Title: A parallel group, double-blind, randomised, placebo-controlled trial comparing the effectiveness and cost-consequence and cost effectiveness of low dose oral modified release morphine (MRM) versus placebo on the intensity of worst breathlessness in people with chronic breathlessness.
Funder: Department of Health and Social Care

Abstract: WHY THIS IS IMPORTANT?_x000D_ Chronic breathlessness affects most people with advanced lung cancer, lung fibrosis, COPD (chronic obstructive pulmonary disease; 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. _x000D_ WHAT WE PLAN TO DO_x000D_ 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 & 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._x000D_ 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), quality of life, how well the person sleeps, possible harms, 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._x000D_ WHAT WILL WE ACHIEVE_x000D_ If the study shows that morphine helps, and doesn’t harm, we want all suitable patients to be able to have access to it. However, we know some doctors, nurses, patients and carers may have concerns about morphine, so we will find out what support is needed to make sure morphine is available, and used carefully and in accordance with the evidence.

Lay abstract: BACKGROUND: Disabling chronic breathlessness often persists despite optimal treatment of cardiorespiratory disease(s). It is associated with poorer quality of life, shorter survival, limits in daily activities, unplanned hospital attendances/admissions. Some data support short-term use of regular, low-dose morphine for chronic breathlessness but longer term data are lacking. _x000D_ AIM: _x000D_ Test the effectiveness, cost-consequence and cost-effectiveness of regular, low dose oral modified release morphine (MRM) for breathlessness intensity compared with placebo. _x000D_ METHODS: A mixed-methods, phase 3, parallel arm, randomised placebo controlled trial in opioid naïve, ambulant people with moderate/severe (mMRC 3 or 4) breathlessness due to advanced disease. An internal pilot will test recruitment, and proceed to phase 3 if a priori criteria are met. Participants will be randomised (stratified for causal disease) to i) 5mg twice daily oral modified-release morphine and laxative or ii) placebo modified-release morphine and placebo laxative. Non-responders (<1 point improvement 0-10 numerical rating scale [NRS] worst breathlessness2) who are tolerating the treatment at day 7 will receive 10mg twice daily (or placebo) modified-release morphine. At 2 months, participants may enter an open label pharmacovigilance phase until study completion. Carers will be invited to participate. A normalisation process theory (NPT) study will address clinician and patient factors affecting trial equipoise and safe prescribing/monitoring._x000D_ Outcomes: PRIMARY: breathlessness (NRS worst breathlessness/24 hours at 4 weeks) measured at baseline, weeks 1, 2, 3 and 4. _x000D_ SECONDARY: distress due to breathlessness/24 hours (NRS); breathlessness mastery (Chronic Respiratory Questionnaire); quality of life (SF-12; EQ-5D-5L); sleep (Epworth); harms (respiratory, sedation, delirium, nausea, constipation); function (Australian Karnofsky Performance Scale); capability (ICECAP-SCM); healthcare utilisation, costs and cost-effectiveness; survival; carer burden (Zarit 6); safe prescribing. _x000D_ STATISTICAL ANALYSES: The intention-to-treat analysis of the primary outcome will use a repeated measures linear model (weeks 1 to 4), adjusted for baseline covariates and causal disease stratification. Secondary outcomes will be analysed as per the primary outcome with an appropriate generalised linear model. Time to event data will use a suitable survival model. Robustness of findings to missing data will be assessed. The health-economic analysis will report cost consequences and the incremental cost-effectiveness ratio._x000D_ SAMPLE SIZE: For 90% power and 5% level of significance detection of a 0.4 effect size in the primary outcome will need 264 participants. The expected standard deviation is around 2.5 so an effect size of 0.4 translates to an absolute mean difference of 1 in NRS (moderate change). For a post randomisation serial correlation of 0.5 on 4 measures of outcome, this sample size reduces to 168. Further adjustment for baseline covariates (correlation with outcome of 0.5) reduces this to 126. Allowing for 20% attrition increases the sample size to 158. These assumptions will be checked after 50 randomised achieving mature outcome data. _x000D_ A NORMALISATION PROCESS THEORY STUDY will explore attitudes and practices about morphine use (domains: coherence with existing practices; and for clinicians, patients and carers cognitive participation and collective action and reflexive monitoring). A modified Normalisation Measurement Instrument survey will inform interviews (clinicians, patients and carers) and field observations.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY;GENERIC HEALTH RELEVANCE