Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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
Brief Summary: 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.


Options:
A: 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.
B: Inclusion Criteria:

* Patients must be ≥40 years old
* Clinical diagnosis of COPD or pulmonary function testing reflecting an FEV1/FVC ratio of \<0.70
* Current or previous smoker with at least 10 pack-years of cigarette smoking
* Recently hospitalized for an exacerbation of COPD

Exclusion Criteria:

* Patients with a high likelihood of being lost to follow-up or contact (patients with active chemical dependency, are planning to move out of the state, are not living in the healthcare area, or have no telephone at home).
* Patents with characteristics that can confound the analysis of the primary outcome (patients who are living in a nursing home, have unresectable lung cancer, or have another advanced neoplasm).
* Patients with an inability to provide good data or follow commands (patients who are disoriented, have a severe neurologic or psychiatric condition).
* Patients with an inability to do mild exercise, such as cycling or walking, when their COPD is stable (patients who have orthopedic-neurologic problems; patients who have severe heart failure, characterized by an ejection fraction of \<20% or by New York Heart Association Class IV disease; patients who should be at complete rest, confined to a bed or chair; or patients in whom any physical activity brings on discomfort and in whom symptoms occur at rest).
C: Inclusion Criteria:

1. Subjects with the Global Initiative for Obstructive Lung Disease (GOLD) stage 2-4 COPD
2. Subjects who have received HOT for at least 16 hours per day for at least 1 month at the time of informed consent
3. Subjects with PaCO2 \<= 60 torr, and \>= 45 torr at the time of screening
4. Subjects who have signed written informed consent to participate in this study

Exclusion Criteria:

1. Subjects with severe kidney, liver or cardiovascular disease
2. Subjects with active malignant tumor
3. Subjects with acute disease (i.e., acute myocardial infarction)
4. Subjects with a history of obstructive sleep apnea syndrome
5. Subjects with complications affecting efficacy endpoints and who are regarded by the investigator as inadequate for this study
6. Subjects who had experienced COPD exacerbation within the past 6 weeks prior to informed consent
7. Subjects who have been receiving nocturnal noninvasive positive pressure ventilation (NPPV) or had been received within the past 6 weeks prior to informed consent
8. Subjects with a history of tracheotomy or severe pharyngeal nasal cavity surgery within the past 6 months
9. Pregnant women
10. Subjects with cognitive impairment or mental disorder and who are regarded by the investigator as inadequate to be evaluated in this study
11. Subjects who are regarded by the investigator as being unable to operate the myAIRVO2 adequately at home
12. Subjects who are participating or wil participate in the another clinical trial at the time of informed consent
13. Any other cases who are regarded by the investigator as inadequate for enrollment
D: Inclusion Criteria:

* severe COPD (post-bronchodilator Forced expiratory volume in one second (FEV1)/ Forced vital capacity (FVC) \<0.7 and FEV1 \<50%) and stable disease defined as no exacerbation, hospital admission or change in treatment in the previous three months.

Exclusion Criteria:

* The exclusion criteria were: other significant respiratory disease (bronchiectasis, lung fibrosis, asthma, etc.), active smoking, severe cardiovascular, neurological, musculoskeletal and/or metabolic pathology that could interfere with the results, alcoholism (\>80g/day) or severe malnutrition (BMI\<19kg/m2).

Answer: A