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    Clinical Trial Results:
    Randomized, controlled, double-blind, multi-center trial to evaluate the efficacy and safety of an Esflurbiprofen Hydrogel Patch vs. placebo in the local symptomatic and short-term treatment of pain in acute strains, sprains or bruises of the extremities following blunt trauma, e.g. sports injuries

    Summary
    EudraCT number
    		 2020-005165-14
    Trial protocol
    		 DE  
    Global end of trial date
    09 Nov 2021

    Results information
    Results version number
    		 v1
    This version publication date
    07 Jun 2023
    First version publication date
    07 Jun 2023
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    TK-254R-0201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Teikoku Seiyaku Co Ltd.
    Sponsor organisation address
    567 Sanbonmatsu, Higashikagawa, Kagawa, Japan, 769-2695
    Public contact
    Elke Klimmeck, Clinsearch GmbH, 41 417116376, e.klimmeck@clinsearch.de
    Scientific contact
    Elke Klimmeck, Clinsearch GmbH, 41 417116376, e.klimmeck@clinsearch.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
    02 Feb 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a Esflurbiprofen 165 mg Hydrogel Patch applied once a day compared with placebo in patients with acute blunt, soft tissue injuries of the limbs. • The primary efficacy outcome is pain-on-movement (POM) change from baseline assessed by Visual Analogue Scale (VAS) to Visit 5 (72 hours after initiating treatment). • Important secondary efficacy outcomes are POM on VAS at Visit 2, 3, 4, 6 and 7 (12, 24, 48, 96 and 168 hours after initiating treatment).
    Protection of trial subjects
    Prior to recruitment of patients, all relevant documents of the clinical study were submitted and proved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 Rescue medication (paracetamol, 500 mg tablets, up to 3000 mg daily) was allowed during the study, except for the 6 hours prior to V5 (72 h).
    Evidence for comparator
    		 As comparator a placebo patch was used, that did not contain the active ingredient but was otherwise indistinguishable from the investigational drug EFHP.
    Actual start date of recruitment
    20 May 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 200
    Worldwide total number of subjects
    200
    EEA total number of subjects
    200
    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)
    200
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 200 male and female adult patients were screened and randomized to the study drugs "EFHP" (n=98) and "Placebo" (n=102).

    Pre-assignment
    Screening details
    		 In total 200 patients were screened.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Eligible patients were randomized to one of two treatment arms in a ratio of 1:1. (1) Randomization data were kept strictly confidential, accessible only to authorized persons, until the time of unblinding. (2) The identity of the treatments was concealed by the use of study drugs that are all identical in packaging, labeling, schedule of administration, appearance and odor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EFHP (Test)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esflurbiprofen 165 mg Hydrogel Patch (EFHP)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Topical use
    Dosage and administration details
    All patients were treated with one patch of study drug at every visit during the first 6 visits (except for Visit 2). The first five patches were applied at the study center. The site of the first application was marked with a water-resistant pen to ensure the same application site at every treatment. Additional three patches were dispensed at Visit 6. The patients were instructed to apply one patch every day at approx. the same time. Dosing times had to be distributed as evenly as possible, preferably once every 24 hours after the last application.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo patch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    All patients were treated with one patch of study drug at every visit during the first 6 visits (except for Visit 2). The first five patches were applied at the study center. The site of the first application was marked with a water-resistant pen to ensure the same application site at every treatment. Additional three patches were dispensed at Visit 6. The patients were instructed to apply one patch every day at approx. the same time. Dosing times had to be distributed as evenly as possible, preferably once every 24 hours after the last application.

    Number of subjects in period 1
    		EFHP (Test) Placebo
    Started
    98
    102
    Completed
    98
    102

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EFHP (Test)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 EFHP (Test) Placebo Total
    Number of subjects
    		 98 102 200
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 98 102 200
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.2 ( 11.0 ) 34.3 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 55 98
        Male
    		 55 47 102
    Subject analysis sets

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set included all randomized patients who received at least one dose of the study drug. Safety was analyzed in this population.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set was all randomized patients who received at least one dose of study drug. The FAS population was primary population for the analysis of efficacy. Any exclusions from the FAS population were made and documented before unblinding (e.g. never used study medication, randomized twice). Additional secondary populations might be defined before unblinding and were described in detail in the SAP. The Intention to treat (ITT) population was identical to the Full Analysis Set (FAS).

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per protocol population included all patients who are randomized to the clinical trial, satisfied all of the inclusion/exclusion criteria, received the correct IMP (as randomized), had efficacy data at the 72 hours assessment, with an adhesion score of 0, 1, 2, had taken no pain medication and had no other major protocol violations as defined during a blinded review meeting. Only the outcomes relating to the ankle POM by VAS were analyzed using this clinical trial population.

    Subject analysis sets values
    		 SAF FAS PP
    Number of subjects
    200
    200
    196
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    200
    200
    196
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    33.7 ( 10.9 )
    33.7 ( 10.9 )
    33.9 ( 10.9 )
    Gender categorical
    Units: Subjects
        Female
    98
    98
    97
        Male
    102
    102
    99

    End points

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    End points reporting groups
    Reporting group title
    EFHP (Test)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    SAF
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set included all randomized patients who received at least one dose of the study drug. Safety was analyzed in this population.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set was all randomized patients who received at least one dose of study drug. The FAS population was primary population for the analysis of efficacy. Any exclusions from the FAS population were made and documented before unblinding (e.g. never used study medication, randomized twice). Additional secondary populations might be defined before unblinding and were described in detail in the SAP. The Intention to treat (ITT) population was identical to the Full Analysis Set (FAS).

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per protocol population included all patients who are randomized to the clinical trial, satisfied all of the inclusion/exclusion criteria, received the correct IMP (as randomized), had efficacy data at the 72 hours assessment, with an adhesion score of 0, 1, 2, had taken no pain medication and had no other major protocol violations as defined during a blinded review meeting. Only the outcomes relating to the ankle POM by VAS were analyzed using this clinical trial population.

    Primary: Pain-on-movement (baseline vs. V5)

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    End point title
    		 Pain-on-movement (baseline vs. V5)
    End point description
    End point type
    Primary
    End point timeframe
    V1 (baseline) vs. V5
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -50.7 ( 11.1 )
    -21.6 ( 11.9 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 > 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -29.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.2
         upper limit
    		 -26
    Variability estimate
    Standard deviation
    Notes
    [1] - proof-of-concept

    Secondary: Pain-on-movement (baseline vs. V2)

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    End point title
    		 Pain-on-movement (baseline vs. V2)
    End point description
    End point type
    Secondary
    End point timeframe
    V1 (baseline) vs. V2
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -8.8 ( 7.4 )
    -3.6 ( 3.7 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 -3.7
    Variability estimate
    Standard deviation
    Notes
    [2] - proof-of-concept

    Secondary: Pain-on-movement (baseline vs. V3)

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    End point title
    		 Pain-on-movement (baseline vs. V3)
    End point description
    End point type
    Secondary
    End point timeframe
    V1 (baseline) vs. V3
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -21.1 ( 11.0 )
    -7.2 ( 6.3 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -13.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.3
         upper limit
    		 -11.4
    Variability estimate
    Standard deviation
    Notes
    [3] - proof-of-concept

    Secondary: Pain-on-movement (baseline vs. V4)

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    End point title
    		 Pain-on-movement (baseline vs. V4)
    End point description
    End point type
    Secondary
    End point timeframe
    V1 (baseline) vs. V4
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -36.6 ( 11.1 )
    -13.4 ( 8.3 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -23.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.8
         upper limit
    		 -20.5
    Variability estimate
    Standard deviation
    Notes
    [4] - proof-of-concept

    Secondary: Pain-on-movement (baseline vs. V6)

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    End point title
    		 Pain-on-movement (baseline vs. V6)
    End point description
    End point type
    Secondary
    End point timeframe
    V1 (baseline) vs. V6
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -60.7 ( 10.4 )
    -32.7 ( 14.7 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -28.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.5
         upper limit
    		 -24.6
    Variability estimate
    Standard deviation
    Notes
    [5] - proof-of-concept

    Secondary: Pain-on-movement (baseline vs. V7)

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    End point title
    		 Pain-on-movement (baseline vs. V7)
    End point description
    End point type
    Secondary
    End point timeframe
    V1 (baseline) vs. V7
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: mm
        arithmetic mean (standard deviation)
    -67.9 ( 8.7 )
    -50.6 ( 17.9 )
    Statistical analysis title
    		 Change "POM on VAS" from baseline
    Comparison groups
    EFHP (Test) v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment effect
    Point estimate
    -17.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.9
         upper limit
    		 -13.9
    Variability estimate
    Standard deviation
    Notes
    [6] - proof-of-concept

    Secondary: Patch adhesion assessment (12h)

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    End point title
    		 Patch adhesion assessment (12h)
    End point description
    End point type
    Secondary
    End point timeframe
    12-h-application (Visit 2)
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: percent
    number (not applicable)
        Completely detached (4)
    1.0
    0
        ≥ 0 % to < 50 % adhered (3)
    0
    3.9
        ≥ 50 % to < 75 % adhered (2)
    23.5
    26.5
        ≥ 75 % to < 90 % adhered (1)
    46.9
    50.0
        ≥ 90 % adhered (0)
    28.6
    19.6
    No statistical analyses for this end point

    Secondary: Patch adhesion assessment (24h)

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    End point title
    		 Patch adhesion assessment (24h)
    End point description
    End point type
    Secondary
    End point timeframe
    24-h-applications (Visits 3, 4, 5, 6, 7)
    End point values
    		 EFHP (Test) Placebo
    Number of subjects analysed
    98
    102
    Units: percent
    number (not applicable)
        Completely detached (4)
    0
    0.2
        ≥ 0 % to < 50 % adhered (3)
    2.0
    2.0
        ≥ 50 % to < 75 % adhered (2)
    20.6
    28.4
        ≥ 75 % to < 90 % adhered (1)
    41.2
    40.4
        ≥ 90 % adhered (0)
    36.1
    29.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The observation phase for AEs began with the start of the treatment (i.e. 1st administration of IMP) and ended with the discharge of the patient from the clinical trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    EFHP (Test)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 EFHP (Test) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 102 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 EFHP (Test) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    Infections and infestations
    Oropharyngeal pain
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
    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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