Breathlessness Exertion and Morphine Sulphate

NCT02720822 | Completed Phase 3 DMC

• 1 other identifier: 030/15
• Study Type: interventional
• Target: 171
• Locations: 2 countries
• Sites: 15

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.

Conditions

Chronic Obstructive Pulmonary Disease; Dyspnea

Outcome Measures

Primary Outcomes (2)

• Change from baseline worst breathlessness intensity over the previous 24 hours

  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)

  Week 1

• Change from the baseline in the number of steps per day

  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

  Week 3

Secondary Outcomes (37)

• Change from baseline end-tidal carbon dioxide

  Up to week 15

• Change from baseline pulse oximetry

  Up to week 15

• Change from baseline intensity of breathlessness "average"

  Up to week 15

• Change from baseline distress from breathlessness over the previous 24 hours

  Up to week 15

• Change from baseline perceived-impact of breathlessness

  Up to week 3

Study Arms (12)

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo; Drug: Plus placebo laxative; Device: FitBit charge HR (Accelerometer)

Morphine Sulfate (0, 0, 8 mg)

EXPERIMENTAL

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

Drug: Placebo; Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Drug: Plus placebo laxative; Device: FitBit charge HR (Accelerometer)

Morphine sulfate (0, 8, 8 mg)

EXPERIMENTAL

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

Drug: Placebo; Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Drug: Plus placebo laxative; Device: FitBit charge HR (Accelerometer)

Morphine sulfate (0, 8, 16 mg)

EXPERIMENTAL

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

Drug: Placebo; Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Drug: Plus placebo laxative; Device: FitBit charge HR (Accelerometer)

Morphine sulfate (8, 8, 8 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (8, 8, 16 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (8, 16, 16 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (8, 16, 24 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (16, 16, 16 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (16, 16, 24 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (16, 24, 24 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Morphine sulfate (16, 24, 32 mg)

EXPERIMENTAL

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

Drug: Morphine Sulfate; Drug: Plus laxative (Docusate with senna); Device: FitBit charge HR (Accelerometer)

Interventions

Placebo DRUG

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

Also known as: MP342

Morphine Sulfate (0, 0, 8 mg); Morphine sulfate (0, 8, 16 mg); Morphine sulfate (0, 8, 8 mg); Placebo

Morphine Sulfate DRUG

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

Also known as: Kapanol (R)

Morphine Sulfate (0, 0, 8 mg); Morphine sulfate (0, 8, 16 mg); Morphine sulfate (0, 8, 8 mg); Morphine sulfate (16, 16, 16 mg); Morphine sulfate (16, 16, 24 mg); Morphine sulfate (16, 24, 24 mg); Morphine sulfate (16, 24, 32 mg); Morphine sulfate (8, 16, 16 mg); Morphine sulfate (8, 16, 24 mg); Morphine sulfate (8, 8, 16 mg); Morphine sulfate (8, 8, 8 mg)

Plus laxative (Docusate with senna) DRUG

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).

Morphine Sulfate (0, 0, 8 mg); Morphine sulfate (0, 8, 16 mg); Morphine sulfate (0, 8, 8 mg); Morphine sulfate (16, 16, 16 mg); Morphine sulfate (16, 16, 24 mg); Morphine sulfate (16, 24, 24 mg); Morphine sulfate (16, 24, 32 mg); Morphine sulfate (8, 16, 16 mg); Morphine sulfate (8, 16, 24 mg); Morphine sulfate (8, 8, 16 mg); Morphine sulfate (8, 8, 8 mg)

Plus placebo laxative DRUG

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

Morphine Sulfate (0, 0, 8 mg); Morphine sulfate (0, 8, 16 mg); Morphine sulfate (0, 8, 8 mg); Placebo

FitBit charge HR (Accelerometer) DEVICE

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

Morphine Sulfate (0, 0, 8 mg); Morphine sulfate (0, 8, 16 mg); Morphine sulfate (0, 8, 8 mg); Morphine sulfate (16, 16, 16 mg); Morphine sulfate (16, 16, 24 mg); Morphine sulfate (16, 24, 24 mg); Morphine sulfate (16, 24, 32 mg); Morphine sulfate (8, 16, 16 mg); Morphine sulfate (8, 16, 24 mg); Morphine sulfate (8, 8, 16 mg); Morphine sulfate (8, 8, 8 mg); Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Flinders University: lead

Study Sites (15)

Clare Holland House

Canberra, Australian Capital Territory, 2600, Australia

Location

Concord Hospital

Concord, New South Wales, 2139, Australia

Location

St Vincent's Hospital Sydney - Sacred Heart Hospice

Darlinghurst, New South Wales, 2010, Australia

Location

Calvary Health Care Kogarah

Kogarah, New South Wales, 3590, Australia

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Prince Charles Hospital

Brisbane, Queensland, 4032, Australia

Location

Nambour Hospital

Sunshine Coast, Queensland, 4560, Australia

Location

Southern Adelaide Palliative Services

Adelaide, South Australia, 5041, Australia

Location

St Vincent's Hospital Melbourne

Fitzroy, Victoria, 3065, Australia

Location

Barwon Health McKellar Centre

Geelong, Victoria, 3215, Australia

Location

The Austin Hospital

Heidelberg, Victoria, 3084, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3050, Australia

Location

Sir Charles Gairdner Hospital

Perth, Western Australia, 6009, Australia

Location

Canterbury Respiratory Services

Christchurch, 8140, New Zealand

Location

Related Publications (6)

• Ferreira DH, Ryan R, Smyth N, Clow A, Currow DC. The longitudinal impact of low-dose morphine on diurnal cortisol profiles in people with chronic breathlessness and chronic obstructive pulmonary disease (COPD): an exploratory study. Respir Res. 2025 Apr 23;26(1):156. doi: 10.1186/s12931-025-03230-9.

  PMID: 40269943 DERIVED

• Ekstrom M, Alameri F, Chang S, Ferreira D, Johnson MJ, Currow DC. Harms of Morphine for Chronic Breathlessness in Relation to Dose, Duration and Titration Phase. J Pain Symptom Manage. 2025 Jun;69(6):581-588.e2. doi: 10.1016/j.jpainsymman.2025.02.020. Epub 2025 Feb 25.

  PMID: 40015533 DERIVED

• Altree TJ, Toson B, Loffler KA, Ekstrom M, Currow DC, Eckert DJ. Low-Dose Morphine Does Not Cause Sleepiness in Chronic Obstructive Pulmonary Disease: A Secondary Analysis of a Randomized Clinical Trial. Am J Respir Crit Care Med. 2024 Nov 1;210(9):1113-1122. doi: 10.1164/rccm.202310-1780OC.

  PMID: 38477675 DERIVED

• Ekstrom M, Ferreira D, Chang S, Louw S, Johnson MJ, Eckert DJ, Fazekas B, Clark KJ, Agar MR, Currow DC; Australian National Palliative Care Clinical Studies Collaborative. Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease: The BEAMS Randomized Clinical Trial. JAMA. 2022 Nov 22;328(20):2022-2032. doi: 10.1001/jama.2022.20206.

  PMID: 36413230 DERIVED

• Ferreira DH, Kochovska S, Honson A, Phillips JL, Currow DC. Two faces of the same coin: a qualitative study of patients' and carers' coexistence with chronic breathlessness associated with chronic obstructive pulmonary disease (COPD). BMC Palliat Care. 2020 May 6;19(1):64. doi: 10.1186/s12904-020-00572-7.

  PMID: 32375747 DERIVED

• Currow D, Watts GJ, Johnson M, McDonald CF, Miners JO, Somogyi AA, Denehy L, McCaffrey N, Eckert DJ, McCloud P, Louw S, Lam L, Greene A, Fazekas B, Clark KC, Fong K, Agar MR, Joshi R, Kilbreath S, Ferreira D, Ekstrom M; Australian national Palliative Care Clinical Studies Collaborative (PaCCSC). A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol. BMJ Open. 2017 Jul 17;7(7):e018100. doi: 10.1136/bmjopen-2017-018100.

  PMID: 28716797 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Dyspnea

Interventions

Morphine; Laxatives; Dioctyl Sulfosuccinic Acid; Sennosides

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Gastrointestinal Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Succinates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Senna Extract; Anthraquinones; Anthrones; Anthracenes; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Quinones; Glycosides; Carbohydrates; Plant Extracts; Plant Preparations; Biological Products; Complex Mixtures

Study Officials

• David C Currow, MD, PhD

  Study Principal Investigator; Flinders University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor: Palliative and Supportive Services

Study Record Dates

• First Submitted: March 10, 2016
• First Posted: March 28, 2016
• Study Start: August 8, 2016
• Primary Completion: December 20, 2019
• Study Completion: December 20, 2019
• Last Updated: February 11, 2020

Record last verified: 2020-02

Locations

AU (14); NZ (1)