'Recruitment not possible given changes to trial criteria

Breathlessness, the sensation of breathing discomfort, is a major problem in people with chronic obstructive pulmonary disease (COPD). Breathlessness that persists despite optimal management of the underlying disease(s) is said to be refractory.

Preliminary evidence suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, this research on morphine for breathlessness has not defined the best way to adjust the dose of the medication, or refined which people are most likely to have benefit, no response or side effects.

This is a randomized, double-blind phase III trial in people with COPD and significant refractory breathlessness, which will explore several important questions:

• Are regular, low dose opioids (morphine) at four possible doses over 3 weeks more effective than placebo medication (containing no active ingredient) at improving breathlessness?
• Does the medication have any effect on daily activity, breathlessness, and quality of life?
• What are the common side effects of this intervention?
• Does the benefit from the drug outweigh the side effects it produces?
• Are there specific characteristics of people who are more likely to receive benefit from sustained release morphine?

Participants will be allocated to receive three weeks of morphine sulfate (and laxative, docusate with senna), or placebo (and placebo laxative). The dose of morphine may be increased each week for weeks two and three. All medicines will appear the same (blinded) and neither the doctor nor the participant will know which medication the participant is receiving.

Participants will have a medical interview, 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 3 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". The term 'dyspnoea' is used interchangeably with breathlessness, shortness of breath, breathing difficulty and laboured breathing.

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 side effects) on chronic refractory breathlessness in people with chronic obstructive pulmonary disease (COPD) taking once daily, sustained release morphine at two different doses when compared to placebo.

Secondary objectives.

1. Are regular, low dose oral opioids 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 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
7. Does the treatment of breathlessness with regular, low dose morphine have any effect on general health status and quality of life?
8. Determine if there is a change in activities of daily living in those treated with opioids 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 sustained 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?

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 within trial incremental cost and cost effectiveness of the therapy
5. Evaluate any changes in total testosterone from baseline to the end of the three month extension.

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

Alternative hypothesis: The addition of regular, low dose oral sustained release morphine reduces the intensity of breathlessness in people with COPD and that this occurs safely.

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 3 months).

Stage 0. Baseline assessment: All consenting participants will complete 2 full days of baseline diary (morning and evening) in order to become accustomed to completing the diary regularly and to provide stable baseline data regarding breathlessness, symptoms and function (as measured by activPALR actigraphy). 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 KapanolR OR 16mg KapanolR. Twice daily diary. Participants randomised to KapanolR will also receive blinded docusate with sennosides, while those randomised to placebo will receive identical 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 KapanolR. Twice daily diary. Participants who were randomised to placebo in Stage 1 and KapanolR in Stage 2 will have blinded docusate with sennosides replace 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 KapanolR. Twice daily diary. activPALR accelerometer worn this week. Participants who were randomised to placebo in Stages 1 and 2 and KapanolR in Stage 3 will have blinded docusate with sennosides replace 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 three months. Diary one day each week. A blood test at the end of the three months will be taken for total testosterone levels.

Time period: up to 3 months.

Target population: This study is for people with optimally treated people with mild, moderate or severe chronic obstructive pulmonary disease (COPD).

Primary outcome and its assessment: Change from baseline average intensity of breathlessness over the previous 24 hours, measured each morning on a 11 point numerical rating scale.

Significance: The study will answer several practical questions including whether opioids have a net benefit in people with COPD in reducing refractory breathlessness, 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. All analyses will be conducted with Stata version 13.1. 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 KapanolR daily; and placebo compared to 16mg KapanolR daily. Change in breathlessness in the first week between these groups will be evaluated using a random effects mixed model.

Sample size calculations: All calculations assume Type I (familywise error rate (FWER)) error rate of 5% and Type II error rate of 20% (power of 80%) respectively. In order to account for attrition of 20% by the end of week 1, the study will recruit 144*100/ (100-20) = 180 subjects.

Inclusion Criteria:

• 18 years of age or older.
• Physician diagnosed COPD confirmed by spirometry, defined as a prior post-bronchodilator FEV1/FVC < 0.7 in accordance with the GOLD 2014 criteria
• 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 two (2) or higher on the modified Medical Research Council (mMRC) dyspnoea scale
• English speaking with sufficient reading and writing ability to complete the study questionnaires
• Assessed as competent (using SLUMS score of 27 for high school, and 25 for less than high school)
• Able and willing to give written informed consent

Exclusion Criteria:

• On regularly prescribed opioid medications, including codeine preparations at or above 8mg oral morphine equivalent daily 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.
• Chronic alcoholism, or previous 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.