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    Clinical Trial Results:
    A multi-centre, randomised, controlled, double-blind, parallel-group study on the efficacy and safety of Pennsaid-2% topical skin solution in patients with Grade I-II ankle sprain

    Summary
    EudraCT number
    		 2016-002620-92
    Trial protocol
    		 DE  
    Global end of trial date
    30 Mar 2017

    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-C-2016/P-3-02
    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 Road, Unit 610, Mississauga, Canada, L5N 6J5
    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
    01 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2017
    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
    10 Nov 2016
    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: 134
    Worldwide total number of subjects
    134
    EEA total number of subjects
    134
    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)
    131
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 134 outpatients with acute uncomplicated Grade I-II ankle sprain were recruited from 10 German study sites from Nov.2016 to Mar.2017. Enrolled patients were assigned at random to parallel group treatment with either test (Pennsaid 2%) or control (Vehicle Control) medication.

    Pre-assignment
    Screening details
    		 134 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
    		 Subject, Investigator, Monitor, Data analyst, 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
    68
    66
    Completed
    68
    66

    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
    		 68 66 134
    Age categorical
    Eligible: Male or female aged 18 – 75 years (inclusive)
    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)
    		 67 64 131
        From 65-84 years
    		 1 2 3
        85 years and over
    		 0 0 0
    Age continuous
    mean age by treatment group
    Units: years
        arithmetic mean (standard deviation)
    		 36.8 ( 14.0 ) 38.6 ( 13.6 ) -
    Gender categorical
    number of males and females by treatment group
    Units: Subjects
        Female
    		 28 30 58
        Male
    		 40 36 76
    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)
    		 71.0 ( 10.1 ) 71.5 ( 9.3 ) -
    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)
    		 33.0 ( 21.5 ) 30.6 ( 19.3 ) -
    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)
    		 1.74 ( 1.08 ) 1.79 ( 0.98 ) -
    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)
    		 -28.74 ( 13.66 ) -28.37 ( 14.04 ) -
    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)
    		 36.88 ( 12.43 ) 36.53 ( 11.36 ) -

    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 (D03)

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    End point title
    		 POM (D03)
    End point description
    End point type
    Primary
    End point timeframe
    POM on D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    54.95 (51.83 to 58.06)
    56.37 (53.18 to 59.55)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the POM on D03 by treatment; point estimate and SEM of the between-treatment difference and corresponding 95% CI as estimated by ANCOVA with the baseline POM as covariate and treatment and centre as factors [FAS]
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.504
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.61
         upper limit
    		 2.77

    Secondary: POM - Time course (D03)

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    End point title
    		 POM - Time course (D03)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of POM over treatment - D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    54.69 (51.53 to 57.86)
    56.13 (52.90 to 59.37)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the POM and change of POM from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline POM as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5074
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.73
         upper limit
    		 2.85

    Secondary: POM - Time course (D05)

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    End point title
    		 POM - Time course (D05)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of POM over treatment - D05
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    37.93 (33.99 to 41.86)
    41.77 (37.76 to 45.78)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the POM and change of POM from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline POM as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1642
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.28
         upper limit
    		 1.59

    Secondary: POM - Time course (D08)

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    End point title
    		 POM - Time course (D08)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of POM over treatment - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    19.99 (15.64 to 24.33)
    27.98 (23.56 to 32.41)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the POM and change of POM from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline POM as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0099
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.03
         upper limit
    		 -1.96

    Secondary: PAR - Time Course (D03)

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    End point title
    		 PAR - Time Course (D03)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of pain at rest (PAR) over treatment - D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    23.09 (20.52 to 25.66)
    23.54 (20.95 to 26.12)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the PAR and change of PAR from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline PAR as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8026
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.99
         upper limit
    		 3.09

    Secondary: PAR - Time Course (D05)

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    End point title
    		 PAR - Time Course (D05)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of PAR over treatment - D05
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    14.41 (11.81 to 17.02)
    16.23 (13.61 to 18.85)
    Statistical analysis title
    		 Between treatment difference
    Statistical analysis description
    Least square adjusted means of the PAR and change of PAR from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline PAR as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3171
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 1.77

    Secondary: PAR - Time Course (D08)

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    End point title
    		 PAR - Time Course (D08)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of PAR over treatment - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    5.85 (3.28 to 8.43)
    8.43 (5.84 to 11.02)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the PAR and change of PAR from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline PAR as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1512
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.11
         upper limit
    		 0.96

    Secondary: Ankle Swelling - Time Course (D03)

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    End point title
    		 Ankle Swelling - Time Course (D03)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Swelling over treatment - D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    1.51 (1.36 to 1.66)
    1.34 (1.19 to 1.50)
    Statistical analysis title
    		 Between-treatment Difference
    Statistical analysis description
    Least square adjusted means of the Ankle Swelling and change of Ankle Swelling from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Swelling as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.115
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.38

    Secondary: Ankle Swelling - Time Course (D05)

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    End point title
    		 Ankle Swelling - Time Course (D05)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Swelling over treatment - D05
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    1.01 (0.87 to 1.15)
    0.99 (0.84 to 1.13)
    Statistical analysis title
    		 Between-treatment diference
    Statistical analysis description
    Least square adjusted means of the Ankle Swelling and change of Ankle Swelling from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Swelling as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.798
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.22

    Secondary: Ankle Swelling - Time Course (D08)

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    End point title
    		 Ankle Swelling - Time Course (D08)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Swelling over treatment - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: mm
        least squares mean (confidence interval 95%)
    0.46 (0.32 to 0.61)
    0.63 (0.48 to 0.78)
    Statistical analysis title
    		 Between-treatemnt difference
    Statistical analysis description
    Least square adjusted means of the Ankle Swelling and change of Ankle Swelling from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Swelling as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1042
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.04

    Secondary: Ankle Tenderness - Time Course (D03)

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    End point title
    		 Ankle Tenderness - Time Course (D03)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Tenderness - D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: N/cm²
        least squares mean (confidence interval 95%)
    -23.05 (-24.82 to -21.29)
    -24.69 (-26.49 to -22.88)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the Ankle Tenderness and change of Ankle Tenderness from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Tenderness as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1776
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 4.02

    Secondary: Ankle Tenderness - Time Course (D05)

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    End point title
    		 Ankle Tenderness - Time Course (D05)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Tenderness (D05)
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: N/cm²
        least squares mean (confidence interval 95%)
    -17.70 (-19.97 to -15.42)
    -18.80 (-21.12 to -16.48)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the Ankle Tenderness and change of Ankle Tenderness from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Tenderness as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.487
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.04
         upper limit
    		 4.25

    Secondary: Ankle Tenderness - Time Course (D08)

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    End point title
    		 Ankle Tenderness - Time Course (D08)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Tenderness over treatment - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: N/cm²
        least squares mean (confidence interval 95%)
    -12.60 (-15.09 to -10.11)
    -12.82 (-15.35 to -10.28)
    Statistical analysis title
    		 Between-treatemnt difference
    Statistical analysis description
    Least square adjusted means of the Ankle Tenderness and change of Ankle Tenderness from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Tenderness as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9013
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 3.68

    Secondary: Ankle Function | Karlsson Score - Time Course (D03)

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    End point title
    		 Ankle Function | Karlsson Score - Time Course (D03)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Function (Karlsson Score) - D03
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: sum of scores
        least squares mean (confidence interval 95%)
    47.03 (44.73 to 49.33)
    43.73 (41.38 to 46.09)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the Ankle Function and change of Ankle Function from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Function as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0383
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 6.41

    Secondary: Ankle Function | Karlsson Score - Time Course (D05)

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    End point title
    		 Ankle Function | Karlsson Score - Time Course (D05)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Function (Karlsson Score) - D05
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: sum of scores
        least squares mean (confidence interval 95%)
    58.41 (55.74 to 61.09)
    53.34 (50.61 to 56.08)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the Ankle Function and change of Ankle Function from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Function as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0072
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 8.75

    Secondary: Ankle Function | Karlsson Score - Time Course (D08)

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    End point title
    		 Ankle Function | Karlsson Score - Time Course (D08)
    End point description
    End point type
    Secondary
    End point timeframe
    Time course of Ankle Function (Karlsson Score) - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: sum of scores
        least squares mean (confidence interval 95%)
    72.66 (69.53 to 75.80)
    66.45 (63.25 to 69.65)
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Least square adjusted means of the Ankle Function and change of Ankle Function from D01 for the on-treatment visits D03 to D08 estimated by MMRM with the baseline Ankle Function as covariate, treatment, visit and treatment-by-visit as factors [FAS])
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0055
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.87
         upper limit
    		 10.57

    Secondary: PGAB (Patient´s global assessment of benefit)

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    End point title
    		 PGAB (Patient´s global assessment of benefit)
    End point description
    End point type
    Secondary
    End point timeframe
    PGAB (Patient´s global assessment of benefit) - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: number of subjects
        No benefit
    10
    15
        Little benefit
    23
    31
        Much benefit
    35
    20
    Statistical analysis title
    		 Between treatment comparison of number of subjects
    Statistical analysis description
    Cochran-Mantel-Haenzel test of the between-treatment differences stratified by centre (Van Elteren test)
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0164
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: PGAS (Patient Global Assessment Satisafaction)

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    End point title
    		 PGAS (Patient Global Assessment Satisafaction)
    End point description
    End point type
    Secondary
    End point timeframe
    PGAS (Patient Global Assessment Satisfaction) - D08
    End point values
    		 Pennsaid 2% Vehicle Control
    Number of subjects analysed
    68
    66
    Units: number of subjects
        very satisfied
    33
    22
        little satisfied
    24
    25
        little dissatisified
    10
    16
        very dissatisfied
    1
    3
    Statistical analysis title
    		 Between-treatment difference
    Statistical analysis description
    Cochran-Mantel-Haenzel test of the between-treatment differences stratified by centre (Van Elteren test)
    Comparison groups
    Pennsaid 2% v Vehicle Control
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0499
    Method
    		 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
    19.1
    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 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 / 68 (0.00%)
    0 / 66 (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
    6 / 68 (8.82%)
    7 / 66 (10.61%)
    General disorders and administration site conditions
    Application site discomfort
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Application site dryness
         subjects affected / exposed
    5 / 68 (7.35%)
    3 / 66 (4.55%)
         occurrences all number
    5
    3
    Application site erythema
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 66 (4.55%)
         occurrences all number
    1
    4
    Application site exfoliation
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 66 (1.52%)
         occurrences all number
    2
    1
    Application site irritation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 66 (1.52%)
         occurrences all number
    0
    1
    Application site pruritus
         subjects affected / exposed
    3 / 68 (4.41%)
    4 / 66 (6.06%)
         occurrences all number
    3
    4
    Psychiatric disorders
    Stress
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 66 (1.52%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2017
    16.Jan.2017 AM-01: regulating the effectively participating investigators and trial sites

    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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