Morphine and BrEathLessness trial (MABEL)
- Conditions
- Chronic breathlessness due to heart disease, lung disease or cancer or post-COVID breathlessnessDyspnoea, dyspnea, shortness of breathRespiratory
Recruitment & Eligibility
- Status
- Completed
- Sex
- All
- Target Recruitment
- 158
Current participant inclusion criteria as of 19/02/2021:
1. Ambulant people with chronic breathlessness due to the following conditions. Chronic breathlessness is defined as those with persistent disabling breathlessness despite optimum treatment (as described) of their underlying disease in the opinion of the identified clinician.
1.1. Chronic heart failure (New York Heart Association (NYHA) class III or IV) [HFPEF or HFNEF] with left ventricular dysfunction only and meets all of the following:
1.1.1. 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
1.1.2. Reached target dose (or be on maximally tolerated dose, or be intolerant) of a beta adrenoceptor antagonist shown to improve prognosis
1.1.3. Reached target dose (or be on maximally tolerated dose, or be intolerant) of an aldosterone antagonist
1.2. Chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILD) and receiving optimum treatment as follows (based on NICE idiopathic pulmonary fibrosis (IPF)/pirfenidone/nintedanib guidelines, British Thoracic Society ILD guidelines [includes CTD-associated ILD], American Thoracic Society (ATS)/European Respiratory Society (ERS) guideline for IPF):
1.2.1. On optimal immunosuppression for connective tissue disease (CTD) ILD
1.2.2. On anti-fibrotic drug therapy (pirfenidone or nintedanib) for IPF if suitable.
1.2.3. On oxygen therapy (long term or ambulatory) if they fulfill guideline criteria 6
1.2.4. On appropriate treatment for pulmonary hypertension, if applicable
1.3. Post-COVID chronic breathlessness
1.4. Cancer. People with cancer, of any stage (0-4) 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.
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
4. Management of the underlying condition unchanged for the previous 7 days. This, and criterion 5, excludes the very unstable patient who is unlikely to complete the 56-day 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. Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth c
Current participant exclusion criteria as of 19/02/2021:
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 investigator's 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 4 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 2 weeks of discontinuation of their use
11. Within first 24 h post-operation
12. Are taking >20 mg diazepam or equivalent/day, or are unable to reduce dose before randomisation to <20 mg/day for the duration of the study treatment period
13. Persons who cannot or do not wish to take gelatin (used as a medication encapsulation ingredient)
_____
Previous 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method The amount of breathlessness at its most over the previous 24 h (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
Name Time Method