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    Clinical Trial Results:
    Does subcutaneous interleukin-1 receptor antagonist reduce inflammation following ischaemic stroke compared to placebo?

    Summary
    EudraCT number
    		 2013-001757-28
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2019
    First version publication date
    29 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2013/066st
    Additional study identifiers
    ISRCTN number
    		 ISRCTN74236229
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Salford Royal NHS Foundation Trust
    Sponsor organisation address
    Stott Lane, SALFORD, United Kingdom, M6 8HD
    Public contact
    SMITH, SALFORD ROYAL NHS FOUNDATION TRUST, 44 01612060623, craig.smith-2@manchester.ac.uk
    Scientific contact
    CRAIG, SALFORD ROYAL NHS FOUNDATION TRUST, +44 01612060623, craig.smith-2@manchester.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
    16 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of a specific type of anti-inflammatory drug (Interleukin-1 receptor antagonist; IL-1Ra), which is administered as an injection into the skin, have on levels of an inflammation-causing protein (Interleukin-6; IL-6) in blood samples taken between 6 hours and 5-7 days after the onset of a stroke.
    Protection of trial subjects
    Research blood samples collected at same time as those required for clinical purposes (where possible)
    Background therapy
    		 Participation in the trial did not impact on clinical care and no standard treatments were withheld.
    Evidence for comparator
    		 Inteleukin-1 receptor antagonist found to reduce inflammatory markers (IL-6 and CRP) in early phase and experimental models of stroke.
    Actual start date of recruitment
    02 Dec 2013
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    15
    From 65 to 84 years
    53
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants recruited to a single-centre, UK site between 1/3/14 and 31/10/16

    Pre-assignment
    Screening details
    		 Aged over 18 Within 6h of confirmed ischaemic stroke

    Period 1
    Period 1 title
    0-72 hours (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Third party web-based randomisation system, stratified for age, severity and thrombolysis

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment arm
    Arm description
    		 Participants who received at least one dose of IMP within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Interleukin-1 receptor antagonist
    Investigational medicinal product code
    EU/1/02/203/001-003
    Other name
    anakinra, kineret
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100MG in 0.6ml, twice-daily for 3 days. First dose within 6 hours of onset of stroke symptoms. All doses complete within 72 hours of stroke onset

    Arm title
    		 Control arm
    Arm description
    		 Participants who received at least one dose of placebo within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke onset)
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    EU/1/02/203/001-003
    Other name
    placebo
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    twice daily injection 0.6ml maximum 6 doses within 72 hours of stroke onset

    Number of subjects in period 1
    		Treatment arm Control arm
    Started
    39
    41
    primary outcome IL-6/CRP days 1-3
    39
    41
    Completed
    39
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Participants who received at least one dose of IMP within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke)

    Reporting group title
    Control arm
    Reporting group description
    		 Participants who received at least one dose of placebo within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke onset)

    Reporting group values
    		 Treatment arm Control arm Total
    Number of subjects
    		 39 41 80
    Age categorical
    Adults over 18 (all ages)
    Units: Subjects
        All adults over 18
    		 39 41 80
    Gender categorical
    Units: Subjects
        Female
    		 17 13 30
        Male
    		 22 28 50

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Participants who received at least one dose of IMP within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke)

    Reporting group title
    Control arm
    Reporting group description
    		 Participants who received at least one dose of placebo within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke onset)

    Primary: AUC IL-6

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    End point title
    		 AUC IL-6
    End point description
    The primary analysis used linear regression to control for the randomization stratification criteria and for the baseline value of log(IL-6). Where one of the day 1 to day 3 blood samples was unavailable, imputation was undertaken. The fitted value from linear regression of log(IL-6) on “day” was substituted for the missing value.
    End point type
    Primary
    End point timeframe
    Day 1-3
    End point values
    		 Treatment arm Control arm
    Number of subjects analysed
    28 [1]
    35 [2]
    Units: log10 enzyme-linked immunosorbent ass...
        number (confidence interval 95%)
    1.72 (1.28 to 2.17)
    1.72 (1.28 to 21.7)
    Notes
    [1] - 28 participants with sufficient samples to meet primary outcome
    [2] - 35 participants with sufficient data to meet primary outcome
    Statistical analysis title
    		 statistical analysis
    Statistical analysis description
    All analyses were prespecified in a statistical analysis plan before study completion and unblinding of the data set. Demographic and clinical data at baseline were tabulated by allocated test treatment. The primary analysis used linear regression to control for the randomization stratification criteria and for the baseline value of log(IL-6).
    Comparison groups
    Treatment arm v Control arm
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 < 0.005
    Method
    		 regression coefficient
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [3] - Linear regression to control

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days of first dose of IMP
    Adverse event reporting additional description
    If the adverse event is on-going at 30 days, the participant will be followed up until the event has resolved / stabilised / been fully investigated to the satisfaction of the PI and the study Sponsor or the participant is discharged from the study centre
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 Participants who received at least one dose of IMP within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke)

    Reporting group title
    Control arm
    Reporting group description
    		 Participants who received at least one dose of placebo within 6 hours of stroke onset (maximum 6 doses within 72 hours of stroke onset)

    Serious adverse events
    		 Treatment arm Control arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 39 (12.82%)
    9 / 41 (21.95%)
         number of deaths (all causes)
    3
    5
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Haemorrhagic transformation stroke
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Nervous system disorders
    Neurological symptom
    Additional description: Includes deterioration in neurological function, persistent or transient and seizure
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (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
    Pneumonia
    Additional description: Includes general diagnosis of chest infection, upper and lower respiratory tract infection
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 41 (14.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment arm Control arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 39 (17.95%)
    12 / 41 (29.27%)
    Injury, poisoning and procedural complications
    Haemorrhagic transformation stroke
    Additional description: Evidence of haemorrhagic transformation of stroke on 24h brain imaging but asymptomatic
         subjects affected / exposed
    3 / 39 (7.69%)
    2 / 41 (4.88%)
         occurrences all number
    3
    2
    Bleeding time
    Additional description: bleeding from ear post thrombolysis
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Cardiac disorders
    Arrhythmia
    Additional description: atrial fibrillation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Cardiac dysfunction
    Additional description: includes increased cardiac enzyme result, syncopal episode
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    Nervous system disorders
    Neurological symptom
    Additional description: Includes transient deterioration in neurological function and existing diagnosis of seizure
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Infections and infestations
    Pneumonia
    Additional description: Non serious chest infection classed as pneumonia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Vaginal infection
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 41 (4.88%)
         occurrences all number
    2
    2
    Diarrhoea infectious
    Additional description: clostridium deficile
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Bursitis infective
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Pyrexia
    Additional description: Pyrexia of unknown origin
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2013
    temporary arrangements to cover absence of the Chief Investigator
    24 Mar 2014
    Prof Pippa Tyrrell be reinstated as Chief Investigator
    05 Apr 2016
    Amendment to: • Assessment/blood sampling schedule to remove the 5-7 day assessment/sample • Inclusion/exclusion criteria • Inclusion of immune suppression analysis (changes to participant information and inclusion of matched controls) • Change to Sponsor details and other members of the research team • Minor corrections and clarifications to the protocol

    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/29567761
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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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