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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Cancer, Dyspnea, Paroxysmal

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Immediate release morphine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically or cytologically proven cancer of any entity which is non-curable as judged by the referring physician or investigator To be an inpatient during the study 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 History of recurrent episodic breathlessness - episodic breathlessness is defined as an increase in breathlessness occurring intermittently in patients with or without underlying continuous breathlessness Peak intensity of episodic breathlessness ≥ 3 (NRS, 0-10) 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 Life expectancy of at least one month as judged by the referring physician or investigator Exclusion criteria: Uncontrolled breathlessness (i.e. rapidly worsening breathlessness requiring urgent medical or technical intervention) Uncontrolled performance status (i.e. rapid deterioration of performance status) Consideration of any reason by the referring therapeutic team that the patient is not an appropriate participant of a clinical trial Respiratory depression or preconditions with risk of respiratory depression Acute abdomen or ileus or any situation that drug resorption is not possible Renal dysfunction with creatinine clearance (eGFR) calculated as less than 25 ml/minute Medical history of severe hepatic impairment The use of fentanyl transmucosal products for breakthrough cancer pain (BTCP) during the trial The use of a monoamine oxidase inhibitors within the previous 14 days Treatment with any other investigational drugs within the previous 10 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fentanyl<br>Fentanyl buccal tablet Dosage: 100µg - 600 µg Fentanyl (to be determined by titration) Administration: buccal administration (tablet) | Drug: Fentanyl<br> <br> * Other names: Fentanyl citrate;|
| Active Comparator: Immediate release morphine<br>Immediate release morphine, solution Dosage: Start with a minimum of 5mg (to be determined by titration) | Drug: Immediate release morphine<br> <br> * Other names: Morphine Solution;|

What is the study measuring?
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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) |