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    Clinical Trial Results:
    A pilot, phase IIb, randomised, multicentre trial of Argatroban in combination with recombinant tissue plasminogen activator for acute stroke

    Summary
    EudraCT number
    		 2012-002319-25
    Trial protocol
    		 GB  
    Global end of trial date
    07 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Aug 2016
    First version publication date
    15 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HSC-MS-11-0464
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01464788
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne, United Kingdom,
    Public contact
    Prof G Ford , Newcastle University , 44 01912227744, gary.ford@ncl.ac.uk
    Scientific contact
    Prof G Ford , Newcastle University , 44 01912227744, gary.ford@ncl.ac.uk
    Sponsor organisation name
    McGovern Medical School at UTHealth
    Sponsor organisation address
    6431 Fannin Street, Houston, Texas, United States, 77030
    Public contact
    Chris Michels, McGovern Medical School at UTHealth, 001 713-500-7084, Christopher.d.michels@uth.tmc.edu
    Scientific contact
    Andrew Barreto, M.D. , McGovern Medical School at UTHealth, 001 713-500-7002, Andrew.D.Barreto@uth.tmc.edu
    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
    30 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA (alteplase) who are randomised to also receive either low-dose Argatroban, high-dose Argatroban or neither.
    Protection of trial subjects
    Since Argatroban is a drug that prevents blood clotting there was an additional risk of an increase in bleeding complications. Bleeding may have occured at any site in the body the most serious being a bleed inside the brain. Bleeding in the brain causing deterioration is a known risk of thrombolytic treatment for stroke occuring in 3% of patients. Whether this risk of bleeding is increased with Argatroban is unclear and was one of the main focuses of the trial. Patients were monitored continuously throughout the treatment infusion and the treatment discontinued in the event of any suspected bleeding. Participants were informed of the side effects of the study medication in the patient information leaflet and verbally when the study was explained. The side effects of Argatroban on the unborn foetus or nursing infant are unknown at this time. Therefore female patients of childbearing potential underwent a blood pregnancy test prior to receiving treatment. Patients received an extra CT angiogram if participating in the study compared to standard care. The radiation dose for this scan has been reviewed by a medical physics expert and a clinical radiation expert and considered as clinically appropriate as part of the study. Participants were informed of this additional radiation dose in the patient information sheet. Participants had blood samples taken. Venepuncture has a small risk of discomfort and bruising, but was carried out by experienced staff to minimise this risk. The study procedures were carried out in selected hospitals in the UK with experienced research staff who had access to emergency facilities & equipment as required.
    Background therapy
    		 Patients who have had an ischaemic stroke and admitted to the Accident and Emergency Department or Acute Stroke Unit by their treating physician receive IV Recombinant tissue plasminogen activator (rt-PA or Alteplase) as per standard treatment, provided they are able to be treated within 3 hours of the onset of their stroke symptoms (or <4.5 hours according to each site’s local standard).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 65
    Worldwide total number of subjects
    90
    EEA total number of subjects
    25
    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)
    37
    From 65 to 84 years
    39
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited over the following periods: UK: 01 April 2013 through 07 April 2015 USA: 20 December 2011 through 15 March 2015

    Pre-assignment
    Screening details
    		 Patients who met the inclusion criteria received a head CT scan prior to initiation of rt-PA and the Argatroban infusion. If available, patients also underwent intracranial vessel imaging performed before or immediately after IV-tPA bolus (but before Argatroban bolus). Patients could not be randomised until after the CTA demonstrated an occlusion.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    The study was carried out by unblinded caregivers. Every effort was made by treating physician and nursing staff to not divulge the treatment arm. This is especially true for patients enrolled into the Argatroban arms. Patients and family members were not told whether they received the high or low-dose regimen unless they asked. All endpoint assessments were performed by investigators blinded to the treatment arm.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low-dose Argatroban + usual care IV-rt-PA
    Arm description
    		 Low-dose Argatroban (1.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Exembol
    Investigational medicinal product code
    Other name
    Argatroban
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    1.0g/kg/min continuous infusion of Argatroban x 48 hours, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion titrated to achieve an aPTT of 1.75 times baseline - not to exceed 10 g/kg/min PLUS usual care IV-rt-PA.

    Arm title
    		 High-dose Argatroban + usual care IV-rt-PA
    Arm description
    		 High-dose Argatroban (3.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Exembol
    Investigational medicinal product code
    Other name
    Argatroban
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    High-dose Argatroban 3.0g/kg/min continuous infusion of Argatroban X 48 hours, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion will be titrated to achieve an aPTT of 2.25 times baseline - not to exceed 10 g/kg/min PLUS usual care IV-rt-PA

    Arm title
    		 Intravenous-rt-PA alone
    Arm description
    		 Intravenous-rt-PA alone (usual care).
    Arm type
    		 Usual care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The study was carried out by unblinded caregivers. Every effort was made by treating physician and nursing staff to not divulge the treatment arm. This is especially true for patients enrolled into the Argatroban arms. Patients and family members were not told whether they received the high or low-dose regimen unless they asked. All endpoint assessments were performed by investigators blinded to the treatment arm.
    Number of subjects in period 1
    		Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone
    Started
    30
    31
    29
    Completed
    30
    31
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 Low-dose Argatroban (1.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA

    Reporting group title
    High-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 High-dose Argatroban (3.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA

    Reporting group title
    Intravenous-rt-PA alone
    Reporting group description
    		 Intravenous-rt-PA alone (usual care).

    Reporting group values
    		 Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone Total
    Number of subjects
    		 30 31 29 90
    Age categorical
    all subjects had to be 18 years of age or older at the time of enrollment
    Units: Subjects
        Adults (18-64 years)
    		 11 13 13 37
        From 65-84 years
    		 14 15 10 39
        85 years and over
    		 5 3 6 14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.9 ± 15.1 67.1 ± 13.4 68.9 ± 15.4 -
    Gender categorical
    Units: Subjects
        Female
    		 13 15 12 40
        Male
    		 17 16 17 50

    End points

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    End points reporting groups
    Reporting group title
    Low-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 Low-dose Argatroban (1.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA

    Reporting group title
    High-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 High-dose Argatroban (3.0g/kg/min continuous infusion of Argatroban, preceded by a 100 g/kg bolus administered over 3-5 minutes Infusion) + usual care IV-rt-PA

    Reporting group title
    Intravenous-rt-PA alone
    Reporting group description
    		 Intravenous-rt-PA alone (usual care).

    Primary: Excellent functional outcome as measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS)

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    End point title
    		 Excellent functional outcome as measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS)
    End point description
    Excellent functional outcome as measured by the percentage of patients with a 0 or 1 on the modified Rankin Scale (mRS).
    End point type
    Primary
    End point timeframe
    Day 90.
    End point values
    		 Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone
    Number of subjects analysed
    30
    31 [1]
    29
    Units: Relative Risk
    number (not applicable)
        mRS 0-1
    9
    10
    6
        mRS 2-6
    21
    21
    23
    Notes
    [1] - One subject was lost to follow-up, but the endpoint was imputed.
    Statistical analysis title
    		 low dose compared to tPA at 90 day mRS
    Comparison groups
    Low-dose Argatroban + usual care IV-rt-PA v Intravenous-rt-PA alone
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.417 [3]
    Method
    		 Poisson regression
    Parameter type
    		 Relative Risk
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 3.56
    Variability estimate
    Standard error of the mean
    Notes
    [2] - 1) Results are from unadjusted analysis 2) A similar unadjusted Bayesian analysis was performed using a neutral prior of: RR=1.0 and 95% credible intervals of 0.3-3.0. The posterior results were: RR=1.15 and 95% CrI 0.56-2.34.
    [3] - relative risk of Low dose compared to tPA
    Statistical analysis title
    		 High dose compared to tPA at 90 day mRS
    Comparison groups
    Intravenous-rt-PA alone v High-dose Argatroban + usual care IV-rt-PA
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.321 [5]
    Method
    		 Poisson regression
    Parameter type
    		 Relative Risk
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 3.75
    Variability estimate
    Standard error of the mean
    Notes
    [4] - 1) Results are from unadjusted analysis 2) A similar unadjusted Bayesian analysis was performed using a neutral prior of: RR=1.0 and 95% credible intervals of 0.3-3.0. The posterior results were: RR=1.23 and 95% CrI 0.61-2.51.
    [5] - relative risk of High dose compared to tPA

    Secondary: Symptomatic Intracranial Hemorrhage

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    End point title
    		 Symptomatic Intracranial Hemorrhage
    End point description
    Primary safety outcome was incidence of symptomatic intracerebral hemorrhage (sICH).
    End point type
    Secondary
    End point timeframe
    Baseline through end of treatment (48-hours)
    End point values
    		 Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone
    Number of subjects analysed
    30
    31 [6]
    29
    Units: Relative Risk
        number (not applicable)
    4
    2
    3
    Notes
    [6] - 1 Subject was lost to follow-up
    Statistical analysis title
    		 Low dose compared to tPA
    Statistical analysis description
    Relative Risk > 1.0 indicates higher risk of symptomatic intracranial hemorrhage compared to the control group (rt-PA alone).
    Comparison groups
    Low-dose Argatroban + usual care IV-rt-PA v Intravenous-rt-PA alone
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.724
    Method
    		 Poisson Regression
    Parameter type
    		 Relative Risk
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 5.26
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 high dose compared to tPA
    Statistical analysis description
    A relative risk (RR) <1.0 indicates a lower risk of symptomatic ICH compared to control group (rt-PA alone).
    Comparison groups
    Intravenous-rt-PA alone v High-dose Argatroban + usual care IV-rt-PA
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5394
    Method
    		 Poisson Regression
    Parameter type
    		 Relative Risk
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 3.47
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to day 90.
    Adverse event reporting additional description
    AEs regardless of whether thought to be associated with the study or IMP under investigation were graded by the Investigator and recorded on the Electronic Case Report Form. An AE form was completed for any Intracranial Haemorrhage (ICH). A haemorrhage was labelled as symptomatic by either the local principal investigator or the safety monitor.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 As reported
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    Low-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 -

    Reporting group title
    High-dose Argatroban + usual care IV-rt-PA
    Reporting group description
    		 -

    Reporting group title
    Intravenous-rt-PA alone
    Reporting group description
    		 -

    Serious adverse events
    		 Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 30 (50.00%)
    15 / 31 (48.39%)
    14 / 29 (48.28%)
         number of deaths (all causes)
    5
    3
    5
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac Disorders
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
    Additional description: Includes: symptomatic intracranial hemorrhage, neurological worsening, cerebral edema/brain herniation, seizures, etc.
         subjects affected / exposed
    9 / 30 (30.00%)
    10 / 31 (32.26%)
    9 / 29 (31.03%)
         occurrences causally related to treatment / all
    5 / 11
    5 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood - Circulation System
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Electrolyte imbalance
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 31 (9.68%)
    5 / 29 (17.24%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    5 / 5
    3 / 3
    5 / 5
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 31 (12.90%)
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Genitourinary
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Low-dose Argatroban + usual care IV-rt-PA High-dose Argatroban + usual care IV-rt-PA Intravenous-rt-PA alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 30 (90.00%)
    25 / 31 (80.65%)
    20 / 29 (68.97%)
    General disorders and administration site conditions
    Dental
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary
         subjects affected / exposed
    8 / 30 (26.67%)
    0 / 31 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    11
    0
    4
    Psychiatric disorders
    Psychological disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Cardiac Disorders
         subjects affected / exposed
    5 / 30 (16.67%)
    7 / 31 (22.58%)
    9 / 29 (31.03%)
         occurrences all number
    5
    8
    9
    Nervous system disorders
    Nervous System disorders
         subjects affected / exposed
    16 / 30 (53.33%)
    7 / 31 (22.58%)
    4 / 29 (13.79%)
         occurrences all number
    18
    10
    5
    Blood and lymphatic system disorders
    Blood system - Electrolyte Imbalance
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    0
    1
    0
    Blood - circulation system
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 31 (6.45%)
    0 / 29 (0.00%)
         occurrences all number
    0
    2
    0
    Hematologic
    Additional description: Anemia, hematuria, leukopenia, leukocytosis, etc.
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 31 (9.68%)
    4 / 29 (13.79%)
         occurrences all number
    3
    3
    5
    Ear and labyrinth disorders
    Ear, Nose and Throat (ENT)
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 29 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    5 / 30 (16.67%)
    8 / 31 (25.81%)
    0 / 29 (0.00%)
         occurrences all number
    6
    9
    0
    Skin and subcutaneous tissue disorders
    Skin and Subcutaneous tissue
         subjects affected / exposed
    9 / 30 (30.00%)
    6 / 31 (19.35%)
    4 / 29 (13.79%)
         occurrences all number
    11
    8
    5
    Renal and urinary disorders
    Genitourinary
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    1
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 31 (16.13%)
    3 / 29 (10.34%)
         occurrences all number
    7
    5
    3
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    7 / 30 (23.33%)
    10 / 31 (32.26%)
    6 / 29 (20.69%)
         occurrences all number
    9
    12
    6
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    6 / 30 (20.00%)
    2 / 31 (6.45%)
    3 / 29 (10.34%)
         occurrences all number
    8
    2
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2015
    On 07-Apr-2015 a decision to halt enrolment was the result of four landmark randomized clinical trials demonstrating the efficacy of endovascular therapy. Although each trial utilized slightly different eligibility criteria, the overwhelming majority of patients enrolled in these studies would be eligible for enrolment into the ARTSS2, but the current ARTSS2 protocol lists endovascular therapy as an exclusion criterion. As a result of these positive trials, the landscape of acute ischemic stroke (AIS) therapy has now changed dramatically. The role of embolectomy for stroke is now established and consequently, on-going reperfusion clinical trials that prohibit endovascular therapy such as ARTSS2 are no longer feasible and must adjust. A notice of substantial amendment was submitted to the MHRA on 13/04/2015.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Apr 2015
    A temporary halt to the trial as detailed in the substantial amendment dated 13/04/2015.
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    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Endpoint results are for unadjusted analyses only. Final results reported in presentations and manuscript will include both the adjusted and unadjusted results.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26278031
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