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    Clinical Trial Results:
    Efficacy and safety of MRI-based thrombolysis in wake-up stroke: a randomised, double-blind, placebo-controlled trial

    Summary
    EudraCT number
    		 2011-005906-32
    Trial protocol
    		 DE   BE   GB   DK   ES   NL   AT  
    Global end of trial date
    21 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WAKE-UP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01525290
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Medical Center Hamburg-Eppendorf
    Sponsor organisation address
    Martinistr. 52, Hamburg, Germany, 20246
    Public contact
    Götz Thomalla, University Medical Center Hamburg-Eppendorf, +49 40741050137, thomalla@uke.de
    Scientific contact
    Götz Thomalla, University Medical Center Hamburg-Eppendorf, +49 40741050137, thomalla@uke.de
    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
    19 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective is to test efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with unknown symptom onset.
    Protection of trial subjects
    See trial protocol
    Background therapy
    		 See trial protocol
    Evidence for comparator
    		 See trial protocol
    Actual start date of recruitment
    01 Jun 2012
    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
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 47
    Country: Number of subjects enrolled
    Denmark: 144
    Country: Number of subjects enrolled
    France: 62
    Country: Number of subjects enrolled
    Germany: 162
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    United Kingdom: 35
    Worldwide total number of subjects
    503
    EEA total number of subjects
    468
    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)
    308
    From 65 to 84 years
    195
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Date of first enrolment: 12.10.2012, Date of last completed: 21.09.2017 The treatment has been initiated as soon as possible within 60 minutes of the end of the MRI examination.

    Pre-assignment
    Screening details
    		 1362 patients underwent screening at 61 centers in eight European countries. Of these patients, 859 were excluded, including 455 who had no mismatch between findings on MRI diffusion-weighted imaging and FLAIR and 15 for whom thrombectomy was planned.

    Pre-assignment period milestones
    Number of subjects started
    		 1362 [1]
    Number of subjects completed
    		 503

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet inclusion criteria: 859
    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: 1362 patients have been screened for the inclusion in the trial WAKE-UP, only 503 patients could be enrolled as the others did not meet the inclusion and exclusion criteria.
    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active treatment
    Arm description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the active treatment, Alteplase 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) have been given.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Actilyse
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Alteplase 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes)

    Arm title
    		 Placebo
    Arm description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the placebo, matching placebo 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) was given
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes)

    Number of subjects in period 1
    		Active treatment Placebo
    Started
    254
    249
    Completed
    246
    244
    Not completed
    8
    5
         Lost to follow-up
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the active treatment, Alteplase 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) have been given.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the placebo, matching placebo 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) was given

    Reporting group values
    		 Active treatment Placebo Total
    Number of subjects
    		 254 249 503
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 103 92 195
        From 65-84 years
    		 151 157 308
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ( 11.2 ) 65.2 ( 11.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 89 89 178
        Male
    		 165 160 325

    End points

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    End points reporting groups
    Reporting group title
    Active treatment
    Reporting group description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the active treatment, Alteplase 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) have been given.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients were randomized 1:1 to either active treatment (Alteplase, rtPA, Acitlyse®) or placebo. In this arm, the placebo, matching placebo 0.9 mg per kilogram of body weight (with 10% as bolus, the remainder by infusion over 60 minutes) was given

    Primary: MRS 0-1

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    End point title
    		 MRS 0-1
    End point description
    Primary endpoint will be “favourable outcome” defined by a score of 0-1 on the modified Rankin Scale (MRS) 90 days after stroke
    End point type
    Primary
    End point timeframe
    90 days after stroke
    End point values
    		 Active treatment Placebo
    Number of subjects analysed
    254
    249
    Units: 0-1
    number (not applicable)
        Favorable Outcome (mRS 0- 1) at 90 days – no. (%)
    116
    91
    Statistical analysis title
    		 Primary endpoint
    Statistical analysis description
    Unconditional logistic-regression model
    Comparison groups
    Active treatment v Placebo
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 2.36

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse Events were reported regularly, all Serious Adverse Events were reported to the Trial Safety desk from trial sites within 48 hours.
    Adverse event reporting additional description
    SAE was assessed for seriousness, causality and expectedness. Suspected Unexpected Serious Adverse Reactions were directly reported to Eudravigilance EVCTM.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Blood and lymphatic system disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Cardiac disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Congenital, familial and genetic disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Eye disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Gastrointestinal disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    General disorders and administration site conditions
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Hepatobiliary disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Immune system disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Infections and infestations
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Injury, poisoning and procedural complications
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Investigations
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Musculoskeletal and connective tissue disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Neoplasms benign, malignant and unspecified (incl cy)
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Nervous system disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Psychiatric disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Renal and urinary disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Reproductive system and breast disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Respiratory, thoracic and mediastinal disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Social circumstances
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Surgical and medical procedures
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    Reporting group title
    Vascular disorders
    Reporting group description
    		 Subjects affected by non-serious adverse events cannot be reported, therefore 0 has been entered.

    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: Subjects affected by non-serious adverse events have not been recorded in this study.
    Serious adverse events
    		 Blood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl cy) Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Social circumstances Surgical and medical procedures Vascular disorders
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 254 (0.39%)
    9 / 254 (3.54%)
    2 / 254 (0.79%)
    0 / 254 (0.00%)
    2 / 254 (0.79%)
    8 / 254 (3.15%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    5 / 254 (1.97%)
    4 / 254 (1.57%)
    0 / 254 (0.00%)
    2 / 254 (0.79%)
    1 / 254 (0.39%)
    34 / 254 (13.39%)
    1 / 254 (0.39%)
    3 / 254 (1.18%)
    1 / 254 (0.39%)
    5 / 254 (1.97%)
    1 / 254 (0.39%)
    10 / 254 (3.94%)
    3 / 254 (1.18%)
         number of deaths (all causes)
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
    13
         number of deaths resulting from adverse events
    0
    5
    0
    0
    1
    2
    0
    0
    4
    0
    0
    0
    1
    5
    0
    0
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 254 (0.39%)
    9 / 254 (3.54%)
    2 / 254 (0.79%)
    0 / 254 (0.00%)
    2 / 254 (0.79%)
    8 / 254 (3.15%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    5 / 254 (1.97%)
    4 / 254 (1.57%)
    0 / 254 (0.00%)
    2 / 254 (0.79%)
    1 / 254 (0.39%)
    34 / 254 (13.39%)
    1 / 254 (0.39%)
    3 / 254 (1.18%)
    1 / 254 (0.39%)
    5 / 254 (1.97%)
    1 / 254 (0.39%)
    10 / 254 (3.94%)
    3 / 254 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 2
    0 / 0
    0 / 2
    0 / 8
    0 / 0
    0 / 0
    0 / 5
    0 / 4
    0 / 0
    0 / 2
    0 / 1
    0 / 34
    0 / 1
    0 / 3
    0 / 1
    0 / 5
    0 / 1
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    0 / 13
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Blood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl cy) Nervous system disorders Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Social circumstances Surgical and medical procedures Vascular disorders
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)
    0 / 254 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2015
    Amendment due to a new German Summary of Product Characteristics (SmPC, Fachinformation) for Actilyse® provided by the manufacturer. Next to minor changes as to the frequency of adverse events and editorial changes, the new SmPC comprises new information concerning patients under oral anticoagulation therapy. Therefore, the section relating to clinical exclusion criteria in the protocol was adapted in line with the new SmPC. The wording as to the use of anticoagulants as clinical exclusion criterion was modified adding further new oral anticoagulants and specifying the effective use of oral anticoagulants as clinical exclusion criterion. Additionally it was added that the use of Actilyse® can be considered in patients using vitamin K-antagonists when appropriate tests of anti-coagulant activity show no clinically relevant activity. The DSMB has evaluated that these new information are not relevant as to the risk or benefit of Actilyse®, thus the new SmPC does not change the overall risk-benefit-evaluation for Actilyse®.

    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.
    It was decided to stop the trial with 503 randomised patients as the funding from the EU ended. The overall appraisal was that with >500 patients randomized the trial should have sufficient power to demonstrate a beneficial treatment effect.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29766770
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