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    Clinical Trial Results:
    Evaluation of the Safety and Efficacy of Treatment With BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex for Subjects With Facial Rhytides (Forehead Lines, Glabellar Lines, Lateral Canthal Lines)

    Summary
    EudraCT number
    		 2014-001815-38
    Trial protocol
    		 DE   GB   BE  
    Global end of trial date
    20 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jan 2018
    First version publication date
    20 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-143
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02261493
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Allergan Limited
    Sponsor organisation address
    Allergan Limited Marlow International The Parkway, Marlow, United Kingdom, SL7 1YL
    Public contact
    EU Regulatory Dept, Allergan Limited, 44 1628 494444, ml-eu_reg_affairs@allergan.com
    Scientific contact
    EU Regulatory Dept, Allergan Limited, 44 1628 494444, ml-eu_reg_affairs@allergan.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
    19 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a safety and efficacy study of onabotulinumtoxinA in subjects with upper facial rhytides (forehead lines, glabellar lines, lateral canthal lines [crow's feet lines]).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Oct 2014
    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
    Belgium: 70
    Country: Number of subjects enrolled
    Denmark: 217
    Country: Number of subjects enrolled
    United Kingdom: 96
    Country: Number of subjects enrolled
    United States: 404
    Worldwide total number of subjects
    787
    EEA total number of subjects
    383
    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)
    749
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were randomized to placebo, onabotulinumtoxinA Dose A, or onabotulinumtoxinA Dose B in Period 1. Subjects randomized to receive placebo or Dose B in Period 1, who subsequently continued to Period 2, received onabotulinumtoxinA Dose A in Period 2.

    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
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A
    Arm description
    		 Placebo (normal saline) injected into the protocol-specified areas on Day 1. If the subject meets the re-treatment criteria, the subject will receive up to 2 treatments with onabotulinumtoxinA Dose A into the protocol-specified areas.
    Arm type
    		 Placebo followed by experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Placebo (normal saline) injected into the protocol-specified areas on Day 1. If the subject meets the re-treatment criteria, the subject will receive up to 2 treatments with onabotulinumtoxinA Dose A into the protocol-specified areas.

    Arm title
    		 OnabotulinumtoxinA Dose B
    Arm description
    		 OnabotulinumtoxinA Dose B injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    OnabotulinumtoxinA Dose B injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Arm title
    		 OnabotulinumtoxinA Dose A
    Arm description
    		 OnabotulinumtoxinA Dose A injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    OnabotulinumtoxinA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    OnabotulinumtoxinA Dose A injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Number of subjects in period 1
    		Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Started
    156
    318
    313
    Completed
    126
    271
    287
    Not completed
    30
    47
    26
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
         Pregnancy
    1
    2
    -
         Undisclosed alcohol abuse
    -
    1
    -
         Personal Reasons
    14
    14
    16
         Lost to follow-up
    14
    27
    8
         Protocol deviation
    1
    -
    -
         Lack of efficacy
    -
    1
    -
         Noncompliance
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (normal saline) followed by OnabotulinumtoxinA Dose A
    Reporting group description
    		 Placebo (normal saline) injected into the protocol-specified areas on Day 1. If the subject meets the re-treatment criteria, the subject will receive up to 2 treatments with onabotulinumtoxinA Dose A into the protocol-specified areas.

    Reporting group title
    OnabotulinumtoxinA Dose B
    Reporting group description
    		 OnabotulinumtoxinA Dose B injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Reporting group title
    OnabotulinumtoxinA Dose A
    Reporting group description
    		 OnabotulinumtoxinA Dose A injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Reporting group values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A Total
    Number of subjects
    		 156 318 313 787
    Age Categorical
    Units: Subjects
        <65 years
    		 147 300 302 749
        >=65 years
    		 9 18 11 38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.1 ± 9.7 47.6 ± 10.3 45.5 ± 9.6 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 140 278 284 702
        Male
    		 16 40 29 85

    End points

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    End points reporting groups
    Reporting group title
    Placebo (normal saline) followed by OnabotulinumtoxinA Dose A
    Reporting group description
    		 Placebo (normal saline) injected into the protocol-specified areas on Day 1. If the subject meets the re-treatment criteria, the subject will receive up to 2 treatments with onabotulinumtoxinA Dose A into the protocol-specified areas.

    Reporting group title
    OnabotulinumtoxinA Dose B
    Reporting group description
    		 OnabotulinumtoxinA Dose B injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Reporting group title
    OnabotulinumtoxinA Dose A
    Reporting group description
    		 OnabotulinumtoxinA Dose A injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Primary: Percentage of Subjects with an Investigator Rating of None or Mild on the 4-Grade Forehead Wrinkle Scale (FWS) for Forehead Line Severity at Maximum Eyebrow Elevation

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    End point title
    		 Percentage of Subjects with an Investigator Rating of None or Mild on the 4-Grade Forehead Wrinkle Scale (FWS) for Forehead Line Severity at Maximum Eyebrow Elevation [1]
    End point description
    Day 30
    End point type
    Primary
    End point timeframe
    The Investigator assessed the severity of the subject's forehead lines at maximum eyebrow elevation using the 4-point FWS, where 0=none, 1=mild, 2=moderate, and 3=severe. The percentage of subjects assessed as "none" or "mild" on the FWS are reported.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    111
    222
    235
    Units: Percentage of Subjects
        number (confidence interval 95%)
    2.7 (-0.3 to 5.7)
    90.5 (86.7 to 94.4)
    93.6 (90.5 to 96.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects with a Subject Rating of None or Mild on the 4-Grade FWS for Forehead Line Severity at Maximum Eyebrow Elevation

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    End point title
    		 Percentage of Subjects with a Subject Rating of None or Mild on the 4-Grade FWS for Forehead Line Severity at Maximum Eyebrow Elevation [2]
    End point description
    The subject assessed the severity of his/her forehead lines at maximum eyebrow elevation using the 4-point FWS, where 0=none, 1=mild, 2=moderate, and 3=severe. The percentage of subjects assessing forehead lines as "none" or "mild" on the FWS are reported.
    End point type
    Primary
    End point timeframe
    Day 30
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    111
    222
    235
    Units: Percentage of Subjects
        number (confidence interval 95%)
    3.6 (0.1 to 7.1)
    81.5 (76.4 to 86.6)
    88.9 (84.9 to 92.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with ≥2-Grade Improvement from Baseline on Both the Investigator's and Subject's FWS Ratings of Forehead Line Severity at Maximum Eyebrow Elevation

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    End point title
    		 Percentage of Subjects with ≥2-Grade Improvement from Baseline on Both the Investigator's and Subject's FWS Ratings of Forehead Line Severity at Maximum Eyebrow Elevation
    End point description
    The Investigator and subject each assessed the severity of the subject's forehead lines at maximum eyebrow elevation using the 4-grade FWS, where 0=none, 1=mild, 2=moderate, and 3=severe. The percentage of subjects with at least a 2-grade improvement from baseline assessed by both the Investigator and the subject are reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    156
    318
    313
    Units: Percentage of Subjects
        number (confidence interval 95%)
    0.6 (-0.6 to 1.9)
    45.6 (40.1 to 51.1)
    53.0 (47.5 to 58.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with ≥1-Grade Improvement from Baseline on the Investigator's FWS Rating of Forehead Line Severity at Rest

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    End point title
    		 Percentage of Subjects with ≥1-Grade Improvement from Baseline on the Investigator's FWS Rating of Forehead Line Severity at Rest
    End point description
    The Investigator assessed the severity of the subject's forehead lines at rest using the 4-grade FWS, where 0=none, 1=mild, 2=moderate, and 3=severe. The percentage of subjects with at least a 1-grade improvement assessed by the Investigator are reported.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    150
    310
    309
    Units: Percentage of Subjects
        number (confidence interval 95%)
    18.7 (12.4 to 24.9)
    85.2 (81.2 to 89.1)
    84.8 (80.8 to 88.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reporting Mostly Satisfied or Very Satisfied on the 5-Point Facial Line Satisfaction Questionnaire (FLSQ) Item 5

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    End point title
    		 Percentage of Subjects Reporting Mostly Satisfied or Very Satisfied on the 5-Point Facial Line Satisfaction Questionnaire (FLSQ) Item 5
    End point description
    The FLSQ consists of 13 questions that assess subject satisfaction and appearance-related impacts associated with facial lines. Item 5 on the FLSQ asks "How satisfied are you with the effect your treatment had on your facial lines?" Responses included: very satisfied, mostly satisfied, neither satisfied or dissatisfied, mostly dissatisfied, or very dissatisfied. The percentage of subjects reporting a score of mostly satisfied or very satisfied with treatment are reported.
    End point type
    Secondary
    End point timeframe
    Day 60
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    155
    317
    313
    Units: Percentage of Subjects
        number (confidence interval 95%)
    3.2 (0.4 to 6.0)
    81.4 (77.1 to 85.7)
    87.9 (84.2 to 91.5)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with ≥20-Point Improvement from Baseline on the Impact Domain of the FLSQ Among Subjects With Baseline Score ≥ 20 Points

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    End point title
    		 Percentage of Subjects with ≥20-Point Improvement from Baseline on the Impact Domain of the FLSQ Among Subjects With Baseline Score ≥ 20 Points
    End point description
    The FLSQ consists of 13 questions that assess subject satisfaction and appearance-related impacts associated with facial lines. The Impact Domain measures the subject’s appearance-related and emotional impacts of treatment and is composed of 5 questions with a possible range of scores from 0 (worst) to 100 (best), using a transformed scale. Only subjects with baseline scores ≥ 20 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    152
    310
    301
    Units: Percentage of Subjects
        number (confidence interval 95%)
    19.7 (13.4 to 26.1)
    61.0 (55.5 to 66.4)
    76.1 (71.3 to 80.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with a ≥3-Point Improvement from Baseline on Item 4 of the 11-Point Facial Line Outcomes (FLO-11) Questionnaire©

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    End point title
    		 Percentage of Subjects with a ≥3-Point Improvement from Baseline on Item 4 of the 11-Point Facial Line Outcomes (FLO-11) Questionnaire©
    End point description
    The FLO-11 assess the subject's psychological and appearance-related impacts associated with facial lines. Item 4 is "I look older than my actual age because of my facial lines" with a range of possible scores from 0 = not at all to 10 = very much. Only subjects with baseline scores ≥ 3 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    141
    285
    288
    Units: Percentage of Subjects
        number (confidence interval 95%)
    9.9 (5.0 to 14.9)
    66.7 (61.2 to 72.1)
    77.1 (72.2 to 81.9)
    No statistical analyses for this end point

    Secondary: Time to Retreatment Eligibility

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    End point title
    		 Time to Retreatment Eligibility
    End point description
    Time to retreatment eligibility is defined as the number of days from treatment cycle 1 injection to the return to an Investigator FWS rating of moderate or severe at maximum eyebrow elevation. The FWS is a 4-grade scale, where 0=none, 1=mild, 2=moderate, and 3=severe. Only subjects who achieved a ≥ 2-grade improvement on both the Investigator and subject FWS ratings at maximum eyebrow elevation on Day 30 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    12 Months
    End point values
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B OnabotulinumtoxinA Dose A
    Number of subjects analysed
    1 [3]
    143
    161
    Units: Days
        median (standard deviation)
    64.0 ± 999
    120.0 ± 46.4
    126.0 ± 53.7
    Notes
    [3] - The standard deviations was NA; 999 used as a placeholder.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from signing the informed consent to the end of study.
    Adverse event reporting additional description
    The Safety Population includes all subjects who received at least 1 study treatment injection and was used to assess AEs and SAEs. Subjects randomized to receive placebo in Period 1 who subsequently received open-label onabotulinumtoxinA Dose A in Period 2 are included in the onabotulinumtoxinA Dose A group for the Safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo (normal saline) followed by OnabotulinumtoxinA Dose A
    Reporting group description
    		 Placebo (normal saline) injected into the protocol-specified areas on Day 1. If the subject meets the re-treatment criteria, the subject will receive up to 2 treatments with onabotulinumtoxinA Dose A into the protocol-specified areas.

    Reporting group title
    OnabotulinumtoxinA Dose A
    Reporting group description
    		 OnabotulinumtoxinA Dose A injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Reporting group title
    OnabotulinumtoxinA Dose B
    Reporting group description
    		 OnabotulinumtoxinA Dose B injected into the protocol-specified areas on Day 1. Subjects will receive at least 1 and up to 3 treatments.

    Serious adverse events
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 156 (1.28%)
    16 / 746 (2.14%)
    7 / 318 (2.20%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 746 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma stage II
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 746 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    2 / 318 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 746 (0.00%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 746 (0.00%)
    1 / 318 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neuritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporal lobe epilepsy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 746 (0.27%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 746 (0.27%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 746 (0.13%)
    0 / 318 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (normal saline) followed by OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose A OnabotulinumtoxinA Dose B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 156 (13.46%)
    198 / 746 (26.54%)
    90 / 318 (28.30%)
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 156 (5.13%)
    69 / 746 (9.25%)
    30 / 318 (9.43%)
         occurrences all number
    10
    89
    35
    General disorders and administration site conditions
    Injection site bruising
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 156 (3.21%)
    47 / 746 (6.30%)
    26 / 318 (8.18%)
         occurrences all number
    5
    53
    27
    Injection site haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 156 (1.92%)
    34 / 746 (4.56%)
    16 / 318 (5.03%)
         occurrences all number
    3
    39
    20
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 156 (3.21%)
    48 / 746 (6.43%)
    18 / 318 (5.66%)
         occurrences all number
    5
    58
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2015
    A) Topical anesthetics were excluded; B) added requirement for subjects to be observed for adverse events for at least 30 minutes following study treatment; C) added analysis method of MI and added sensitivity analyses for primary variables/analyses; D) defined clinical benefit and clarified that responders for FLSQ Impact Domain score only included subjects who had baseline scores ≥ 20 points for secondary efficacy variables/analyses; and E) added FWS ratings of FHL severity at maximum eyebrow elevation based on independent physician reviewers’ assessment of photographs for other efficacy variables/analyses.

    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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