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    Clinical Trial Results:
    BOTOX® Treatment in Pediatric Lower Limb Spasticity: Open-label Study

    Summary
    EudraCT number
    2012-000084-24
    Trial protocol
    DE   PL   HU   IT  
    Global end of trial date
    25 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Mar 2019
    First version publication date
    13 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-112
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01603641
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan Ltd.
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@allergan.com
    Scientific contact
    Therapeutic Area Head, Allergan plc, 001 862-261-7000, clinicaltrials@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
    25 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the long-term safety of repeated doses of BOTOX® (botulinum toxin type A) for the treatment of paediatric lower limb spasticity.
    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
    05 Nov 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
    Poland: 133
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 93
    Country: Number of subjects enrolled
    United States: 81
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Thailand: 7
    Country: Number of subjects enrolled
    Philippines: 4
    Worldwide total number of subjects
    370
    EEA total number of subjects
    151
    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)
    313
    Adolescents (12-17 years)
    57
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Paediatric participants with lower limb spasticity who were previously treated with BOTOX® in study191622-111 [NCT01603628] and de novo participants received up to 5 BOTOX® treatments in this study.

    Pre-assignment period milestones
    Number of subjects started
    370
    Number of subjects completed
    367

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Did Not Receive Treatment: 3
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    BOTOX®
    Arm description
    Participants received maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into a single lower limb muscles or divided between both lower limb muscles or into the lower limb muscles and/or upper limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment not to exceed a maximum of 8 unit per kilogram (U/kg) of body weight (not to exceed 300 U) in treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 or 8 U/kg into the lower limb in the previous study or were de novo participants who were not enrolled in the previous study.
    Arm type
    Experimental

    Investigational medicinal product name
    BOTOX®
    Investigational medicinal product code
    Other name
    Botulinum Toxin Type A OnabotulinumtoxinA
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Participants received intramuscular injections of BOTOX® into the lower and/or upper limbs at a minimum of 12 weeks apart for a maximum of 5 treatments.

    Number of subjects in period 1 [1]
    BOTOX®
    Started
    367
    Modified Intent-to-treat Population
    366
    Completed
    335
    Not completed
    32
         Adverse Event
    1
         Personal Reasons
    18
         Lost to follow-up
    6
         Other Miscellaneous Reasons
    6
         Lack of efficacy
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics were available for safety population, which included all treated participants.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BOTOX®
    Reporting group description
    Participants received maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into a single lower limb muscles or divided between both lower limb muscles or into the lower limb muscles and/or upper limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment not to exceed a maximum of 8 unit per kilogram (U/kg) of body weight (not to exceed 300 U) in treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 or 8 U/kg into the lower limb in the previous study or were de novo participants who were not enrolled in the previous study.

    Reporting group values
    BOTOX® Total
    Number of subjects
    367 367
    Age categorical
    Units: Subjects
        2 - 11 years
    311 311
        12 - 17 years
    56 56
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    6.9 ± 3.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    167 167
        Male
    200 200
    Race/Ethnicity, Customized
    Units: Subjects
        White
    224 224
        Black
    9 9
        Asian
    109 109
        Hispanic
    21 21
        Other
    4 4

    End points

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    End points reporting groups
    Reporting group title
    BOTOX®
    Reporting group description
    Participants received maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into a single lower limb muscles or divided between both lower limb muscles or into the lower limb muscles and/or upper limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment not to exceed a maximum of 8 unit per kilogram (U/kg) of body weight (not to exceed 300 U) in treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 or 8 U/kg into the lower limb in the previous study or were de novo participants who were not enrolled in the previous study.

    Primary: Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE)

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    End point title
    Percentage of Participants with at Least One Treatment-emergent Adverse Event (TEAE) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE was an AE that occurred after receiving the first dose of investigational product or an AE present prior to first dose but increased in severity during the Treatment Period. Safety population included all treated participants.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 12 weeks post last dose (Up to 60 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: Statistical analysis was not planned for this endpoint.
    End point values
    BOTOX®
    Number of subjects analysed
    367
    Units: percentage of participants
        number (not applicable)
    65.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 12 weeks post last dose (Up to 60 weeks)
    Adverse event reporting additional description
    Safety Population included all treated participants.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    BOTOX®
    Reporting group description
    Participants received maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into a single lower limb muscles or divided between both lower limb muscles or into the lower limb muscles and/or upper limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment not to exceed a maximum of 8 unit per kilogram (U/kg) of body weight (not to exceed 300 U) in treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 4 or 8 U/kg into the lower limb in the previous study or were de novo participants who were not enrolled in the previous study.

    Serious adverse events
    BOTOX®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 367 (6.54%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cancer
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hemiplegia
         subjects affected / exposed
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Entropion
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Strabismus
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 367 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 367 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 367 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BOTOX®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 367 (39.51%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    27 / 367 (7.36%)
         occurrences all number
    40
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    67 / 367 (18.26%)
         occurrences all number
    135
    Nasopharyngitis
         subjects affected / exposed
    65 / 367 (17.71%)
         occurrences all number
    101
    Bronchitis
         subjects affected / exposed
    21 / 367 (5.72%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2012
    •Revised the pronator teres dose from 2 U/kg to 1.5 U/kg and the number of sites from 2 to 1 •Revised approximate volume of blood collection for hematology and chemistry laboratory assessments from 5 millilitres (mL) to 7 mL (participants weighing < 15 kg) and from 12 to 14 mL (participants weighing ≥ 15 kg) to meet revised central laboratory requirements.
    28 Nov 2012
    •Added language for diplegic participants, allowing injection of a dose up to 10 U/kg and not to exceed 340 U during Treatment Cycles 2 to 5 when both lower limbs were treated •Changed designation of visit for Exclusion Criterion 23 regarding history of fracture in the study upper limb within 12 months from “prior to the screening visit” to “prior to the Day 1 visit,” for consistency with other criteria •For Treatment Cycle 1 for de novo participants, clarified that 8 U/kg was to be injected either in the single study lower limb or divided between both study lower limbs only for diplegic participants; for Treatment Cycles 2 through 5 for all participants, clarified the description of dose limitations • Clarified that participants who met the retreatment criteria “may be reinjected” rather than “should be reinjected” •Clarified language regarding retreatment visits, including determination of whether the dose was clinically appropriate or dose reduction relative to the last injection received was required •Added for Modified Tardieu Scale (MTS) that it should be done with knee extended • For de novo participants, revised to specify Modified Ashworth Scale – Bohannon (MAS-B) was to be done in the ankle of the study limb(s) only (deleted the knee) •Added MAS-B for knee flexors and any other muscles in the treatment plan •Deleted Edinburgh Visual Gait (EVG) score at subsequent Treatment/Retreatment Visit •At Early Discontinuation, corrected “Study Week 42” to “Study Week 48” •Revised language to allow therapists to perform MAS-B.
    28 Jan 2014
    •Specified that Columbia-Suicide Severity Rating Scale (C-SSRS) was to be performed as a safety measure for participants ≥ 6 years of age at Day 1, and provided description of scale, data handling, and reference information. Request from US Food and Drug Administration (FDA) •Added a +14-day window to Study Week 48 visit •Modified Exclusion Criterion 13a regarding seizure frequency for exclusion •Modified Exclusion Criterion 14 regarding vulnerable respiratory state •Added Exclusion Criterion 29 to exclude participants with significant suicidality from treatment •Added collection of patient-reported benefit of injection •Clarified that anti-epileptics were permissible during the study •Amended retreatment criteria to specify that participants who experienced certain adverse events, including compromised respiratory function, aspiration, difficulty swallowing, or clinically significant excessive salivation, would not receive further study treatments •Removed requirement of true equinus foot deformity •Updated serious adverse event (SAE) language •Clarified that physician investigator, not investigator, was to conduct Clinical Global Impression of Overall Change (CGI) by Physician.

    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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