Clinical trial NCT02429050: Morphine for Treatment of Dyspnea in Patients With COPD
Official title: Morphine for Palliative Treatment of Refractory Dyspnea in Patients With Advanced COPD: Benefits and Respiratory Adverse Effects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Chronic Obstructive Pulmonary Disease
Dyspnea
Breathlessness
Morphine
Opioid
Symptom Management
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2015-04-29
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Dyspnea is the most reported symptom of patients with advanced Chronic Obstructive Pulmonary Disease (COPD) and is undertreated. Morphine is an effective treatment for dyspnea and is recommended in clinical practice guidelines, but questions concerning benefits and concerns about respiratory adverse effects remain. For example, the effect on health-related quality of life and functional capacity is unknown. In one-third of the patients oral sustained release morphine (morphine SR) doesn't relieve dyspnea and it remains unknown whether severity and descriptors of breathlessness may predict a response to morphine. Finally, cost-effectiveness of morphine SR in this patient group is unknown. Therefore, prescription of morphine to patients with COPD is limited.

Objectives of this double blind randomized controlled trial are to study the effect of oral administration of morphine SR on health-related quality of life, respiratory adverse effects, and functional capacity; to explore whether description and severity of breathlessness are related with a clinically relevant response to morphine and to analyse the cost-effectiveness of morphine SR. The study population will consist of 124 clinically stable outpatients with COPD and severe dyspnea despite optimal pharmacological and non-pharmacological treatment.

Detailed description: Participants will be outpatients with a confirmed diagnosis of COPD, who suffer from severe dyspnea despite optimal pharmacological and non-pharmacological treatment. Participants will be recruited at CIRO, a center for pulmonary rehabilitation in the Netherlands after they completed a pulmonary rehabilitation program. After providing informed consent, patients will be randomized. Members of the research team who perform measurements will be blinded for treatment allocation.

Patients in the intervention group will receive regular clinical care and morphine SR 10mg, administered twice daily (20mg/24h), which can be increased after one or two weeks to three times per day 10mg (30mg/24h) in non-responders. Patients will be defined as non-responders if the mean dyspnea numeric rating scale (NRS) score was not reduced by 1 point in comparison with baseline. The control group will receive regular clinical care and placebo medication. Patients will receive morphine or placebo for four weeks. In addition, both groups will receive a prescription for a laxative and metoclopramide at the start of the intervention and will be instructed to adjust the dose as needed.

When the intervention period has ended, participants can choose to continue morphine treatment. They will be followed for twelve weeks to assess their healthcare use, use of morphine and number of adverse effects and exacerbations.

Measurements at baseline will include: demographics, medical history, medication, co-morbidities, exercise capacity, respiratory parameters, generic and disease-specific health-related quality of life (HRQoL), severity of dyspnea, sensory and affective dimensions of dyspnea, impact of dyspnea, cognition, level of daytime sleepiness, and functional capacity. A member of the research team will visit patients after 1 and 2 weeks in their home environment to assess adverse effects, compliance, exacerbations, disease-specific HRQoL, mobility, severity of dyspnea, and some respiratory parameters. A member of the research team will call the patient after 2 days and 3 weeks to assess adverse effects, compliance, exacerbations, and severity of dyspnea. After 4 weeks the following measurements will be performed: respiratory parameters, exercise capacity, general and disease-specific HRQoL, sensory and affective dimensions of dyspnea, impact of dyspnea, functional capacity, and adverse effects. Overnight oximetry will be performed in the home environment at baseline and after four weeks. A diary for costs and healthcare use will be filled in during four weeks.

Measurements during the twelve weeks following the intervention include: retrospective cost questionnaire, generic and disease-specific quality of life severity of dyspnea and adverse effects.

Statistical analyses Baseline characteristics will be compared between the intervention and control group using descriptive statistics. Chi square tests will be used for categorical variables. Independent sample T-tests and Mann-Whitney U-tests will be used for continuous variables, according to the variable distribution. Change in CAT-score, respiratory parameters and 6MWD between baseline and four weeks will be compared between patients in the intervention and the control group. First, mean change in CAT-score, respiratory parameters and 6MWD will be compared between the two groups using an independent sample T-test or Mann-Whitney U test, according to the variable distribution. Afterwards, multivariate analyses for longitudinal data will be performed. Analyses will be done using an intention-to-treat approach. The relationship between response to opioids and severity of dyspnea and descriptors of breathlessness will be explored using univariate analysis, followed by a binary logistic regression model. A trial-based economic evaluation will be performed, based on empirical data obtained in the RCT. The economic evaluation will be performed from the societal and healthcare perspective, the first including costs inside and outside the health care sector, and will follow published international guidelines. The time horizon of the trial-based economic evaluation will be four weeks. The outcomes of the twelve weeks following the intervention will be used in the model-based economic evaluation. The model will probably take the form of a Markov model; however this will be decided upon during the study.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of COPD according to the current Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (GOLD);
* Optimal pharmacological treatment, including including treatment with a combination of a long-acting muscarinic antagonist and an ultra-long-acting β-agonist;
* Grade 3 or 4 dyspnea on the mMRC dyspnea scale;
* Optimal non-pharmacological treatment defined as completed a comprehensive pulmonary rehabilitation program.

Exclusion Criteria:

* History of substance misuse;
* Exacerbation of COPD within two weeks of study enrolment;
* Waiting list for lung transplantation;
* Pregnant or childbearing potential not using contraception;
* Renal failure (creatinine clearance \<15mL/min);
* Not being able to read or fill in the questionnaires or diary;
* Allergy for morphine or its excipients;
* Concomitant use of irreversible MAO blockers;
* Use of opioids;
* History of convulsions;
* Head injury;
* Intestinal obstruction;
* Gastroparesis;
* Liver disease.

Primary outcomes:
measure: Disease-specific health-related quality of life (COPD Assessment Test (CAT))
timeFrame: sixteen weeks
measure: Change in partial pressure of CO2 (pCO2)
timeFrame: four weeks
measure: Change in partial pressure of O2 (pO2)
timeFrame: four weeks
measure: Respiratory rate
timeFrame: four weeks
measure: Pulse oximetric saturation (SpO2)
timeFrame: four weeks
measure: Transcutaneous carbon dioxide (PtcCO2)
timeFrame: four weeks
measure: Oxygen saturation during the night
timeFrame: four weeks
Secondary outcomes:
measure: distance walked in 6 Minute Walking Test (6-MWT)
timeFrame: four weeks
measure: Care dependency (Care Dependency Scale (CDS)
timeFrame: four weeks
measure: Mobility (Timed 'Up & Go' (TUG) test)
timeFrame: four weeks
measure: Sensory and affective dimensions of dyspnea (Multidimensional Dyspnea Profile (MDP)
timeFrame: four weeks
measure: Impact of dyspnea (Pulmonary Functional Status and Dyspnea Questionnaire, PFSDQ-M)
timeFrame: four weeks
measure: Severity of dyspnea (Numeric Rating Scale (NRS)
timeFrame: sixteen weeks
measure: Daytime sleepiness (Epworth Sleep Questionnaire)
timeFrame: four weeks
measure: Cognition (Montreal Cognitive Assessment, (MoCA)
timeFrame: four weeks
measure: Number of patients with adverse effects
timeFrame: sixteen weeks
measure: Intake of medication
timeFrame: four weeks
measure: Number of exacerbations
timeFrame: sixteen weeks
measure: Cost of healthcare use in euro's
timeFrame: sixteen weeks
Other outcomes:
Locations:
city: Horn
country: Netherlands
facility: Ciro centre of expertise for chronic organ failure
Study officials:
affiliation: Maastricht UMC
name: Daisy JA Janssen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Maastricht UMC
name: E. FM Wouters, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Verberkt CA, van den Beuken-van Everdingen MHJ, Dirksen CD, Schols JMGA, Wouters EFM, Janssen DJA. Cost-effectiveness of sustained-release morphine for refractory breathlessness in COPD: A randomized clinical trial. Respir Med. 2021 Apr;179:106330. doi: 10.1016/j.rmed.2021.106330. Epub 2021 Feb 10.
citation: Verberkt CA, van den Beuken-van Everdingen MHJ, Schols JMGA, Hameleers N, Wouters EFM, Janssen DJA. Effect of Sustained-Release Morphine for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease on Health Status: A Randomized Clinical Trial. JAMA Intern Med. 2020 Oct 1;180(10):1306-1314. doi: 10.1001/jamainternmed.2020.3134.