Primary Outcomes

Description: 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.

Measure: Change from baseline intensity of breathlessness over the previous 24 hours

Time: Week 1

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Secondary Outcomes

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

Measure: Change from baseline unpleasantness of breathlessness over the previous 24 hours

Time: Week 3

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

Measure: Change from baseline intensity of breathlessness "right now"

Time: Week 3

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

Measure: Change from baseline in the intensity of breathlessness

Time: Week 1

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

Measure: Current medication use and compliance

Time: At study end for up to 15 weeks.

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Description: Collected in a diary in the evening.

Measure: Number of participants with adverse events

Time: At study end for up to 15 weeks.

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

Measure: Change from baseline physical activity using an accelerometer

Time: Week 3

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

Measure: Change from baseline in concurrent symptoms

Time: Week 1

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Description: Measures the functional impact of breathlessness.

Measure: The modified Medical Research Council (mMRC) breathlessness scale

Time: At study end for up to 15 weeks.

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

Measure: Change from baseline serum testosterone level

Time: At the end of the 3 month follow-up stage, after up to 15 weeks.

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Description: 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.

Measure: Change from baseline pharmacogenomic opioid blood profile

Time: Week 1

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Description: 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.

Measure: Pharmacodynamic/-kinetic blood samples

Time: Week 1

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Description: Exhaled gas measured using a non-invasive capnometer.

Measure: Change from baseline end-tidal carbon dioxide

Time: Week 3

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

Measure: Change from baseline pulse oximetry

Time: Week 3

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Description: 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.

Measure: Change from baseline sleep quality

Time: The final night of week 3

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

Measure: Change from baseline sleep quality

Time: During the study for up to 15 weeks.

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

Measure: Change from baseline sleep quality and sleep-related problems

Time: Week 3

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

Measure: Change from baseline bowel function index

Time: Week 1

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Description: Measured on the CRQ-SAS Dyspnoea sub-scale.

Measure: Change from baseline breathlessness-related quality of life

Time: Week 3

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Description: Measured using the EQ-5D questionnaire.

Measure: Change from baseline health-related quality of life

Time: During the study for up to 15 weeks.

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

Measure: Change from baseline Life-space

Time: During the study for up to 15 weeks.

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Description: 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.

Measure: Change from baseline Australian Karnofsky Performance Status

Time: During the study for up to 15 weeks.

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

Measure: Change from baseline Hospital Anxiety and Depression Scale

Time: Week 3

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

Measure: Global Impression of Change

Time: During the study for up to 15 weeks.

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Description: 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?')

Measure: Blinded patient preference to continue treatment

Time: At study end after up to 15 weeks.

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Description: 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.

Measure: Health economy composite

Time: During the study for up to 15 weeks.

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Primary Outcomes

Description: 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)

Measure: Change from baseline worst breathlessness intensity over the previous 24 hours

Time: Week 1

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Description: 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

Measure: Change from the baseline in the number of steps per day

Time: Week 3

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Secondary Outcomes

Description: 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.

Measure: Change from baseline end-tidal carbon dioxide

Time: Up to week 15

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Description: 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.

Measure: Change from baseline pulse oximetry

Time: Up to week 15

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

Measure: Change from baseline intensity of breathlessness "average"

Time: Up to week 15

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

Measure: Change from baseline distress from breathlessness over the previous 24 hours

Time: Up to week 15

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

Measure: Change from baseline perceived-impact of breathlessness

Time: Up to week 3

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

Measure: Change from baseline functional impact of breathlessness

Time: Up to week 15

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

Measure: Change from baseline sleep minutes

Time: Week 3

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Description: 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.

Measure: Change from baseline sleep activity

Time: Week 3

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Description: 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.

Measure: Change from baseline in activity levels

Time: Week 3

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

Measure: Change from baseline total energy expenditure

Time: Week 3

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

Measure: Change from baseline performance status

Time: Up to week 15

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Description: Measured using Barthel Index. Baseline and Stage 4.

Measure: Change from baseline activities of daily living

Time: Up to week 15

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

Measure: Change from baseline in sleep quality

Time: Up to week 15

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Description: 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.

Measure: Change from baseline in objective sleep testing

Time: Week 3

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

Measure: Change from baseline Polysomnography

Time: Week 3

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

Measure: Change from baseline Driving ability

Time: Week 3 + 2 days

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

Measure: Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms

Time: Baseline (1 day)

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

Measure: Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)

Time: Baseline (1 day)

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

Measure: Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism

Time: Baseline (1 day)

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

Measure: Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism

Time: Baseline (1 day)

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Description: 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).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax]

Time: Week 1

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

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC)

Time: Week 1

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Description: 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).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax]

Time: Week 1

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

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC)

Time: Week 1

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Description: 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).

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax]

Time: Week 1

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

Measure: Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC)

Time: Week 1

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

Measure: Change from baseline serum testosterone level

Time: Week 15

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Description: 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.

Measure: Adverse Effects

Time: Up to 15 weeks

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Description: Measured using the Edmonton Symptoms Assessment Scale (ESAS)

Measure: Change from baseline in concurrent symptoms

Time: Up to 15 weeks

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

Measure: Change from the baseline anxiety and depression

Time: Up to Week 15

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Description: 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.

Measure: Change in baseline global impression of change

Time: Up to 15 weeks

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

Measure: Change from baseline health-related quality of life

Time: Up to 15 weeks

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

Measure: Change from baseline health-status in COPD

Time: Week 3

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

Measure: Blinded-patient preference to continue the treatment [3-point Likert Scale]

Time: Up to week 15

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

Measure: Change from baseline caregiver Impact

Time: Up to week 15

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Description: 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.

Measure: Economic Evaluation - Cost per responder

Time: Up to week 4

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

Measure: Opioid Withdrawal

Time: Up to week 15 + 3 days

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