Clinical trial NCT03834363: Morphine or Fentanyl for Refractory Dyspnea in COPD
Official title: Morphine or Fentanyl for Refractory Dyspnea in COPD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COPD
Keywords: COPD
Refractory Dyspnea
Morphine
Fentanyl
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Dutch Foundation for Asthma Prevention
name: Innovatiefonds Zorgverzekeraars
First posted: 2019-02-07
Enrollment: 59
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Crossover, double blind, double dummy Randomized Controlled Trial
Primary purpose: TREATMENT

Brief summary: Rationale: The most important complaint in severe COPD is dyspnea which is associated with a diminished exercise tolerance, reduced quality of life and can lead to anxiety and depression. If dyspnea continues to exist despite optimal therapy it is called refractory dyspnea. There is evidence that morphine is effective and can safely be prescribed for treating refractory dyspnea.

However, a Dutch study recently showed that few pulmonologists actually prescribe opioids for this indication. The main reasons for this are concerns about side effects and respiratory insufficiency as well as negative emotions for the patient and families at the thought of using morphine.

Most studies investigating opioids for treatment of dyspnea are conducted with morphine tablets, and only a part of these patients suffered from COPD. To our knowledge there has not been a randomized controlled trial investigating fentanyl patches for refractory dyspnea in COPD patients. However, studies comparing fentanyl and morphine in pain management show that patients may prefer fentanyl patches and have less problems with obstipation.

Objective: There are three main objectives for this study.

First, the investigators will investigate the following hypothesis: Both fentanyl and morphine provide a reduction of dyspnea which is better than placebo. Fentanyl has less side effects than morphine.

Secondly, with this Dutch multi-center study the investigators would like to enlarge the evidence base and contribute to the experience with opioids for refractory dyspnea in COPD thereby greatly facilitating its implementation in the Netherlands.

Finally, the investigators will develop and evaluate educational material about opioid use for dyspnea in COPD.

Study design: This is a multi-center double blind, double-dummy cross-over randomized placebo-controlled trial with three study arms. A total of 60 COPD patients will be included in this study.

Participants will be treated sequentially with three combinations of medication and/or placebo medication in a random order. They will receive either a Fentanyl patch in combination with placebo tablets, a placebo patch with Morphine Slow release tablets or a placebo patch with placebo tablets. Main study parameters/endpoints: The primary endpoint is change in dyspnea sensation Secondary endpoints are change in HR-QoL, anxiety, sleep quality, hypercapnia and the number and seriousness of side effect.


Eligibility criteria: Inclusion Criteria:

* Age ≥ 40 years.
* Read, understood and signed the Informed Consent form.
* COPD GOLD class III or IV, according to GOLD criteria (Post-bronchodilation FEV/FVC \<70% and FEV1 \< 50%pred.
* Complaints of refractory dyspnea as established by patient and doctor.
* mMRC score ≥ 3.
* Life expectancy of ≥ 2 months.
* Optimized standard therapy according to Dutch LAN guideline for diagnosis and treatment of COPD.

Exclusion Criteria:

* Other severe disease with chronic pain or chronic dyspnea (a non substantial component of left sided heart failure is acceptable).
* Current use of opioids for whatever indication.
* Allergy / intolerance for opioids
* Psychiatric disease, not related to severe COPD.
* Exacerbation of COPD 8 weeks prior to inclusion or between screening and randomization.
* Problematic (leading to medical help or social problems) substance abuse during the last five years.
* Active malignancy, with the exception of planocellular or basal cell carcinoma of the skin.
* eGFR \<15 ml/min

Primary outcomes:
measure: Change in dyspnea sensation
timeFrame: Daily during the six week treatment period
Secondary outcomes:
measure: Change in CCQ (HR-QoL)
timeFrame: Daily during the six week treatment period
measure: Change in CRQ (HR-QoL)
timeFrame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
measure: Change in CRQ mastery (HR-QoL)
timeFrame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
measure: Change on the HADS-A questionnaire (Anxiety)
timeFrame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
measure: Side effects
timeFrame: Daily during the six week treatment period
measure: Hypercapnia
timeFrame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
measure: Sleep quality
timeFrame: Daily during the six week treatment period
measure: Continued opioid use
timeFrame: Once, three months after the end of the treatment period
Other outcomes:
measure: Survival
timeFrame: One week after the end of the treatment period, which is 7 weeks after start of the study.
Locations:
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis Assen
state: Drenthe
city: Scheemda
country: Netherlands
facility: Ommelander Ziekenhuis Groningen
state: Groningen
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
state: Noord-Brabant
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep Alkmaar
state: Noord-Holland
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
state: Noord-Holland
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
state: Noord-Holland
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Overijssel
city: Zwolle
country: Netherlands
facility: Isala Klinieken
state: Overijssel
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Huib AM Kerstjens, MD PhD
role: PRINCIPAL_INVESTIGATOR
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citation: Hui D, Kilgore K, Frisbee-Hume S, Park M, Liu D, Balachandran DD, Bruera E. Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial. J Pain Symptom Manage. 2017 Dec;54(6):798-805. doi: 10.1016/j.jpainsymman.2017.08.001. Epub 2017 Aug 10.
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