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    Clinical Trial Results:
    Effentora® for Dyspnoea (EffenDys) - Fentanyl buccal tablet (FBT) for the relief of episodic dyspnoea (ED) in cancer patients: an open label, randomized, morphine-controlled, crossover, phase II trial

    Summary
    EudraCT number
    		 2011-005797-32
    Trial protocol
    		 DE  
    Global end of trial date
    29 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2020
    First version publication date
    26 Oct 2020
    Other versions
    Summary report(s)
    		 EffenDys summary report [German]

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1412
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: 00004353
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Prof. Dr.med Raymond Voltz Zentrum für Palliativmedizin Center for Integrated Oncology (CIO), University Hospital Cologne Zentrum Palliativmedizin, raymond.voltz@uk-koeln.de
    Scientific contact
    Prof. Dr. med. Steffen Simon Zentrum für Palliativmedizin Center for Integrated Oncology (CIO), University Hospital Cologne Zentrum Palliativmedizin, steffen.simon@uk-koeln.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the time to onset of meaningful dyspnoea relief of fentanyl buccal tablet (FBT) in comparison to immediate-release morphine (IRM)
    Protection of trial subjects
    none further specific measures; Patient’s usual rescue medication for the relief of dyspnoea will be used as rescue medication. Rescue medication is allowed at any time of the study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    7
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between March 2013 and October 2014 (20 months, extended from a planned 12 month period) in 3 hospitals (palliative care and oncology wards) in Germany.

    Pre-assignment
    Screening details
    		 Around 1.000 patients were screened in a 20 month recruitment phase. 25 patients were considered eligible and offered participation. 10 patients provided informed consent and were included.

    Period 1
    Period 1 title
    First treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fentanyl buccal tablet (FBT; Effentora®)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl 100/200/400/600μg
    Investigational medicinal product code
    SUB02129MIG
    Other name
    Effentora®
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Buccal use
    Dosage and administration details
    Dosage: 100μg - 600 μg (to be determined by titration)

    Arm title
    		 Immediate release morphine (IRM)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphin Merck Tropfen 2%
    Investigational medicinal product code
    SUB14596MIG
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage: Start with a minimum of 5mg (to be determined by titration)

    Number of subjects in period 1
    		Fentanyl buccal tablet (FBT; Effentora®) Immediate release morphine (IRM)
    Started
    5
    5
    Efficacy phase
    5
    4
    Completed
    5
    4
    Not completed
    0
    1
         Disease progression
    -
    1
    Period 2
    Period 2 title
    Second (cross-over) treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fentanyl buccal tablet (FBT; Effentora®)
    Arm description
    		 Second treatment period with FBT after receiving IRM in period 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fentanyl 100/200/400/600μg
    Investigational medicinal product code
    SUB02129MIG
    Other name
    Effentora®
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Buccal use
    Dosage and administration details
    Dosage: 100μg - 600 μg (to be determined by titration)

    Arm title
    		 Immediate release morphine (IRM)
    Arm description
    		 Second treatment period with IRM after receiving FBT in period 1
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphin Merck Tropfen 2%
    Investigational medicinal product code
    SUB14596MIG
    Other name
    Pharmaceutical forms
    Oral drops, liquid
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage: Start with a minimum of 5mg (to be determined by titration)

    Number of subjects in period 2
    		Fentanyl buccal tablet (FBT; Effentora®) Immediate release morphine (IRM)
    Started
    4
    5
    Efficacy phase
    2
    4
    Completed
    2
    4
    Not completed
    2
    1
         Consent withdrawn by subject
    1
    -
         Disease progression
    1
    -
         Detoriation of health status
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First treatment period
    Reporting group description
    		 Patients randomized into the trial after being successfully screened

    Reporting group values
    		 First treatment period Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 7 7
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.0 ( 11.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    all randomized patients

    Subject analysis sets values
    		 Intention-to-treat
    Number of subjects
    10
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    7
        From 65-84 years
    3
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.0 ( 11.3 )
    Gender categorical
    Units: Subjects
        Female
    4
        Male
    6

    End points

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    End points reporting groups
    Reporting group title
    Fentanyl buccal tablet (FBT; Effentora®)
    Reporting group description
    		 -

    Reporting group title
    Immediate release morphine (IRM)
    Reporting group description
    		 -
    Reporting group title
    Fentanyl buccal tablet (FBT; Effentora®)
    Reporting group description
    		 Second treatment period with FBT after receiving IRM in period 1

    Reporting group title
    Immediate release morphine (IRM)
    Reporting group description
    		 Second treatment period with IRM after receiving FBT in period 1

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    all randomized patients

    Primary: Time to onset of meaningful dyspnoea relief

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    End point title
    		 Time to onset of meaningful dyspnoea relief [1]
    End point description
    End point type
    Primary
    End point timeframe
    Time to onset of meaningful dyspnoea relief will be measured by stopwatch: time in minutes between administration of study medication and onset of meaningful dyspnoea relief. ‘Meaningful dyspnoea relief’ is defined by the patient.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary analysis of the trial is a comparison of periods in a cross-over design that cannot be properly documented in the results database. Additionally planned methods were adjusted in the SAP because the planned sample size was not reached. Data from both periods were available for 6 patients. The mean difference (FBT minus IRM) is -14.2 min with 95% confidence interval -27.1 to -1.4 min, p=0.036 (paired t-test). See PDF summary report for details and secondary endpoints.
    End point values
    		 Intention-to-treat
    Number of subjects analysed
    Units: whole
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First Treatment until 3 days after last application of study drug
    Adverse event reporting additional description
    Signs or symptoms of expected progression of the underlying disease or worsening of pre-existing conditions were exempt from AE reporting unless meeting SAE criteria or being CTCAE Grade>2. Also, treatment measures planned before start of the trial were exempt from reporting. Death from underlying disease was considered an AE but not an SAE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Intention-to-treat
    Reporting group description
    		 Note that the 3 (fatal) serious adverse events reported were not considered serious events in the study (death from underlying disease). Numbers were adjusted in this section to be able to pass result validation.

    Serious adverse events
    		 Intention-to-treat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 10 (30.00%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    3
    General disorders and administration site conditions
    Death
    Additional description: Death from underlying disease. Note that death from underlying disease was not considered a serious adverse event in the study but only an adverse event. Events were moved to this section to pass result validation.
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intention-to-treat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    Nervous system disorders
    Coma
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2013
    Changes in Exclusion criteria (protocol version V9-02-F, 10-sep-2013): Deletion of „Severe chronic obstructive pulmonary disease (COPD; GOLD classification stage III or IV or long term oxygen therapy (LTOT, defined as oxygen therapy at least 16 hours per day))” Change of „History of opioid abuse (as reported by the patient, referring physician or investigator)” to “Ongoing opioid abuse (as reported by the patient, referring physician or investigator)”.
    01 Jul 2014
    (protocol version V10-01, 15-apr-2014) Changes in exclusion criteria - use of a monoamine oxidase inhibitors, "..SSRIs or SNRIs ...".within the previous 14 days updated SmPC for Fentanyl buccal tablet (FBT; Effentora®)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Despite best efforts only 10 of 30 planned patients could be enrolled and only 6 received both treatment periods. This severely limits both efficacy and safety conclusions The main result is that this design is not feasibile in this population.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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