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

    Summary
    EudraCT number
    2012-000043-27
    Trial protocol
    DE   PL   HU   IT  
    Global end of trial date
    03 Sep 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    191622-105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01603615
    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, 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
    03 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 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 upper 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
    30 Oct 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: 75
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    United States: 58
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Turkey: 2
    Worldwide total number of subjects
    220
    EEA total number of subjects
    83
    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)
    165
    Adolescents (12-17 years)
    55
    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 Upper Limb Spasticity who were previously treated with BOTOX® in study 191622-101 [NCT01603602] and de novo participants received up to 5 BOTOX® treatments in this study.

    Pre-assignment period milestones
    Number of subjects started
    220
    Number of subjects completed
    213

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Did Not Receive Treatment: 7
    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 a maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into upper limb and/or lower limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment, de novo participants received at least 6 U/kg of body weight or a maximum of 8 U/kg of body weight (not to exceed 300 U). Rollover participants received up to a maximum of 8 U/kg of body weight (not to exceed 300 U) for treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Rolled over participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 or 6 U/kg into upper limb in previous study or were de novo participants who were not enrolled in 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 upper and/or lower limb at a minimum of 12 weeks apart for a maximum of 5 treatments.

    Number of subjects in period 1 [1]
    BOTOX®
    Started
    213
    Completed
    186
    Not completed
    27
         Personal Reasons
    17
         Lost to follow-up
    9
         Other Miscellaneous Reasons
    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 a maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into upper limb and/or lower limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment, de novo participants received at least 6 U/kg of body weight or a maximum of 8 U/kg of body weight (not to exceed 300 U). Rollover participants received up to a maximum of 8 U/kg of body weight (not to exceed 300 U) for treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Rolled over participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 or 6 U/kg into upper limb in previous study or were de novo participants who were not enrolled in previous study.

    Reporting group values
    BOTOX® Total
    Number of subjects
    213 213
    Age categorical
    Units: Subjects
        2 - 11 years
    159 159
        12 - 17 years
    54 54
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    8.3 ( 4.1 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    85 85
        Male
    128 128
    Race/Ethnicity, Customized
    Units: Subjects
        White
    130 130
        Black
    9 9
        Asian
    61 61
        Hispanic
    10 10
        Other
    3 3

    End points

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    End points reporting groups
    Reporting group title
    BOTOX®
    Reporting group description
    Participants received a maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into upper limb and/or lower limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment, de novo participants received at least 6 U/kg of body weight or a maximum of 8 U/kg of body weight (not to exceed 300 U). Rollover participants received up to a maximum of 8 U/kg of body weight (not to exceed 300 U) for treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Rolled over participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 or 6 U/kg into upper limb in previous study or were de novo participants who were not enrolled in 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
    213
    Units: percentage of participants
        number (not applicable)
    58.7
    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
    19.0
    Reporting groups
    Reporting group title
    BOTOX®
    Reporting group description
    Participants received a maximum of 5 treatments of intramuscular injections of BOTOX® (botulinum toxin Type A) into upper limb and/or lower limb muscles at a minimum of 12 weeks apart. Treatment dosing was according to investigator judgment, de novo participants received at least 6 U/kg of body weight or a maximum of 8 U/kg of body weight (not to exceed 300 U). Rollover participants received up to a maximum of 8 U/kg of body weight (not to exceed 300 U) for treatment Cycle 1. Dose could be increased to a maximum of 10 U/kg (not to exceed 340 U) in treatment Cycles 2-5. Rolled over participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 or 6 U/kg into upper limb in previous study or were de novo participants who were not enrolled in previous study.

    Serious adverse events
    BOTOX®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 213 (6.10%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint contracture
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Juvenile idiopathic arthritis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
         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
    57 / 213 (26.76%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 213 (6.10%)
         occurrences all number
    14
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 213 (13.62%)
         occurrences all number
    38
    Nasopharyngitis
         subjects affected / exposed
    22 / 213 (10.33%)
         occurrences all number
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2012
    •Revised to clarify the ideal order of Clinical Global Impression of Overall Change (CGI) and spasticity assessments •Revised the heading from “(2 to 4 Weeks Before Study Day 1)” to “(Up to 4 Weeks Before Study Day 1)” in order to match the schedule of events •Revised approximate volume of blood collection for haematology and chemistry from 5 to 7 mL based on the revised central laboratory requirements.
    07 Dec 2012
    •Added language for triplegic participants, to allow dose up to 10 U/kg and not to exceed 340 U to be injected during treatment cycles 2 to 5 when only both lower limbs were treated •Changed exclusion criteria 21 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 •Added to the wording that requires a participant to remain on a stable dose of antispastic medications: to the extent possible unless judged by the investigator to be clinically inappropriate for clarification in Prohibited Medications/Treatments •Added at the study Day 1 visit for both de novo and rollover, the site accessed the IVRS/IWRS to enroll the participant in Method of assignment •The wordings were revised in Treatment Regimen and Dosing to “If a participant met the retreatment criteria, including no indication of an unacceptable safety risk, and it was considered to be clinically appropriate by the investigator, the participant should receive at least 6 U/kg in the study upper limb every 12 to 14 weeks, with the total dose not to exceed the maximum specified for each treatment cycle •Clarified title (Maximum Per-muscle, Per-limb, and Total Body Dose), added row for total maximum dose for both lower limbs, and added footnote to indicate that only 1 upper limb is to be injected •Added For purposes of dose calculation, the participants weight would be rounded to the nearest whole kilogram •Revised to “Participants should may be retreated” if they met the retreatment criteria •Added that study Day 1 is treatment 1/ day 1 for participants who received treatment on that day •Added obtaining study medication kit numbers from and entering exit status to the IVRS/IWRS •Passive range of motion was performed as part of the Modified Tardieu Scale (MTS) and therefore did not need to be identified as a separate procedure.
    07 Dec 2012
    •For de novo participants revised to specify (Modified Ashworth Scale-Bohannon) MAS-B was to be done on the elbow and wrist of the study limb •Revised study week 42 to study week 48 in “Early Discontinuation of Patients” section •Added that participants will be withdrawn from the study if they develop a medically significant hypersensitivity reaction to the study drug such as angioedema or anaphylaxis, or if a participant becomes pregnant during the study •Added the same investigator should perform this measure at each visit, if possible in section 12.1.10 MAS for consistency across evaluation •Deleted description of how to measure R1 and R2 in section 12.1.11 MTS.
    01 Aug 2016
    •Specified that the Columbia-Suicide Severity Rating Scale (C-SSRS) is 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 as requested by the United States Food and Drug Administration’s (US FDA's) Division of Neurology Products •Added a +14-day window to study week 48 visit •Modified Exclusion Criterion 11a regarding seizure frequency for exclusion •Modified Exclusion Criterion 12 regarding vulnerable respiratory state •Added Exclusion Criterion 27 to exclude participants with significant suicidality from treatment •Added patient-reported benefit of injection •Added a sentence on use of anti-epileptics •Amended retreatment criteria to specify that participants who experience certain adverse events will not receive further study treatments •Revised paragraph regarding retreatment for participant with adverse events of compromised respiratory function, aspiration, difficulty swallowing, or clinically significant excessive salivation •Clarified that passive range of motion can be performed during the MTS •Clarified to remove time frame for blood sample collection •Clarified regarding patient not receiving treatment or retreatment •Clarification on requirements for weight measurements and that weight must be measured in kilograms •Added “temporal, rectal” to body temperature •Revised MAS-B description to say “study specified” instead of “non-study-specified” velocity and provided detail on scoring to clarify that we do instruct the sites on a specific velocity for MAS-B assessment •Clarified “investigator” to “physician investigator."

    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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