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    Clinical Trial Results:
    A phase III, double blind, randomised, placebo controlled study to assess the efficacy and safety of a single treatment of Clostridium botulinum toxin type A to improve the appearance of moderate to severe glabellar lines

    Summary
    EudraCT number
    		 2013-002321-34
    Trial protocol
    		 DE  
    Global end of trial date
    31 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2018
    First version publication date
    04 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Y-52-52120-189
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02353871
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Innovation
    Sponsor organisation address
    5 Avenue du Canada, Les Ulis, Cedex, France, 91940
    Public contact
    Medical Director, Neurology, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Neurology, Ipsen, clinical.trials@ipsen.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
    31 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of a single treatment of an injectable liquid form of Clostridium Botulinum toxin type A haemagglutinin complex (BTX-A-HAC) next generation (NG) at 50 Units (U), used for the improvement in the appearance of moderate to severe glabellar lines at maximum frown.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki and in accordance with the International Council for Harmonisation Consolidated Guideline on Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 76
    Country: Number of subjects enrolled
    Germany: 109
    Worldwide total number of subjects
    185
    EEA total number of subjects
    185
    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)
    183
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects with moderate or severe vertical glabellar lines at maximum frown were recruited to nine active sites in France and Germany from January 2015. The study was completed in August 2015.

    Pre-assignment
    Screening details
    		 Overall, 190 subjects were screened, five of whom were screening failures. A total of 185 subjects were enrolled and randomised to receive treatment. One of the subjects who was randomised to placebo did not receive study treatment due to violation of an inclusion criterion.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BTX-A-HAC NG 50 U
    Arm description
    		 Subjects were randomised to receive BTX-A-HAC NG. A total dose of 50 U was injected on Day 1. The total treatment volume (0.25 millilitres [mL]) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BTX-A-HAC NG Solution 50 U
    Investigational medicinal product code
    Other name
    BTX-A-HAC
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received a single total dose of 50 U BTX-A-HAC NG solution (10 U/0.05 mL) divided into five equal injections (0.05 mL per injection) to be administered into five predefined sites in the glabellar region.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were randomised to receive placebo. The total placebo volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The placebo solution for injection contained only the excipients of BTX-A-HAC NG. Subjects received a single dose of 0.25 mL divided into five equal injections (0.05 mL per injection) to be administered into five predefined sites in the glabellar region.

    Number of subjects in period 1
    		BTX-A-HAC NG 50 U Placebo
    Started
    125
    60
    Completed
    122
    51
    Not completed
    3
    9
         Lost to follow-up
    2
    -
         Consent withdrawn
    1
    8
         Protocol deviation
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    BTX-A-HAC NG 50 U
    Reporting group description
    		 Subjects were randomised to receive BTX-A-HAC NG. A total dose of 50 U was injected on Day 1. The total treatment volume (0.25 millilitres [mL]) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo. The total placebo volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region

    Reporting group values
    		 BTX-A-HAC NG 50 U Placebo Total
    Number of subjects
    		 125 60
    Age categorical
    Units: Subjects
    Age continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 47.7 ( 9.75 ) 48.0 ( 9.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 108 52 160
        Male
    		 17 8 25
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 125 60 185
        Unknown or Not Reported
    		 0 0 0
    Race, Customised
    Units: Subjects
        Caucasion/White
    		 124 59 183
        Black/African American
    		 0 1 1
        Other
    		 1 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    BTX-A-HAC NG 50 U
    Reporting group description
    		 Subjects were randomised to receive BTX-A-HAC NG. A total dose of 50 U was injected on Day 1. The total treatment volume (0.25 millilitres [mL]) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo. The total placebo volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region

    Primary: The percentage of responders at Day 29 assessed by the Investigator's live assessment (ILA) of the appearance of glabellar lines at maximum frown.

    		 Close Top of page
    End point title
    		 The percentage of responders at Day 29 assessed by the Investigator's live assessment (ILA) of the appearance of glabellar lines at maximum frown.
    End point description
    The ILA was used to assess the appearance of glabellar lines at maximum frown on Day 29, and consists of a validated 4-point photographic scale: Grade 0 - none; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown on Day 29 and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1, pretreatment). The adjusted percentage of responders in each treatment group is presented and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The modified intent-to-treat (mITT) population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) and Day 29
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    124
    58
    Units: Adjusted percentage of responders
        number (confidence interval 95%)
    88.3 (76.1 to 94.7)
    1.4 (0.3 to 6.5)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    86.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 80.5
         upper limit
    		 93.3
    Notes
    [1] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of responders at each post-treatment visit to the study centre (except Day 29) as measured by the ILA at maximum frown.

    		 Close Top of page
    End point title
    		 The percentage of responders at each post-treatment visit to the study centre (except Day 29) as measured by the ILA at maximum frown.
    End point description
    The ILA was used to assess the appearance of glabellar lines at maximum frown on Days 8, 15, 57, 113, 148 and 183 and consists of a validated 4-point photographic scale: Grade 0 - none; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown on a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1, pretreatment). The adjusted percentage of responders in each treatment group is presented for each post-treatment visit and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Days 1 (Baseline), 8, 15, 57, 85, 113, 148 and 183 (End of Study).
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    124
    59
    Units: Adjusted percentage of responders
    number (confidence interval 95%)
        Day 8 (n=124 BTX-A-HAC; n=57 Placebo)
    80.5 (65.3 to 90.0)
    1.3 (0.3 to 6.2)
        Day 15 (n=124 BTX-A-HAC; n=59 Placebo)
    87.0 (74.5 to 93.9)
    1.5 (0.3 to 7.0)
        Day 57 (n=124 BTX-A-HAC; n=58 Placebo)
    77.4 (63.0 to 87.3)
    1.0 (0.2 to 5.4)
        Day 85 (n=121 BTX-A-HAC; n=57 Placebo)
    51.3 (35.1 to 67.3)
    1.0 (0.2 to 5.6)
        Day 113 (n=123 BTX-A-HAC; n=56 Placebo)
    34.0 (20.5 to 50.7)
    0.8 (0.1 to 5.1)
        Day 148 (n=121 BTX-A-HAC; n=51 Placebo)
    17.1 (7.9 to 33.1)
    1.8 (0.3 to 9.8)
        Day 183 (n=122 BTX-A-HAC; n=51 Placebo)
    4.9 (0.9 to 23.2)
    0.9 (0.1 to 8.9)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 8
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 8 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    79.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 71.6
         upper limit
    		 86.7
    Notes
    [2] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 15
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 15 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    85.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 78.8
         upper limit
    		 92.2
    Notes
    [3] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    76.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 68.5
         upper limit
    		 84.2
    Notes
    [4] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    50.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 41
         upper limit
    		 59.6
    Notes
    [5] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    33.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.5
         upper limit
    		 41.9
    Notes
    [6] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 148
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 148 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0035 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    15.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.6
         upper limit
    		 22.9
    Notes
    [7] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0441 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 8.7
    Notes
    [8] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of responders on Day 29 who remained responders on Days 57, 85, 113, 148 and 183 as measured by the ILA at maximum frown.

    		 Close Top of page
    End point title
    		 The percentage of responders on Day 29 who remained responders on Days 57, 85, 113, 148 and 183 as measured by the ILA at maximum frown.
    End point description
    The ILA was used to assess the appearance of glabellar lines at maximum frown and consists of a validated 4-point photographic scale: Grade 0 - none; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe. A responder at maximum frown was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at maximum frown on a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). Subjects who were not responders at Day 29 were excluded from the analysis. The adjusted percentage of remaining responders in each treatment group following Day 29 is presented and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The modified mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Days 57, 85, 113, 148 and 183 (End of Study).
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    112
    2
    Units: Adjusted percentage of responders
    number (confidence interval 95%)
        Day 57 (n=112 BTX-A-HAC; n=2 Placebo)
    87.3 (72.4 to 94.8)
    47.0 (2.8 to 96.5)
        Day 85 (n=109 BTX-A-HAC; n=2 Placebo)
    61.1 (42.5 to 77.0)
    4.9 (0.1 to 73.4)
        Day 113 (n=111 BTX-A-HAC; n=2 Placebo)
    39.6 (23.9 to 57.9)
    24.0 (0.7 to 93.5)
        Day 148 (n=109 BTX-A-HAC; n=2 Placebo)
    20.1 (9.0 to 39.0)
    32.1 (1.8 to 92.6)
        Day 183 (n=110 BTX-A-HAC; n=2 Placebo)
    5.3 (0.9 to 26.6)
    8.0 (0.2 to 76.9)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of remaining responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2422 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    40.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.1
         upper limit
    		 100
    Notes
    [9] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of remaining responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0917 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    56.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.8
         upper limit
    		 87.5
    Notes
    [10] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of remaining responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7064 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    15.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.3
         upper limit
    		 75.5
    Notes
    [11] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 148
    Statistical analysis description
    The difference in the adjusted percentage of remaining responders between the treatment groups at Day 148 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.701 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    -11.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.1
         upper limit
    		 53.2
    Notes
    [12] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of remaining responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7894 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.5
         upper limit
    		 35.2
    Notes
    [13] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of responders at each post-treatment visit to the study centre as measured by the ILA at rest.

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    End point title
    		 The percentage of responders at each post-treatment visit to the study centre as measured by the ILA at rest.
    End point description
    The ILA was used to assess the appearance of glabellar lines at rest and consists of a validated 4-point photographic scale: Grade 0 - none; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe. A responder at rest was defined as having a severity grade of none (Grade 0) or mild (Grade 1) at rest at a given visit and a severity grade of moderate (Grade 2) or severe (Grade 3) at Baseline (Day 1). The adjusted percentage of responders in each treatment group is presented for each post-treatment visit and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. Day 148 results (BTX-A-HAC NG 50 U) were not calculable due to quasi-complete separation of data point. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Days 1 (Baseline), 8, 15, 29, 57, 85, 113, 148 and 183 (End of Study).
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    53 [14]
    59 [15]
    Units: Adjusted percentage of responders
    number (confidence interval 95%)
        Day 8 (n=53 BTX-A-HAC; n=31 Placebo)
    73.2 (38.4 to 92.3)
    2.0 (0.2 to 15.8)
        Day 15 (n=53 BTX-A-HAC; n=32 Placebo)
    74.5 (37.7 to 93.3)
    1.3 (0.1 to 12.7)
        Day 29 (n=53 BTX-A-HAC; n=32 Placebo)
    81.1 (46.5 to 95.5)
    1.5 (0.1 to 14.4)
        Day 57 (n=53 BTX-A-HAC; n=32 Placebo)
    77.2 (41.7 to 94.1)
    0.5 (0.0 to 10.6)
        Day 85 (n=53 BTX-A-HAC; n=32 Placebo)
    58.5 (24.0 to 86.2)
    0.5 (0.0 to 8.0)
        Day 113 (n=53 BTX-A-HAC; n=31 Placebo)
    74.7 (43.5 to 91.8)
    4.8 (0.8 to 24.6)
        Day 148 (n=51 BTX-A-HAC; n=29 Placebo)
    99999999 (99999999 to 99999999)
    99999999 (99999999 to 99999999)
        Day 183 (n=53 BTX-A-HAC; n=29 Placebo)
    56.0 (26.4 to 81.9)
    10.4 (2.2 to 37.9)
    Notes
    [14] - Not calculable denoted 99999999.
    [15] - Not calculable denoted 99999999.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 8
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 8 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    71.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 58.2
         upper limit
    		 84.1
    Notes
    [16] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 15
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 15 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    73.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 60.9
         upper limit
    		 85.6
    Notes
    [17] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 29
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 29 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    79.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 68.2
         upper limit
    		 90.9
    Notes
    [18] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    76.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 65.1
         upper limit
    		 88.2
    Notes
    [19] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 44.5
         upper limit
    		 71.5
    Notes
    [20] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [21]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    69.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56
         upper limit
    		 83.8
    Notes
    [21] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015 [22]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    45.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.3
         upper limit
    		 63
    Notes
    [22] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of subjects with a reduction of two or more grades in the severity of glabellar lines at each post-treatment visit to the study centre as measured by the ILA at maximum frown

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    End point title
    		 The percentage of subjects with a reduction of two or more grades in the severity of glabellar lines at each post-treatment visit to the study centre as measured by the ILA at maximum frown
    End point description
    The ILA was used to assess the appearance of glabellar lines at maximum frown and consists of a validated 4-point photographic scale: Grade 0 - none; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe. Adjusted percentages of subjects with a reduction of two or more grades in the severity of glabellar lines at each post-treatment visit compared with Baseline are presented, and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown
    End point type
    Secondary
    End point timeframe
    Days 1 (Baseline), 8, 15, 29, 57, 85, 113, 148 and 183 (End of Study).
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    124
    59
    Units: Adjusted percentage of subjects
    number (confidence interval 95%)
        Day 8 (n=124 BTX-A-HAC; n=57 Placebo)
    56.2 (37.1 to 73.6)
    0.2 (0.0 to 3.0)
        Day 15 (n=124 BTX-A-HAC; n=59 Placebo)
    69.7 (52.0 to 83.0)
    0.2 (0.0 to 3.1)
        Day 29 (n=124 BTX-A-HAC; n=58 Placebo)
    63.6 (46.4 to 77.9)
    0.1 (0.0 to 1.8)
        Day 57 (n=124 BTX-A-HAC; n=58 Placebo)
    48.0 (31.6 to 64.9)
    0.1 (0.0 to 2.6)
        Day 85 (n=121 BTX-A-HAC; n=57 Placebo)
    24.3 (13.4 to 39.9)
    0.3 (0.0 to 4.8)
        Day 113 (n=123 BTX-A-HAC; n=56 Placebo)
    10.1 (4.3 to 21.7)
    0.3 (0.0 to 4.4)
        Day 148 (n=121 BTX-A-HAC; n=51 Placebo)
    3.5 (0.8 to 13.5)
    0.3 (0.0 to 5.4)
        Day 183 (n=122 BTX-A-HAC; n=51 Placebo)
    3.4 (0.8 to 12.6)
    1.3 (0.1 to 12.0)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 8
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 8 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [23]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.2
         upper limit
    		 64.8
    Notes
    [23] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 15
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 15 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    69.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 61.3
         upper limit
    		 77.7
    Notes
    [24] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 29
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 29 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [25]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    63.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55
         upper limit
    		 72
    Notes
    [25] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    47.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.1
         upper limit
    		 56.7
    Notes
    [26] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [27]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.2
         upper limit
    		 31.7
    Notes
    [27] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065 [28]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    9.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.3
         upper limit
    		 15.3
    Notes
    [28] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 148
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 148 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0643 [29]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 6.8
    Notes
    [29] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.367 [30]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 6.5
    Notes
    [30] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of responders at each post-treatment visit as measured by the subject's self-assessment (SSA) at maximum frown

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    End point title
    		 The percentage of responders at each post-treatment visit as measured by the subject's self-assessment (SSA) at maximum frown
    End point description
    The SSA was used to assess the appearance of glabellar lines at maximum frown and consists of a validated 4-point categorical scale: Grade 0 - no wrinkles; Grade 1 - mild wrinkles; Grade 2 - moderate wrinkles; Grade 3 - severe wrinkles. A responder at maximum frown was defined as having a severity grade of no wrinkles (Grade 0) or mild wrinkles (Grade 1) at maximum frown at a given visit and a severity grade of moderate wrinkles (Grade 2) or severe wrinkles (Grade 3) at Baseline (Day 1, pretreatment). The adjusted percentage of responders in each treatment group is presented for each post-treatment visit and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Days 1 (Baseline), 8, 15, 29, 57, 85, 113, 148 and 183 (End of Study).
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    124
    59
    Units: Adjusted percentage of responders
    number (confidence interval 95%)
        Day 8 (n=124 BTX-A-HAC; n=57 Placebo)
    62.0 (47.2 to 74.9)
    5.1 (1.6 to 14.8)
        Day 15 (n=124 BTX-A-HAC; n=59 Placebo)
    75.6 (61.8 to 85.6)
    4.4 (1.3 to 13.7)
        Day 29 (n=124 BTX-A-HAC; n=58 Placebo)
    76.0 (62.2 to 85.9)
    5.2 (1.7 to 15.0)
        Day 57 (n=124 BTX-A-HAC; n=58 Placebo)
    67.5 (52.4 to 79.6)
    2.2 (0.6 to 8.3)
        Day 85 (n=121 BTX-A-HAC; n=57 Placebo)
    61.8 (46.1 to 75.3)
    3.9 (1.1 to 12.6)
        Day 113 (n=123 BTX-A-HAC; n=56 Placebo)
    46.2 (32.8 to 60.2)
    9.8 (3.9 to 22.5)
        Day 148 (n=121 BTX-A-HAC; n=51 Placebo)
    44.1 (31.2 to 57.7)
    13.1 (5.3 to 28.9)
        Day 183 (n=122 BTX-A-HAC; n=51 Placebo)
    27.0 (16.4 to 41.1)
    6.0 (1.8 to 17.8)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 8
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 8 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [31]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    56.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.6
         upper limit
    		 67.2
    Notes
    [31] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 15
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 15 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [32]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    71.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62
         upper limit
    		 80.4
    Notes
    [32] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 29
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 29 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [33]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    70.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 61.4
         upper limit
    		 80.2
    Notes
    [33] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [34]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    65.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56.2
         upper limit
    		 74.3
    Notes
    [34] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [35]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    57.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.9
         upper limit
    		 67.9
    Notes
    [35] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [36]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    36.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.7
         upper limit
    		 48.2
    Notes
    [36] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 148
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 148 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011 [37]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    30.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.1
         upper limit
    		 43.7
    Notes
    [37] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0036 [38]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.7
         upper limit
    		 31.2
    Notes
    [38] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The percentage of responders at each post-treatment visit as measured by the subject’s level of satisfaction with the appearance of their glabellar lines

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    End point title
    		 The percentage of responders at each post-treatment visit as measured by the subject’s level of satisfaction with the appearance of their glabellar lines
    End point description
    The subject's level of satisfaction with the appearance of their glabellar lines was assessed with a validated 4-point categorical scale: Grade 0 - very satisfied; Grade 1 - satisfied; Grade 2 - dissatisfied; Grade 3 - very dissatisfied. A responder was defined as having a satisfaction rating of very satisfied (Grade 0) or satisfied (Grade 1) at a given visit and a satisfaction rating of dissatisfied (Grade 2) or very dissatisfied (Grade 3) at Baseline (Day 1, pretreatment). The adjusted percentage of responders in each treatment group is presented for each post-treatment visit and was calculated using a multivariate logistic regression model with treatment group, centre and stratification factors (gender and baseline ILA score at maximum frown) as fixed effects. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Day 8, 15, 29, 57, 85, 113, 148 and 183
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    124
    59
    Units: Adjusted percentage of responders
    number (confidence interval 95%)
        Day 8 (n=124 BTX-A-HAC; n=57 Placebo)
    72.7 (58.9 to 83.2)
    4.9 (1.6 to 14.5)
        Day 15 (n=124 BTX-A-HAC; n=59 Placebo)
    80.6 (68.4 to 88.9)
    7.9 (3.1 to 19.1)
        Day 29 (n=124 BTX-A-HAC; n=58 Placebo)
    80.9 (68.7 to 89.1)
    8.3 (3.1 to 20.2)
        Day 57 (n=124 BTX-A-HAC; n=58 Placebo)
    74.7 (61.2 to 84.6)
    5.9 (2.1 to 15.3)
        Day 85 (n=121 BTX-A-HAC; n=57 Placebo)
    70.9 (56.1 to 82.3)
    7.3 (2.7 to 18.7)
        Day 113 (n=123 BTX-A-HAC; n=56 Placebo)
    61.9 (48.3 to 73.8)
    9.8 (4.0 to 22.2)
        Day 148 (n=121 BTX-A-HAC; n=51 Placebo)
    58.9 (45.4 to 71.3)
    12.3 (5.0 to 27.3)
        Day 183 (n=122 BTX-A-HAC; n=51 Placebo)
    49.8 (36.3 to 63.3)
    11.3 (4.5 to 25.6)
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 8
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 8 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [39]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    67.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 58.1
         upper limit
    		 77.4
    Notes
    [39] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 15
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 15 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [40]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    72.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62.9
         upper limit
    		 82.5
    Notes
    [40] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 29
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 29 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [41]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    72.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62.7
         upper limit
    		 82.5
    Notes
    [41] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 57
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 57 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [42]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    68.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 59
         upper limit
    		 78.6
    Notes
    [42] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 85
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 85 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [43]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    63.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53
         upper limit
    		 74.1
    Notes
    [43] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 113
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 113 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [44]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 40.4
         upper limit
    		 63.6
    Notes
    [44] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 148
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 148 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [45]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    46.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.1
         upper limit
    		 59.2
    Notes
    [45] - Statistical tests were two-sided with a type I error rate at 5%.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo at Day 183
    Statistical analysis description
    The difference in the adjusted percentage of responders between the treatment groups at Day 183 is presented.
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [46]
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment difference
    Point estimate
    38.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 26
         upper limit
    		 50.9
    Notes
    [46] - Statistical tests were two-sided with a type I error rate at 5%.

    Secondary: The time to onset of treatment response based on the subject’s diary card.

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    End point title
    		 The time to onset of treatment response based on the subject’s diary card.
    End point description
    The median time to onset of treatment response is presented and was based on the subject's diary card in which subjects were asked to record their assessment of study treatment response on Days 1 to 7. They responded 'yes' or 'no' to the following question: 'Since being injected have you noticed an improvement in the appearance of your glabellar lines (lines between your eyebrows)?'. The onset of response was defined as the first day the subject responded 'yes'. The median time to onset of treatment response was not calculable for the placebo treatment group due to the small number of subjects who answered 'yes'. The mITT population consisted of subjects who had received at least one injection and had a baseline and at least one post-baseline value for the ILA of glabellar lines at maximum frown.
    End point type
    Secondary
    End point timeframe
    Day 1 to 7
    End point values
    		 BTX-A-HAC NG 50 U Placebo
    Number of subjects analysed
    125
    58 [47]
    Units: Days
        median (confidence interval 95%)
    3.0 (2.0 to 3.0)
    99999999 (99999999 to 99999999)
    Notes
    [47] - Not calculable denoted as 99999999.
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo- Log rank
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 BTX-A-HAC NG 50 U versus Placebo - Cox analysis
    Comparison groups
    BTX-A-HAC NG 50 U v Placebo
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cox proportional hazard model
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events were collected from Day 1 until end of study (Day 183)/early withdrawal (approximately 7 months).
    Adverse event reporting additional description
    Adverse events were reported for the safety population which consisted of all randomised subjects who received at least one injection of study treatment into at least one injection site.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BTX-A-HAC NG 50 U
    Reporting group description
    		 Subjects were randomised to receive Botulinum toxin type A haemagglutinin complex (BTX-A-HAC) next generation (NG). A single total dose of 50 U was injected on Day 1. The total treatment volume (0.25 millilitres [mL]) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to receive placebo. A single total dose of 50 U was injected on Day 1. The total treatment volume (0.25 mL) was divided into five injections (0.05 mL per injection) injected into five predefined sites across the glabellar region

    Serious adverse events
    		 BTX-A-HAC NG 50 U Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 125 (1.60%)
    1 / 59 (1.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Eye disorders
    Mydriasis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 BTX-A-HAC NG 50 U Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 125 (32.80%)
    17 / 59 (28.81%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Spinal column injury
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 125 (14.40%)
    2 / 59 (3.39%)
         occurrences all number
    27
    2
    Balance disorder
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    10 / 125 (8.00%)
    3 / 59 (5.08%)
         occurrences all number
    10
    3
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Blepharochalasis
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Brow ptosis
         subjects affected / exposed
    3 / 125 (2.40%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Papule
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Pruritis generalised
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Tendon calcification
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 125 (8.00%)
    5 / 59 (8.47%)
         occurrences all number
    10
    6
    Influenza
         subjects affected / exposed
    3 / 125 (2.40%)
    3 / 59 (5.08%)
         occurrences all number
    4
    3
    Tonsillitis
         subjects affected / exposed
    3 / 125 (2.40%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Cystitis
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Oral herpes
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    Bronchitis
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 59 (1.69%)
         occurrences all number
    1
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    0
    1

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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