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    Clinical Trial Results:
    A randomized, double-blind, multi-center, placebo-controlled, parallel group study to evaluate the efficacy and safety of an Diclofenac 2% (w/w) cutaneous solution applied twice daily in patients with acute uncomplicated unilateral ankle sprain for a period of 7 consecutive days. Abbreviated title: Randomized, controlled, double-blind, multi-center trial to evaluate the efficacy and safety of a diclofenac 2% cutaneous solution vs. placebo in the treatment of acute uncomplicated unilateral ankle sprain

    Summary
    EudraCT number
    		 2014-005574-11
    Trial protocol
    		 DE  
    Global end of trial date
    21 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2018
    First version publication date
    26 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Pennsaid-2014/P-3-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nuvo Pharmaceuticals Inc.
    Sponsor organisation address
    6733 Mississauga Rd. Suite 610, Mississauga, Canada, ON L5N 6J
    Public contact
    Bernard Chiasson, Nuvo Pharmaceuticals Inc., +01 905 673 3623, bchiasson@nuvopharm.com
    Scientific contact
    Christian de Mey, ACPS-Network GmbH, +49611 44762110, c.demey@acps-network.com
    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
    08 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is: To assess the efficacy of diclofenac sodium 2% w/w cutaneous solution for the treatment of Pain and Inflammation associated with acute soft tissue injury/ankle sprain
    Protection of trial subjects
    Patients were monitored throughout participation in the study for occurrence of adverse events after the start of investigational treatment (subjective) and the incidence of abnormal findings in measurements for objective tolerability: vital signs and physical findings
    Background therapy
    		 Paracetamol, 500 mg tablets, were made available by the investigator as non-IMP to the trial participants at the baseline visit; paracetamol was to be used as rescue medication if and as needed (up to 1000 mg per day); use of rescue medication was not allowed within 6 hours before attending the study clinic for the study visits. At each visit, the patient was expected to bring the box with rescue medication and a record was to be made of the use since the last visit (total number of tablets used; number of days with use of more than 2 tablets per day)
    Evidence for comparator
    		 Vehicle control cutaneous solution indistinguishable from the investigational test drug Pennsaid 2% w/w cutaneous solution
    Actual start date of recruitment
    01 Jun 2015
    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: 126
    Worldwide total number of subjects
    126
    EEA total number of subjects
    126
    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)
    125
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 126 outpatients with acute uncomplicated Grade I-II ankle sprain were recruited from 7 German study sites from 05.Aug.2015 to 14.Dec.2015. Enrolled patients were assigned at random to parallel group treatment with either test (Pennsaid 2%) or control (Vehicle Control) medication

    Pre-assignment
    Screening details
    		 126 female and male outpatients with acute uncomplicated grade I-II ankle sprain of recent onset without confounding co-morbidity or co-medications were screened and enrolled. At the first visit, eligible patients were evaluated for baseline criteria, were then randomised, and self-applied the 1st dose under supervision by investigator

    Period 1
    Period 1 title
    Treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject, Carer, Assessor
    Blinding implementation details
    The clinical trial was double-blind. Patients, Investigator staff, persons performing the assessments, monitors and data analysts remained blinded to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) Randomization data kept strictly confidential, accessible only to authorized persons, (2) identity of the treatments was concealed by use of IMPs identical in packaging, labeling, schedule of administration, appearance, odor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pennsaid-2%
    Arm description
    		 Pennsaid-2% w/w cutaneous solution (containing 2% w/w diclofenac sodium plus 45.5% w/w DMSO) for topical application; Nuvo Pharmaceuticals Inc.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pennsaid 2% w/w cutaneous solution
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Two 1-gram actuations one to each side of the injured ankle twice daily for seven days. The first dose was administered at the trial site immediately after randomisation under supervision and on instruction of the investigator; subsequent doses were self-administered by the patient while ambulatory. Treatment lasted until the morning of the last treatment day (day D08).

    Arm title
    		 Vehicle Control
    Arm description
    		 Matched control cutaneous solution for topical application containing no diclofenac sodium, but 45.5% w/w DMSO; Nuvo Pharmaceuticals Inc.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle Control
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Two 1-gram actuations one to each side of the injured ankle twice daily for seven days. The first dose was administered at the trial site immediately after randomisation under supervision and on instruction of the investigator; subsequent doses were self-administered by the patient while ambulatory. Treatment lasted until the morning of the last treatment day (day D08).

    Number of subjects in period 1
    		Pennsaid-2% Vehicle Control
    Started
    63
    63
    Completed
    61
    63
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pennsaid-2%
    Reporting group description
    		 Pennsaid-2% w/w cutaneous solution (containing 2% w/w diclofenac sodium plus 45.5% w/w DMSO) for topical application; Nuvo Pharmaceuticals Inc.

    Reporting group title
    Vehicle Control
    Reporting group description
    		 Matched control cutaneous solution for topical application containing no diclofenac sodium, but 45.5% w/w DMSO; Nuvo Pharmaceuticals Inc.

    Reporting group values
    		 Pennsaid-2% Vehicle Control Total
    Number of subjects
    		 63 63 126
    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)
    		 62 63 125
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.57 ± 13.09 33.33 ± 12.02 -
    Gender categorical
    Units: Subjects
        Female
    		 29 34 63
        Male
    		 34 29 63
    POM (Pain on Movement)
    Pain intensity on controlled standardised movement of the injured ankle executed by the investigator and scored on a 100 mm visual analogue scale (VAS)
    Units: mm
        arithmetic mean (standard deviation)
    		 73.70 ± 12.32 73.87 ± 11.14 -
    PAR (Pain at Rest)
    After relaxing for about at least 10 minutes, the patient was asked to score his pain at rest in answer to the question: "How would you describe your ankle pain right now?" ("Wie würden Sie die Schmerzen in Ihrem Sprunggelenk in diesem Moment beschreiben?"). The answer was to be scored on a 100 mm VAS
    Units: mm
        arithmetic mean (standard deviation)
    		 30.32 ± 20.81 33.37 ± 22.19 -
    Ankle Swelling
    Ankle swelling was measured by the Figure-of-eight-method. Circumference was measured on both ankles. Swelling is calculated as the difference between the injured and the non-injured contralateral ankle
    Units: mm
        arithmetic mean (standard deviation)
    		 1.93 ± 1.14 1.58 ± 1.11 -
    Ankle Tenderness
    Tenderness was measured using a calibrated algometer on an area of 1 cm² at one of the four points of reference at the centre of the injured area that was first tested and confirmed to be the most sensitive on palpation; this selected point was then used throughout. The patient was instructed to indicate onset of pain with a verbal cue such as "Yes" or "Stop" or raising his/her hand. Effect-relevant tenderness was calculated as the difference in PPT (algometer pressure when the patient reports onset of pain) for the injured minus the non-injured foot
    Units: N/cm²
        arithmetic mean (standard deviation)
    		 36.40 ± 14.34 31.97 ± 11.25 -
    Ankle function (Karlsson Score)
    The patient scored (VRS) eight domains: pain, swelling, instability, stiffness, stair climbing, running, work activities, and the use of a support device. The maximum score equals 90. The patient scores his replies to the various questions on a printed questionnaire in national language made available to this purpose
    Units: sum of scores
        arithmetic mean (standard deviation)
    		 34.49 ± 12.57 37.06 ± 15.50 -

    End points

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    End points reporting groups
    Reporting group title
    Pennsaid-2%
    Reporting group description
    		 Pennsaid-2% w/w cutaneous solution (containing 2% w/w diclofenac sodium plus 45.5% w/w DMSO) for topical application; Nuvo Pharmaceuticals Inc.

    Reporting group title
    Vehicle Control
    Reporting group description
    		 Matched control cutaneous solution for topical application containing no diclofenac sodium, but 45.5% w/w DMSO; Nuvo Pharmaceuticals Inc.

    Primary: POM (Pain on Movement) - D05

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    End point title
    		 POM (Pain on Movement) - D05
    End point description
    End point type
    Primary
    End point timeframe
    POM: D05 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -29.59 (-34.23 to -24.94)
    -26.11 (-30.76 to -21.45)
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.243
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.36
         upper limit
    		 2.39

    Secondary: POM (Pain on Movement) - D03

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    End point title
    		 POM (Pain on Movement) - D03
    End point description
    End point type
    Secondary
    End point timeframe
    POM (Pain on Movement) - D03 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -17.17 (-20.36 to -13.98)
    -11.96 (-15.15 to -8.76)
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0119
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.25
         upper limit
    		 -1.17

    Secondary: POM (Pain on Movement) - D08

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    End point title
    		 POM (Pain on Movement) - D08
    End point description
    End point type
    Secondary
    End point timeframe
    POM (Pain on Movement) - D08 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -46.53 (-52.09 to -40.97)
    -42.52 (-48.08 to -36.95)
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2603
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.05
         upper limit
    		 3.02

    Secondary: PAR (Pain at Rest) - D03

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    End point title
    		 PAR (Pain at Rest) - D03
    End point description
    End point type
    Secondary
    End point timeframe
    PAR (Pain at Rest) - D03 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -6.25 (-8.63 to -3.86)
    -5.10 (-7.65 to -2.56)
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4283
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.99
         upper limit
    		 1.7

    Secondary: PAR (Pain at Rest) - D05

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    End point title
    		 PAR (Pain at Rest) - D05
    End point description
    End point type
    Secondary
    End point timeframe
    PAR (Pain at Rest) - D05 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -11.27 (-14.22 to -8.32)
    -11.83 (-14.97 to -8.68)
    Statistical analysis title
    		 between-treatemnt difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7549
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.96
         upper limit
    		 4.08

    Secondary: PAR (Pain at Rest) - D08

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    End point title
    		 PAR (Pain at Rest) - D08
    End point description
    End point type
    Secondary
    End point timeframe
    PAR (Pain at Rest) - D08 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: mm
        least squares mean (confidence interval 95%)
    -17.44 (-20.36 to -14.52)
    -18.56 (-21.67 to -15.44)
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Mean changes from baseline were compared between treatment by analysis of covariance (ANCOVA) with treatment group and center as main effects and baseline as covariate. Treatment-by-center interaction was not part of the primary efficacy analysis model. LOCF was used for patients with premature study treatment discontinuation; LO before any non-allowed use of rescue treatment was carried forward for all patients with any non-allowed use of rescue medication
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.528
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.37
         upper limit
    		 4.6

    Secondary: Tenderness - D03

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    End point title
    		 Tenderness - D03
    End point description
    End point type
    Secondary
    End point timeframe
    Tenderness - D03 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: n/cm2
        arithmetic mean (standard deviation)
    -9.10 ± 11.06
    -4.52 ± 6.32
    Statistical analysis title
    		 Between treatment difference
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0055
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.77
         upper limit
    		 -1.4
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0055
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.77
         upper limit
    		 -1.4

    Secondary: Tenderness - D05

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    End point title
    		 Tenderness - D05
    End point description
    End point type
    Secondary
    End point timeframe
    Tenderness - D05 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: n/cm2
        arithmetic mean (standard deviation)
    -15.49 ± 12.63
    -10.78 ± 8.18
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Students t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.47
         upper limit
    		 -0.95

    Secondary: Tenderness - D08

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    End point title
    		 Tenderness - D08
    End point description
    End point type
    Secondary
    End point timeframe
    Tenderness - D08 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    61
    63
    Units: n/cm2
        arithmetic mean (standard deviation)
    -24.23 ± 14.68
    -18.25 ± 10.41
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0104
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.49
         upper limit
    		 -1.47

    Secondary: Ankle swelling - D03

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    End point title
    		 Ankle swelling - D03
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle swelling - D03 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: mm
        arithmetic mean (standard deviation)
    -0.69 ± 0.86
    -0.29 ± 0.51
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 -0.15

    Secondary: Ankle Swelling - D05

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    End point title
    		 Ankle Swelling - D05
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle Swelling - D05 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: mm
        arithmetic mean (standard deviation)
    -1.05 ± 1.04
    -0.57 ± 0.59
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Vehicle Control v Pennsaid-2%
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 -0.19

    Secondary: Ankle Swelling - D08

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    End point title
    		 Ankle Swelling - D08
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle Swelling - D08 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    61
    63
    Units: mm
        arithmetic mean (standard deviation)
    -1.44 ± 1.20
    -0.97 ± 0.89
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0142
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 -0.1

    Secondary: Ankle joint function (Karlsson Score) - D03

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    End point title
    		 Ankle joint function (Karlsson Score) - D03
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle joint function (Karlsson Score) - D03 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: sum of scores
        arithmetic mean (standard deviation)
    10.68 ± 10.19
    6.59 ± 7.35
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0115
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 7.23

    Secondary: Ankle joint function (Karlsson Score) - D05

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    End point title
    		 Ankle joint function (Karlsson Score) - D05
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle joint function (Karlsson Score) - D05 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    62
    63
    Units: sum of scores
        arithmetic mean (standard deviation)
    21.21 ± 12.86
    17.92 ± 12.83
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1549
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 7.84

    Secondary: Ankle joint function (Karlsson Score) - D08

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    End point title
    		 Ankle joint function (Karlsson Score) - D08
    End point description
    End point type
    Secondary
    End point timeframe
    Ankle joint function (Karlsson Score) - D08 change from D01
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    61
    63
    Units: sum of scores
        arithmetic mean (standard deviation)
    35.52 ± 14.87
    29.03 ± 16.50
    Statistical analysis title
    		 Between-treatment difference of change from D01
    Statistical analysis description
    Student t-test
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0232
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 12.08

    Secondary: PGAB (Patient General Assessment of Benefit)

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    End point title
    		 PGAB (Patient General Assessment of Benefit)
    End point description
    End point type
    Secondary
    End point timeframe
    End-of-treatment (D08)
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: number of subjects
        very good
    21
    6
        good
    27
    24
        fair
    10
    28
        poor
    3
    5
        very poor
    0
    0
        missing
    2
    0
    Statistical analysis title
    		 PGAB - Between-treatment difference
    Statistical analysis description
    Cochran-Mantel-Haenzel test stratified by visit (D05, D08)
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: PGAS (Patient General Assessment of Satisfaction)

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    End point title
    		 PGAS (Patient General Assessment of Satisfaction)
    End point description
    End point type
    Secondary
    End point timeframe
    End-of-treatment (D08)
    End point values
    		 Pennsaid-2% Vehicle Control
    Number of subjects analysed
    63
    63
    Units: number of subjects
        excellent
    1
    2
        very good
    18
    4
        good
    26
    22
        fair
    13
    28
        poor
    3
    7
        missing
    2
    0
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Cochran-Mantel-Haenzel test stratified by visit (D05, D08)
    Comparison groups
    Pennsaid-2% v Vehicle Control
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout study, from enrolment to end-of-trial on D08; in the event of unresolved safety findings at D08, post-D08 follow-up was provided
    Adverse event reporting additional description
    Adverse events (AE) were defined as any untoward change in wellbeing on study. AE were either reported by the trial participants to the investigator or were observed findings by the investigator on visits D03, D05, or D08. The event was categorised as treatment-emergent if its onset was subsequent to administration of the first dose
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Pennsaid-2%
    Reporting group description
    		 Treatment with Pennsaid 2% w/w cutaneous solution two 1-gram actuations, on to each side of the injured ankle twice daily for 7 days

    Reporting group title
    Vehicle Control
    Reporting group description
    		 Treatment with Pennsaid matched vehicle control cutaneous solution two 1-gram actuations, on to each side of the injured ankle twice daily for 7 days

    Serious adverse events
    		 Pennsaid-2% Vehicle Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 63 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    		 Pennsaid-2% Vehicle Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 63 (20.63%)
    13 / 63 (20.63%)
    Injury, poisoning and procedural complications
    Wrist fracture
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application site dryness
         subjects affected / exposed
    5 / 63 (7.94%)
    5 / 63 (7.94%)
         occurrences all number
    5
    5
    Application site pruritus
         subjects affected / exposed
    5 / 63 (7.94%)
    5 / 63 (7.94%)
         occurrences all number
    5
    5
    Application site paraesthesia
         subjects affected / exposed
    3 / 63 (4.76%)
    2 / 63 (3.17%)
         occurrences all number
    3
    2
    Application site exfoliation
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 63 (3.17%)
         occurrences all number
    2
    2
    Application site erythema
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    0
    2
    Product taste abnormal
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 63 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    0
    1
    Infections and infestations
    Rash pustular
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 63 (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
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