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    Clinical Trial Results:
    A Clinical Study to Assess the Efficacy and Onset of Pain Relief of Topical MFC51123 Diclofenac-Menthol Gel versus Controls in Ankle Sprain

    Summary
    EudraCT number
    		 2013-000992-33
    Trial protocol
    		 DE  
    Global end of trial date
    22 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jul 2016
    First version publication date
    14 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RH01805
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlakosmithKline
    Sponsor organisation address
    1500 Littleton Road, Parsippany, United States, NJ 07054
    Public contact
    GSK CH Clinical Trials, GlaxoSmithKline Consumer Healthcare, +44 1932826987, rd.gskch-clinical-trials@gsk.com
    Scientific contact
    GSK CH Clinical Trials, GlaxoSmithKline Consumer Healthcare, +44 1932826987, rd.gskch-clinical-trials@gsk.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
    12 Apr 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess efficacy of MFC51123 gel over placebo as measured by Area Under the Curve of Pain Intensity on Movement (walking 5 steps on flat surface) for the period from 24 to 72 hours of treatment (AUC1-3days).
    Protection of trial subjects
    The study was conducted according to the ethical principles of the Declaration of Helsinki. The study drug was to be discontinued if continuing would result in a significant safety risk for the subject as per the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2013
    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: 385
    Worldwide total number of subjects
    385
    EEA total number of subjects
    385
    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)
    13
    Adults (18-64 years)
    372
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 16 centers in the Germany.

    Pre-assignment
    Screening details
    		 The study population consisted of a representative group of male and female subjects aged minimum of 16 years and maximum of 63 years suffering from ankle sprain. Of the 388 subjects screened, 385 were randomized in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diclofenac plus(+) Menthol
    Arm description
    		 1% Diclofenac sodium and 3% menthol gel was supplied in 30 gram (g) tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    1% diclofenac sodium+ 3% menthol gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects were instructed to apply approximately 4 grams of the assigned topical gel product 4 times daily to the injured ankle. The subject were instructed to fill the circle on a the Gel Strip, a 90mm x 50mm piece of glycine paper designed to gauge the amount of gel to apply for a single dose.

    Arm title
    		 Diclofenac
    Arm description
    		 1% Diclofenac sodium + 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    1% diclofenac sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects were instructed to apply approximately 4 grams of the assigned topical gel product 4 times daily to the injured ankle. The subject were instructed to fill the circle on a the Gel Strip, a 90mm x 50mm piece of glycine paper designed to gauge the amount of gel to apply for a single dose.

    Arm title
    		 Menthol
    Arm description
    		 3% menthol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    3% menthol gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects were instructed to apply approximately 4 grams of the assigned topical gel product 4 times daily to the injured ankle. The subject were instructed to fill the circle on a the Gel Strip, a 90mm x 50mm piece of glycine paper designed to gauge the amount of gel to apply for a single dose.

    Arm title
    		 Placebo
    Arm description
    		 Placebo with 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects were instructed to apply approximately 4 grams of the assigned topical gel product 4 times daily to the injured ankle. The subject were instructed to fill the circle on a the Gel Strip, a 90mm x 50mm piece of glycine paper designed to gauge the amount of gel to apply for a single dose.

    Number of subjects in period 1
    		Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Started
    118
    113
    78
    76
    Completed
    105
    106
    74
    75
    Not completed
    13
    7
    4
    1
         Consent withdrawn by subject
    -
    1
    1
    -
         Protocol violation
    -
    1
    -
    1
         Other Reason
    2
    2
    -
    -
         Adverse Events
    10
    3
    3
    -
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diclofenac plus(+) Menthol
    Reporting group description
    		 1% Diclofenac sodium and 3% menthol gel was supplied in 30 gram (g) tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Diclofenac
    Reporting group description
    		 1% Diclofenac sodium + 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Menthol
    Reporting group description
    		 3% menthol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo with 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo Total
    Number of subjects
    		 118 113 78 76 385
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.3 ( 11.82 ) 32.2 ( 11.43 ) 33.7 ( 12.09 ) 33 ( 11.61 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 41 39 36 166
        Male
    		 68 72 39 40 219

    End points

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    End points reporting groups
    Reporting group title
    Diclofenac plus(+) Menthol
    Reporting group description
    		 1% Diclofenac sodium and 3% menthol gel was supplied in 30 gram (g) tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Diclofenac
    Reporting group description
    		 1% Diclofenac sodium + 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Menthol
    Reporting group description
    		 3% menthol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo with 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Primary: Area Under the Curve from Day 1 to Day 3 (AUC1-3 days) of Pain Intensity (PI) on Movement for Diclofenac/Methanol gel and Placebo gel

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    End point title
    		 Area Under the Curve from Day 1 to Day 3 (AUC1-3 days) of Pain Intensity (PI) on Movement for Diclofenac/Methanol gel and Placebo gel [1]
    End point description
    AUC of pain intensity (PI) on movement was measured by numerical rating scale (NRS) during the 48 hour time interval from Day 1 to 3. AUC1-3 day was calculated based on trapezoidal method. PI was measured in NRS scale from 0 (no pain) to 10 (extreme pain). Subjects assessed the severity of ankle pain using NRS scale at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.
    End point type
    Primary
    End point timeframe
    Upto 72 hours
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint required the descriptive and statistical data for Diclofenac/Methanol gel and Placebo gel only, not for all the treatments group involved in this study.
    End point values
    		 Diclofenac plus(+) Menthol Placebo
    Number of subjects analysed
    117
    75
    Units: Score on scale
        arithmetic mean (standard deviation)
    276.97 ( 111.356 )
    282.88 ( 100.958 )
    Statistical analysis title
    		 1% Diclofenac sodium (sod.) +3% Menthol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4144
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -9.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.45
         upper limit
    		 12.98

    Secondary: Pain Intensity Difference (PID) on Movement

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    End point title
    		 Pain Intensity Difference (PID) on Movement
    End point description
    PID on movement (after walking 5 steps on a flat surface), calculated as PI at a given time 't' subtracted by the PI at baseline, measured on movement using NRS scale. Participants assessed the severity of ankle pain using the NRS scale at baseline (prior to treatment) and at 10, 30 minutes (min.) and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing. ITT population included all participants who fulfilled all the study entry criteria, received the study treatment and had at least one post-baseline efficacy assessment. This analysis was conducted on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to 10 days
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on scale
    arithmetic mean (standard deviation)
        At Baseline (117, 112, 77, 75)
    7.8 ( 1.55 )
    7.4 ( 1.44 )
    7.8 ( 1.6 )
    7.7 ( 1.47 )
        At 10 min. (117, 112, 77, 75)
    7.54 ( 1.808 )
    7.23 ( 1.571 )
    7.47 ( 1.854 )
    7.37 ( 1.6 )
        At 30 min. (117, 112, 77, 75)
    7.33 ( 1.974 )
    7.06 ( 1.689 )
    7.26 ( 1.852 )
    7.15 ( 1.706 )
        At 1 hour (117, 112, 77, 75)
    7.21 ( 2.05 )
    6.92 ( 1.761 )
    7.12 ( 2.039 )
    7.05 ( 1.8 )
        At 4 hour (117, 112, 77, 75)
    7.06 ( 2.147 )
    6.94 ( 1.802 )
    6.96 ( 2.112 )
    7 ( 1.748 )
        At 6 hour (117, 112, 77, 75)
    6.98 ( 2.141 )
    6.75 ( 1.758 )
    6.84 ( 2.213 )
    6.83 ( 1.855 )
        At 12 hour (117, 112, 77, 75)
    6.93 ( 2.148 )
    6.43 ( 1.93 )
    6.58 ( 2.347 )
    6.75 ( 2.08 )
        At 18 hour (117, 112, 77, 75)
    6.58 ( 2.163 )
    6.1 ( 2.022 )
    6.31 ( 2.429 )
    6.53 ( 2.107 )
        At 24 hour (117, 112, 77, 75)
    6.15 ( 2.273 )
    5.84 ( 2.078 )
    6 ( 2.487 )
    6.16 ( 2.137 )
        At 36 hour (117, 112, 77, 75)
    6.18 ( 2.427 )
    5.77 ( 2.058 )
    6.21 ( 2.478 )
    6.37 ( 2.065 )
        At 48 hour (117, 112, 77, 75)
    5.85 ( 2.447 )
    5.41 ( 2.099 )
    5.71 ( 2.665 )
    5.77 ( 2.436 )
        At 60 hour (117, 112, 77, 75)
    5.36 ( 2.398 )
    5.16 ( 2.192 )
    5.19 ( 2.616 )
    5.64 ( 2.21 )
        At 72 hour (117, 112, 77, 75)
    5.22 ( 2.492 )
    5 ( 2.144 )
    5.21 ( 2.657 )
    5.41 ( 2.218 )
        At 84 hour (113, 107, 75, 75)
    4.92 ( 2.342 )
    4.77 ( 2.108 )
    4.65 ( 2.549 )
    5.01 ( 2.293 )
        At 96 hour (112, 107, 75, 74)
    4.64 ( 2.189 )
    4.67 ( 2.162 )
    4.71 ( 2.572 )
    4.88 ( 2.196 )
        At 108 hour (112, 107, 75, 74)
    4.38 ( 2.306 )
    4.44 ( 2.093 )
    4.25 ( 2.526 )
    4.49 ( 2.115 )
        At 120 hour (111, 107, 74, 74)
    4.35 ( 2.131 )
    4.28 ( 2.145 )
    4.36 ( 2.594 )
    4.53 ( 1.995 )
        At 132 hour (110, 107, 74, 74)
    4.03 ( 2.178 )
    3.92 ( 2.001 )
    4 ( 2.449 )
    4.19 ( 2.194 )
        At 144 hour (110, 107, 74, 74)
    3.96 ( 2.209 )
    3.67 ( 2.05 )
    4.04 ( 2.551 )
    4.07 ( 2.179 )
        At 156 hour (109, 107, 74, 74)
    3.54 ( 2.154 )
    3.4 ( 2.041 )
    3.77 ( 2.497 )
    3.78 ( 2.198 )
        At 168 hour (105, 104, 73, 74)
    3.5 ( 2.034 )
    3.33 ( 1.923 )
    3.81 ( 2.548 )
    3.72 ( 2.123 )
        At 180 hour (105, 104, 73, 72)
    3.18 ( 2.129 )
    2.98 ( 1.961 )
    3.34 ( 2.341 )
    3.6 ( 2.046 )
        At 192 hour (101, 102, 71, 72)
    3.18 ( 1.962 )
    2.85 ( 1.9 )
    3.56 ( 2.506 )
    3.46 ( 2.055 )
        At 204 hour (101, 100, 71, 72)
    2.56 ( 1.824 )
    2.51 ( 1.91 )
    2.9 ( 2.331 )
    3.13 ( 2.096 )
        At 216 hour (95, 100, 69, 72)
    2.48 ( 1.85 )
    2.27 ( 1.89 )
    2.9 ( 2.177 )
    2.9 ( 1.944 )
        At 228 hour (95, 100, 69, 72)
    2.06 ( 1.844 )
    1.86 ( 1.831 )
    2.49 ( 2.266 )
    2.67 ( 1.891 )
        At 240 hour (32, 43, 22, 42)
    2.13 ( 2.136 )
    2 ( 2.204 )
    1.95 ( 2.058 )
    2.12 ( 1.626 )
    No statistical analyses for this end point

    Secondary: Pain Intensity Difference (PID) at Rest

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    End point title
    		 Pain Intensity Difference (PID) at Rest
    End point description
    PID at rest was calculated as PI at a given time ‘t’ at rest subtracted by the PI at baseline measured using NRS scale at baseline (prior to treatment) and at 10, 30 min. and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.
    End point type
    Secondary
    End point timeframe
    Baseline to 10 days
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on scale
    arithmetic mean (standard deviation)
        At Baseline (117, 112, 77, 75)
    7.8 ( 1.55 )
    7.4 ( 1.44 )
    7.8 ( 1.6 )
    7.7 ( 1.47 )
        At 10 min. (117, 112, 77, 75)
    0.34 ( 1.146 )
    0.43 ( 1.145 )
    0.17 ( 0.715 )
    0.25 ( 1.175 )
        At 30 min. (117, 112, 77, 75)
    0.56 ( 1.185 )
    0.45 ( 1.314 )
    0.32 ( 0.818 )
    0.44 ( 1.328 )
        At 1 hour (117, 112, 77, 75)
    0.64 ( 1.283 )
    0.62 ( 1.187 )
    0.48 ( 0.94 )
    0.41 ( 1.62 )
        At 4 hour (117, 112, 77, 75)
    0.62 ( 1.413 )
    0.53 ( 1.115 )
    0.66 ( 1.071 )
    0.43 ( 1.678 )
        At 6 hour (117, 112, 77, 75)
    0.68 ( 1.473 )
    0.62 ( 1.18 )
    0.75 ( 1.183 )
    0.53 ( 1.554 )
        At 12 hour (117, 112, 77, 75)
    0.76 ( 1.501 )
    0.86 ( 1.432 )
    0.9 ( 1.429 )
    0.68 ( 1.535 )
        At 18 hour (117, 112, 77, 75)
    1.03 ( 1.597 )
    1.14 ( 1.482 )
    1.1 ( 1.594 )
    0.85 ( 1.666 )
        At 24 hour (117, 112, 77, 75)
    1.32 ( 1.579 )
    1.39 ( 1.448 )
    1.47 ( 1.535 )
    1.13 ( 1.711 )
        At 36 hour (117, 112, 77, 75)
    1.2 ( 1.549 )
    1.32 ( 1.49 )
    1.22 ( 1.635 )
    1.09 ( 1.787 )
        At 48 hour (117, 112, 77, 75)
    1.43 ( 1.604 )
    1.53 ( 1.464 )
    1.51 ( 1.698 )
    1.45 ( 1.84 )
        At 60 hour (117, 112, 77, 75)
    1.91 ( 1.603 )
    1.83 ( 1.593 )
    1.88 ( 1.747 )
    1.64 ( 1.893 )
        At 72 hour (117, 112, 77, 75)
    1.91 ( 1.776 )
    1.91 ( 1.545 )
    1.86 ( 1.782 )
    1.76 ( 1.972 )
        At 84 hour (113, 107, 75, 75)
    2.11 ( 1.754 )
    2.19 ( 1.655 )
    2.19 ( 1.799 )
    2.03 ( 1.931 )
        At 96 hour (112, 107, 75, 74)
    2.26 ( 1.79 )
    2.17 ( 1.707 )
    2.23 ( 1.721 )
    2 ( 1.72 )
        At 108 hour (112, 107, 75, 74)
    2.46 ( 1.795 )
    2.43 ( 1.833 )
    2.48 ( 1.743 )
    2.27 ( 1.889 )
        At 120 hour (111, 107, 74, 74)
    2.59 ( 1.836 )
    2.48 ( 1.75 )
    2.3 ( 1.856 )
    2.09 ( 1.917 )
        At 132 hour (110, 107, 74, 74)
    2.76 ( 1.877 )
    2.78 ( 1.819 )
    2.68 ( 1.873 )
    2.49 ( 1.967 )
        At 144 hour (110, 107, 74, 74)
    2.77 ( 1.989 )
    2.77 ( 1.789 )
    2.59 ( 1.965 )
    2.49 ( 1.918 )
        At 156 hour (109, 107, 74, 74)
    3.06 ( 2.011 )
    3.11 ( 1.755 )
    2.77 ( 1.884 )
    2.65 ( 2.129 )
        At 168 hour (105, 104, 73, 74)
    3.08 ( 2.037 )
    3.15 ( 1.805 )
    2.75 ( 1.869 )
    2.64 ( 2.004 )
        At 180 hour (105, 104, 73, 72)
    3.37 ( 2.1 )
    3.38 ( 1.871 )
    2.95 ( 1.747 )
    2.88 ( 2.103 )
        At 192 hour (101, 102, 71, 72)
    3.38 ( 2.24 )
    3.3 ( 2.067 )
    2.9 ( 1.928 )
    3 ( 2.035 )
        At 204 hour (101, 100, 71, 72)
    3.67 ( 2.25 )
    3.61 ( 2.03 )
    3.37 ( 1.853 )
    3.21 ( 2.021 )
        At 216 hour (95, 100, 69, 72)
    3.77 ( 2.372 )
    3.87 ( 2.028 )
    3.22 ( 2.306 )
    3.26 ( 1.936 )
        At 228 hour (95, 100, 69, 72)
    4.09 ( 2.348 )
    4.02 ( 2.074 )
    3.64 ( 2 )
    3.53 ( 2.083 )
        At 240 hour (32, 43, 22, 42)
    3.94 ( 2.862 )
    4.23 ( 2.01 )
    3.36 ( 2.61 )
    3.67 ( 2.149 )
    No statistical analyses for this end point

    Secondary: Pain Relief Score (PRS)

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    End point title
    		 Pain Relief Score (PRS)
    End point description
    PRS was measured at each time point using a 5-point Pain Relief Scale ranging from 0-4 while at rest (where: 0- No pain relief; 1-a little or perceptible pain relief; 2- meaningful pain relief; 3- a lot of relief; 4- complete relief). Subjects assessed the degree of ankle pain relief using the PRS scores at 10, 30 min. and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after the first day of treatment.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 7
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on scale
    arithmetic mean (standard deviation)
        At 10 min. (117, 111, 77, 74)
    0.33 ( 0.616 )
    0.29 ( 0.609 )
    0.32 ( 0.498 )
    0.36 ( 0.61 )
        At 30 min. (117, 111, 77, 75)
    0.44 ( 0.635 )
    0.36 ( 0.585 )
    0.49 ( 0.599 )
    0.44 ( 0.683 )
        At 1 hour (116, 112, 77, 75)
    0.48 ( 0.625 )
    0.46 ( 0.599 )
    0.57 ( 0.677 )
    0.4 ( 0.717 )
        At 4 hour (115, 110, 74, 71)
    0.47 ( 0.626 )
    0.45 ( 0.552 )
    0.51 ( 0.579 )
    0.49 ( 0.673 )
        At 6 hour (109, 105, 70, 69)
    0.5 ( 0.603 )
    0.54 ( 0.605 )
    0.63 ( 0.618 )
    0.45 ( 0.607 )
        At 12 hour (77, 89, 53, 58)
    0.6 ( 0.591 )
    0.72 ( 0.707 )
    0.74 ( 0.684 )
    0.62 ( 0.745 )
        At 18 hour (76, 78, 53, 57)
    0.71 ( 0.689 )
    0.73 ( 0.715 )
    0.83 ( 0.753 )
    0.7 ( 0.68 )
        At 24 hour (111, 105, 72, 72)
    0.79 ( 0.662 )
    0.74 ( 0.68 )
    0.9 ( 0.754 )
    0.81 ( 0.642 )
        At 36 hour (116, 112, 77, 74)
    0.84 ( 0.709 )
    0.84 ( 0.705 )
    0.88 ( 0.76 )
    0.78 ( 0.781 )
        At 48 hour (116, 112, 77, 75)
    0.9 ( 0.806 )
    0.84 ( 0.651 )
    0.99 ( 0.716 )
    0.99 ( 0.846 )
        At 60 hour (115, 111, 77, 75)
    1.07 ( 0.78 )
    1 ( 0.714 )
    1.16 ( 0.745 )
    0.96 ( 0.779 )
        At 72 hour (114, 109, 75, 74)
    0.93 ( 0.784 )
    1.06 ( 0.743 )
    1.16 ( 0.806 )
    0.97 ( 0.81 )
        At 84 hour (113, 106, 75, 75)
    1.07 ( 0.81 )
    1 ( 0.756 )
    1.25 ( 0.737 )
    1.11 ( 0.746 )
        At 96 hour (112, 106, 75, 74)
    1.09 ( 0.823 )
    1.03 ( 0.762 )
    1.01 ( 0.83 )
    1.09 ( 0.743 )
        At 108 hour (111, 105, 75, 74)
    1.18 ( 0.876 )
    1.13 ( 0.809 )
    1.28 ( 0.894 )
    1.15 ( 0.734 )
        At 120 hour (111, 107, 74, 72)
    1.11 ( 0.918 )
    1.14 ( 0.782 )
    1.24 ( 0.904 )
    1.1 ( 0.772 )
        At 132 hour (110, 107, 73, 74)
    1.34 ( 0.931 )
    1.24 ( 0.878 )
    1.34 ( 0.931 )
    1.3 ( 0.887 )
        At 144 hour (110, 107, 74, 73)
    1.21 ( 1.015 )
    1.21 ( 0.919 )
    1.3 ( 0.947 )
    1.27 ( 0.886 )
        At 156 hour (109, 106, 74, 74)
    1.41 ( 1.011 )
    1.3 ( 1.053 )
    1.47 ( 0.968 )
    1.32 ( 0.952 )
        At 168 hour (105, 103, 73, 73)
    1.41 ( 1.026 )
    1.31 ( 0.99 )
    1.34 ( 1.003 )
    1.4 ( 0.924 )
    No statistical analyses for this end point

    Secondary: Sum of Pain Intensity Difference (SPID)

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    End point title
    		 Sum of Pain Intensity Difference (SPID)
    End point description
    SPID was measured as SPIDt = ∑PIDt x (timet - timet-1) (h) by PID for periods 0-6, 0-12 hours and 0 to 1, 1 to 3 and 0 to 7 days after initial treatment between treatment groups.
    End point type
    Secondary
    End point timeframe
    0-6, 0-12 hours, 0 to 1, 1-3 days, 0-7 days
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
    arithmetic mean (standard deviation)
        At 0-6 hours
    4.16 ( 9.299 )
    3.19 ( 5.862 )
    4.72 ( 6.306 )
    4.37 ( 8.287 )
        At 0-12 hours
    9.19 ( 18.788 )
    9.13 ( 13.284 )
    11.74 ( 14.675 )
    10.05 ( 16.706 )
        At 0-1 days
    26.01 ( 38.722 )
    26.54 ( 28.497 )
    30.91 ( 34.158 )
    26.21 ( 34.877 )
        At 1 to 3 days
    101.54 ( 87.184 )
    100.07 ( 71.085 )
    104.26 ( 83.689 )
    90.88 ( 82.626 )
        At 0 to 7 days
    451.12 ( 265.919 )
    452.44 ( 244.488 )
    464.96 ( 281.243 )
    438.45 ( 287.369 )
    No statistical analyses for this end point

    Secondary: Time of Onset of Pain Relief (TOPR)

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    End point title
    		 Time of Onset of Pain Relief (TOPR)
    End point description
    TOPR was measured by the time when subjects reported PRS ≥ 1, i.e. a “little” or “perceptible” pain relief.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 3
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
        median (full range (min-max))
    1.03 (0.2 to 157)
    4 (0.2 to 168)
    1 (0.2 to 94.3)
    4 (0.2 to 187.5)
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5404
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.48
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs 3% Menthol
    Comparison groups
    Diclofenac plus(+) Menthol v Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4639
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.2
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs 1% Diclofenac
    Comparison groups
    Diclofenac plus(+) Menthol v Diclofenac
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5118
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.43

    Secondary: Time of Onset of meaningful Pain Relief (TOMR)

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    End point title
    		 Time of Onset of meaningful Pain Relief (TOMR)
    End point description
    TOMR was measured by the time when subjects reported PRS ≥ 2, i.e. “some” or “meaningful” pain relief.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 4
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
        median (full range (min-max))
    92.5 (0.2 to 203.8)
    76.83 (0.2 to 184.1)
    72 (0.2 to 203.5)
    93.5 (0.2 to 203)
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6918
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.31
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs 3% Menthol
    Comparison groups
    Diclofenac plus(+) Menthol v Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2389
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.73
    Statistical analysis title
    		 1%Diclofenac sod.+3% Menthol vs 1% Diclofenac sod.
    Comparison groups
    Diclofenac plus(+) Menthol v Diclofenac
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9817
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.37

    Secondary: Time of Onset of Cooling Sensation (TOCS)

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    End point title
    		 Time of Onset of Cooling Sensation (TOCS)
    End point description
    Time of onset of cooling sensation was measured by the time when subjects reported to have a ‘cooling effect as an enhancement of pain relief’. To assess this endpoint subjects were asked at 10, 30 min. and at 1, 4, 6 hours post first dose “Have you felt a cooling sensation at the injured ankle from the study gel?”
    End point type
    Secondary
    End point timeframe
    Baseline to 6 hours
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
        median (full range (min-max))
    0.17 (0.17 to 6)
    0.17 (0.17 to 6)
    0.17 (0.17 to 6)
    0.17 (0.17 to 6)
    Statistical analysis title
    		 1% Diclofenac sod. +3% Menthol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7003
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.43
    Statistical analysis title
    		 1% Diclofenac sod.+3% Menthol vs 3% Menthol
    Comparison groups
    Menthol v Diclofenac plus(+) Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9565
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.35
    Statistical analysis title
    		 1% Diclofenac Sod +3% Menthol vs 1%Diclofenac Sod
    Comparison groups
    Diclofenac plus(+) Menthol v Diclofenac
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6216
    Method
    		 Chi-squared
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.4

    Secondary: Total Pain Relief (TOTPAR)

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    End point title
    		 Total Pain Relief (TOTPAR)
    End point description
    TOTPAR was calculated as sum of the products of PRS with time interval from one time point to other. Descriptive analysis was provided for each time point.
    End point type
    Secondary
    End point timeframe
    0 - 6, 0 - 12 hours and 0 - 1, 1 - 3, and 0 - 7 days
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
    arithmetic mean (standard deviation)
        At 0 - 6 hours
    2.81 ( 3.162 )
    2.64 ( 2.902 )
    3.27 ( 3.176 )
    2.75 ( 3.184 )
        At 0 - 12 hours
    6.86 ( 6.125 )
    6.81 ( 6.178 )
    8.02 ( 7.045 )
    6.35 ( 6.732 )
        At 0 - 1 days
    16.04 ( 12.048 )
    16.14 ( 12.479 )
    18.85 ( 14.517 )
    15.71 ( 13.146 )
        At 1 - 3 days
    44.1 ( 29.344 )
    45.11 ( 26.431 )
    47.84 ( 29.102 )
    43.04 ( 31.57 )
        At 0 - 7 days
    172.97 ( 98.838 )
    170.73 ( 97.187 )
    184.17 ( 102.787 )
    174 ( 94.917 )
    No statistical analyses for this end point

    Secondary: Skin Temperature

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    End point title
    		 Skin Temperature
    End point description
    Skin temperature was measured by thermal imaging.
    End point type
    Secondary
    End point timeframe
    At 10, 30, 60 minute (min.) and 4 and 6 hours
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    11
    10
    6
    6
    Units: degree Celsius (°C)
    arithmetic mean (standard deviation)
        At 10 min.
    27.69 ( 3.706 )
    29.31 ( 2.61 )
    29.92 ( 2.118 )
    30.93 ( 2.842 )
        At 30 min.
    28.26 ( 3.161 )
    29.81 ( 2.595 )
    30.5 ( 2.117 )
    31.47 ( 3.386 )
        At 60 min.
    28.64 ( 2.986 )
    30.74 ( 2.781 )
    30.22 ( 2.388 )
    31.78 ( 3.213 )
        At 4 hours
    30.52 ( 2.88 )
    31.26 ( 2.981 )
    31.15 ( 3.221 )
    31.57 ( 2.7 )
        At 6 hours
    31.02 ( 2.951 )
    31.53 ( 3.299 )
    31.27 ( 3.925 )
    32.07 ( 3.482 )
    No statistical analyses for this end point

    Secondary: Ankle Swelling

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    End point title
    		 Ankle Swelling
    End point description
    Reduction in ankle swelling as change from baseline measured by “figure of eight” method of injured ankle measurement. No overall statistical analyses for this endpoint.
    End point type
    Secondary
    End point timeframe
    Days 1, 3 and 7
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1
    573.9 ( 57.77 )
    573.6 ( 50.2 )
    577.1 ( 55.35 )
    576.1 ( 50.19 )
        Day 3
    566.2 ( 57.03 )
    566.9 ( 49.55 )
    567 ( 56.48 )
    565.4 ( 52.67 )
        Day 7
    558.3 ( 56.02 )
    558.8 ( 46.37 )
    558.4 ( 56.88 )
    557 ( 50.85 )
    No statistical analyses for this end point

    Secondary: Time to Complete Recovery

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    End point title
    		 Time to Complete Recovery
    End point description
    Time to complete recovery was measured as the day with complete relief of ankle pain (subject-rated NRS scores were 0 for pain intensity at rest and pain) and swelling (subject did not have any apparent swelling nor experience any pain or limitation of movement of the injured ankle as determined by the Principal Investigator or designee during the course of an ankle exam).
    End point type
    Secondary
    End point timeframe
    Baseline to Day 10
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: score on a scale
        median (full range (min-max))
    240 (17 to 240)
    240 (48.2 to 240)
    240 (53.2 to 240)
    240 (145.5 to 240)
    Statistical analysis title
    		 % Diclofenac Sod+3% Menthol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0408
    Method
    		 t-test, 2-sided
    Parameter type
    		 Cox proportional hazard
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 5.7
    Statistical analysis title
    		 1% Diclofenac Sod+3% Menthol vs 3% Menthol
    Comparison groups
    Diclofenac plus(+) Menthol v Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4507
    Method
    		 t-test, 2-sided
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.65
    Statistical analysis title
    		 1% Diclofenac Sod+3% Menthol vs 1% Diclofenac Sod
    Comparison groups
    Diclofenac plus(+) Menthol v Diclofenac
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.315
    Method
    		 t-test, 2-sided
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.61

    Secondary: Patient’s Global Assessment in Response to Treatment (PGART)

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    End point title
    		 Patient’s Global Assessment in Response to Treatment (PGART)
    End point description
    PGART was measured at the end of study in a scale from 0-4 (where: 0- Poor; 1-Fair; 2- Good; 3-Very Good; 4- Excellent)
    End point type
    Secondary
    End point timeframe
    Baseline to Day 10
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: number of participants
        Poor=0
    3
    13
    6
    9
        Fair=1
    24
    20
    12
    14
        Good=2
    44
    46
    26
    27
        Very Good=3
    35
    26
    26
    21
        Excellent=4
    9
    6
    5
    4
    Statistical analysis title
    		 Diclofenac Sodium + Methanol vs Placebo
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1114
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.52
    Statistical analysis title
    		 Diclofenac + Methanol vs Methanol
    Comparison groups
    Diclofenac plus(+) Menthol v Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5808
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.37
    Statistical analysis title
    		 Diclofenac + Methanol vs Diclofenac
    Comparison groups
    Diclofenac plus(+) Menthol v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.03
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.55

    Secondary: AUC1-3 days of PI on Movement for Diclofenac Sodium + Methanol, Diclofenac, Methanol and Placebo

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    End point title
    		 AUC1-3 days of PI on Movement for Diclofenac Sodium + Methanol, Diclofenac, Methanol and Placebo
    End point description
    AUC of PI on movement was measured by a numerical rating scale (NRS) during the 48 hour time interval from Day 1 to 3. AUC1-3 day was calculated based on trapezoidal method. Pain intensity was measured in NRS scale from 0 (no pain) to 10 (extreme pain). Participants assessed the severity of ankle pain using the NRS scale at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.
    End point type
    Secondary
    End point timeframe
    Baseline to 72 hours
    End point values
    		 Diclofenac plus(+) Menthol Diclofenac Menthol Placebo
    Number of subjects analysed
    117
    112
    77
    75
    Units: score on a scale
        arithmetic mean (standard deviation)
    276.97 ( 111.356 )
    261.11 ( 96.791 )
    272.65 ( 118.196 )
    282.88 ( 100.958 )
    Statistical analysis title
    		 1% diclofenac+3% menthol vs 1% diclofenac
    Comparison groups
    Diclofenac plus(+) Menthol v Diclofenac
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8761
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.34
         upper limit
    		 21.5
    Statistical analysis title
    		 1% diclofenac+3% menthol vs 3% menthol
    Comparison groups
    Diclofenac plus(+) Menthol v Menthol
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8164
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.46
         upper limit
    		 24.67
    Statistical analysis title
    		 1% diclofenac vs 3% menthol
    Comparison groups
    Diclofenac v Menthol
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9279
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.27
         upper limit
    		 23.33
    Statistical analysis title
    		 1% Diclofenac vs Placebo
    Comparison groups
    Diclofenac v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3442
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -10.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.26
         upper limit
    		 11.64

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline upto Day 10 of administration of investigational product
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    1% Diclofenac plus + 3% Menthol
    Reporting group description
    		 1% Diclofenac sodium+ 3% menthol gel was supplied in 30 gram (g) tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    1% Diclofenac
    Reporting group description
    		 1% Diclofenac sodium + 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    3% Menthol
    Reporting group description
    		 3% menthol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo with 0.09% methanol gel was supplied in 30g tubes for each subject to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.

    Serious adverse events
    		 1% Diclofenac plus + 3% Menthol 1% Diclofenac 3% Menthol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 1% Diclofenac plus + 3% Menthol 1% Diclofenac 3% Menthol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 117 (36.75%)
    26 / 112 (23.21%)
    22 / 77 (28.57%)
    17 / 75 (22.67%)
    Injury, poisoning and procedural complications
    Arthropod Sting
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 112 (0.89%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Skin Abrasion
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle Injury
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 117 (3.42%)
    2 / 112 (1.79%)
    4 / 77 (5.19%)
    3 / 75 (4.00%)
         occurrences all number
    4
    2
    4
    3
    Hypoaesthesia
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 112 (0.89%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Burning Sensation
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    Application Site Dryness
         subjects affected / exposed
    15 / 117 (12.82%)
    7 / 112 (6.25%)
    3 / 77 (3.90%)
    4 / 75 (5.33%)
         occurrences all number
    15
    7
    3
    4
    Application site pain
         subjects affected / exposed
    7 / 117 (5.98%)
    0 / 112 (0.00%)
    2 / 77 (2.60%)
    1 / 75 (1.33%)
         occurrences all number
    7
    0
    2
    1
    Application site pruritus
         subjects affected / exposed
    5 / 117 (4.27%)
    3 / 112 (2.68%)
    1 / 77 (1.30%)
    1 / 75 (1.33%)
         occurrences all number
    5
    3
    1
    1
    Application Site Erythema
         subjects affected / exposed
    4 / 117 (3.42%)
    1 / 112 (0.89%)
    2 / 77 (2.60%)
    0 / 75 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Application Site Eczema
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Application Site Discolouration
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Application Site Rash
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Application Site Reaction
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Application Site Vesicles
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Necrosis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Application Site Hypersensitivity
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 112 (0.89%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Application Site Burn
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Application Site Swelling
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 112 (0.89%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nausea
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    10 / 117 (8.55%)
    10 / 112 (8.93%)
    10 / 77 (12.99%)
    4 / 75 (5.33%)
         occurrences all number
    10
    10
    10
    4
    Pruritus
         subjects affected / exposed
    7 / 117 (5.98%)
    4 / 112 (3.57%)
    3 / 77 (3.90%)
    1 / 75 (1.33%)
         occurrences all number
    8
    5
    3
    1
    Erythema
         subjects affected / exposed
    6 / 117 (5.13%)
    2 / 112 (1.79%)
    3 / 77 (3.90%)
    1 / 75 (1.33%)
         occurrences all number
    6
    2
    3
    1
    Blister
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis Contact
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin Exfoliation
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin Wrinkling
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 112 (0.89%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash Vesicular
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    0
    1
    Skin Reaction
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Back Pain
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    2 / 75 (2.67%)
         occurrences all number
    0
    0
    1
    2
    Bone Swelling
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Exostosis
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 112 (0.00%)
    1 / 77 (1.30%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyoderma
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 112 (0.00%)
    0 / 77 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    1
    0
    0
    0

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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
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    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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