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

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

"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.

Study Overview

• Status: Completed
• Conditions: Cancer; Dyspnea, Paroxysmal
• Intervention / Treatment: Drug: Fentanyl; Drug: Immediate release morphine

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Hessen
    • Göttingen, Hessen, Germany, 37075
      • University Hospital Göttingen Center of Palliative Medicine
  • NRW
    • Cologne, NRW, Germany, 50937
      • Study Center Palliative Medicine
    • Essen, NRW, Germany, 45136
      • Hospital Essen- Mitte, Departement of Palliative Medicine

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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 citrate; Fentanyl buccal tablet
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 Names: Morphine Solution

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breathlessness intensity	Breathlessness intensity measured by NRS (range 0-10)	at 0, 3, 5, 10, 15, 20, 30, 45 and 60 minutes after application of FBT/IRM
Numbers of rescue medication doses	If adequate breathlessness relief was not reached after 30 min, the patient could use his standard rescue medication.	Numbers of rescue medication doses through study completion, assessed at day 10 (final visit)
Patient's & investigator's satisfaction	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).	through study completion, day 10 (e.g. final visit)
Preferences of study drugs	FBT or IRM or both/none	through study completion, day 10 (e.g. final visit)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of (serious) adverse events (AE/SAE; Safety of FBNT/IRM)	Counts of adverse events	through study completion, day 10 (e.g. final visit)
Severity of AE/SAE (Safety of FBNT/IRM)	CTCAE tool v4.03 (National Cancer Institute Common Terminology Criteria)	through study completion, day 10 (e.g. final visit)
Oxygen saturation (Safety of FBNT/IRM)	finger clip pulse oximetry (Contec Medical Systems Co., China)	through study completion, day 10 (e.g. final visit)
Patient's vigilance (Safety of FBNT/IRM)	Glasgow Coma Scale (GCS)	through study completion, day 10 (e.g. final visit)
Respiratory rate (Safety of FBNT/IRM)	breaths per minute	through study completion, day 10 (e.g. final visit)
Enrollment rate (Feasibility of study procedures)	Ratio of patients screened to patient with informed consent	day 10 (e.g. final visit)
Completion rate (Feasibility of study procedure)	Ratio of patients that were randomly assigned to the experimental vs active comparator arm to patients that completed the study	day 10 (e.g. final visit)
Drop outs (Feasibility of study procedures)	Counts of drop out per visit (TPh+EPh)	day 10 (e.g. final visit)
Reasons for rejection of study participation of screened patient (Feasibility of study procedures)	List of reasons/ free text responses	day 10 (e.g. final visit)
Acceptability of study procedures	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	day 10 (e.g. final visit)
Acceptability of measurement tools	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	day 10 (e.g. final visit)
Acceptability of rescue procedures	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	day 10 (e.g. final visit)

Collaborators and Investigators

• Sponsor: University of Cologne
• Collaborators: Teva Branded Pharmaceutical Products R&D, Inc.
• Investigators: Principal Investigator: Raymond Voltz, Professor, Department of Palliative Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2013
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: January 10, 2014
• First Submitted That Met QC Criteria: November 13, 2020
• First Posted (Actual): November 19, 2020

Study Record Updates

• Last Update Posted (Actual): November 19, 2020
• Last Update Submitted That Met QC Criteria: November 13, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Heart Failure; Dyspnea; Dyspnea, Paroxysmal; 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; Morphine
• Other Study ID Numbers: Uni-Koeln-1412; 2011-005797-32 (EudraCT Number); DRKS00004353 (Other Identifier: DRKS)