Effect of Sublingual Fentanyl on Breathlessness in COPD

Copd Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04004117
• Other study ID #: RIMUHCCOPDJB
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: July 2019
• Est. completion date: March 2020

Study information

• Verified date: July 2019
• Source: McGill University
• Contact: Jean Bourbeau, MD
• Phone: 5149440126
• Email: jean.bourbeau[@]mcgill.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 single centre randomized clinical trial, double-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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 24
• Est. completion date: March 2020
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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-ß2-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 arterialized capillary (earlobe) 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

Related Conditions & MeSH terms

• Copd
• Dyspnea

Intervention

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.
• Placebo oral liquid
Placebo will consist in simple syrup (simple syrup B.P. - NPN: 00050121) administered sublingually with syringe.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
McGill University

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Exercise capacity	Post-dose difference in exercise endurance time (EET)	Up to 10 days after visit 1
Secondary	Number and description of adverse effects	Number and description of adverse effects	Up to 48 hours after treatment administration
Secondary	Locus of Symptoms	Percentage contribution of breathlessness and leg discomfort to exercise cessation	Up to 10 days after visit 1
Secondary	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
Secondary	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
Secondary	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
Secondary	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