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    Clinical Trial Results:
    Is it clinically effective to treat arm flexor spasticity, with Botulinum toxin – type A (BoNTA) and physiotherapy, as soon as signs of abnormal muscle activity are observed?

    Summary
    EudraCT number
    		 2010-021257-39
    Trial protocol
    		 GB  
    Global end of trial date
    28 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Apr 2016
    First version publication date
    02 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PB-PG-0808-16319
    Additional study identifiers
    ISRCTN number
    		 ISRCTN57435427
    US NCT number
    		 NCT01882556
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Research Ethics Committee Reference: 10/H1003/111
    Sponsors
    Sponsor organisation name
    Sandwell and West Birmingham Hospitals NHS Trust
    Sponsor organisation address
    City Hospital, Dudley Road, Birmingham, United Kingdom, B18 7QH
    Public contact
    Dr Jocelyn Bell, Sandwell and West Birmingham Hospitals NHS Trust, 0121 507 4811 , jocelyn.bell@nhs.net
    Scientific contact
    Dr Jocelyn Bell, Sandwell and West Birmingham Hospitals NHS Trust, 0121 507 4811 , jocelyn.bell@nhs.net
    Sponsor organisation name
    Keele University
    Sponsor organisation address
    Keele University, Keele, United Kingdom, ST5 5BG
    Public contact
    Professor Anand Pandyan, Keele University, 01782 734252, a.d.pandyan@keele.ac.uk
    Scientific contact
    Professor Anand Pandyan, Keele University, 01782 734252, a.d.pandyan@keele.ac.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
    28 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to establish whether treating spasticity using a combination of BoNTA and standardised physiotherapy, as soon as signs of abnormal muscle activity are observed is more effective in facilitating the recovery of arm function following stroke than standardised physiotherapy alone by evaluating the clinical effects of BOTOX® and Physiotherapy when compared against placebo and Physiotherapy, in patients with focal spasticity post-stroke, identified on clinical and neurophysiological grounds, in facilitating the recovery of arm function (measured using the Action Research Arm Test). NB: The scores range from 0 (no arm function) to 57 (good arm function) and an improvement of 6 in this scale is considered a clinically important.
    Protection of trial subjects
    Patients who have had a stroke are often clinically unwell and may also have communication problems making obtaining informed consent difficult. The approach used was to obtain consent from the patient directly whenever possible. However, where they were deemed unable to provide informed consent, their legal representative or next of kin was asked to provide consent and the patient's cooperation with the procedures taken as assent to participation in the trial. Where third party consent was not available or the patient actively resisted the procedure then the intervention did not proceed and the patient did not participate in the study. It was vital to optimise the selection of patients with high tone who might benefit from treatment.We were concerned that reliance on clinical detection of high tone is very unreliable. We therefore utilised an additional method (surface EMG) , to identify patients with early spasticity who might benefit from treatment if there was a positive effect. Botulinum toxin is a powerful agent but enjoys a relatively low side-effect profile. Risks of side effects were minimised by use of the smallest known effective dose in the setting of upper limb spasticity and injections were given only by clinicians highly experienced in botulinum injection technique.
    Background therapy
    		 To prevent secondary complications the treatment ensured that the joint was not held in a shortened position for prolonged periods of time. Joints were also mobilised through full range as often as possible using electrical stimulation as this was the easiest to apply and most cost effective to use. Treatment could be carried out independently by the patients themselves and/or their carers and the devices could be used at home. A secondary benefit of electrical stimulation was its potential to prevent atrophy and hence reduce the rate at which secondary complications set in. The exercise protocol involved cyclical stimulation to the wrist and elbow. Although unlikely, treatment with electrical stimulation may contribute to a transient reduction in spasticity but this was accounted for in the study design. Recovery of function is associated with the return of strength and is normally facilitated by functionally relevant therapy. In current practice rehabilitation therapy incorporates functionally relevant exercises when a patient has sufficient strength to participate. In order to reflect this progression in a systematic way for the purpose of this study all patients who achieved an MRC grade of 2 (i.e. movement through full range with mass of limb supported) carried out functionally relevant tasks (e.g. pick and place objects of varying sizes).
    Evidence for comparator
    		 In this trial half the participants receive the active agent botulinum and half received saline injections instead. The use of a placebo with neither the patient or the injecting clinician knowing whether active drug or saline is being administered was justified because there is a state of clinical equipoise with respect to our knowledge of this treatment. We know that botulinum has powerful effects on muscle tone and can be useful in established spasticity but we do not know if it is clinically useful or not when given early on in the course of rehabilitaion. There are good theoretical reasons to believe that it may be helpful when given in this way. The only ethical course of action was to seek to scientifically answer the question "Is the use of botulinum toxin in this way genuinely helpful to patients." Since no one knows the answer to that question, patients who do not receive the active agent are not being deprived of treatment they would benefit from. Likewise patients receiving the agent were not being given something that would be harmful. Advice was taken from a patient group formed to specifically advise us on these issues. This approach has also been used in previous protocols of trials with botulinum and other agents in the management of stroke.
    Actual start date of recruitment
    30 Jan 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 Kingdom: 93
    Worldwide total number of subjects
    93
    EEA total number of subjects
    93
    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)
    32
    From 65 to 84 years
    47
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial recruited between January 2012 and December 2013 in the UK only. Subjects were recruited from clinical case loads. Subjects were consented, enrolled and screened in the first instance and then monitored until confirmed as eligible for randomisation. Eligible patients were then randomised.

    Pre-assignment
    Screening details
    		 1143 patients were admitted during the trial period, 345 patients fulfilled the criteria of no arm function. 120 consented in to the trial and subsequently screened for eligibility. Of the subsequent 100 patients found to be eligible, 97 progressed from screening to randomisation and 93 patients received treatment and were included in analysis.

    Pre-assignment period milestones
    Number of subjects started
    		 120 [1]
    Number of subjects completed
    		 93

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Recovered function, developed spasticity: 16
    Reason: Number of subjects
    		 Adverse event, serious fatal: 1
    Reason: Number of subjects
    		 Refused injection: 3
    Reason: Number of subjects
    		 Developed no spasticity, recovered no arm function: 3
    Reason: Number of subjects
    		 Adverse event, non-fatal: 3
    Reason: Number of subjects
    		 Protocol deviation: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 120 patients consented in to the trial and subsequently screened for eligibility. Of the subsequent 100 patients found to be eligible, 93 patients progressed to treatment and were considered enrolled in the trial.
    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Research Pharmacist was responsible for randomisation using sealed envelopes held securely in Pharmacy. The dispensed drug was taken to the ward in a sealed opaque bag where an independent clinician filled the syringes according to the randomisation. Separate sharps bins were used for preparation/reconstitution and injecting. Placebo and active injection appeared indistinguishable in the syringe and the injecting clinician and patient remained blind to treatment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMP (treatment)
    Arm description
    		 OnabotulinumtoxinA + CDP (Clearly Defined Physiotherapy)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Onabotulinumtoxin
    Investigational medicinal product code
    PR1
    Other name
    Botox purified neurotoxin complex, BoNTA, botulinum toxin, Botox
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Maximum dose allowed was 200 Botox units in total, as follows; Biceps 50units, Brachialis 50units; Flexor Digitorum Profundus 30units; Flexor Digitorum Superficialis 30units; Flexor Carpi Radialis 20units; Flexor Carpi Ulnaris 20units. Patients received between 4 and 6 injections, with the exact dosage and number of injection sites tailored to the individual based on: size, number and location of muscles involved; severity of spasticity; presence of local muscle weakness. Reconstituted BOTOX® and placebo was injected using a sterile 25-, 27-, or 30-gauge needle for superficial muscles. Localisation of the involved muscles was be determined clinically by superficialanatomical landmarks and using electrical stimulation techniques. Where localisation of the muscles proved to be difficult using surface anatomy and EMG, ultrasound was used to guide the injection procedure and check accuracy of placement of the needle.

    Arm title
    		 Placebo
    Arm description
    		 Placebo + CDP (Clearly Defined Physiotherapy)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    0.9% Sodium Chloride Solution for injection. Patients received between 4 and 6 injections, with the exact dosage and number of injection sites tailored to the individual based on: size, number and location of muscles involved; severity of spasticity; presence of local muscle weakness. Maximum dose allowed was 200 Botox units in total, as follows; Biceps 50units, Brachialis 50units; Flexor Digitorum Profundus 30units; Flexor Digitorum Superficialis 30units; Flexor Carpi Radialis 20units; Flexor Carpi Ulnaris 20units. Reconstituted BOTOX® and placebo was injected using a sterile 25-, 27-, or 30-gauge needle for superficial muscles. Localisation of the involved muscles was be determined clinically by superficialanatomical landmarks and using electrical stimulation techniques. Where localisation of the muscles proved to be difficult using surface anatomy and EMG, ultrasound was used to guide the injection procedure and check accuracy of needle placement.

    Number of subjects in period 1
    		IMP (treatment) Placebo
    Started
    45
    48
    Completed
    45
    48
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All individuals remained blind during the follow-up period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IMP (treatment)
    Arm description
    		 OnabotulinumtoxinA + CDP (Clearly Defined Physiotherapy)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Onabotulinumtoxin
    Investigational medicinal product code
    PR1
    Other name
    Botox purified neurotoxin complex, BoNTA, botulinum toxin, Botox
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    Maximum dose allowed was 200 Botox units in total, as follows; Biceps 50units, Brachialis 50units; Flexor Digitorum Profundus 30units; Flexor Digitorum Superficialis 30units; Flexor Carpi Radialis 20units; Flexor Carpi Ulnaris 20units. Patients received between 4 and 6 injections, with the exact dosage and number of injection sites tailored to the individual based on: size, number and location of muscles involved; severity of spasticity; presence of local muscle weakness. Reconstituted BOTOX® and placebo was injected using a sterile 25-, 27-, or 30-gauge needle for superficial muscles. Localisation of the involved muscles was be determined clinically by superficialanatomical landmarks and using electrical stimulation techniques. Where localisation of the muscles proved to be difficult using surface anatomy and EMG, ultrasound was used to guide the injection procedure and check accuracy of placement of the needle.

    Arm title
    		 Placebo
    Arm description
    		 Placebo + CDP (Clearly Defined Physiotherapy)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    0.9% Solution for injection. Patients received between 4 and 6 injections, with the exact dosage and number of injection sites tailored to the individual based on: size, number and location of muscles involved; severity of spasticity; presence of local muscle weakness. Maximum dose allowed was 200 Botox units in total, as follows; Biceps 50units, Brachialis 50units; Flexor Digitorum Profundus 30units; Flexor Digitorum Superficialis 30units; Flexor Carpi Radialis 20units; Flexor Carpi Ulnaris 20units. Reconstituted BOTOX® and placebo was injected using a sterile 25-, 27-, or 30-gauge needle for superficial muscles. Localisation of the involved muscles was be determined clinically by superficialanatomical landmarks and using electrical stimulation techniques. Where localisation of the muscles proved to be difficult using surface anatomy and EMG, ultrasound was used to guide the injection procedure and check accuracy of needle placement.

    Number of subjects in period 2
    		IMP (treatment) Placebo
    Started
    45
    48
    Completed
    40
    43
    Not completed
    5
    5
         Adverse event, serious fatal
    4
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IMP (treatment)
    Reporting group description
    		 OnabotulinumtoxinA + CDP (Clearly Defined Physiotherapy)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo + CDP (Clearly Defined Physiotherapy)

    Reporting group values
    		 IMP (treatment) Placebo Total
    Number of subjects
    		 45 48 93
    Age categorical
    All subjects were aged 18 years and over.
    Units: Subjects
        Adults (18 years and over)
    		 45 48 93
    Age continuous
    Mean age of treatment group
    Units: years
        arithmetic mean (standard deviation)
    		 67 ( 17.1 ) 68.1 ( 14.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 24 45
        Male
    		 24 24 48
    Stroke Classification
    Following stroke classification was used: Total Anterior Circulation Stroke (TACS), Partial Anterior Circulation Syndrome (PACS), Lacunar Syndrome (LACS)
    Units: Subjects
        LACS
    		 2 7 9
        PACS
    		 15 4 19
        TACS
    		 28 37 65
    NIHSS
    The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. The NIHSS was originally designed as a research tool to measure baseline data on patients in acute stroke clinical trials. Now, the scale is also widely used as a clinical assessment tool to evaluate acuity of stroke patients, determine appropriate treatment, and predict patient outcome
    Units: score
        arithmetic mean (standard deviation)
    		 16 ( 6.2 ) 16.4 ( 6.2 ) -
    Barthel
    The Barthel scale or Barthel ADL index is an ordinal scale used to measure performance in activities of daily living (ADL).
    Units: score
        arithmetic mean (standard deviation)
    		 1.9 ( 2.9 ) 1.5 ( 3.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    IMP (treatment)
    Reporting group description
    		 OnabotulinumtoxinA + CDP (Clearly Defined Physiotherapy)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo + CDP (Clearly Defined Physiotherapy)
    Reporting group title
    IMP (treatment)
    Reporting group description
    		 OnabotulinumtoxinA + CDP (Clearly Defined Physiotherapy)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo + CDP (Clearly Defined Physiotherapy)

    Primary: Change in Action Research Arm Test (ARAT) between baseline and 3 months

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    End point title
    		 Change in Action Research Arm Test (ARAT) between baseline and 3 months
    End point description
    The Action Research Arm Test consists of 20 questions categorised relating to as Grasp, Grip, Pinch, Gross Movement. Scores range from 0 (no function) to 57 (good arm function) and an improvement of 6 in this scale is considered to be clinically important.
    End point type
    Primary
    End point timeframe
    Primary endpoint measured at 3 months
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: Score
        arithmetic mean (standard deviation)
    10.9 ( 17.3 )
    9.1 ( 17.2 )
    Statistical analysis title
    		 ARAT change during treatment phase
    Statistical analysis description
    Independent sample T-test
    Comparison groups
    Placebo v IMP (treatment)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.61
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Primary: Change in Action Research Arm Test (ARAT) between 3 months and 6 months

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    End point title
    		 Change in Action Research Arm Test (ARAT) between 3 months and 6 months
    End point description
    End point type
    Primary
    End point timeframe
    Mean change to ARAT between 3months (end of treatment) and 6months (end of follow-up)
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: Score
        arithmetic mean (standard deviation)
    3.4 ( 7.6 )
    2.9 ( 6.7 )
    Statistical analysis title
    		 Mean change during follow-up
    Comparison groups
    Placebo v IMP (treatment)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.52
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 3.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Secondary: Change in elbow spasticity-EMG between baseline and 3months

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    End point title
    		 Change in elbow spasticity-EMG between baseline and 3months
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 3 months
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: microV
        arithmetic mean (standard deviation)
    6 ( 5 )
    14 ( 28 )
    Statistical analysis title
    		 INdependent sample T-test
    Comparison groups
    IMP (treatment) v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.045
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 17
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Secondary: Change in elbow spasticity-EMG between 3 months and 6 months

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    End point title
    		 Change in elbow spasticity-EMG between 3 months and 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Change between 3months and 6months
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: microV
        arithmetic mean (standard deviation)
    2 ( 7 )
    -3 ( 15 )
    Statistical analysis title
    		 Independent sample t-test
    Comparison groups
    IMP (treatment) v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.051
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 10
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Secondary: Change in wrist spasticity-EMG between baseline and 3 months

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    End point title
    		 Change in wrist spasticity-EMG between baseline and 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    between baseline and 3 months
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: microV
        arithmetic mean (standard deviation)
    3 ( 8 )
    3 ( 7 )
    Statistical analysis title
    		 Independent sample t-test
    Comparison groups
    IMP (treatment) v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.82
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Secondary: Change in wrist spasticity-EMG between 3 months and 6 months

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    End point title
    		 Change in wrist spasticity-EMG between 3 months and 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    3 months to 6 months
    End point values
    		 IMP (treatment) Placebo
    Number of subjects analysed
    45
    48
    Units: microV
        arithmetic mean (standard deviation)
    2 ( 5 )
    2 ( 6 )
    Statistical analysis title
    		 Independent 2 sided t-test
    Comparison groups
    IMP (treatment) v Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Serious adverse events occurring between Informed Consent and the participant's last visit are reported here for those who were randomised.
    Adverse event reporting additional description
    Investigators recorded all SAEs and assessed for classification of seriousness. SAEs required immediate notification to the CI and Sponsor (SWBHT). Causality and expectedness were assessed by the CI and Sponsor. All SAEs were reviewed by the independent Trial Steering Committee.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    IMP (treatment)
    Reporting group description
    		 IMP group includes 2 participants who were randomised to IMP but did not receive the injection due to SAEs. 3 SAEs were experienced by these 2 patients, both of whom died.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Not randomised
    Reporting group description
    		 Patients consented to be screened but did not reach enrollment.

    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: Only serious adverse events were recorded for this low risk study.
    Serious adverse events
    		 IMP (treatment) Placebo Not randomised
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 45 (44.44%)
    25 / 48 (52.08%)
    18 / 27 (66.67%)
         number of deaths (all causes)
    4
    5
    7
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 48 (4.17%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Aorto-Illiac Thrombotic Occlusion
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ischaemic collitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
    Additional description: Multiple emboli
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood disorder
    Additional description: Low Hb
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema
    Additional description: Leg Oedema
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorder
    Additional description: Chest pain, cardiac event, end stage cardiac failure
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 48 (2.08%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Surgical and medical procedures
    Elective surgery
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 48 (4.17%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgery
    Additional description: Treatment for Cancer of the larynx
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 48 (4.17%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    dural venous sinus thrombosis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Confusional state
    Additional description: Acute delerium
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Parotiditis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 48 (4.17%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    anorexia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
    Additional description: GI pain plus Enteritis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GI Bleed
    Additional description: GI bleed plus Dropped GCS
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
    Additional description: Combination of aspiration pneumonia and hospital acquired pneumonia
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 48 (6.25%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    Chronic obstructive pulmonary disease
    Additional description: Exacerbation of COPD
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 48 (2.08%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 48 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 48 (4.17%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 48 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 IMP (treatment) Placebo Not randomised
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 48 (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? Yes
    Date
    Amendment
    24 Aug 2011
    Amendment to go to V3.0 of protocol, dated 04/07/2011 • Explicit that IMP only given after assessment and prescription by medic • Amendment to Inclusion Criteria to clarify patients must be within 1-42 days of symptom onset • Addition of modified rankin scale to endpoint measures
    11 Oct 2011
    Amendment to go to V4.0 of protocol, dated 11/10/2011 • Introduction of ultrasound guidance for injection
    12 Jan 2013
    Amendment to go to V5.0 of protocol, dated 12/01/2013 • Clarification of AE and AR reporting process • Addition of advice for nurses caring for patients after IMP received • Modification of method of data collection • Personnel changes, including contact details of CI and change of PI at Sandwell and West Birmingham Hospitals Trust • Addition of new participating site

    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.
    Treatment with electrical stimulation is not considered routine treatment. However, in local practice this was therapeutic stimulation was routinely applied. Although treatment was given to both control and treatment groups this could be confounding.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24401159
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    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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