Chronic breathlessness due to heart disease, lung disease or cancer or post-COVID breathlessness Respiratory Dyspnoea, dyspnea, shortness of breath
Conditions
Interventions
Randomised patients will receive either modified release morphine 5 mg capsules twice daily with docusate laxative 100 mg capsules twice daily (intervention arm 1) or placebo “5mg” morphine capsules t
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 clinicia
Sponsors
Hull University Teaching Hospitals NHS Trust (UK)
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: 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
Exclusion criteria
Exclusion criteria: 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 19/02/2021: All measured at baseline, and day 2, 4, 7, 14, 28, 56 1. Distress due to breathlessness using 0-10 NRS distress/past 24 h 2. Assessment of related symptoms using 0-10 NRS (pain, cough) 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 12; VOICES survey for those bereaved during the study time course 8. Opioid withdrawal: Subjective opioid withdrawal scale (SOWS) _____ Previous 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) | — |
Countries
England, United Kingdom
Outcome results
None listed