Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.

Placebo on weeks one and two. Morphine 8 mg/day on week three.

Placebo on week one. Morphine 8 mg/day on weeks two and three.

Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.

Morphine 8 mg/day on weeks one, two and three.

Morphine 8 mg/day on weeks one and two. Morphine 16 mg/day on week three.

Morphine 8 mg/day on week one. Morphine 16 mg/day on weeks two and three.

Morphine 8 mg/day on week one. Morphine 16 mg/day on week two. Morphine 24 mg/day on week three.

Morphine 16 mg/day on weeks one, two and three.

Morphine 16 mg/day on weeks one and two. Morphine 24 mg/day on week three.

Morphine 16 mg/day on week one. Morphine 24 mg/day on weeks two and three.

Morphine 16 mg/day on week one. Morphine 24 mg/day on week two. Morphine 32 mg/day on week three.

Chronic Obstructive Pulmonary Disease

Dyspnea

Treatment with placebo is given as one double-blind capsule in the morning.

Placebo

Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.

Morphine Sulfate

If patients are taking morphine, a laxative will be offered. This applies whatever the dose of morphine being taken (8mg, 16mg, 24mg or 32 mg).

Plus laxative (Docusate with senna)

If the patients are taking placebo, a placebo laxative will be offered.

Plus placebo laxative

A Fitbit will be worn by patients during week 1 and week 3.

FitBit charge HR (Accelerometer)

Clare Holland House

Concord Hospital

St Vincent's Hospital Sydney - Sacred Heart Hospice

Calvary Health Care Kogarah

Liverpool Hospital

Westmead Hospital

Prince Charles Hospital

Nambour Hospital

Southern Adelaide Palliative Services

St Vincent's Hospital Melbourne

Barwon Health McKellar Centre

The Austin Hospital

Royal Melbourne Hospital

Sir Charles Gairdner Hospital

Canterbury Respiratory Services

Breathlessness Exertion and Morphine Sulphate

A Pragmatic, Phase III, Multi-site, Double-blind, Placebo Controlled, Parallel Arm, Dose Increment Randomised Trial of Regular, Low Dose Extended Release Morphine for Chronic Refractory Breathlessness

Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is:
The difference between morphine sulphate 8mg and placebo (end of week1)
The difference of morphine sulphate 16 mg and placebo (end of week 1)

Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is:
The difference between morphine sulphate 8mg and placebo (end of week 1)
The difference between morphine sulphate 16mg and placebo (end of week 1)
Comparison between baseline and end of week 3

Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Stages 1-4.

Measured at baseline and at the weekly visit for the randomisation phase, and then at the study exit in order to assess the theoretical risk of opioids worsening respiratory failure. Concomitant use of oxygen will be recorded. Stages 1-4.

Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Chronic Respiratory Questionnaire - Dyspnoea and Mastery Subscales. Baseline and end of Weeks 1-3.

Rated on the Modified Medical Research Council Breathlessness Scale (mMRC). Measured at baseline and at the conclusion of the study.

Measured using the Fitbit(Charge HR). Assessed at baseline (2 days), weeks 1 and 3.

Measured using the Fitbit(Charge HR). Given in number of movements per night (e.g. rolling over). Assessed at baseline (2 days), weeks 1 and 3.

Measured using the Fitbit(Charge HR). Difference from baseline in the number of active minutes per day. Assessed at baseline (2 days), weeks 1 and 3.

Measured using the Fitbit(Charge HR). Difference from baseline number of calories spent per day. Assessed at baseline (2 days), weeks 1 and 3.

Measured using Australian-modified Karnofsky Performance Status (AKPS). Baseline, Stage1, Stage2, Stage3 and Stage 4.

Measured using Barthel Index. Baseline and Stage 4.

Rated on a 4 point Likert scale. Measured at baseline, weeks 1-3 (daily diary) and stage 4 (weekly diary).

Thirty (30) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device. Baseline and Stage3.

Up to ten (10) participants will also undergo two (baseline and Stage 1) in-laboratory overnight sleep studies in Sydney and Adelaide.

Twenty (20) participants in Adelaide and Sydney. Baseline and on day 2 and 7 of the first week in an office-based simulator - AusEd.

The baseline blood samples will be analysed to detect the presence of UGT2B7*2 and *28 polymorphisms.

The baseline blood samples will be analysed to detect the presence of P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

The baseline blood samples will be analysed to detect the presence of 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

The baseline blood samples will be analysed to detect the presence of Mu receptor (A118G) polymorphism

In a subset of 55 participants, morphine peak plasma concentrations will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

In a subset of 55 participants, morphine AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

In a subset of 55 participants, M6G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

In a subset of 55 participants, M6G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

In a subset of 55 participants, M3G Peak Plasma Concentration will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

In a subset of 55 participants, M3G AUC will be analysed (4 blood samples over 8 hours) at steady state (end of week 1).

Baseline and study completion. To explore whether longer term morphine treatment is associated with decreased levels of testosterone.

Rated on a Lickert Scale. Baseline, weeks 1-3 (daily diary), Stage 4 (weekly diary): Includes constipation, anxiety, appetite, nausea, vomiting, drowsiness, difficulty thinking clearly, problems passing urine, itch, other symptoms.

Measured using the Edmonton Symptoms Assessment Scale (ESAS)

Rated using the Hospital Anxiety and Depression Scale (HADS). At baseline, completion of randomization stage and study exit.

Participant-rated 7 point scale of the perception of their change, specifically their improvement since the commencement of the study. Measured at the end of Stages 1-3 and conclusion.

Measured with EQ-5D-5L questionnaire. Baseline, Stages 1-3, Stage 4, conclusion.

Measured with the COPD Assessment Test (CAT) Baseline, Stages 1-3, Stage 4 and conclusion.

Asked at the end of week 1 and at the conclusion/drop-out of the study. A 3-point Likert scale will be used.

Scored using the Zarit Burden Interview (ZBI) 12 item short-form questionnaire. Baseline, end of weeks 1-3, stage 4.

From randomisation to 28 days post treatment or death (whichever is the shorter period). Estimated based on all health-care contacts including length of hospitalizations, emergency department visits, DRG codes, community health visits, GP and community nurse visits, outpatient visits and date of death. These participant level data allow within trial modeling using bootstrapping methods of replicates for costs and consequences of alternative strategies, allowing for covariance between costs and effects. Incremental net monetary benefit and cost-effectiveness acceptability curves will be estimated at potential threshold values for an additional responder.

Evaluation using the Subjective Opioid Withdrawal Scale (SOWS) for 3 consecutive days. After the completion of the study (Weeks 1-15).

David Currow

Professor: Palliative and Supportive Services

Flinders University

Placebo during treatment week one and two and morphine 8 mg per day week three.

Placebo during treatment week one and morphine 8 mg per day week two and three.

Placebo week one, morphine 8 mg per day week two, and morphine 16 mg per day week three.

Morphine 8 mg per day during all three treatment weeks.

Morphine 8 mg per day week one and two and morphine 16 mg per day week three.

Morphine 8 mg per day week one and morphine 16 mg per day week two and three.

Morphine 8 mg per day week one, morphine 16 mg per day week two, and morphine 24 mg per day week three.

Morphine 16 mg per day during all three treatment weeks.

Morphine 16 mg per day week one and two, and morphine 24 mg per day week three.

Morphine 16 mg per day week one and morphine 24 mg per day during week two and three.

Morphine 16 mg per day week one, morphine 24 mg per day week two, and morphine 32 mg per day week three.

Morphine sulfate

Opioids for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease

A Multi-site, Double-blind, Parallel Arm, Block Randomised, Placebo Controlled, Factorial Phase III Study of Opioids for Chronic Refractory Breathlessness in People With Chronic Obstructive Pulmonary Disease.

Rated on a 0-10 numerical rating scale (NRS) in a diary each evening. The primary endpoint is the difference between placebo, morphine sulfate 8 mg, or 16 mg after the first treatment week.

Rated on a 0-10 numerical rating scale (NRS) in a diary each evening.

Rated on a 0-10 numerical rating scale (NRS) in a diary each morning.

In addition to the NRS ratings, the intensity of breathlessness is rated on a 0-10 modified Borg scale in a evening diary.

Collected in a diary in the evening, including of any rescue medication used.

Measured during two days at baseline and during at least five days of treatment week three.

Measured using the revised Edmonton Symptoms Assessment Scale (ESAS-r).

Measures the functional impact of breathlessness.

To explore whether longer term morphine treatment is associated with decreased levels of testosterone.

From the baseline sample, the UGT2B7*2 and *28 polymorphisms, P-glycoprotein (ABCB1 5SNPs in a haplotype block), the 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572, and mu opioid receptor (A118G) polymorphisms will be measured. Interleukin 1ß, TNFalpha and Il-6 will be measured at baseline and at the end of the first treatment week.

In a subset of 55 participants, blood parameters for morphine and its metabolites will be analysed (4 blood samples over 8 hours) at steady state of the treatment at the end of the week 1.

Exhaled gas measured using a non-invasive capnometer.

Non-invasive measurement of the oxygen saturation, respiratory rate, and heart rate.

Twenty (20) participants at the Sydney and Adelaide sites will be invited to undertake a simple, non-invasive home sleep study using the ResMed ApneaLink Plus device.

Rated on a 4 point Likert scale in a morning diary.

The questionnaires used are the Epworth Sleepiness Scale, Leeds Sleep Questionnaire, and the Karolinska Sleepiness Scale.

Measure of the bowel function, during treatment with placebo / morphine sulfate 8 or 16 mg.

Measured on the CRQ-SAS Dyspnoea sub-scale.

Life-Space is a measure of where a person goes, the frequency of going there, and the dependency in getting there.

A score of 0 to 100 (in increments of 10) is assigned to participants based on their ability to undertake a range of daily tasks. The score gives an indication of the participant condition in terms of physical ability.

A 14-item questionnaire used to measure anxiety and/or depression.

Participant-rated seven point scale of the perception of their change, specifically their improvement since the commencement of the study.

Participants will be asked for their preference to continue at study exit ('Is this a therapy which, on balance, you would continue to take for your breathlessness?')

Data on all health care contacts including lenght of hospitalizations, emergency department visits, DRG codes, outpatient visits to general practitioner and community nurse, and date of death.

sennoside/dyspnea

Breathlessness Exertion and Morphine Sulphate

Opioids for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease

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