Fentanyl Buccal Tablet for the Relief of Episodic Breathlessness in Cancer Patients (EFFENDYS)

• ClinicalTrials.gov Identifier: NCT04635852
• Recruitment Status: Completed
• First Posted: November 19, 2020
• Last Update Posted: November 19, 2020
• Sponsor: University of Cologne
• Collaborator: Teva Branded Pharmaceutical Products R&D, Inc.
• Information provided by (Responsible Party): Prof. Dr. Steffen Simon, University of Cologne

Study Description

Brief Summary:

"Episodic breathlessness (or dyspnea) is one form of chronic refractory breathlessness characterized by a severe worsening of breathlessness intensity or unpleasantness beyond usual fluctuations in the patient's perception. Episodes are time-limited (seconds to hours) and occur intermittently, with or without underlying continuous breathlessness. Episodes may be predictable or unpredictable, depending on whether any trigger(s) can be identified. There is a range of known triggers which can interact (e.g. exertion, emotions, comorbidities or external environment). One episode can be caused by one or more triggers." ( definition by an international expert consensus [Simon et al. 2013]). Approximately half of patients with cancer complain about breathlessness with the highest prevalence in pulmonary malignancies. Episodic breathlessness is reported by 81% of breathless cancer patients with significant impairment on quality of life and limitations on activity. Although episodic breathlessness show some similar characteristics like episodes of pain (breakthrough cancer pain, BTCP; median duration 30minutes), they are often shorter: 91% last less than 20minutes (min). Other evidence supports these findings with duration between 2-15minutes which is a real challenge for the treatment of episodic breathlessness. In the majority of cases, episodic breathlessness occur 1-4 times per day and peak intensity is rated moderate or severe.

There is evidence for the effectiveness of opioids for the relief of chronic refractory breathlessness. There is no evaluated and proven standard treatment for the relief of episodic breathlessness at the moment but immediate-release morphine (IRM) as solution or tablet is most frequently used in clinical practice to treat episodic breathlessness. Time to onset of action of IRM is about 20-30min for pain. Fentanyl is a potent opioid and shows good evidence for the treatment of BTCP through its quick onset of action (5-15min) and short duration of action (50-60min). Because of its pharmacodynamic properties fentanyl might be appropriate and effective for the relief of episodic breathlessness. However, the efficacy of fentanyl for the relief of breathlessness and time to onset is unknown.

This pilot study aims to evaluate relative efficacy, feasibility and time to onset of two different opioids (fentanyl and morphine) in order to improve the management of episodic breathlessness.

Condition or disease	Intervention/treatment	Phase
Cancer; Dyspnea, Paroxysmal	Drug: Fentanyl; Drug: Immediate release morphine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effentora® for Dyspnoea - Fentanyl Buccal Tablet for the Relief of Episodic Breathlessness in Cancer Patients: A Multicenter, Open Label, Randomized, Morphine-controlled, Crossover, Phase II-TRIAL
• Actual Study Start Date: March 2013
• Actual Primary Completion Date: November 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fentanyl; Fentanyl buccal tablet Dosage: 100µg - 600 µg Fentanyl (to be determined by titration) Administration: buccal administration (tablet)	Drug: Fentanyl; Other Names: Fentanyl buccal tablet; Fentanyl citrate
Active Comparator: Immediate release morphine; Immediate release morphine, solution Dosage: Start with a minimum of 5mg (to be determined by titration)	Drug: Immediate release morphine; Other Name: Morphine Solution

Outcome Measures

Primary Outcome Measures :

1. Time to onset of meaningful breathlessness relief [ Time Frame: minutes (by stop watch) from drug application of FBT/IRM up to breathlessness relief ]
   To determine the time to onset of meaningful breathlessness relief of fentanyl buccal tablet (FBT) in comparison to immediate-release morphine (IRM)

Secondary Outcome Measures :

1. Breathlessness intensity [ Time Frame: at 0, 3, 5, 10, 15, 20, 30, 45 and 60 minutes after application of FBT/IRM ]
   Breathlessness intensity measured by NRS (range 0-10)
2. Numbers of rescue medication doses [ Time Frame: Numbers of rescue medication doses through study completion, assessed at day 10 (final visit) ]
   If adequate breathlessness relief was not reached after 30 min, the patient could use his standard rescue medication.
3. Patient's & investigator's satisfaction [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   Patient's and investigator's satisfaction of breathlessness relief and route of application regarding ease of administration (4-point verbal rating scale: 0 = poor/unsatisfied and 4 = excellent/very satisfied).
4. Preferences of study drugs [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   FBT or IRM or both/none

Other Outcome Measures:

1. Number of (serious) adverse events (AE/SAE; Safety of FBNT/IRM) [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   Counts of adverse events
2. Severity of AE/SAE (Safety of FBNT/IRM) [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   CTCAE tool v4.03 (National Cancer Institute Common Terminology Criteria)
3. Oxygen saturation (Safety of FBNT/IRM) [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   finger clip pulse oximetry (Contec Medical Systems Co., China)
4. Patient's vigilance (Safety of FBNT/IRM) [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   Glasgow Coma Scale (GCS)
5. Respiratory rate (Safety of FBNT/IRM) [ Time Frame: through study completion, day 10 (e.g. final visit) ]
   breaths per minute
6. Enrollment rate (Feasibility of study procedures) [ Time Frame: day 10 (e.g. final visit) ]
   Ratio of patients screened to patient with informed consent
7. Completion rate (Feasibility of study procedure) [ Time Frame: day 10 (e.g. final visit) ]
   Ratio of patients that were randomly assigned to the experimental vs active comparator arm to patients that completed the study
8. Drop outs (Feasibility of study procedures) [ Time Frame: day 10 (e.g. final visit) ]
   Counts of drop out per visit (TPh+EPh)
9. Reasons for rejection of study participation of screened patient (Feasibility of study procedures) [ Time Frame: day 10 (e.g. final visit) ]
   List of reasons/ free text responses
10. Acceptability of study procedures [ Time Frame: day 10 (e.g. final visit) ]
    closed questions: 4-point verbal rating scale between 0=poor/unsatisfied and 4=excellent/very satisfied, and yes/no; reports by patients, investigators and clinical team
11. Acceptability of measurement tools [ Time Frame: day 10 (e.g. final visit) ]
    closed questions: 4-point verbal rating scale between 0=poor/unsatisfied and 4=excellent/very satisfied, and yes/no; reports by patients, investigators and clinical team
12. Acceptability of rescue procedures [ Time Frame: day 10 (e.g. final visit) ]
    closed questions: 4-point verbal rating scale between 0=poor/unsatisfied and 4=excellent/very satisfied, and yes/no; reports by patients, investigators and clinical team

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Histologically or cytologically proven cancer of any entity which is non-curable as judged by the referring physician or investigator
2. To be an inpatient during the study
3. Refractory breathlessness - this study applies only to 'refractory breathlessness ' and is defined: a patient is still breathless although the underlying disease (e.g. lung cancer) or cause of breathlessness (e.g. pleural effusion) is treated optimal as judged by the referring physician or investigator
4. History of recurrent episodic breathlessness - episodic breathlessness is defined as an increase in breathlessness occurring intermittently in patients with or without underlying continuous breathlessness
5. Peak intensity of episodic breathlessness ≥ 3 (NRS, 0-10)
6. Opioid tolerance for at least one day - opioid tolerance is defined: patient who receive per day at least 30mg oral morphine, 15mg oral oxycodone, 4mg oral hydromorphone, 12µg/h transdermal fentanyl or an analgetic equivalent of a different opioid or a different routes of application
7. Life expectancy of at least one month as judged by the referring physician or investigator

Exclusion criteria:

1. Uncontrolled breathlessness (i.e. rapidly worsening breathlessness requiring urgent medical or technical intervention)
2. Uncontrolled performance status (i.e. rapid deterioration of performance status)
3. Consideration of any reason by the referring therapeutic team that the patient is not an appropriate participant of a clinical trial
4. Respiratory depression or preconditions with risk of respiratory depression
5. Acute abdomen or ileus or any situation that drug resorption is not possible
6. Renal dysfunction with creatinine clearance (eGFR) calculated as less than 25 ml/minute
7. Medical history of severe hepatic impairment
8. The use of fentanyl transmucosal products for breakthrough cancer pain (BTCP) during the trial
9. The use of a monoamine oxidase inhibitors within the previous 14 days
10. Treatment with any other investigational drugs within the previous 10 days

Contacts and Locations

Locations

Germany

University Hospital Göttingen Center of Palliative Medicine

Göttingen, Hessen, Germany, 37075

Study Center Palliative Medicine

Cologne, NRW, Germany, 50937

Hospital Essen- Mitte, Departement of Palliative Medicine

Essen, NRW, Germany, 45136

Sponsors and Collaborators

University of Cologne

Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Principal Investigator: Raymond Voltz, Professor; Department of Palliative Medicine

More Information

• Responsible Party: Prof. Dr. Steffen Simon, prof, University of Cologne
• ClinicalTrials.gov Identifier: NCT04635852
• Other Study ID Numbers: Uni-Koeln-1412; 2011-005797-32 ( EudraCT Number ); DRKS00004353 ( Other Identifier: DRKS )
• First Posted: November 19, 2020
• Last Update Posted: November 19, 2020
• Last Verified: November 2020

Additional relevant MeSH terms:

Dyspnea; Dyspnea, Paroxysmal; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Heart Failure; Heart Diseases; Cardiovascular Diseases; Fentanyl; Morphine; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Adjuvants, Anesthesia; Anesthetics, Intravenous; Anesthetics, General; Anesthetics