Effect of Sublingual Fentanyl on Breathlessness in COPD

Effect of Sublingual Fentanyl on Breathlessness in COPD : A Randomized Cross-over Trial

There is actually no physiologic or clinical data in the literature to clearly define the potential benefits and side effects of sublingual fentanyl in patients with COPD. Therefore, the purpose of this study is to test the hypothesis that sublingual fentanyl will improve exercise capacity and dyspnea control in severe COPD patients experiencing persistent breathlessness despite optimal management.

Study Overview

• Status: Terminated
• Conditions: Copd
• Intervention / Treatment: Drug: Fentanyl citrate solution sublingual; Drug: Placebo oral liquid

Detailed Description

The purpose of this study is to test the hypothesis that sublingual fentanyl will improve exercise capacity and dyspnea control in severe COPD patients experiencing persistent breathlessness despite optimal management.

To demonstrate the effectiveness of sublingual fentanyl, the investigators suggest a dose of 12,5 mcg. The investigators base this decision on several considerations :

• Local practice and experience : the safety of a dose of 12,5 mcg of sublingual fentanyl has been show in the investigators local experience (see section 1.3 Clinical experience with fentanyl).
• Although there is not enough information to determine the exact equivalence between sublingual fentanyl and oral morphine, the conversion between intravenous fentanyl and oral morphine can be done. Based on the monograph of fentanyl citrate, 10 mcg of intravenous fentanyl citrate are equivalent to 10 mg of intravenous morphine, which are equivalent to 20 to 30 mg of oral morphine. Subsequently, 12,5 mcg of sublingual fentanyl may be equivalent to a oral morphine dose between 2,5 and 3,75 milligrams. This represent a smaller dose than the dose of 0,1 mg/kg oral morphine that was demonstrated to be safe in a recent study done by a group at McGill in a severe COPD population (Abdallah et al. Eur Respir J 2017; 50: 1701235).
• The study will only include patients who are already on morphine, because they represent the target population and have less risk of adverse events than an opioid-naive population.
• To ensure safety, participants will be actively monitored during the study. A doctor will be present at administration of the drug and the antidote, naloxone, will be readily available if needed. Participants will be monitored on-site for 30 minutes after completion of CPET and discharge only if no evidence of side effects. Participants will be informed to not drive for 24 hours following each period of treatment. A phone call follow-up will be done 24-48 hours after treatment visits.

General Objective:

The general objective is to demonstrate the role of sublingual fentanyl liquid to improve exertional shortness of breath in patients with severe to very severe COPD.

Primary Objective :

The primary objective is to evaluate in severe/very-severe COPD the effect of 12,5 mcg fentanyl sublingual liquid as compared with placebo, on i) post-dose difference in exertional breathlessness at isotime (Isotime definition : highest equivalent 2 min interval of exercise completed by a given participant) ii) Post-dose difference in exercise endurance time (EET)

The study is a multicentred randomized clinical trial, triple-blinded, cross-over design, comparing fentanyl sublingual at a dose 12,5 mcg to placebo in severe/very-severe COPD already taking low dose of morphine because of refractory dyspnea.

To detect a minimally clinically important (MCID) difference of 1 Borg unit (40) at iso-time between treatments, we assume an α of 0.05 and a within-subject standard deviation of 1 Borg unit: a total of 20 patients will provide >80% power; assuming an attrition rate of 20%, a total of 24 patients will be recruited for this study.

All data will be de-nominalized in order to respect privacy. Data will be collected in an anonymous data sheet, protected by a password. Only investigators and statistician will have access to this data sheet.

The principal analysis of the relative change in dyspnea intensity at iso-time (primary end-point) after treatment with morphine sulfate vs. placebo will be conducted using an unadjusted paired t-test. Secondary analyses to assess treatment responses on secondary end-points (e.g. arterialized capillary PCO2, EET, dyspnea unpleasantness, ventilation, breathing pattern, operating lung volumes, etc.) will be done using paired t-tests adjusted (Bonferroni) for multiple comparisons. Pearson correlations will be used to establish associations between intra-subject post-dose differences in iso-time dyspnea intensity ratings and relevant independent variables (e.g. arterialized capillary PCO2, ventilation, breathing pattern, MDP results, etc.) and various baseline patient characteristics (possible covariates). Stepwise multiple regression analysis will then be carried out with significant independent variables and relevant covariates.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N0W8
      • Royal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female aged ≥ 40 years
• Cigarette smoking history ≥10 pack years
• Clinical diagnosis of severe to very severe COPD, i.e. post-β2-agonist FEV1 <50% and FEV1/FVC <0.70
• Chronic activity-related dyspnea, define as any one or combination of a modified MRC of 3-4 or a BDI focal score ≤ 8
• Uncontrolled daily activity-related dyspnea despite optimal medical treatment, including oral morphine treatment at a dose of a least 4 mg per day
• No change in medication dosage or frequency of administration in the previous 2 weeks
• No exacerbations or hospitalizations in the preceding 4 weeks

Exclusion Criteria:

• CO2 retention, defined as a resting arterial/capillary PCO2 of >50 mmHg
• Self-reported history of addiction/substance abuse
• Acute alcoholism
• Presence of important contraindications to cardiopulmonary exercise testing (CPET)
• History of hypersensitivity to fentanyl or any component of the formulation
• Actual use of methadone
• Concurrent use or use within 14 days of a monoamine oxidase (MAO) inhibitor
• Severe CNS depression
• Convulsive disorders
• Known or suspected mechanical GI obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type)
• Increased cerebrospinal or intracranial pressure and head injury
• Active mouth mucositis
• Dementia diagnosis or significant neurocognitive problems
• History of severe chronic kidney disease (stage 4-5)
• Women of child bearing potential (defined as not having gone at least 12 months without a menstrual period) will be required to take a routine (urine) pregnancy test to rule out the possibility of pregnancy
• Breast-Feeding women
• Acute or unstable, clinically significant abnormal findings in physical exam, vital signs or ECG (as per Investigators opinion)
• Patients receiving long-term treatment with Oxygen >4.0 liters/minute (L/min). They must be ambulatory and be able to attend clinic visits. While breathing supplemental oxygen, they must demonstrate an oxyhemoglobin saturation ≥ 89%.
• Malignancy, current or within the past 2 years. that the patient is not stable
• Scheduled major surgical procedure during the course of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fentanyl s/l; Sublingual fentanyl will consist in liquid fentanyl at a concentration of 25 mcg/mL, with preparation by the pharmacist of pre-dosed syringes of 12,5 mcg (0,5 mL).	Drug: Fentanyl citrate solution sublingual; Solution of fentanyl citrate (DIN : 02384124 / 02240434 / 02385406) will be administered sublingually by syringe. The dose is 12,5 mcg.; Drug: Placebo oral liquid; Placebo will consist in simple syrup (simple syrup B.P. - NPN: 00050121) administered sublingually with syringe.
Placebo Comparator: Placebo; Placebo will consist in simple syrup (simple syrup B.P. - NPN: 00050121) administered sublingually with syringe.	Drug: Fentanyl citrate solution sublingual; Solution of fentanyl citrate (DIN : 02384124 / 02240434 / 02385406) will be administered sublingually by syringe. The dose is 12,5 mcg.; Drug: Placebo oral liquid; Placebo will consist in simple syrup (simple syrup B.P. - NPN: 00050121) administered sublingually with syringe.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breathlessness	Post-dose difference in exertional breathlessness at isotime (isotime definition : highest equivalent 2 min interval of exercise completed by a given participant).	Up to 10 days after visit 1
Exercise capacity	Post-dose difference in exercise endurance time (EET)	Up to 10 days after visit 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and description of adverse effects	Number and description of adverse effects	Up to 48 hours after treatment administration
Locus of Symptoms	Percentage contribution of breathlessness and leg discomfort to exercise cessation	Up to 10 days after visit 1
Qualitative descriptors of breathlessness at end exercise	Description by patients of the characteristics of breathlessness at the end of exercise	Up to 10 days after visit 1
Change in multidimensional evaluation of dyspnea	Evaluation of the multidimensional components of dyspnea following each intervention and using the Multidimensional Dyspnea Profile (MDP) questionnaire. The questionnaire contains a total of 11 questions to characterize dyspnea. Each questions is a symptom or a sensation that need to be rated on scale from 0 to 10 depending on the intensity of the symptom/sensation, with 0 representing the absence of symptom and 10 representing the higher perception of symptom. There is no combination to form a total score.	Up to 10 days after visit 1
Participant blinded preference	At the last visit, the investigators will ask to patients which intervention they preferred regarding relief of breathlessness and comfort during exercise	Up to 10 days after visit 1
Difference in the locus of symptoms limiting exercise during a cardio-pulmonary exercise test response when comparing responders to non-responders.	Responders will be define as participant with ≥ 1-point improvement in Borg dyspnea. The locus of symptom is the symptom that limit the exercise test (breathlessness, leg fatigue or both).	Up to 10 days after visit 1

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborators: Canadian Institutes of Health Research (CIHR); Royal University Hospital, Saskatoon
• Investigators: Principal Investigator: Jean Bourbeau, MD, Reseach Institute MUHC

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): February 4, 2026

Study Registration Dates

• First Submitted: May 27, 2019
• First Submitted That Met QC Criteria: June 27, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Fentanyl
• Other Study ID Numbers: RIMUHCCOPDJB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to have the data share by other researcher. All data will be denominalized in order to respect privacy. Data will be collected in an anonymous data sheet, protected by a password. Only investigators and statistician will have access to this data sheet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No