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    Clinical Trial Results:
    A prospective, randomised, double-blind, placebo-controlled, multicenter study with an open-label extension period to investigate the efficacy and safety of NT 201 in the simultaneous treatment of upper facial lines (horizontal forehead lines, glabellar frown lines, and lateral canthal lines)

    Summary
    EudraCT number
    		 2019-004113-13
    Trial protocol
    		 DE  
    Global end of trial date
    08 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M602011070
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04622254
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merz Pharmaceuticals GmbH
    Sponsor organisation address
    Eckenheimer Landstrasse 100, Frankfurt/M, Germany, 60318
    Public contact
    Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, Aesthetic.Trials@merz.com
    Scientific contact
    Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, Aesthetic.Trials@merz.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to investigate the safety and efficacy of NT 201 (active ingredient: Botulinum (neuro)toxin type A, free from complexing proteins) in the combined treatment of wrinkles in the upper face (upper facial lines [UFL]): Horizontal Forehead Lines [HFL], Glabellar Frown Lines [GFL], and Lateral Canthal Lines [LCL]). It is a prospective, randomised, double-blind, placebo-controlled, multicenter study with a placebo-control main period (MP) followed by an open-label extension (OLEX) period.
    Protection of trial subjects
    High medical and ethical standards were followed in accordance with Good Clinical Practice and other applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Nov 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 368
    Worldwide total number of subjects
    368
    EEA total number of subjects
    368
    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)
    356
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited at 12 investigational sites in Germany.

    Pre-assignment
    Screening details
    		 Of the 395 screened subjects, 27 subjects exited as screen failures and 368 subjects were randomised and enrolled to receive a treatment with NT 201 or placebo in the main period of the study. Out of 358 subjects who completed the main period, 346 subjects received treatment in the OLEX period of the study.

    Period 1
    Period 1 title
    Main Period (Up to 22 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Main Period: Placebo (Group P)
    Arm description
    		 Subjects received placebo injection in all three upper facial lines (UFL): (glabellar frown lines [GFL], horizontal forehead lines [HFL] and lateral canthal lines [LCL]) on Day 1 of main period.
    Arm type
    		 Experimental

    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
    Subjects received placebo, solution for injection, intramuscularly in HFL, GFL and LCL areas on Day 1 of main period.

    Arm title
    		 Main Period: NT 201 (Group U)
    Arm description
    		 Subjects received a total of 64 Units (U) of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    Other name
    IncobotulinumtoxinA, Clostridium Botulinum neurotoxin type A, Xeomin, Bocouture, Xeomin Cosmetic and Xeomeen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received NT 201, 64 U, powder for solution for injection, intramuscularly in HFL, GFL, and LCL areas on Day 1 of main period.

    Arm title
    		 Main Period: NT 201 and Placebo (Group L)
    Arm description
    		 Subjects received a total of 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    Other name
    IncobotulinumtoxinA, Clostridium Botulinum neurotoxin type A, Xeomin, Bocouture, Xeomin Cosmetic and Xeomeen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received NT 201, 24 U, powder for solution for injection, intramuscularly in LCL area on Day 1 of main period.

    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
    Subjects received placebo, solution for injection, intramuscularly in HFL, GFL areas on Day 1 of main period.

    Number of subjects in period 1
    		Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Started
    94
    184
    90
    Completed
    91
    180
    87
    Not completed
    3
    4
    3
         Consent withdrawn by subject
    -
    1
    2
         Adverse event, non-fatal
    -
    1
    -
         Lost to follow-up
    -
    2
    1
         Protocol deviation
    1
    -
    -
         Withdrawal by subject
    2
    -
    -
    Period 2
    Period 2 title
    OLEX Period (Up to 39 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OLEX: NT 201 (Main Period: Group P)
    Arm description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    Other name
    IncobotulinumtoxinA, Clostridium Botulinum neurotoxin type A, Xeomin, Bocouture, Xeomin Cosmetic and Xeomeen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received NT 201, 64 U, powder for solution for injection, intramuscularly in HFL, GFL, LCL areas on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Arm title
    		 OLEX: NT 201 (Main Period: Group U)
    Arm description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    Other name
    IncobotulinumtoxinA, Clostridium Botulinum neurotoxin type A, Xeomin, Bocouture, Xeomin Cosmetic and Xeomeen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received NT 201, 64 U, powder for solution for injection, intramuscularly in HFL, GFL, LCL areas on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Arm title
    		 OLEX: NT 201 (Main Period: Group L)
    Arm description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NT 201
    Investigational medicinal product code
    Other name
    IncobotulinumtoxinA, Clostridium Botulinum neurotoxin type A, Xeomin, Bocouture, Xeomin Cosmetic and Xeomeen
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received NT 201, 64 U, powder for solution for injection, intramuscularly in HFL, GFL, LCL areas on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Number of subjects in period 2 [1]
    		OLEX: NT 201 (Main Period: Group P) OLEX: NT 201 (Main Period: Group U) OLEX: NT 201 (Main Period: Group L)
    Started
    89
    170
    87
    Completed
    81
    156
    76
    Not completed
    8
    14
    11
         Adverse event, non-fatal
    1
    -
    -
         Other
    -
    -
    2
         Pregnancy
    1
    -
    -
         Lost to follow-up
    3
    -
    2
         Other eligibility criteria for reinjection not met
    1
    -
    -
         No need for re-injection
    1
    9
    3
         Withdrawal by subject
    1
    5
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Several subjects who completed MP did not receive treatment in the OLEX period due to non-eligibility or other reasons.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Period: Placebo (Group P)
    Reporting group description
    		 Subjects received placebo injection in all three upper facial lines (UFL): (glabellar frown lines [GFL], horizontal forehead lines [HFL] and lateral canthal lines [LCL]) on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 (Group U)
    Reporting group description
    		 Subjects received a total of 64 Units (U) of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 and Placebo (Group L)
    Reporting group description
    		 Subjects received a total of 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.

    Reporting group values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L) Total
    Number of subjects
    		 94 184 90 368
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 94 177 85 356
        From 65-84 years
    		 0 7 5 12
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.8 ± 9.15 46.0 ± 9.92 45.9 ± 9.88 -
    Gender categorical
    Units: Subjects
        Female
    		 84 147 72 303
        Male
    		 10 37 18 65
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 2 2 5
        Not Hispanic or Latino
    		 93 182 88 363
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 0 0 1 1
        White
    		 94 182 89 365
        Black or African American
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Main Period: Placebo (Group P)
    Reporting group description
    		 Subjects received placebo injection in all three upper facial lines (UFL): (glabellar frown lines [GFL], horizontal forehead lines [HFL] and lateral canthal lines [LCL]) on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 (Group U)
    Reporting group description
    		 Subjects received a total of 64 Units (U) of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 and Placebo (Group L)
    Reporting group description
    		 Subjects received a total of 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.
    Reporting group title
    OLEX: NT 201 (Main Period: Group P)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Reporting group title
    OLEX: NT 201 (Main Period: Group U)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Reporting group title
    OLEX: NT 201 (Main Period: Group L)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Primary: Main Period: Percentage of Glabellar Frown Line (GFL) Responders at Day 30

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    End point title
    		 Main Period: Percentage of Glabellar Frown Line (GFL) Responders at Day 30 [1]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. GFL response was score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of MP on MAS for GFL at maximum contraction as assessed by investigator and subject. MAS for GFL ranged as 0 to 4, where 0 is “No glabellar lines”, 1 is “Mild glabellar lines”, 2 is “Moderate glabellar lines”, 3 is “Severe glabellar lines” and 4 is “Very severe glabellar lines”. Target population of main primary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Primary
    End point timeframe
    Day 30
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main primary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    0
    49.5
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Primary: Main Period: Percentage of Horizontal Forehead Lines (HFL) Responders at Day 30

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    End point title
    		 Main Period: Percentage of Horizontal Forehead Lines (HFL) Responders at Day 30 [2]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. HFL-response was defined as a score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of MP on MAS for HFL at maximum contraction as assessed by both the investigator and the subject. MAS for HFL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main primary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Primary
    End point timeframe
    Day 30
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main primary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    0
    57.7
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Primary: Main Period: Percentage of Lateral Canthal Lines (LCL) Responders at Day 30

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    End point title
    		 Main Period: Percentage of Lateral Canthal Lines (LCL) Responders at Day 30 [3]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. LCL-response was defined as a score of 0 (no) or 1 (mild) and at least two-grade improvement from baseline to Day 30 of MP on MAS for both left and right LCL at maximum contraction as assessed by both the investigator and the subject. MAS for LCL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main primary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Primary
    End point timeframe
    Day 30
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main primary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    0
    32.4
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Investigator at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Investigator at Day 30 [4]
    End point description
    MAS : 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for GFL ranged as 0 to 4, where 0 is “No glabellar lines”, 1 is “Mild glabellar lines”, 2 is “Moderate glabellar lines”, 3 is “Severe glabellar lines” and 4 is “Very severe glabellar lines”. Target population of main key secondary estimand included subjects with HFL, GFL, and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    0
    86.8
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Investigator at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Investigator at Day 30 [5]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for HFL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main key secondary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    1.1
    86.3
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator at Day 30 [6]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for LCL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main key secondary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    2.1
    75.8
    Statistical analysis title
    		 Main Period: NT 201 (Group P), Main Period: NT 201
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Subject at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for GFL at Maximum Contraction as Assessed by the Subject at Day 30 [7]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for GFL ranged as 0 to 4, where 0 is “No glabellar lines”, 1 is “Mild glabellar lines”, 2 is “Moderate glabellar lines”, 3 is “Severe glabellar lines” and 4 is “Very severe glabellar lines”. Target population of main key secondary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    1.1
    73.6
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Subject at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for HFL at Maximum Contraction as Assessed by the Subject at Day 30 [8]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for HFL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main key secondary estimand subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    2.1
    79.1
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Subject at Day 30

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    End point title
    		 Main Period: Percentage of Subjects With a Score of 0 (no) or 1 (Mild) on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Subject at Day 30 [9]
    End point description
    MAS: 5-point scale used to identify responders in clinical context and validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for LCL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. Target population of main key secondary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: percentage of subjects
        number (not applicable)
    3.2
    65.4
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Subjects

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    End point title
    		 Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Subjects [10]
    End point description
    The GAIS is a 7-point Likert scale capturing the global aesthetic improvement ranging from +3 (very much improved); +2 (much improved); +1 (improved); 0 (no change); -1 (worse); -2 (much worse); -3 (very much worse), as assessed by the subject. GAIS as assessed by the subject at Day 30 was analysed using an ANCOVA model. Target population of main key secondary estimand included subjects with HFL, GFL and LCL of moderate to severe intensity at maximum contraction as assessed by investigator and subject according to MAS, as randomised in this study: Subset of subjects randomised to UFL (Group U) or to placebo (Group P) groups, grouped by randomised treatment assignment.
    End point type
    Secondary
    End point timeframe
    Day 30
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis population for the endpoint is the target population of main key secondary estimand, which only includes subjects randomized to Group U and Group P.
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U)
    Number of subjects analysed
    94
    182
    Units: score on a scale
        least squares mean (confidence interval 95%)
    0.02 (-0.11 to 0.15)
    2.00 (1.90 to 2.09)
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for GFL at Maximum Contraction as Assessed by the Investigator

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    End point title
    		 Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for GFL at Maximum Contraction as Assessed by the Investigator
    End point description
    MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for GFL ranged as 0 to 4 where 0 is “No glabellar lines”, 1 is “Mild glabellar lines”, 2 is “Moderate glabellar lines”, 3 is “Severe glabellar lines” and 4 is “Very severe glabellar lines”. The full analysis set (FAS) consisted of all randomised subjects. Here “number of subjects analysed” were subjects who had non-missing data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Number of subjects analysed
    91
    181
    88
    Units: percentage of subjects
        number (not applicable)
    5.5
    96.7
    4.5
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: NT 201 (Group U) v Main Period: Placebo (Group P)
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for HFL at Maximum Contraction as Assessed by the Investigator

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    End point title
    		 Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for HFL at Maximum Contraction as Assessed by the Investigator
    End point description
    MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for HFL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. FAS. Here “number of subjects analysed” were subjects who had non-missing data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Number of subjects analysed
    91
    181
    88
    Units: percentage of subjects
        number (not applicable)
    3.3
    96.1
    3.4
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator

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    End point title
    		 Main Period: Percentage of Subjects With at Least One-grade Improvement From Baseline to Day 30 of MP on MAS for Both Left and Right LCL at Maximum Contraction as Assessed by the Investigator
    End point description
    MAS are 5-point scales used to identify responders in a clinical context. They are validated photograph-based outcome instruments designed specifically for assessment of each upper facial area. MAS for LCL ranged as 0 to 4 where 0 is “No lines”, 1 is “Mild lines”, 2 is “Moderate lines”, 3 is “Severe lines” and 4 is “Very severe lines”. FAS. Here “overall number of subjects analysed” were subjects who had non-missing data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Number of subjects analysed
    91
    181
    88
    Units: percentage of subjects
        number (not applicable)
    8.8
    91.7
    68.2
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 (Group U)
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group L
    Comparison groups
    Main Period: NT 201 and Placebo (Group L) v Main Period: Placebo (Group P)
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mantel-Haenszel
    Confidence interval

    Secondary: Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Investigator

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    End point title
    		 Main Period: Global Aesthetic Improvement Scale (GAIS) at Day 30 as Assessed by the Investigator
    End point description
    The GAIS is a 7-point Likert scale capturing the global aesthetic improvement ranging from +3 (very much improved); +2 (much improved); +1 (improved); 0 (no change); -1 (worse); -2 (much worse); -3 (very much worse), as assessed by the investigator. GAIS as assessed by the investigator at Day 30 was analysed using an ANCOVA model. FAS. Here “number of subjects analysed” were subjects who had non-missing data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 30
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Number of subjects analysed
    91
    181
    88
    Units: score on a scale
        least squares mean (confidence interval 95%)
    0.03 (-0.09 to 0.14)
    2.23 (2.14 to 2.31)
    0.68 (0.56 to 0.80)
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group U
    Comparison groups
    Main Period: NT 201 (Group U) v Main Period: Placebo (Group P)
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Main Period: NT 201 Group P Versus Group L
    Comparison groups
    Main Period: Placebo (Group P) v Main Period: NT 201 and Placebo (Group L)
    Number of subjects included in analysis
    179
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Main Period: Number of Subjects With Related Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Main Period: Number of Subjects With Related Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs during the Main Period are defined as adverse events (AEs) with onset or worsening on or after date and time of first dose of study treatment and before date and time of first administration of study treatment in the OLEX period or the final study visit, if subject was not treated in the OLEX period. An AE is considered to be related if a causal relationship between study treatment and the AE is at least reasonably possible. The Safety Evaluation Set (SES) included all subjects treated.
    End point type
    Secondary
    End point timeframe
    Up to 22 weeks
    End point values
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L)
    Number of subjects analysed
    94
    184
    90
    Units: subjects
    12
    35
    10
    No statistical analyses for this end point

    Secondary: OLEX: Number of Subjects With Related TEAEs

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    End point title
    		 OLEX: Number of Subjects With Related TEAEs
    End point description
    TEAEs of the OLEX period are defined as AEs with onset or worsening on or after date and time of first dose of study treatment in the OLEX period up to and including the final study visit. An AE is considered to be related if a causal relationship between study treatment and the AE is at least reasonably possible. SES.
    End point type
    Secondary
    End point timeframe
    Up to 39 weeks
    End point values
    		 OLEX: NT 201 (Main Period: Group P) OLEX: NT 201 (Main Period: Group U) OLEX: NT 201 (Main Period: Group L)
    Number of subjects analysed
    89
    170
    87
    Units: subjects
    18
    32
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Main Period: Up to 22 weeks; OLEX Period: Up to 39 weeks
    Adverse event reporting additional description
    SES. The investigator reported AEs systematically at each visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Main Period: Placebo (Group P)
    Reporting group description
    		 Subjects received placebo injection in all three UFL: GFL, HFL and LCL on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 (Group U)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL area and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.

    Reporting group title
    Main Period: NT 201 and Placebo (Group L)
    Reporting group description
    		 Subjects received a total of 24 U NT 201: placebo injection both in the GFL and HFL area, and 24 U NT 201 injection in the LCL area (12 U per side) on Day 1 of main period.

    Reporting group title
    OLEX: NT 201 (Main Period: Group P)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Reporting group title
    OLEX: NT 201 (Main Period: Group U)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Reporting group title
    OLEX: NT 201 (Main Period: Group L)
    Reporting group description
    		 Subjects received a total of 64 U of NT 201: 20 U of NT 201 injection both in the GFL and in the HFL area, and 24 U of NT 201 injection in the LCL area (12 U per side) on Day 1 (Visit 8) and Visit 13 of OLEX period.

    Serious adverse events
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L) OLEX: NT 201 (Main Period: Group P) OLEX: NT 201 (Main Period: Group U) OLEX: NT 201 (Main Period: Group L)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 184 (0.54%)
    2 / 90 (2.22%)
    2 / 89 (2.25%)
    6 / 170 (3.53%)
    3 / 87 (3.45%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leiomyoma
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 184 (0.54%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial hypotension
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 184 (0.54%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 184 (0.54%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal septum deviation
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid mass
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 170 (0.59%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-acute COVID-19 syndrome
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 184 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 184 (0.54%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 170 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Main Period: Placebo (Group P) Main Period: NT 201 (Group U) Main Period: NT 201 and Placebo (Group L) OLEX: NT 201 (Main Period: Group P) OLEX: NT 201 (Main Period: Group U) OLEX: NT 201 (Main Period: Group L)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 94 (24.47%)
    43 / 184 (23.37%)
    23 / 90 (25.56%)
    39 / 89 (43.82%)
    74 / 170 (43.53%)
    29 / 87 (33.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 94 (8.51%)
    18 / 184 (9.78%)
    7 / 90 (7.78%)
    9 / 89 (10.11%)
    9 / 170 (5.29%)
    2 / 87 (2.30%)
         occurrences all number
    8
    23
    7
    11
    11
    3
    General disorders and administration site conditions
    Injection site haematoma
         subjects affected / exposed
    8 / 94 (8.51%)
    15 / 184 (8.15%)
    9 / 90 (10.00%)
    11 / 89 (12.36%)
    22 / 170 (12.94%)
    9 / 87 (10.34%)
         occurrences all number
    8
    17
    10
    12
    29
    11
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    2 / 94 (2.13%)
    10 / 184 (5.43%)
    9 / 90 (10.00%)
    4 / 89 (4.49%)
    8 / 170 (4.71%)
    8 / 87 (9.20%)
         occurrences all number
    2
    20
    12
    5
    14
    12
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 94 (4.26%)
    2 / 184 (1.09%)
    0 / 90 (0.00%)
    13 / 89 (14.61%)
    33 / 170 (19.41%)
    12 / 87 (13.79%)
         occurrences all number
    4
    2
    0
    13
    34
    12
    Nasopharyngitis
         subjects affected / exposed
    4 / 94 (4.26%)
    3 / 184 (1.63%)
    3 / 90 (3.33%)
    9 / 89 (10.11%)
    22 / 170 (12.94%)
    11 / 87 (12.64%)
         occurrences all number
    4
    3
    3
    10
    22
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2020
    The first Amendment occurred before first subject first visit. The amendment was due to new government regulations and restrictions caused by the COVID-19 pandemic and due to the advice/deficiency letters issued respectively by the Food and drug administration (FDA) and The federal institute for drug and medical devices (BfArM). The purpose of this amendment was to assure subjects’ safety and mitigate the impact on assessments of AEs and on assessments of efficacy parameters which were based on subjects’ self- assessment in case subjects could not attend on-site visits during the pandemic.
    02 Sep 2020
    The second amendment also occurred before first subject first visit. In addition to minor formatting changes, this amendment was issued to implement measures that might had to be taken in case of a second outbreak of a pandemic leading to a public health emergency, and, as requested by the Ethics Committee (EC) Hamburg, to specify who would inform the subject in case of pathological laboratory values and to inform the subject that the improvement of wrinkles following treatment with NT 201 would only be temporary.
    24 Jun 2021
    The third protocol amendment occurred after first subject first visit. This amendment was made due to the advice/information request letter issued to study protocol M602011071 by the FDA on 06-JAN-2021 and the meeting request/written responses issued by the FDA on 30-APR-2021. In addition to minor formatting/spelling changes and administrative changes were made.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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