisation

Hull University Teaching Hospitals NHS Trust (UK)

Sponsor details

2nd Floor
Daisy Building
Castle Hill Hospital
Castle Road
Hull
HU16 5JQ
United Kingdom
01482 461903
james.illingworth@hey.nhs.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

Health Technology Assessment Programme

Alternative name(s)

NIHR Health Technology Assessment Programme, HTA

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date

Intention to publish date

30/09/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes