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    Clinical Trial Results:
    A randomized, evaluator-blinded, comparative study to evaluate the efficacy and safety of different injection volumes of botulinum toxin type A, Azzalure®, in the glabellar lines.

    Summary
    EudraCT number
    		 2013-004646-42
    Trial protocol
    		 SE  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2020
    First version publication date
    06 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    05PF1311
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Q-Med AB
    Sponsor organisation address
    Seminariegatan 21, Uppsala, Sweden, SE-752 28
    Public contact
    Head of Medical Affairs, Q-Med AB, +46 184749000, info.q-med@galderma.com
    Scientific contact
    Head of Medical Affairs, Q-Med AB, +46 184749000, info.q-med@galderma.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
    02 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To evaluate the compound muscle action potential (CMAP) using electroneurography - To assess the severity of glabellar lines, live and from photographs and video, at rest and at maximum frown - To assess the subject’s satisfaction with the treatment by using the Subject Satisfaction Questionnaire - To evaluate the subjects experience of onset of effect by response to the question “Since being injected, have you noticed any effect on the appearance of your glabellar lines?” - To evaluate the safety of two different injection volumes of Azzalure® in the glabellar lines by collecting Adverse Events - To evaluate the subjects pain on injection using the Visual Analogue Scale
    Protection of trial subjects
    As required by the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Apr 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
    Sweden: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    62
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first subject was recruited 10-Apr-2014 and the last subject on 21-May-2014.

    Pre-assignment
    Screening details
    		 84 subjects screened. 22 subjects not included due to glabellar lines at rest outside of grade 2–3 (11), previous medical history/physical examination findings/other conditions that made them unsuitable (6), signs and symptoms of eyelid ptosis (3), previous botulinum toxin treatment (1), withdrawn consent (1).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    A blinded evaluator assessed primary efficacy endpoints in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A - Azzalure recommended reconstitution volume
    Arm description
    		 Subjects in this arm received Azzalure treatment according to label: Dilution volume: 0.63ml NaCl Dose: 5 injections of 0.05ml/injection point, total dose 50 sU
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Azzalure
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dilution volume: 0.63ml NaCl Dose: 5 injections of 0.05ml/injection point, total dose 50 sU (labeled injection volume) One administration at baseline (blinded), and one optional (unblinded) at the last study visit 6 months after baseline.

    Arm title
    		 Group B - two-fold recommended reconstitution volume
    Arm description
    		 Subjects in this arm received Azzalure treatment with twice-fold the labeled dilution volume: Dilution volume: 1.25ml NaCl Dose: 5 injections of 0.1ml/injection point, total dose 50 sU
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azzalure
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Dilution volume: 1.25ml NaCl Dose: 5 injections of 0.1ml/injection point, total dose 50 sU (twice-fold the labeled injection volume) One administration at baseline (blinded), and one optional (unblinded) at the last study visit 6 months after baseline.

    Number of subjects in period 1
    		Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Started
    30
    32
    Completed
    30
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A - Azzalure recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment according to label: Dilution volume: 0.63ml NaCl Dose: 5 injections of 0.05ml/injection point, total dose 50 sU

    Reporting group title
    Group B - two-fold recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment with twice-fold the labeled dilution volume: Dilution volume: 1.25ml NaCl Dose: 5 injections of 0.1ml/injection point, total dose 50 sU

    Reporting group values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume Total
    Number of subjects
    		 30 32 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 30 32 62
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 50.5 (30 to 63) 49 (38 to 58) -
    Gender categorical
    Units: Subjects
        Female
    		 30 32 62
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Group A - Azzalure recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment according to label: Dilution volume: 0.63ml NaCl Dose: 5 injections of 0.05ml/injection point, total dose 50 sU

    Reporting group title
    Group B - two-fold recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment with twice-fold the labeled dilution volume: Dilution volume: 1.25ml NaCl Dose: 5 injections of 0.1ml/injection point, total dose 50 sU

    Primary: Percentage of subjects with improved wrinkle severity - dynamic

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    End point title
    		 Percentage of subjects with improved wrinkle severity - dynamic
    End point description
    The severity of the subject’s glabellar lines at maximum frown (dynamic) was assessed live at all visits. A 5-graded validated Scale for Glabella lines were used. A wrinkle was defined as improved if a one-grade decrease on the scale was achieved.
    End point type
    Primary
    End point timeframe
    1, 3, 7, and 14 days, and 1, 3, 4, and 6 months
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    30
    32
    Units: percentage
    number (not applicable)
        Day 1
    50
    53.1
        Day 3
    76.7
    93.8
        Day 7
    93.3
    93.8
        Day 14
    96.7
    96.9
        Month 1
    96.7
    100
        Month 3
    70
    90.3
        Month 4
    58.6
    67.7
        Month 6
    17.2
    28.1
    Statistical analysis title
    		 Comparison of groups at Month 1
    Comparison groups
    Group A - Azzalure recommended reconstitution volume v Group B - two-fold recommended reconstitution volume
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Primary: Percentage of subjects with improved wrinkle severity - at rest

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    End point title
    		 Percentage of subjects with improved wrinkle severity - at rest
    End point description
    The severity of the subject’s glabellar lines at rest was assessed live at all visits. A 5-graded validated Scale for Glabella lines was used. A wrinkle was defined as improved if a one-grade decrease on the scale was achieved.
    End point type
    Primary
    End point timeframe
    1, 3, 7, and 14 days, and 1, 3, 4, and 6 months
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    30
    32
    Units: percentage
    number (not applicable)
        Day 1
    20
    28.1
        Day 3
    66.7
    84.4
        Day 7
    76.7
    90.6
        Day 14
    83.3
    96.9
        Month 1
    100
    96.8
        Month 3
    86.7
    93.5
        Month 4
    62.1
    80.6
        Month 6
    55.2
    59.4
    Statistical analysis title
    		 Comparison of groups at Month 1
    Comparison groups
    Group A - Azzalure recommended reconstitution volume v Group B - two-fold recommended reconstitution volume
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.492
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Compound Muscle Action Potential

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    End point title
    		 Compound Muscle Action Potential
    End point description
    Compound Muscle Action Potential (CMAP) was measured separately for each corrugator supercilii muscle in the forehead using electroneurography in subjects (n= 31) at one of the study sites. Surface recording over the corrugator supercilii muscles examined the degree of contraction measured in millivolts. CMAP values are presented as percentage of baseline values (mean of left side and right side values per subject).
    End point type
    Secondary
    End point timeframe
    Measurements were made at baseline (pre-treatment) and also at Day 1, Day 3, Day 7, Month 1, Month 3, and Month 6.
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    15 [1]
    16
    Units: percentage
    number (not applicable)
        Day 1
    79.5
    69.5
        Day 3
    54.8
    44.1
        Day 7
    42.2
    32.6
        Month 1
    34.5
    24.9
        Month 3
    40.4
    35.4
        Month 6
    59.7
    51.6
    Notes
    [1] - At Month 6, 14 subjects in this group were analysed.
    No statistical analyses for this end point

    Secondary: Subject experience of onset of effect

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    End point title
    		 Subject experience of onset of effect
    End point description
    The subjects were asked at Day 1 and onwards (until their response was Yes) if they had noticed any effects on the appearance of their glabellar lines since the injections. Reported results are percentage of of subjects answering Yes on corresponding Day.
    End point type
    Secondary
    End point timeframe
    1, 3, 7, and 14 days.
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    30
    32
    Units: percentage
    number (not applicable)
        Day 1
    30
    28.1
        Day 3
    46.7
    65.6
        Day 7
    23.3
    6.3
        Day 14
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects satisfied with aesthetic outcome

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    End point title
    		 Percentage of subjects satisfied with aesthetic outcome
    End point description
    The subjects were asked at the Month 1, Month 3 and Month 6 visits: ‘How satisfied are you with the aesthetic outcome of the injected area?’, and chose between Very satisfied/Satisfied/Neutral/Dissatisfied/Very dissatisfied. Results are presented as percentage of subjects answering 'Very satisfied' or 'Satisfied', at the pre-specified timepoints.
    End point type
    Secondary
    End point timeframe
    Month 1, Month 3, Month 6
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    30 [2]
    32 [3]
    Units: percentage
    number (not applicable)
        Month 1
    93
    88
        Month 3
    90
    87
        Month 6
    86
    78
    Notes
    [2] - 29 subjects at Month 6
    [3] - 31 subjects at Month 3.
    No statistical analyses for this end point

    Secondary: Assessment of pain on Visual Analogue Scale

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    End point title
    		 Assessment of pain on Visual Analogue Scale
    End point description
    Injection pain was assessed both immediately and 10 minutes after injection. The pain was assessed by a 100-mm visual analog scale (VAS) where 0 mm was defined as “no pain” and 100 mm as “the worst pain imaginable.”
    End point type
    Secondary
    End point timeframe
    Immediately (0 minutes) and 10 minutes after injection.
    End point values
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Number of subjects analysed
    30
    32
    Units: mm
    arithmetic mean (standard deviation)
        0 minutes
    7.0 ± 5.9
    6.9 ± 7.8
        10 minutes
    3.3 ± 6.0
    4.3 ± 5.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    7 months, 1 week (first enrolment - last completed)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Group A - Azzalure recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment according to label: Dilution volume: 0.63ml NaCl Dose: 5 injections of 0.05ml/injection point, total dose 50 sU

    Reporting group title
    Group B - two-fold recommended reconstitution volume
    Reporting group description
    		 Subjects in this arm received Azzalure treatment with twice-fold the labeled dilution volume: Dilution volume: 1.25ml NaCl Dose: 5 injections of 0.1ml/injection point, total dose 50 sU

    Serious adverse events
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A - Azzalure recommended reconstitution volume Group B - two-fold recommended reconstitution volume
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 30 (26.67%)
    7 / 32 (21.88%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 32 (12.50%)
         occurrences all number
    2
    4
    Tension headache
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Intervertrebal disc protrusion
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2

    More information

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

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27399956
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