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    Clinical Trial Results:
    BOTOX® Treatment in Adult Patients With Poststroke Lower Limb Spasticity

    Summary
    EudraCT number
    		 2011-004980-63
    Trial protocol
    		 HU   DE   GB   CZ   PL  
    Global end of trial date
    01 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2016
    First version publication date
    07 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01575054
    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
    Allergan Limited EU Regulatory Dept, Allergan Limited, 44 1628 494444, ml-eu_reg_affairs@allergan.com
    Scientific contact
    Allergan Limited 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
    14 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To primary objective of this trial was to evaluate the efficacy and safety of a single treatment of BOTOX compared with placebo in the treatment of adult poststroke lower limb spasticity involving the ankle plantar flexors.
    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
    23 May 2012
    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
    United States: 84
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    Czech Republic: 28
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Hungary: 47
    Country: Number of subjects enrolled
    Poland: 136
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Russian Federation: 53
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Worldwide total number of subjects
    468
    EEA total number of subjects
    246
    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)
    344
    From 65 to 84 years
    124
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients were screened up to 42 days prior to randomization on Day 1.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 botulinum toxin Type A
    Arm description
    		 Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BOTOX®
    Investigational medicinal product code
    Other name
    onabotulinumtoxinA, botulinum toxin Type A
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Arm title
    		 Normal Saline (Placebo) Followed by botulinum toxin Type A
    Arm description
    		 Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.
    Arm type
    		 Placebo followed by experimental

    Investigational medicinal product name
    Normal Saline (Placebo) Followed by botulinum toxin Type A
    Investigational medicinal product code
    Other name
    BOTOX®
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Number of subjects in period 1
    		botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Started
    233
    235
    Completed
    204
    209
    Not completed
    29
    26
         Adverse event, non-fatal
    9
    8
         Other Reasons
    5
    3
         Personal Reasons
    10
    11
         Lost to follow-up
    3
    3
         Protocol deviation
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    botulinum toxin Type A
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Reporting group title
    Normal Saline (Placebo) Followed by botulinum toxin Type A
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Reporting group values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A Total
    Number of subjects
    		 233 235 468
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 173 171 344
        From 65-84 years
    		 60 64 124
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 56 ( 12.6 ) 57 ( 11.88 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 85 80 165
        Male
    		 148 155 303

    End points

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    End points reporting groups
    Reporting group title
    botulinum toxin Type A
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Reporting group title
    Normal Saline (Placebo) Followed by botulinum toxin Type A
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles. Open Label Study Phase: Up to 3 treatments with botulinum toxin Type A up to 400 U will be given by intramuscular injections to the lower limb approximately every 12 weeks over a 42 week period.

    Primary: Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale

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    End point title
    		 Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Ankle Plantar Flexors Using a 6-Point Scale [1]
    End point description
    The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the ankle flexors by passively moving the ankle plantar flexor muscles through their range of motion. The score ranges from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. The average of the weeks 4 and 6 MAS-B ankle change from baseline is the primary end point. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening.
    End point type
    Primary
    End point timeframe
    Baseline, 6 Weeks
    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: The MAS-B change from baseline was analyzed by ANCOVA with treatment and study center as factors, and baseline ankle MAS-B (3 vs 4) and muscles injected (mandatory muscles only vs mandatory muscles plus toe muscles vs mandatory muscles plus rectus femoris) as covariates.
    End point values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Number of subjects analysed
    233
    235
    Units: Scores on a Scale
    least squares mean (standard deviation)
        Baseline
    4.1 ( 0.27 )
    4.1 ( 0.25 )
        Change from Baseline at 6 weeks
    -0.81 ( 0.874 )
    -0.61 ( 0.835 )
    No statistical analyses for this end point

    Secondary: Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale

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    End point title
    		 Clinical Global Impression (CGI) of Overall Change by Physician Using a 9-Point Scale
    End point description
    The CGI is a 9-point scale evaluating change from baseline status by the Physician. Scores range from +4 (very marked improvement) to -4 (very marked worsening). The average of the weeks 4 and 6 CGI by Physician score is used as a secondary end point. Higher scores indicate a greater improvement from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, 6 weeks
    End point values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Number of subjects analysed
    233
    235
    Units: Scores on a Scale
        least squares mean (standard deviation)
    0.86 ( 0.953 )
    0.65 ( 0.902 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Average Pain Score While Walking on the 11-Point Pain Scale

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    End point title
    		 Change from Baseline in Average Pain Score While Walking on the 11-Point Pain Scale
    End point description
    The patient is asked to select a number that best describes his/her pain while walking on an 11-point scale from 0 = “no pain” to 10 = “pain as bad as can be imagined”. Patients are instructed to recall their average pain in the study limb during the 48-hour period prior to the visit. Patients with a baseline pain score >0 are included in the analyses.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Number of subjects analysed
    180
    164
    Units: Scores on a Scale
    least squares mean (standard deviation)
        Baseline
    4.5 ( 1.95 )
    4.5 ( 2.13 )
        Change from Baseline at Week 6 (N=175, 158)
    -0.8 ( 2.3 )
    -1.1 ( 2.38 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale

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    End point title
    		 Change from Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of Optional Muscles Using a 6-Point Scale
    End point description
    The MAS-B is a 6-point scale used to evaluate spasticity based on grading the resistance encountered in the optional muscles by passively moving the muscles through their range of motion. Optional muscles treated include: Rectus Femoris, Flexor Digitorum Longus, Flexor Hallucis Longus, and Extensor Hallucis. The scores range from 0 (no increase in muscle tone) to 4 (affected part(s) rigid in flexion or extension). Scores are converted to a 0 to 5 grade. A negative number change from baseline indicates an improvement and a positive number change from baseline indicates a worsening.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6
    End point values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Number of subjects analysed
    143
    133
    Units: Scores on a Scale
    least squares mean (standard deviation)
        Baseline Rectus Femoris (N=25, 25)
    3.3 ( 0.58 )
    3.2 ( 0.59 )
        Chng from BL at Wk6 in Rectus Femoris (N=24,25)
    -0.9 ( 0.87 )
    -1 ( 1.14 )
        Baseline Flexor Digitorum Longus (N=86,88)
    3.3 ( 0.76 )
    3.4 ( 0.7 )
        Chng from BL at Wk6 in Digitorum Longus (N=85,84)
    -0.9 ( 1.11 )
    -0.8 ( 1.22 )
        Baseline Flexor Hallucis Longus (N=73,67)
    3.1 ( 0.81 )
    3.2 ( 0.83 )
        Chng frm BL at Wk6 Flexor Hallucis Longus(N=72,66)
    -1 ( 1.3 )
    -0.6 ( 1.2 )
        Baseline Extensor Hallucis (N=23,13)
    3.6 ( 0.49 )
    3.6 ( 0.51 )
        Chng from BL at Wk6 in Extensor Hallucis (N=23,13)
    -1.3 ( 1.22 )
    -1.3 ( 1.09 )
    No statistical analyses for this end point

    Secondary: Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS)

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    End point title
    		 Goal Attainment Scores on the 6-Point Physician-Assessed Goal Attainment Scale (GAS)
    End point description
    The physician-assessed GAS is an individualized, goal-oriented 6-point scale used to track functional improvement toward active and passive goals. GAS scoring ranged from −3 to 2 (−3 = worse than start; 0 = expected goal/attained the defined therapeutic goal; 2 = much more than expected/improvements clearly exceeded the defined therapeutic goal). Active and Passive Goal scores are presented.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 botulinum toxin Type A Normal Saline (Placebo) Followed by botulinum toxin Type A
    Number of subjects analysed
    233
    235
    Units: Scores on a Scale
    least squares mean (standard deviation)
        Active Goals (N=226, 228)
    -0.8 ( 1.34 )
    -1 ( 1.33 )
        Passive Goals (N=214, 217)
    -0.5 ( 1.42 )
    -0.8 ( 1.33 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were monitored from informed consent signature to the end of study for each subject.
    Adverse event reporting additional description
    The safety population during the 12-week double-blind phase included all enrolled patients who received at least 1 treatment injection in the study. The double-blind safety population is used to assess adverse events and serious adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    botulinum toxin Type A
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, botulinum toxin Type A 300 U will be given by intramuscular injections into specified muscles of the lower limb, and an optional dose of 100 U may be injected into additional lower limb muscles.

    Reporting group title
    Normal Saline (Placebo)
    Reporting group description
    		 Double-Blind Study Phase (12 weeks): On Day 1, normal saline (placebo) will be given by intramuscular injections into specified muscles of the lower limb, and optional injections may be administered into additional lower limb muscles.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious AEs that met the 5% reporting level.
    Serious adverse events
    		 botulinum toxin Type A Normal Saline (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 231 (4.33%)
    9 / 233 (3.86%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bullous lung disease
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal haemorrhage
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Barbiturates positive
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opiates positive
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bifascicular block
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 botulinum toxin Type A Normal Saline (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 233 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2012
    1) Patients with contralateral spasticity of clinical significance were excluded; 2) Physical therapy was limited to the study limb and only stated modalities were excluded; 3) An exclusion criterion was added to allow initiation of physical therapy or use of splints prior to randomization, but not afterwards; 4) An exclusion criterion was added to exclude patients with significant weakness in the contralateral leg; 5) An exclusion criterion was added to exclude any other surgeries that may have created scar tissues and could have confounded the efficacy results; 6) A requirement to the secondary efficacy measures was added that the distribution of baseline (randomization) MAS B ankle score throughout enrollment would be monitored to ensure that at least 75% of the enrolled patients had a baseline MAS B ankle score of 3; 7) The measure on MAS B for optional muscles and the Pain scale was changed from “other efficacy measure” to a secondary efficacy measure; 8) A requirement that GAS was to be rated both by the physician and patient was added; and 9) Collection of a BDI-II score at baseline was added.
    01 Aug 2012
    1) It was clarified that the BDI-II was to be administered at selected sites only.
    01 Jul 2013
    1) The C-SSRS assessment was specified to be performed at all visits; 2) An exclusion criterion was added to exclude patients with significant suicidality from treatment; 3) The CGI by Physician was added as a primary measure; 4) An imputation method was added for the primary efficacy variable; and 5) A subgroup analysis for the 400 U total dose group was added.
    01 Sep 2013
    1) Study center was added as a factor to the ANCOVA model for the primary and secondary efficacy analyses; 2) The sample size was revised; and 3) The imputation method was modified to use within-group means.

    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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