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    Clinical Trial Results:
    Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis – pilot phase

    Summary
    EudraCT number
    		 2010-024541-67
    Trial protocol
    		 GB  
    Global end of trial date
    10 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Mar 2020
    First version publication date
    13 Mar 2020
    Other versions
    Summary report(s)
    		 ATTEST Study Publication Summary

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01472926
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow & Clyde
    Sponsor organisation address
    Grahamston Road, Paisley, UK, United Kingdom, PA2 7DE
    Public contact
    Prof Keith Muir, University of Glasgow, 44 141 451 5892, k.muir@clinmed.gla.ac.uk
    Scientific contact
    Dr Maureen Travers, NHS Greater Glasgow & Clyde, 44 141 314 4012 ,
    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
    01 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The ATTEST pilot phase is a Prospective Randomised Open Blinded End-point (PROBE) study that will compare markers of biological activity to inform the design of a larger definitive trial comparing the efficacy and safety of alteplase and tenecteplase as thrombolytic agents in eligible patients with acute ischaemic stroke.
    Protection of trial subjects
    Written informed consent was obtained from each participant, alternatively, if the patient was unable to consent for themselves, then informed assent was provided by the next of kin, or professional. If the participant regains capacity, the participant will be asked to sign a consent form. Participants underwent baseline measurements followed by routine post-thrombolysis monitoring including adverse event assessment. Participants were followed up at 90 days by the research nurses for evaluation and assessment which included the modified rankin scale (mRS).
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Intravenous (IV) thrombolysis with the recombinant tissue Plasminogen Activator (rt-PA) alteplase significantly reduces the odds of death or dependence in acute ischaemic stroke when given within 4.5 hours of symptom onset. Alteplase is currently the only treatment licensed for acute stroke. In this study, alteplase will be used in accordance with the current Summary of Product Characteristics with the exception that patients who present within 4.5 hours of stroke symptom onset will be eligible for treatment as per current European Stroke Organisation guidelines. Subjects randomised to treatment this arm will receive the recommended treatment dose of 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10 % of the total dose administered as an initial intravenous bolus.
    Actual start date of recruitment
    01 Jan 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    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
    60
    85 years and over
    12

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The pilot study was set in a single site in Glasgow, Scotland

    Pre-assignment
    Screening details
    		 355 screened, 157 eligible, 104 enrolled. 8 were excluded final diagnosis of non-stroke 96 full data sets. Inclusion criteria: Males/females>18yr; eligible for treatment with IV alteplase. Exclusion: contraindications to thrombolytic drug treatment for stroke, known impaired renal function precluding contrast CT; allergy to radiological contrast.

    Period 1
    Period 1 title
    Pre-randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Comparator
    Arm description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alteplase
    Investigational medicinal product code
    Other name
    Actilyse
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    0.9mg/kg with 10% of the total dose administered as a initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Arm title
    		 Test IMP
    Arm description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenecteplase
    Investigational medicinal product code
    Other name
    Metalyse
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.25mg/kg administered as a single rapid IV bolus

    Number of subjects in period 1
    		Comparator Test IMP
    Started
    52
    52
    Completed
    52
    52
    Period 2
    Period 2 title
    Randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Comparator
    Arm description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alteplase
    Investigational medicinal product code
    Other name
    Actilyse
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    0.9mg/kg with 10% of the total dose administered as a initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Arm title
    		 Test IMP
    Arm description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenecteplase
    Investigational medicinal product code
    Other name
    Metalyse
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.25mg/kg administered as a single rapid IV bolus

    Number of subjects in period 2
    		Comparator Test IMP
    Started
    52
    52
    Completed
    49
    47
    Not completed
    3
    5
         Study treatment not received
    1
    -
         excluded final diagnosis of non-stroke
    2
    5
    Period 3
    Period 3 title
    Post treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Comparator
    Arm description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Alteplase
    Investigational medicinal product code
    Other name
    Actilyse
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous drip use , Intravenous bolus use
    Dosage and administration details
    0.9mg/kg with 10% of the total dose administered as a initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Arm title
    		 Test IMP
    Arm description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tenecteplase
    Investigational medicinal product code
    Other name
    Metalyse
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    0.25mg/kg administered as a single rapid IV bolus

    Number of subjects in period 3
    		Comparator Test IMP
    Started
    49
    47
    Completed
    49
    47

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Comparator
    Reporting group description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Reporting group title
    Test IMP
    Reporting group description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.

    Reporting group values
    		 Comparator Test IMP Total
    Number of subjects
    		 52 52 104
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 16 16 32
        From 65-84 years
    		 30 30 60
        85 years and over
    		 6 6 12
    Gender categorical
    Units: Subjects
        Female
    		 26 26 52
        Male
    		 26 26 52
    smoking history
    Units: Subjects
        current
    		 26 26 52
        former
    		 26 26 52
        never
    		 0 0 0
    Alcohol Consumption
    Units: Subjects
        Current
    		 0 0 0
        Former
    		 0 0 0
        Never
    		 0 0 0
        Don't know
    		 52 52 104
    Living Status
    Units: Subjects
        Home alone
    		 26 26 52
        Home with family/friends
    		 26 26 52
        Sheltered Housing alone
    		 0 0 0
        Sheltered housing with family/friends
    		 0 0 0
        Residential home (supervised care)
    		 0 0 0
        Nursing Home
    		 0 0 0
        Long-stay hospitalisation
    		 0 0 0
    Systolic Blood Pressure (mmHg)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    Diastolic Blood Pressure (mmHg)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    Heart rate (bpm)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    Temperature (degrees Celsius)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    Weight (kg)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    Glucose (mmol/L)
    Units: Subjects
        Mean
    		 26 26 52
        Median
    		 26 26 52
        Min
    		 0 0 0
        Max
    		 0 0 0
    ECG Result
    Units: Subjects
        Normal
    		 26 26 52
        Abnormal
    		 26 26 52
    Pre-morbid modified Rankin Scale (mRS)
    Units: Subjects
        No symptoms at all
    		 52 52 104
        No significant disability
    		 0 0 0
        Slight disability
    		 0 0 0
        Moderate disability
    		 0 0 0
        Moderately severe disability
    		 0 0 0
        Severe disability
    		 0 0 0
        Dead
    		 0 0 0
    NIH Stroke Scale
    Units: Subjects
        Mean
    		 52 52 104
        Median
    		 0 0 0
        Min
    		 0 0 0
        Max
    		 0 0 0
    ASPECT Score
    Units: Subjects
        Mean
    		 52 52 104
        Median
    		 0 0 0
        Min
    		 0 0 0
        Max
    		 0 0 0
    Stroke subtype (side)
    Units: Subjects
        Right
    		 52 52 104
        Left
    		 0 0 0
        Both
    		 0 0 0
    Stroke subtype (class)
    Units: Subjects
        TACS
    		 52 52 104
        PACS
    		 0 0 0
        POCS
    		 0 0 0
        LACS
    		 0 0 0
    Time from symptom onset and treatment (minutes)
    Units: Subjects
        Mean
    		 52 52 104
        Median
    		 0 0 0
        Min
    		 0 0 0
        Max
    		 0 0 0
    Risk factors: myocardial infarction
    Units: Subjects
        Yes
    		 52 52 104
    Risk factors: Heart disease
    Units: Subjects
        Yes
    		 52 52 104
    Risk factors: stroke
    Units: Subjects
        Yes
    		 52 52 104
    Risk factors: time since previous stroke (days)
    Units: Subjects
        Mean
    		 52 52 104
        Median
    		 0 0 0
        Min
    		 0 0 0
        Max
    		 0 0 0
    Risk factors: type of stroke
    Units: Subjects
        Ischaemic
    		 0 0 0
        Haemoragic
    		 0 0 0
        Unknown
    		 52 52 104
    Risk factors: Transient Ischaemic Attack (TIA)
    Units: Subjects
        Yes
    		 0 0 0
        Unknown
    		 52 52 104
    Risk factors: time since previous TIA (days)
    Units: Subjects
        Mean
    		 52 52 104
        Median
    		 0 0 0
        Min
    		 0 0 0
        Max
    		 0 0 0
    Established peripheral vascular disease
    Units: Subjects
        Yes
    		 52 52 104
    Heart failure
    Units: Subjects
        Yes
    		 52 52 104
    History of diabetes
    Units: Subjects
        Yes
    		 52 52 104
    History of high blood pressure
    Units: Subjects
        Yes
    		 52 52 104
    History of raised cholesterol
    Units: Subjects
        Yes
    		 52 52 104
    Atrial Fibrillation
    Units: Subjects
        Yes
    		 52 52 104
    Type of atrial fibrillation
    Units: Subjects
        Paroxysmal
    		 26 26 52
        Permanent
    		 26 26 52
    Carotid endarterectomy
    Units: Subjects
        Yes
    		 52 52 104
    Side of carotid endarterectomy
    Units: Subjects
        Left
    		 52 52 104
        Right
    		 0 0 0
    Medical History
    Units: Subjects
        Blood and lymphatic system disorders
    		 52 52 104
        Cardiac Disorders
    		 0 0 0
        Congenital, familial and genetic disorders
    		 0 0 0
        Ear and labyrinth disorders
    		 0 0 0
        Endocrine Disorders
    		 0 0 0
        Eye disorders
    		 0 0 0
        Gastrointestinal disorders
    		 0 0 0
        General disorders & Administration site conditions
    		 0 0 0
        Hepatobiliary disorders
    		 0 0 0
        Infections and infestations
    		 0 0 0
        Injury, poisoning & procedural complications
    		 0 0 0
        Investigations
    		 0 0 0
        Metabolism and nutrition disorders
    		 0 0 0
        Musculoskeletal & connective tissue disorders
    		 0 0 0
        Neoplasms benign, malignant & unspecified
    		 0 0 0
        Nervous System disorders
    		 0 0 0
        Psychiatric disorders
    		 0 0 0
        Renal and urinary disorders
    		 0 0 0
        Reproductive system and breast disorders
    		 0 0 0
        Respiratory, thoracic & mediastinal disorders
    		 0 0 0
        Social circumstances
    		 0 0 0
        Surgical and medical procedures
    		 0 0 0
        Vascular disorders
    		 0 0 0
    History of concomitant medication
    Units: Subjects
        Antidiarrheals, intestinal antiinflammatory,infect
    		 52 52 104
        Antiemetics and antinauseants
    		 0 0 0
        Digestives, incl. enzymes
    		 0 0 0
        Drugs for acid related disorders
    		 0 0 0
        Drugs for functional GI disorders
    		 0 0 0
        Drugs used in diabetes
    		 0 0 0
        Laxatives
    		 0 0 0
        Mineral supplements
    		 0 0 0
        stomatological preparations
    		 0 0 0
        Vitamins
    		 0 0 0
        Antimycotics for systemic use
    		 0 0 0
        Antibacterials for systemic use
    		 0 0 0
        Immunosuppressants
    		 0 0 0
        Antiprotozoals
    		 0 0 0
        Antianemic preparations
    		 0 0 0
        Antithrombotic agents
    		 0 0 0
        Agents acting on the renin-angiotensin system
    		 0 0 0
        Antihypertensives
    		 0 0 0
        Beta blocking agents
    		 0 0 0
        Calcium channel blockers
    		 0 0 0
        Cardiac Therapy
    		 0 0 0
        Diuretics
    		 0 0 0
        Lipid modifying agents
    		 0 0 0
        Antibiotics & chemotherapeutics for dermatological
    		 0 0 0
        Antifungals for dermatological use
    		 0 0 0
        Corticosteroids, dermatological preparations
    		 0 0 0
        Emollients and protectives
    		 0 0 0
        Other dermatological preparations
    		 0 0 0
        Urologicals
    		 0 0 0
        Antigout preparations
    		 0 0 0
        Antiinflammatory and antirheumatic products
    		 0 0 0
        Drugs for treatment of bone diseases
    		 0 0 0
        Muscle relaxants
    		 0 0 0
        Other drugs for disorders of the MSK system
    		 0 0 0
        Topical products for joint and muscular pain
    		 0 0 0
        Analgesics
    		 0 0 0
        Anesthetics
    		 0 0 0
        Anti-parkinson drugs
    		 0 0 0
        Anti-epileptics
    		 0 0 0
        Other nervous system drugs
    		 0 0 0
        Psychoanaleptics
    		 0 0 0
        Psycholeptics
    		 0 0 0
        Antihistamines for systemic use
    		 0 0 0
        Cough and cold preparations
    		 0 0 0
        Drugs for obstructive airway diseases
    		 0 0 0
        Ophthalmological and otological preparations
    		 0 0 0
        Ophthamologicals
    		 0 0 0
        Corticosteroids for systematic use
    		 0 0 0
        Systematichormonalpreps excl. sex hormone&insulin
    		 0 0 0
        Pituitary&Hypothalamic hormones & analogues
    		 0 0 0
        Thyroid Therapy
    		 0 0 0
        All other non-therapeutic products
    		 0 0 0
        All other therapeutic products
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Comparator (Alteplase)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    49 subjects were included in the protocol analysis as 3 patients were excluded as they had a final diagnosis of non-stroke, also one of those 3 was not treated

    Subject analysis set title
    Test IMP (Tenecteplase)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    47 subjects were included in the protocol analysis as 5 patients were excluded as they had a final diagnosis of non-stroke

    Subject analysis sets values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects
    49
    47
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    18
    17
        Male
    31
    30
    smoking history
    Units: Subjects
        current
    10
    13
        former
    15
    10
        never
    24
    24
    Alcohol Consumption
    Units: Subjects
        Current
    43
    33
        Former
    1
    2
        Never
    5
    11
        Don't know
    0
    1
    Living Status
    Units: Subjects
        Home alone
    10
    13
        Home with family/friends
    39
    33
        Sheltered Housing alone
    0
    0
        Sheltered housing with family/friends
    0
    0
        Residential home (supervised care)
    0
    0
        Nursing Home
    0
    0
        Long-stay hospitalisation
    0
    1
    Systolic Blood Pressure (mmHg)
    Units: Subjects
        Mean
    151
    146
        Median
    153
    143
        Min
    110
    105
        Max
    188
    192
    Diastolic Blood Pressure (mmHg)
    Units: Subjects
        Mean
    78
    75
        Median
    78
    76
        Min
    32
    38
        Max
    110
    112
    Heart rate (bpm)
    Units: Subjects
        Mean
    79
    78
        Median
    79
    72
        Min
    52
    40
        Max
    120
    150
    Temperature (degrees Celsius)
    Units: Subjects
        Mean
    36
    36
        Median
    36
    36
        Min
    35
    35
        Max
    37
    37
    Weight (kg)
    Units: Subjects
        Mean
    75
    76
        Median
    74
    76
        Min
    49
    47
        Max
    109
    102
    Glucose (mmol/L)
    Units: Subjects
        Mean
    7
    7
        Median
    7
    7
        Min
    4
    4
        Max
    15
    10
    ECG Result
    Units: Subjects
        Normal
    31
    28
        Abnormal
    18
    19
    Pre-morbid modified Rankin Scale (mRS)
    Units: Subjects
        No symptoms at all
    45
    41
        No significant disability
    1
    3
        Slight disability
    3
    3
        Moderate disability
    0
    0
        Moderately severe disability
    0
    0
        Severe disability
    0
    0
        Dead
    0
    0
    NIH Stroke Scale
    Units: Subjects
        Mean
    12
    13
        Median
    11
    12
        Min
    3
    2
        Max
    27
    26
    ASPECT Score
    Units: Subjects
        Mean
    7
    7
        Median
    7
    8
        Min
    3
    2
        Max
    10
    10
    Stroke subtype (side)
    Units: Subjects
        Right
    23
    23
        Left
    26
    24
        Both
    0
    0
    Stroke subtype (class)
    Units: Subjects
        TACS
    28
    27
        PACS
    16
    16
        POCS
    2
    2
        LACS
    3
    2
    Time from symptom onset and treatment (minutes)
    Units: Subjects
        Mean
    192
    184
        Median
    200
    180
        Min
    95
    92
        Max
    270
    265
    Risk factors: myocardial infarction
    Units: Subjects
        Yes
    6
    4
    Risk factors: Heart disease
    Units: Subjects
        Yes
    9
    12
    Risk factors: stroke
    Units: Subjects
        Yes
    4
    6
    Risk factors: time since previous stroke (days)
    Units: Subjects
        Mean
    3484
    1016
        Median
    2619
    973
        Min
    0
    234
        Max
    8697
    2043
    Risk factors: type of stroke
    Units: Subjects
        Ischaemic
    4
    6
        Haemoragic
    0
    0
        Unknown
    0
    0
    Risk factors: Transient Ischaemic Attack (TIA)
    Units: Subjects
        Yes
    8
    6
        Unknown
    0
    1
    Risk factors: time since previous TIA (days)
    Units: Subjects
        Mean
    3562
    1736
        Median
    3201
    1087
        Min
    67
    0
        Max
    8321
    7025
    Established peripheral vascular disease
    Units: Subjects
        Yes
    4
    0
    Heart failure
    Units: Subjects
        Yes
    1
    2
    History of diabetes
    Units: Subjects
        Yes
    7
    7
    History of high blood pressure
    Units: Subjects
        Yes
    28
    20
    History of raised cholesterol
    Units: Subjects
        Yes
    7
    4
    Atrial Fibrillation
    Units: Subjects
        Yes
    15
    19
    Type of atrial fibrillation
    Units: Subjects
        Paroxysmal
    7
    10
        Permanent
    8
    9
    Carotid endarterectomy
    Units: Subjects
        Yes
    1
    0
    Side of carotid endarterectomy
    Units: Subjects
        Left
    0
    0
        Right
    1
    0
    Medical History
    Units: Subjects
        Blood and lymphatic system disorders
    0
    1
        Cardiac Disorders
    1
    2
        Congenital, familial and genetic disorders
    2
    0
        Ear and labyrinth disorders
    1
    0
        Endocrine Disorders
    4
    0
        Eye disorders
    1
    0
        Gastrointestinal disorders
    8
    4
        General disorders & Administration site conditions
    0
    1
        Hepatobiliary disorders
    2
    0
        Infections and infestations
    0
    1
        Injury, poisoning & procedural complications
    3
    0
        Investigations
    0
    1
        Metabolism and nutrition disorders
    1
    2
        Musculoskeletal & connective tissue disorders
    2
    5
        Neoplasms benign, malignant & unspecified
    8
    5
        Nervous System disorders
    2
    0
        Psychiatric disorders
    2
    4
        Renal and urinary disorders
    3
    0
        Reproductive system and breast disorders
    0
    2
        Respiratory, thoracic & mediastinal disorders
    8
    2
        Social circumstances
    0
    1
        Surgical and medical procedures
    5
    6
        Vascular disorders
    0
    3
    History of concomitant medication
    Units: Subjects
        Antidiarrheals, intestinal antiinflammatory,infect
    35
    1
        Antiemetics and antinauseants
    6
    7
        Digestives, incl. enzymes
    1
    0
        Drugs for acid related disorders
    221
    22
        Drugs for functional GI disorders
    1
    6
        Drugs used in diabetes
    4
    3
        Laxatives
    13
    13
        Mineral supplements
    4
    8
        stomatological preparations
    0
    3
        Vitamins
    5
    4
        Antimycotics for systemic use
    0
    2
        Antibacterials for systemic use
    17
    21
        Immunosuppressants
    1
    0
        Antiprotozoals
    0
    1
        Antianemic preparations
    4
    2
        Antithrombotic agents
    42
    45
        Agents acting on the renin-angiotensin system
    19
    11
        Antihypertensives
    2
    0
        Beta blocking agents
    14
    17
        Calcium channel blockers
    9
    3
        Cardiac Therapy
    13
    10
        Diuretics
    14
    7
        Lipid modifying agents
    40
    39
        Antibiotics & chemotherapeutics for dermatological
    0
    1
        Antifungals for dermatological use
    1
    0
        Corticosteroids, dermatological preparations
    0
    1
        Emollients and protectives
    1
    0
        Other dermatological preparations
    0
    1
        Urologicals
    6
    3
        Antigout preparations
    1
    4
        Antiinflammatory and antirheumatic products
    2
    3
        Drugs for treatment of bone diseases
    2
    2
        Muscle relaxants
    0
    1
        Other drugs for disorders of the MSK system
    0
    2
        Topical products for joint and muscular pain
    2
    0
        Analgesics
    32
    31
        Anesthetics
    1
    1
        Anti-parkinson drugs
    2
    1
        Anti-epileptics
    7
    3
        Other nervous system drugs
    3
    3
        Psychoanaleptics
    12
    6
        Psycholeptics
    13
    9
        Antihistamines for systemic use
    9
    9
        Cough and cold preparations
    1
    0
        Drugs for obstructive airway diseases
    13
    8
        Ophthalmological and otological preparations
    1
    0
        Ophthamologicals
    5
    4
        Corticosteroids for systematic use
    1
    4
        Systematichormonalpreps excl. sex hormone&insulin
    6
    5
        Pituitary&Hypothalamic hormones & analogues
    0
    1
        Thyroid Therapy
    5
    0
        All other non-therapeutic products
    5
    1
        All other therapeutic products
    1
    1

    End points

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    End points reporting groups
    Reporting group title
    Comparator
    Reporting group description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Reporting group title
    Test IMP
    Reporting group description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.
    Reporting group title
    Comparator
    Reporting group description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Reporting group title
    Test IMP
    Reporting group description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.
    Reporting group title
    Comparator
    Reporting group description
    		 Alteplase 0.9mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour

    Reporting group title
    Test IMP
    Reporting group description
    		 Tenecteplase 0.25mg/kg administered as a single rapid intravenous bolus.

    Subject analysis set title
    Comparator (Alteplase)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    49 subjects were included in the protocol analysis as 3 patients were excluded as they had a final diagnosis of non-stroke, also one of those 3 was not treated

    Subject analysis set title
    Test IMP (Tenecteplase)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    47 subjects were included in the protocol analysis as 5 patients were excluded as they had a final diagnosis of non-stroke

    Primary: Percent Penumbral salvage

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    End point title
    		 Percent Penumbral salvage
    End point description
    End point type
    Primary
    End point timeframe
    24-48hrs
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    36 [1]
    35 [2]
    Units: percentage
        Mean
    72
    68
        Median
    79
    79
        Min
    15
    13
        Max
    100
    100
    Notes
    [1] - 13 missing
    [2] - 12 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Test IMP (Tenecteplase) v Comparator (Alteplase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.8127
    Method
    		 Regression, Linear
    Parameter type
    		 regression coefficient
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.55
         upper limit
    		 12.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.53

    Secondary: Total brain infarct volume

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    End point title
    		 Total brain infarct volume
    End point description
    End point type
    Secondary
    End point timeframe
    24-48 hrs
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    47 [3]
    46 [4]
    Units: mL
        Mean
    66
    75
        Median
    31
    38
        Min
    0
    0
        Max
    422
    474
    Notes
    [3] - 2 missing
    [4] - 1 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7517
    Method
    		 Regression, Linear
    Parameter type
    		 regression coefficient
    Point estimate
    4.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.63
         upper limit
    		 35.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.57

    Secondary: Co-registered infarct volume

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    End point title
    		 Co-registered infarct volume
    End point description
    End point type
    Secondary
    End point timeframe
    24 - 48 hours
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    45 [5]
    45 [6]
    Units: Percentage
        Mean
    47
    50
        Median
    26
    30
        Min
    0
    0
        Max
    243
    212
    Notes
    [5] - 4 missing
    [6] - 2 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9953
    Method
    		 Regression, Linear
    Parameter type
    		 regression coefficient
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.43
         upper limit
    		 19.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.94

    Secondary: Recanalisation (TIMI>1 or TICI>2)

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    End point title
    		 Recanalisation (TIMI>1 or TICI>2)
    End point description
    End point type
    Secondary
    End point timeframe
    24-48 hours
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    35 [7]
    32 [8]
    Units: Number
        No
    9
    11
        Yes
    26
    21
    Notes
    [7] - 14 missing
    [8] - 15 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.3789
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.55

    Secondary: Early clinical improvement in NIHSS scores

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    End point title
    		 Early clinical improvement in NIHSS scores
    End point description
    End point type
    Secondary
    End point timeframe
    at 24 hours
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [9]
    47
    Units: Number
        No
    36
    28
        Yes
    12
    19
    Notes
    [9] - 1 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1024
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 5.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46

    Secondary: Intra-cranial haemorrhage (ICH) and type

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    End point title
    		 Intra-cranial haemorrhage (ICH) and type
    End point description
    End point type
    Secondary
    End point timeframe
    at 24 - 48 hours
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [10]
    47
    Units: Number
        No
    34
    40
        Yes HI1
    5
    4
        Yes HI2
    3
    1
        Yes PH1
    2
    0
        Yes PH2
    3
    0
        Yes SAH
    0
    1
        Yes HI1 & SAH
    1
    0
        Yes PH1 & SAH
    0
    1
    Notes
    [10] - 1 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.6666
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 1.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56

    Secondary: Symptomatic ICH (SITS-MOST definition)

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    End point title
    		 Symptomatic ICH (SITS-MOST definition)
    End point description
    End point type
    Secondary
    End point timeframe
    at 24-48 hours
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [11]
    47
    Units: Number
        No
    46
    46
        Yes
    2
    1
    Notes
    [11] - 1 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.548
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 5.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26

    Secondary: mRS favourable clinical outcome (0-1) day 30

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    End point title
    		 mRS favourable clinical outcome (0-1) day 30
    End point description
    End point type
    Secondary
    End point timeframe
    day 30
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [12]
    47
    Units: Number
        No
    41
    40
        Yes
    7
    7
    Notes
    [12] - 1 missing
    Statistical analysis title
    		 mRS0-1:Treatment effect Tenecteplase vs. alteplase
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.8925
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 3.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6

    Secondary: mRS favourable clinical outcome (0-1) day 90

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    End point title
    		 mRS favourable clinical outcome (0-1) day 90
    End point description
    End point type
    Secondary
    End point timeframe
    day 90
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [13]
    47
    Units: Number
        No
    38
    34
        Yes
    10
    13
    Notes
    [13] - 1 missing
    Statistical analysis title
    		 mRS0-1:Treatment effect Tenecteplase vs. alteplase
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2793
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 5.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56

    Secondary: Number of days at home by day 90

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    End point title
    		 Number of days at home by day 90
    End point description
    End point type
    Secondary
    End point timeframe
    Day 90
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [14]
    45 [15]
    Units: Number
        Mean
    50
    45
        Median
    65
    61
        Min
    0
    0
        Max
    96
    104
    Notes
    [14] - 1 missing
    [15] - 2 missing
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.6347
    Method
    		 Regression, Linear
    Parameter type
    		 regression coefficient
    Point estimate
    -3.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.76
         upper limit
    		 9.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.48

    Secondary: Mortality at day 90

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    End point title
    		 Mortality at day 90
    End point description
    End point type
    Secondary
    End point timeframe
    day 90
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    49
    47
    Units: Number
        No
    43
    39
        Yes
    6
    8
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5135
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 5.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.63
    Statistical analysis title
    		 Treatment effect (Tenecteplase - Alteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.6602
    Method
    		 Cox proportional hazard model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 3.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.54

    Secondary: mRS favourable clinical outcome (0-2) day 30

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    End point title
    		 mRS favourable clinical outcome (0-2) day 30
    End point description
    End point type
    Secondary
    End point timeframe
    day 30
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [16]
    47
    Units: Number
        No
    32
    33
        Yes
    16
    14
    Notes
    [16] - 1 missing
    Statistical analysis title
    		 mRS0-2:Treatment effect (TenecteplasevsAlteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7833
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 2.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Secondary: mRS favourable clinical outcome (0-2) day 90

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    End point title
    		 mRS favourable clinical outcome (0-2) day 90
    End point description
    End point type
    Secondary
    End point timeframe
    day 90
    End point values
    		 Comparator (Alteplase) Test IMP (Tenecteplase)
    Number of subjects analysed
    48 [17]
    47
    Units: Number
        No
    29
    30
        Yes
    19
    17
    Notes
    [17] - 1 missing
    Statistical analysis title
    		 mRS0-2:Treatment effect (TenecteplasevsAlteplase)
    Comparison groups
    Comparator (Alteplase) v Test IMP (Tenecteplase)
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.8132
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    To death or 90 day follow up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Comparator
    Reporting group description
    		 Alteplase 0.9 mg/kg with 10% of the total dose administered as an initial intravenous bolus and remaining 90% of the total dose administered as an intravenous infusion over 1 hour.

    Reporting group title
    Test (Tenecteplase)
    Reporting group description
    		 Tenecteplase 0.25 mg/kg administered as a single rapid IV bolus

    Serious adverse events
    		 Comparator Test (Tenecteplase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 51 (31.37%)
    22 / 52 (42.31%)
         number of deaths (all causes)
    6
    8
         number of deaths resulting from adverse events
    6
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant glioma
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Endarterectomy
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tube insertion
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint resurfacing surgery
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy uterus
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysteroscopy
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    3 / 3
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Embolic stroke
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 52 (5.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 52 (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
    Bronchopneumopathy
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 52 (1.92%)
         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
    		 Comparator Test (Tenecteplase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant glioma
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    1
    Haematoma
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Haemorrhage
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    2
    Surgical and medical procedures
    Cardiac pacemaker insertion
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Carotid endarterectomy
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    1
    Cataract operation
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Hospitalisation
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Joint resurfacing surgery
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    3
    Device occlusion
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Drug withdrawal syndrome
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    General physical health deterioration
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    2
    Pneumonia aspiration
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    7
    9
    Pulmonary embolism
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    2
    Respiratory disorder
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    3
    Depression
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    1
    Intentional self-injury
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Hysteroscopy
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    0
    Weight decreased
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    4
    3
    Scratch
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Wound haemorrhage
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Atrial flutter
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Atrial tachycardia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    6
    Bradycardia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    4
    1
    Cerebrovascular accident
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Convulsions local
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    2
    Embolic stroke
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Haemorrhage intracranial
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    3
    2
    Haemorrhagic transformation stroke
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    8
    3
    Headache
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    4
    Intracranial aneurysm
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Partial seizures
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Visual field defect
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Eye disorders
    Blindness
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    5
    4
    Diarrhoea
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Haematemesis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Melaena
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Renal impairment
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Arthropathy
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    0
    Joint swelling
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchopneumopathy
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    2
    Pneumonia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    0
    Sepsis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    1
    3
    Urinary tract infection
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    2
    7
    Urosepsis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    2
    Vulvovaginal candidiasis
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Gout
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         occurrences all number
    0
    1
    Hyponatraemia
         subjects affected / exposed
    36 / 51 (70.59%)
    42 / 52 (80.77%)
         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
    17 Nov 2011
    Protocol amendment addressing points raised by the MHRA during its review. Within NHS GG&C the amended protocol (version 2) was approved as part of the Health Board management approval process
    09 Oct 2012
    Protocol v2.1 - Addition of definition of acronym (TAT) - Additional tests added (blood test for future coagulation assays) and wording to describe need for additional test - Additional evidence on test drug - Additional wording regarding witnessed verbal consent - Introduction of additional consent form (witnessed verbal consent)

    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.
    The baseline characteristics 'reporting groups' data is dummy data as we do not have the data for 104 patients. Data only for 96 patients, as 8 patient excluded as final diagnosis as non-stroke.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25726502
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