Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion.

Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms).

This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions:

• Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness?
• Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness?
• Does the medication have any effect on daily activity and quality of life?
• What are the common or serious side effects of this intervention?
• Does the benefit from the medication outweigh the side effects it produces?
• Are there specific characteristics of people who are more likely to receive benefit from extended release morphine?

Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses.

Participants will have a medical interview and physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples.

Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 6 month extension stage.

The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.

Background: Three hundred thousand (300,000) Australians are breathless at rest or on minimal exertion, often for years, despite optimal treatment of the underlying cause(s). This includes more than 70,000 people who are too breathless to leave their homes often for long periods of time. Underlying causes for such severe and ongoing breathlessness include chronic obstructive pulmonary disease (COPD), interstitial lung disease, heart failure, neurodegenerative diseases such as motor neurone disease and cachexia from any cause. The prevalence of chronic refractory breathlessness will continue to increase as the population ages because the chronic progressive diseases where breathlessness is common are increasing in prevalence. Nearly one half of all people experience distressing breathlessness during the last year of life.

The American Thoracic Society defines breathlessness as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity".

Internationally, no medication is registered for the symptomatic reduction of chronic refractory breathlessness despite recommendations from the American Thoracic Society, the American College of Physicians, the Canadian Thoracic Society and the American College of Chest Physicians that regular, low-dose morphine is the evidence-based pharmaceutical option.

Aim: To enhance the evidence base for the pharmacological treatment of chronic refractory breathlessness using potential therapies compared to placebo.

Primary objective: To compare the difference of the net clinical effect (benefits and harms) on chronic refractory breathlessness in people with chronic obstructive pulmonary disease (COPD) and baseline breathlessness of 3 or 4 on the modified Medical Research Council breathlessness scale (mMRC) taking once daily, extended release oral morphine at two different doses when compared to placebo.

Co-primary objective: To compare the difference in steps per day measured using the FitbitR between people taking once daily, extended release oral morphine , by dosing level.

Secondary objectives

1. Is regular, low dose extended release oral morphine safe, including when the dose is titrated upwards, in a population of people with refractory breathlessness and COPD?
2. Do people whose breathlessness is helped by regular, low dose extended release oral morphine get additional benefit by further increasing the dose of morphine?
3. Over what period of time does benefit continue to increase once a dose level with benefit is achieved?
4. What percentage of people derive clinically significant benefit at each of four dosing levels, over and above placebo?
5. At the lower doses, is there evidence that any benefit does not last the full 24 hours? (end-of-dose failure)
6. Can we predict response, benefit and side effects from baseline demographic and clinical data in those people who get morphine?
7. Does the treatment of breathlessness with regular, low dose morphine have any effect on general health status and quality of life?
8. Is there any difference in activities of daily living in those treated with regular, low dose extended release oral morphine when compared to placebo.
9. Assess any effects of each treatment on anxiety and depression.
10. Understand the longer term benefits and side effects from extended release morphine in people with COPD when compared to placebo.
11. Do participants, while still blinded, have any preference at the end of the three week study?
12. Do caregivers notice any change in the burden and challenge of caregiving if the person they care for receives regular, low dose, extended release oral morphine for chronic breathlessness?
13. Do participants experience withdrawal from opioids at the end of the study as study medication ceases?

Sub-studies

1. Identify pharmacokinetic and pharmacodynamic parameters that may help to predict which individuals will achieve the greatest benefit in week one of therapy (8mg/day, 16mg/day).
2. Identify pharmacogenomic variations in opioid receptors and signaling that may help to predict clinical response (benefit, side effects or no response).
3. Study the effect on sleep in people participating in the study
4. Compare the impact on simulated driving in a sub-group of participants using commercially available driving simulators
5. Compare caregiver self-efficacy at the end of weeks one and three between groups when compared to baseline.
6. Compare the within trial incremental cost and cost effectiveness of the therapy
7. Evaluate any changes in total testosterone from baseline to the end of the 6-month extension.

Null hypothesis #1: In people who have COPD with refractory breathlessness, there is no difference in worst breathlessness intensity in the previous 24 hours with the addition of regular, low dose oral extended release morphine when compared to placebo.

Alternative hypothesis #1: The addition of regular, low dose oral extended release morphine reduces the intensity of worst breathlessness in the previous 24 hours in people with COPD and chronic breathlessness.

Null hypothesis #2: In people who have COPD with refractory breathlessness, there is no difference in the number of steps taken each day with the addition of regular, low dose oral extended release morphine when compared to placebo.

Alternative hypothesis #2: The addition of regular, low dose oral extended release morphine increases people's activities in people with COPD and chronic breathlessness.

Study design:

A five stage, national, multi-site, double-blind, parallel arm, block randomised, placebo controlled, factorial, dose increment phase III study of opioids for chronic refractory breathlessness in people with COPD:

Stage 0 - baseline (2 days); Stage 1 - randomisation #1 (1 week); Stage 2 - randomisation #2 (1 week); Stage 3 - randomisation #3 (1 week); and Stage 4 - an optional blinded extension arm (up to 6 months).

Stage 0. Baseline assessment: All consenting participants will complete 2 full days of baseline diary (evening) in order to become accustomed to completing the diary regularly and to provide stable baseline data regarding breathlessness, symptoms and activity (as measured by FitBit®). At completion of the 2 days, the participant will be reviewed, complete the remaining baseline assessments (questionnaires, measures and baseline safety data), and will then be eligible to be randomised the first time.

Time period: Two full days (4 diary entries)

Stage 1. Randomisation #1: Randomisation to mane orally: placebo OR 8mg extended release morphine OR 16mg extended release morphine. Daily diary. A FitBit will be worn this week. Participants randomised to extended release morphine will also receive blinded docusate with sennosides, while those randomised to placebo will receive identical laxative placebo. This is the primary outcome (end point) of the study.

Time period: 1 week

Stage 2. Randomisation #2: While continuing the arm assigned in Stage 1, add a randomisation to mane orally: placebo OR 8mg extended release morphine. Daily diary. Participants who were randomised to placebo in Stage 1 and extended release morphine in Stage 2 will have blinded docusate with sennosides replace the laxative placebo.

Time period: 1 week

Stage 3. Randomisation #3: While continuing the arm assigned in Stages 1 and 2, add a third randomisation to mane orally: placebo OR 8mg extended release morphine. Daily diary. A FitBit will be worn this week. Participants who were randomised to placebo in Stages 1 and 2 and extended release morphine in Stage 3 will have blinded docusate with sennosides replace the laxative placebo.

Time period: 1 week

Stage 4. Extension (optional for each individual participant): Continue double blind medications from Stages 1, 2 and 3 for up to six months. Diary one day each week. A blood test at the end of the six months will be taken for total testosterone levels.

Time period: up to 6 months.

Target population: This study is for people with optimally treated chronic breathlessness (modified Medical Research Council Scale (mMRC) of 3 or 4) and chronic obstructive pulmonary disease (COPD).

Primary outcome and its assessment: Change in the worst intensity of breathlessness in the previous 24 hours each morning, measured using an 11 point Numerical Rating Scale, recorded in the evening diary entry by participants.

Significance: The study will answer several practical questions including whether regular, low dose extended release oral morphine delivers a net benefit in people with COPD in reducing breathlessness on exertion (worst breathlessness in a 24 hour period) in steady state; whether dose increases beyond initial response provide a greater net benefit; the pattern of symptomatic response in the days after successful titration; and the proportion of people who derive a clinically meaningful symptomatic benefit at each dose level.

Analysis plan: All analyses will be conducted on an intention-to-treat basis. Missing data will be imputed using multiple imputation with 50 resamples drawn. The primary comparisons on which the study is powered are at the end of week 1: placebo compared to 8mg extended release morphine daily; and placebo compared to 16mg extended release morphine daily. Change in breathlessness in the first week between these groups will be evaluated using a random effects mixed model.

Sample size calculation All calculations assume Type I (family wise error rate (FWER)) error rate of 5% and Type II error rate of 20% (power of 80%) respectively. The primary analyses comprise two comparisons made at the end of week 1 (placebo compared to 8mg and placebo compared to 16mg), each assessed at alpha = 0.025 (two-sided) to protect the overall type 1 error rate. Using the variance-covariance matrix and mean responses from data arising from the MOP study, it was found through simulations (n = 1000) and using a mixed model analysis over 8 days, that 45 subjects per group are required to detect a difference of 1.09 NRS units where the standard deviation at each day varied between 2.0 and 2.5 NRS units.

The second family comprises one comparison, involving only those subjects who improved by 1.09 NRS unit after receiving a given dose vs. not. Based on this 38 per group are needed. Using the same dataset 52% of those in the active group improved by at least this amount. For a total sample of N, there are N/3 subjects who receive 0mg, 8mgand 16mg at week 1. In the control arm (0mg) there are no responses at the end of the first week. For the N/6 subjects receiving 8mg at the start of week 2, N/6*0.52 are expected to respond. In the arm receiving 8mg, N/3*0.52 are expected to respond at the end of the first week. Of the N/3*0 .48 that didn't respond in the first week 52% are expected to respond at the end of the second week. The same situation pertains to the group receiving 16mg at the start of week 1. For the sample of 135 subjects this implies that 82 in total are expected to respond. Assuming equal numbers are randomised to receiving the next incremental dose or remaining on the same dose this provides over 80% power.

Allowing for 20% attrition requires a total sample size of 171 subjects.

Inclusion Criteria:

• 18 years of age or older.
• Physician diagnosed COPD confirmed by spirometry with the most recent result available defined as a prior post-bronchodilator FEV1/FVC < 0.7 in accordance with the GOLD 2014 criteria.
• Respiratory physician confirmed optimisation of treatment of COPD.
• On stable medications relating to the optimal treatment of COPD or its symptomatic management over the prior week except routine "as needed" medications.
• Breathlessness of a level three (3) or four (4) on the modified Medical Research Council (mMRC) breathlessness scale.
• worst breathlessness intensity in the previous 24 hours was at least 3/10 on a 0-10 numerical rating scale (NRS).
• English speaking with sufficient reading and writing ability to complete the study questionnaires
• Assessed as competent (using St Louise University Mental Status Examination (SLUMS) score of 27/30 for people whose highest level of education was high school, and 25/30 for people who did not complete high school).
• Able and willing to give written informed consent.

Exclusion Criteria:

• On any opioid for breathlessness in the previous seven (7) days.
• On regularly prescribed opioid medications for other conditions, including codeine preparations at or above 8mg oral morphine equivalent daily dose (MEDD) in the previous seven (7) days.
• History of adverse reactions to any of the study medications or constituents in the placebo;
• Australian-modified Karnofsky performance score (AKPS) less than 50 at the beginning of the study.
• Respiratory or cardiac event in the previous one week (excluding upper respiratory tract infections). Illness must have resolved completely prior to baseline evaluation, as judged by the person's treating physician.
• Evidence of respiratory depression with resting respiratory rate <8/min.
• Documented central hypoventilation syndrome.
• Current history of abuse of alcohol, or recent history of substance misuse.
• Uncontrolled nausea, vomiting or evidence of a gastrointestinal tract obstruction.
• Renal dysfunction with creatinine clearance calculated (MDRD) less than 20 mls/minute.
• Evidence of severe hepatic impairment defined as transaminases or bilirubin >4x normal (Excluding Gilbert's syndrome)
• Pregnant or breastfeeding.