Opioids for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease

NCT02455362 | Withdrawn Phase 3 DMC

• 1 other identifier: 022/13 V.3.2.3
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Chronic Obstructive Pulmonary Disease; Dyspnea

Outcome Measures

Primary Outcomes (1)

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

  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.

  Week 1

Secondary Outcomes (25)

• Change from baseline unpleasantness of breathlessness over the previous 24 hours

  Week 3

• Change from baseline intensity of breathlessness "right now"

  Week 3

• Change from baseline in the intensity of breathlessness

  Week 1

• Current medication use and compliance

  At study end for up to 15 weeks.

• Number of participants with adverse events

  At study end for up to 15 weeks.

Study Arms (12)

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Morphine sulfate (0, 0, 8 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (0, 8, 8 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (0, 8, 16 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (8, 8, 8 mg)

EXPERIMENTAL

Morphine 8 mg per day during all three treatment weeks.

Drug: Morphine sulfate

Morphine sulfate (8, 8, 16 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (8, 16, 16 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (8, 16, 24 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (16, 16, 16 mg)

EXPERIMENTAL

Morphine 16 mg per day during all three treatment weeks.

Drug: Morphine sulfate

Morphine sulfate (16, 16, 24 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (16, 24, 24 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Morphine sulfate (16, 24, 32 mg)

EXPERIMENTAL

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

Drug: Morphine sulfate

Interventions

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)

Placebo DRUG

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, 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Flinders University: lead

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Dyspnea

Interventions

Morphine

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

Study Officials

• David C Currow, MD, PhD

  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: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 20, 2015
• First Posted: May 27, 2015
• Study Start: May 1, 2015
• Primary Completion: December 1, 2017
• Study Completion: April 1, 2018
• Last Updated: January 12, 2016

Record last verified: 2016-01