Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Opioids for Refractory Breathlessness in Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02455362
Recruitment Status : Withdrawn ('Recruitment not possible given changes to trial criteria)
First Posted : May 27, 2015
Last Update Posted : January 12, 2016
Sponsor:
Information provided by (Responsible Party):
David Currow, Flinders University

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.


Condition or disease Intervention/treatment Phase
Chronic Obstructive Pulmonary Disease Dyspnea Drug: Morphine sulfate Drug: Placebo Phase 3

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-site, Double-blind, Parallel Arm, Block Randomised, Placebo Controlled, Factorial Phase III Study of Opioids for Chronic Refractory Breathlessness in People With Chronic Obstructive Pulmonary Disease.
Study Start Date : May 2015
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : April 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.
Drug: Placebo
Experimental: Morphine sulfate (0, 0, 8 mg)
Placebo during treatment week one and two and morphine 8 mg per day week three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (0, 8, 8 mg)
Placebo during treatment week one and morphine 8 mg per day week two and three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (0, 8, 16 mg)
Placebo week one, morphine 8 mg per day week two, and morphine 16 mg per day week three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (8, 8, 8 mg)
Morphine 8 mg per day during all three treatment weeks.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (8, 8, 16 mg)
Morphine 8 mg per day week one and two and morphine 16 mg per day week three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (8, 16, 16 mg)
Morphine 8 mg per day week one and morphine 16 mg per day week two and three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (8, 16, 24 mg)
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
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (16, 16, 16 mg)
Morphine 16 mg per day during all three treatment weeks.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (16, 16, 24 mg)
Morphine 16 mg per day week one and two, and morphine 24 mg per day week three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (16, 24, 24 mg)
Morphine 16 mg per day week one and morphine 24 mg per day during week two and three.
Drug: Morphine sulfate
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)

Experimental: Morphine sulfate (16, 24, 32 mg)
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
Treatment with sustained-release morphine sulfate is given as one double-blind capsule in the morning.
Other Name: Kapanol(R)




Primary Outcome Measures :
  1. Change from baseline intensity of breathlessness over the previous 24 hours [ Time Frame: Week 1 ]
    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.


Secondary Outcome Measures :
  1. Change from baseline unpleasantness of breathlessness over the previous 24 hours [ Time Frame: Week 3 ]
    Rated on a 0-10 numerical rating scale (NRS) in a diary each evening.

  2. Change from baseline intensity of breathlessness "right now" [ Time Frame: Week 3 ]
    Rated on a 0-10 numerical rating scale (NRS) in a diary each morning.

  3. Change from baseline in the intensity of breathlessness [ Time Frame: Week 1 ]
    In addition to the NRS ratings, the intensity of breathlessness is rated on a 0-10 modified Borg scale in a evening diary.

  4. Current medication use and compliance [ Time Frame: At study end for up to 15 weeks. ]
    Collected in a diary in the evening, including of any rescue medication used.

  5. Number of participants with adverse events [ Time Frame: At study end for up to 15 weeks. ]
    Collected in a diary in the evening.

  6. Change from baseline physical activity using an accelerometer [ Time Frame: Week 3 ]
    Measured during two days at baseline and during at least five days of treatment week three.

  7. Change from baseline in concurrent symptoms [ Time Frame: Week 1 ]
    Measured using the revised Edmonton Symptoms Assessment Scale (ESAS-r).

  8. The modified Medical Research Council (mMRC) breathlessness scale [ Time Frame: At study end for up to 15 weeks. ]
    Measures the functional impact of breathlessness.

  9. Change from baseline serum testosterone level [ Time Frame: At the end of the 3 month follow-up stage, after up to 15 weeks. ]
    To explore whether longer term morphine treatment is associated with decreased levels of testosterone.

  10. Change from baseline pharmacogenomic opioid blood profile [ Time Frame: Week 1 ]
    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.

  11. Pharmacodynamic/-kinetic blood samples [ Time Frame: Week 1 ]
    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.

  12. Change from baseline end-tidal carbon dioxide [ Time Frame: Week 3 ]
    Exhaled gas measured using a non-invasive capnometer.

  13. Change from baseline pulse oximetry [ Time Frame: Week 3 ]
    Non-invasive measurement of the oxygen saturation, respiratory rate, and heart rate.

  14. Change from baseline sleep quality [ Time Frame: The final night of week 3 ]
    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.

  15. Change from baseline sleep quality [ Time Frame: During the study for up to 15 weeks. ]
    Rated on a 4 point Likert scale in a morning diary.

  16. Change from baseline sleep quality and sleep-related problems [ Time Frame: Week 3 ]
    The questionnaires used are the Epworth Sleepiness Scale, Leeds Sleep Questionnaire, and the Karolinska Sleepiness Scale.

  17. Change from baseline bowel function index [ Time Frame: Week 1 ]
    Measure of the bowel function, during treatment with placebo / morphine sulfate 8 or 16 mg.

  18. Change from baseline breathlessness-related quality of life [ Time Frame: Week 3 ]
    Measured on the CRQ-SAS Dyspnoea sub-scale.

  19. Change from baseline health-related quality of life [ Time Frame: During the study for up to 15 weeks. ]
    Measured using the EQ-5D questionnaire.

  20. Change from baseline Life-space [ Time Frame: During the study for up to 15 weeks. ]
    Life-Space is a measure of where a person goes, the frequency of going there, and the dependency in getting there.

  21. Change from baseline Australian Karnofsky Performance Status [ Time Frame: During the study for up to 15 weeks. ]
    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.

  22. Change from baseline Hospital Anxiety and Depression Scale [ Time Frame: Week 3 ]
    A 14-item questionnaire used to measure anxiety and/or depression.

  23. Global Impression of Change [ Time Frame: During the study for up to 15 weeks. ]
    Participant-rated seven point scale of the perception of their change, specifically their improvement since the commencement of the study.

  24. Blinded patient preference to continue treatment [ Time Frame: At study end after up to 15 weeks. ]
    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?')

  25. Health economy composite [ Time Frame: During the study for up to 15 weeks. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 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

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02455362


Sponsors and Collaborators
Flinders University
Investigators
Layout table for investigator information
Principal Investigator: David C Currow, MD, PhD Flinders University

Layout table for additonal information
Responsible Party: David Currow, Professor, Flinders University
ClinicalTrials.gov Identifier: NCT02455362     History of Changes
Other Study ID Numbers: 022/13 V.3.2.3
First Posted: May 27, 2015    Key Record Dates
Last Update Posted: January 12, 2016
Last Verified: January 2016

Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Dyspnea
Respiratory Tract Diseases
Respiration Disorders
Signs and Symptoms, Respiratory
Signs and Symptoms
Morphine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents