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    Clinical Trial Results:
    Measuring effects on pain and quality of life after Dysport® injection in children with cerebral palsy

    Summary
    EudraCT number
    		 2017-004497-33
    Trial protocol
    		 DK  
    Global end of trial date
    31 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jan 2023
    First version publication date
    20 Jan 2023
    Other versions
    Summary report(s)
    		 article

    Trial information

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    Trial identification
    Sponsor protocol code
    Protocol_Dysport_v3__13.12.2017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    hvidovre hospital
    Sponsor organisation address
    keettegaards alle 30, hvidovre, Denmark,
    Public contact
    Christian Wong, Copenhagen University Hospital at Hvidovre, 0045 38626966, cwon0002@regionh.dk
    Scientific contact
    Christian Wong, Copenhagen University Hospital at Hvidovre, 0045 38626966, cwon0002@regionh.dk
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine the effect of botulinum toxin injections in regards to pain and quality of life in children with cerebral Palsy
    Protection of trial subjects
    following rules of the EC
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    15
    Adolescents (12-17 years)
    10
    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
    		 The subjects were paediatric patients with predominantly spastic CP and belonged to all gross motor function classification system (GMFCS) levels. They were recruited from our hospital service area as a convenience sample. Inclusion criteria were children between two and eighteen years of age with spastic cerebral palsy who were botulinum toxin naï

    Pre-assignment
    Screening details
    		 Children with CP in our general service area were screened for eligibility. Fifty-one of them had pain and were contacted through their caregivers for inclusion after a formal invitation by letter. After caregivers accepted participation, their medical records were screened according to the inclusion and exclusion criteria. If still eligible, the p

    Period 1
    Period 1 title
    Inclusion (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No bilinding

    Arms
    Arm title
    		 followup
    Arm description
    		 Followup to 28 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dysport
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution and suspension for suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    A single ultrasound-guided intramuscular injection of AboA was administered without or under general anaesthesia by the discretion of the treating physician. Dosing was determined by the treating physician using 30 units per kilo (U/kg) and 15 U/kg for bilateral and unilateral CP, respectively, with a maximum dose of 1000 units. Small and large muscles were injected within a range of 3–6 U/kg and 8–12 U/kg, respectively. Small muscles were defined as an ultrasound-measured muscle thickness of a ‘diameter’ of less than 0.95 cm at the injection site and large muscles were defined as having a ‘diameter’ larger than 0.95 cm at the injection site [26,27]. Five hundred units of AboA were diluted in 2.5 mL of sterile NaCl in sterile syringes.

    Number of subjects in period 1
    		followup
    Started
    25
    Completed
    25

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    followup
    Reporting group description
    		 Followup to 28 weeks

    Subject analysis set title
    rflacc score
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    2.3. Assessments The subjects were assessed with observational pain, questionnaires pertaining to pain, function, and quality of life at baseline before injection and after 4, 12, and 28 weeks. Our primary endpoint was the change in pain status from baseline to the initial follow up at four weeks since AboA is considered to have an optimal effect at this time [14]. The subjects were monitored continuously for adverse effects as well as changes in medication or therapeutic interventions. 2.4. Pain Tools The observational pain tools of the Paediatric pain profile (PPP) and r-FLACC were utilized to captivate different aspects of localized pain. A systematic pain interview was carried out by a single rater. 2.4.1. Localized Muscular Pain Using the Revised Face, Legs Activity, Cry, Consolability Scale Initial clinical evaluation entailed pROM of all muscles of the lower extremity to identify potential localized muscular pain using the r-FLACC. The r-FLACC scale is a validated behaviou

    Primary: rflacc score

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    End point title
    		 rflacc score
    End point description
    Localized Muscular Pain Using the Revised Face, Legs Activity, Cry, Consolability Scale Initial clinical evaluation entailed pROM of all muscles of the lower extremity to identify potential localized muscular pain using the r-FLACC. The r-FLACC scale is a validated behavioural pain intensity tool with five categories with a three-point ordinal scale (0–2), thus ranging from 0 to 10 possible points. Each category entails a description of behavioural signs in the facial expression, legs, activity, cry and consolability [28]. The r-FLACC scores were evaluated during the examination and were videotaped systematically using two iPads, thus enabling us to re-evaluate the subject in the frontal and sagittal view [29]. The caregivers added a unique descriptive ‘pain’ behaviour of the child to ensure that our ratings were individual and accurate. The localized pain was evaluated for the treated muscles during the follow ups. Since injections of AboA are presumed to have a localized effect, ou
    End point type
    Primary
    End point timeframe
    after 6 weeks
    End point values
    		 followup rflacc score
    Number of subjects analysed
    25 [1]
    25 [2]
    Units: rflacc score
    number (not applicable)
        rflacc
    25
    25
    Notes
    [1] - all analyzed
    [2] - all analyzed
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    he overall comparisons were between the data at baseline and follow-ups. Shapiro–Wilk for normality was utilized to determine normal distribution. Data from r-FLACC, PPP, and CPCHILD scores were continuous variables and analysed using the paired t-test. Ordinal variables such as impact on activity and SMART goals were not normally distributed and analysed using the Wilcoxon signed-rank test. p-values of ≤0.05 were considered statistically significant. Bonferroni corrections were applied to the r
    Comparison groups
    followup v rflacc score
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 ≥ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2
    Notes
    [3] - he overall comparisons were between the data at baseline and follow-ups. Shapiro–Wilk for normality was utilized to determine normal distribution. Data from r-FLACC, PPP, and CPCHILD scores were continuous variables and analysed using the paired t-test. Ordinal variables such as impact on activity and SMART goals were not normally distributed and analysed using the Wilcoxon signed-rank test. p-values of ≤0.05 were considered statistically significant. Bonferroni corrections were applied

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from 2018 to september 2021
    Adverse event reporting additional description
    Eleven subjects experienced adverse events during the study. In total, there were sixteen adverse events. The majority were related (12). These were temporary mild (5) and moderate (1) muscle weakness, mild nausea (2), and mild soreness/local bruising (2) at the injection site. Two had moderate pain (2) at the injection site that subsided within th
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 overnight stay
    Dictionary version
    1
    Reporting groups
    Reporting group title
    total number
    Reporting group description
    		 Eleven subjects experienced adverse events during the study. In total, there were sixteen adverse events. The majority were related (12). These were temporary mild (5) and moderate (1) muscle weakness, mild nausea (2), and mild soreness/local bruising (2) at the injection site. Two had moderate pain (2) at the injection site that subsided within the first week. An additional three caregivers reported unrelated adverse events with weight gain (1), mild dyspnoea (1), and mild diarrhoea (1) during the study. At the study initiation, one subject (1) had an uneventful admission overnight since the ultrasound-guided injection of AboA was delivered close to an intramuscular vessel. This was classified as a serious adverse event. There was otherwise no expected or unexpected serious adverse events or reactions.

    Serious adverse events
    		 total number
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    admission overnight
    Additional description: At the study initiation, one subject (1) had an uneventful admission overnight since the ultrasound-guided injection of AboA was delivered close to an intramuscular vessel. This was classified as a serious adverse event.
         subjects affected / exposed
    1 / 25 (4.00%)
         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
    		 total number
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 25 (60.00%)
    Product issues
    as described
    Additional description: temporary mild (5) and moderate (1) muscle weakness, mild nausea (2), and mild soreness/local bruising (2) at the injection site. Two had moderate pain (2) at the injection site that subsided within the first week.
         subjects affected / exposed [1]
    15 / 15 (100.00%)
         occurrences all number
    15
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Eleven subjects experienced adverse events during the study. In total, there were sixteen adverse events. The majority were related (12). These were temporary mild (5) and moderate (1) muscle weakness, mild nausea (2), and mild soreness/local bruising (2) at the injection site. Two had moderate pain (2) at the injection site that subsided within the first week. An additional three caregivers reported unrelated adverse events with weight gain (1), mild dyspnoea (1), and mild diarrhoea (1) during

    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/35051020
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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