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    Clinical Trial Results:
    Post-operative pain in children with cerebral palsy following major hip surgery: a double blind randomised placebo controlled trial of pre-operative Botulinum toxin type A. [The Post-Operative Pain in cerebral Palsy (POPPIES) trial]

    Summary
    EudraCT number
    2010-023240-33
    Trial protocol
    GB  
    Global end of trial date
    07 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Aug 2019
    First version publication date
    04 Aug 2019
    Other versions
    Summary report(s)
    FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    POPPIES
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01437644
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Guy's and St Thomas' NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE19RT
    Public contact
    Dr Fabian Norman-Taylor, Guy's and St Thomas' NHS Foundation Trust, 0044 020 7188 4658, fabian.norman-taylor@gstt.nhs.uk
    Scientific contact
    Dr Fabian Norman-Taylor, Guy's and St Thomas' NHS Foundation Trust, 0044 020 7188 4658, fabian.norman-taylor@gstt.nhs.uk
    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
    07 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the benefit to children with cerebral palsy of having botulinum toxin injections prior to major hip surgery, in order to reduce their post-operative pain. To describe the pain experience of children with cerebral palsy undergoing major hip surgery.
    Protection of trial subjects
    A single dose of active drug or placebo was administered immediately prior to surgery. The injections were given to the anaesthetised child before the surgical procedure began.
    Background therapy
    None
    Evidence for comparator
    None
    Actual start date of recruitment
    21 Sep 2011
    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
    United Kingdom: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    26
    Adolescents (12-17 years)
    28
    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
    Participants were recruited from one clinical paediatric hospital in London between 2011 and 2015

    Pre-assignment
    Screening details
    Inclusion Criteria 1. The child has displaced hips requiring bony orthopaedic surgery (osteotomy) due to cerebral palsy 2. Is between the ages of 2 and 15 years (inclusive). 3. Has a GMFCS level of IV or V 4. Has a diagnosis of hypertonic cerebral palsy (or a diagnosis consistent with this nomenclature) 5. Does not communicate verbally

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer
    Blinding implementation details
    The surgeon or physician will administer medication in syringes containing the trial drug which he is unable to identify as active drug or placebo. The trial drug will be drawn up in six identical syringes for administration to the six muscle groups targeted with either 2 units per kilogram of Botulinum Toxin A or an equivalent volume of normal saline.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ACTIVE
    Arm description
    Injections of Botulinum neurotoxin A were given by the surgeon under ultrasound guidance into the adductor muscles, medial hamstrings and iliopsoas muscles on both sides, after the patient was (including anaesthetised on the day of surgery
    Arm type
    Experimental

    Investigational medicinal product name
    Botox®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    2 administration and units of Botox® per kilogram c at each site, up to a total of 50 units each site, and a total maximum of 300 units per child. Administered by the surgeon under ultrasound guidance into the adductor muscles, medial hamstrings and iliopsoas muscles on both sides, after the patient was anaesthetised on the day of surgery.

    Arm title
    PLACEBO
    Arm description
    Injections of normal saline were given by the surgeon under ultrasound guidance into the adductor muscles, medial hamstrings and iliopsoas muscles on both sides, after the patient was (including anaesthetised on the day of surgery
    Arm type
    Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The volume of saline to be prepared per syringe is decided by referring to the study dosing chart and checking the volume related to the child’s weight. This chart will be available to the pharmacist, study nurse and anaesthetist to double check in each case.

    Number of subjects in period 1
    ACTIVE PLACEBO
    Started
    27
    27
    Completed
    24
    26
    Not completed
    3
    1
         Adverse event, serious fatal
    -
    1
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    54 54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
        <7 years
    26 26
        > 7 years
    28 28
    Gender categorical
    Units: Subjects
        Female
    23 23
        Male
    31 31

    End points

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    End points reporting groups
    Reporting group title
    ACTIVE
    Reporting group description
    Injections of Botulinum neurotoxin A were given by the surgeon under ultrasound guidance into the adductor muscles, medial hamstrings and iliopsoas muscles on both sides, after the patient was (including anaesthetised on the day of surgery

    Reporting group title
    PLACEBO
    Reporting group description
    Injections of normal saline were given by the surgeon under ultrasound guidance into the adductor muscles, medial hamstrings and iliopsoas muscles on both sides, after the patient was (including anaesthetised on the day of surgery

    Primary: Post-operative pain score using a validated numerical system (PPP).

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    End point title
    Post-operative pain score using a validated numerical system (PPP). [1]
    End point description
    The primary endpoint is the change in pain score during the six weeks following the operation. Pain will be measured using a validated questionnaire, the Paediatric Pain Profile. This scores pain by rating twenty different items of observed behaviour on an ordinal scale of 0 to 3 with a composite score of 0 to 60. It has been validated in children with severe cerebral palsy
    End point type
    Primary
    End point timeframe
    Until six weeks post operation.
    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: Please see attached document for full results.
    End point values
    ACTIVE PLACEBO
    Number of subjects analysed
    24
    27
    Units: whole
    24
    27
    Attachments
    Results
    No statistical analyses for this end point

    Secondary: Secondary

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    End point title
    Secondary
    End point description
    Secondary endpoints The following assessments will be made pre-operatively, at 6 weeks, at 3 months and at 6 months post-surgery: • Clinical examination of the hips with measurement of ranges of movement • X-ray measurement of hip displacement using the Migration Index (%), and dysplasia using the Acetabular Index (degrees). • Quality of life using the CP-CHILD questionnaire The following secondary endpoints will also be recorded: • Immediate post-operative pain measured each day while in hospital by a simple parent (or carer) visual analogue scale (and continued weekly at home by the parents or carers for the first six weeks post-operatively with the help of the weekly telephone call). • Drugs prescribed and given on the ward (from the drug chart). • Length of hospital stay in days • Estimated analgesia requirement by recall of analgesia use in the 24 hours prior to each weekly pain assessment during the weekly telephone call.
    End point type
    Secondary
    End point timeframe
    Until 6 weeks post operation.
    End point values
    ACTIVE PLACEBO
    Number of subjects analysed
    27
    27
    Units: whole
    27
    27
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    0 to six months post operation.
    Adverse event reporting additional description
    Ongoing assessment during inpatient stay then follow up as out patient
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    BTX-A
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    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 302 adverse events in total (n=156 inBoNT-A group). Of these, none were related to the trial drug, and 219 were unremarkable postoperative findings.There was no evidence of a relationship between trial arm and intensity of adverse events (v2=0.83,p=0.66).
    Serious adverse events
    BTX-A Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 27 (22.22%)
    10 / 27 (37.04%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Surgical and medical procedures
    Hospitalisation - Chest Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical replacement of loose screw in hip
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical repair of bony protrusion in hip joint
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testes exploration -- de-torsion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar Pontine Giloma
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension & Hypoxia during surgery
    Additional description: Hip surgery abandoned post administration of anaesthesia and IMP due to hypoxia and hypotension.
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hospitalisation - due to constipation
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation - due to vomiting & dehydration
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture Left arm
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Wound Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospital admission - Pyrexia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prolonged Hospitalisation - Urinary Tract Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    BTX-A Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 27 (0.00%)

    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/30644541
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