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    Clinical Trial Results:
    RE-SPECT CVT: a randomised, open-label, exploratory trial with blinded endpoint adjudication (PROBE), comparing efficacy and safety of oral dabigatran etexilate versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over a 24-week period

    Summary
    EudraCT number
    2015-004412-38
    Trial protocol
    PT   NL   ES   DE  
    Global end of trial date
    27 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jun 2019
    First version publication date
    23 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1160.248
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    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
    08 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the net clinical benefit of the treatment arms, as measured by the composite of venous thrombotic event (VTE) (recurring cerebral venous thrombosis [CVT]; deep vein thrombosis [DVT] of any limb, pulmonary embolism [PE], or splanchnic vein thrombosis) or major bleeding events (MBEs) according to ISTH (International Society on Thrombosis and Haemostasis) criteria, after up to 24 weeks. Secondary objectives included a comparison of additional efficacy and safety parameters. A substudy at selected trial centres looked at the development of dural fistulas during the 24-week treatment period following the qualifying CVT.
    Protection of trial subjects
    Only participants that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All participants were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all participants was adhered to throughout the trial conduct. Rescue medication was allowed for all participants as required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 2016
    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
    Germany: 13
    Country: Number of subjects enrolled
    India: 20
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 22
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Spain: 4
    Worldwide total number of subjects
    123
    EEA total number of subjects
    81
    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)
    110
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This is a randomised, open-label, exploratory trial with blinded endpoint adjudication (PROBE [prospective, randomised, open-label, blinded endpoint] design), comparing efficacy and safety of oral dabigatran etexilate versus oral warfarin in patients with cerebral venous and dural sinus thrombosis over a 24-week period.

    Pre-assignment
    Screening details
    All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that they (all participants) met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was a randomised, open-label, exploratory trial with blinded endpoint adjudication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dabigatran etexilate
    Arm description
    Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Dabigatran etexilate
    Investigational medicinal product code
    Other name
    Pradaxa®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.

    Arm title
    Warfarin
    Arm description
    Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.

    Number of subjects in period 1 [1]
    Dabigatran etexilate Warfarin
    Started
    60
    60
    Completed
    59
    58
    Not completed
    1
    2
         Adverse event, non-fatal
    1
    -
         Reason not listed
    -
    1
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dabigatran etexilate
    Reporting group description
    Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.

    Reporting group title
    Warfarin
    Reporting group description
    Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.

    Reporting group values
    Dabigatran etexilate Warfarin Total
    Number of subjects
    60 60 120
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): The set includes patients who received at least one dose of study medication and were analysed according to the treatment they received.
    Units: years
        arithmetic mean (standard deviation)
    44.4 ± 14.06 46.0 ± 13.64 -
    Sex: Female, Male
    TS
    Units: Subjects
        Female
    33 33 66
        Male
    27 27 54
    Race (NIH/OMB)
    TS
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    12 7 19
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    45 49 94
        More than one race
    0 0 0
        Unknown or Not Reported
    3 4 7
    Ethnicity (NIH/OMB)
    TS
    Units: Subjects
        Hispanic or Latino
    4 11 15
        Not Hispanic or Latino
    52 43 95
        Unknown or Not Reported
    4 6 10

    End points

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    End points reporting groups
    Reporting group title
    Dabigatran etexilate
    Reporting group description
    Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.

    Reporting group title
    Warfarin
    Reporting group description
    Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.

    Primary: Percentage of participants with composite of Venous Thrombotic Event (VTE) or major bleeding event (MBE) according to International Society on Thrombosis and Haemostasis (ISTH) criteria in full observation period

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    End point title
    Percentage of participants with composite of Venous Thrombotic Event (VTE) or major bleeding event (MBE) according to International Society on Thrombosis and Haemostasis (ISTH) criteria in full observation period [1]
    End point description
    Composite of the percentage of participants with MBE according to ISTH criteria and VTE (recurring cerebral venous thrombosis (CVT); deep venous thrombosis (DVT) of any limb, pulmonary embolism (PE), splanchnic vein thrombosis) in full observation period. All components were adjudicated in a blinded manner. Major bleeds were defined according to the ISTH definition of a major bleed, as follows: -Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or -Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or -Fatal bleed.
    End point type
    Primary
    End point timeframe
    From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [2]
    60 [3]
    Units: Percentage of participants
        number (confidence interval 95%)
    1.7 (0.0 to 8.9)
    3.3 (0.4 to 11.5)
    Notes
    [2] - Full analysis set (FAS)
    [3] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of participants with recurring cerebral venous and dural sinus thrombosis; DVT of any limb, PE or splanchnic vein thrombosis in full observation period

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    End point title
    Percentage of participants with recurring cerebral venous and dural sinus thrombosis; DVT of any limb, PE or splanchnic vein thrombosis in full observation period
    End point description
    VTE criteria: -New neurological signs/symptoms or worsening of previous signs/symptoms with new CVT on neuroimaging. -DVT of any limb was documented by: Abnormal compression ultrasonography; An intraluminal filling defect on venography; At autopsy -Splanchnic vein thrombosis: The presence of endoluminal material/absence of flow in the extrahepatic portal veins/mesenteric veins as shown by duplex-Doppler ultrasound/contrast-enhanced CT scan/MRI. -PE was documented by: An intraluminal filling defect in segmental/more proximal branches on spiral CT scan; An intraluminal filling defect/an extension of an existing defect/a sudden cut-off of vessels>2.5 mm in diameter on the pulmonary angiogram; Perfusion defect of at least 75% of a segment with a local normal ventilation result on ventilation/perfusion lung scan; Inconclusive spiral CT, pulmonary angiography/lung scintigraphy with demonstration of DVT in the lower extremities by compression ultrasonography/venography; At autopsy.
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [4]
    60 [5]
    Units: Percentage of participants
    number (confidence interval 95%)
        Recurring CVT
    0.0 (0.0 to 6.0)
    0.0 (0.0 to 6.0)
        DVT of any limb
    0.0 (0.0 to 6.0)
    0.0 (0.0 to 6.0)
        PE
    0.0 (0.0 to 6.0)
    0.0 (0.0 to 6.0)
        Splanchnic vein thrombosis
    0.0 (0.0 to 6.0)
    0.0 (0.0 to 6.0)
    Notes
    [4] - FAS
    [5] - FAS
    No statistical analyses for this end point

    Secondary: Cerebral venous recanalisation as measured by the change in number of occluded cerebral veins and sinuses at week 24

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    End point title
    Cerebral venous recanalisation as measured by the change in number of occluded cerebral veins and sinuses at week 24
    End point description
    Cerebral venous recanalisation was assessed by imaging and was adjudicated. Occlusion of cerebral veins and sinuses was scored as: 1 = full occlusion; 0 = no occlusion/partial occlusion. This score was applied using the below conventions: Superior sagittal, straight, cavernous sinuses, left and right jugular veins each scored individually as either 0 or 1; Right lateral transverse and sigmoid sinus were scored together, Left lateral transverse and sigmoid sinus were scored together, Superior petrous sinus and inferior petrous sinus were scored together, these were scored together as 0 = neither was fully occluded and 1 = at least 1 of them was fully occluded; Deep venous system, Superficial cortical veins, Cerebellar veins were scored as systems with conventions as 0 = none was fully occluded and 1 = at least 1 was fully occluded. For each patient a total score was calculated at baseline and at EOT and the recanalisation score was calculated as EOT - baseline total scores.
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    55 [6]
    52 [7]
    Units: Units on scale
        arithmetic mean (standard deviation)
    -0.8 ± 0.78
    -1.0 ± 0.92
    Notes
    [6] - FAS - Patients with missing/not analysable MRI scan at EOT are excluded from the analysis
    [7] - FAS - Patients with missing/not analysable MRI scan at EOT are excluded from the analysis
    No statistical analyses for this end point

    Secondary: Percentage of participants with major bleeding according to ISTH criteria in full observation period

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    End point title
    Percentage of participants with major bleeding according to ISTH criteria in full observation period
    End point description
    Major bleeds were defined according to the ISTH definition of a major bleed, as follows: -Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or -Bleeding associated with a reduction in haemoglobin of at least 2 grams/deciLitre (1.24 millimole/Litre) within 24 h, or leading to transfusion of 2 or more units of blood or packed cells and/or -Fatal bleed
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [8]
    60 [9]
    Units: Percentage of participants
        number (confidence interval 95%)
    1.7 (0.0 to 8.9)
    3.3 (0.4 to 11.5)
    Notes
    [8] - TS
    [9] - TS
    No statistical analyses for this end point

    Secondary: Composite endpoint of percentage of participants with new Intracranial haemorrhage or worsening of the haemorrhagic component of a previous lesion after up to 24 weeks

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    End point title
    Composite endpoint of percentage of participants with new Intracranial haemorrhage or worsening of the haemorrhagic component of a previous lesion after up to 24 weeks
    End point description
    Intracranial haemorrhage (ICH) comprised the subtypes of intracerebral bleeds, subdural bleeds, epidural bleeds and subarachnoid bleeds that were recorded.
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until end of treatment visit, up to 24 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    56 [10]
    53 [11]
    Units: Percentage of participants
        number (confidence interval 95%)
    1.8 (0.0 to 9.6)
    3.8 (0.5 to 13.0)
    Notes
    [10] - TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis
    [11] - TS - Patients with missing/not analysable MRI scan at baseline or EOT are excluded from the analysis
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinically relevant non-major bleeding events in full observation period

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    End point title
    Percentage of participants with clinically relevant non-major bleeding events in full observation period
    End point description
    A clinically relevant non-major bleeding event (CRNMBE) was a clinically overt bleed that did not meet the criteria for a major bleed but prompted a clinical response, in that it led to at least 1 of the following: A hospital admission (i.e. overnight stay in the hospital) for bleeding / A physician guided medical or surgical treatment for bleeding / A physician guided change, interruption or discontinuation of trial medication.
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [12]
    60 [13]
    Units: Percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 6.0)
    1.7 (0.0 to 8.9)
    Notes
    [12] - TS
    [13] - TS
    No statistical analyses for this end point

    Secondary: Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks

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    End point title
    Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks
    End point description
    Percentage of participants with major bleeding according to ISTH criteria or CRNMBEs after up to 24 weeks.
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until end of treatment visit, up to 24 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [14]
    60 [15]
    Units: Percentage of participants
        number (confidence interval 95%)
    1.7 (0.0 to 8.9)
    5.0 (1.0 to 13.9)
    Notes
    [14] - TS
    [15] - TS
    No statistical analyses for this end point

    Secondary: Percentage of participants with any bleeding event after up to 24 weeks

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    End point title
    Percentage of participants with any bleeding event after up to 24 weeks
    End point description
    Percentage of participants with any bleeding event after up to 24 weeks where any bleeding event is the sum of all major and non-major bleeding events.
    End point type
    Secondary
    End point timeframe
    From first administration of trial medication until end of treatment visit, up to 24 weeks.
    End point values
    Dabigatran etexilate Warfarin
    Number of subjects analysed
    60 [16]
    60 [17]
    Units: Percentage of participants
        number (confidence interval 95%)
    20.0 (10.8 to 32.3)
    20.0 (10.8 to 32.3)
    Notes
    [16] - TS
    [17] - TS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of trial medication until 6 days after last administration of trial medication, up to 25 weeks.
    Adverse event reporting additional description
    TS
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Warfarin
    Reporting group description
    Participants were orally treated with Warfarin 1 mg/3 mg/5 mg tablet, as needed to maintain a target international normalised ratio (INR) of 2.0 - 3.0, once daily for 24 weeks.

    Reporting group title
    Dabigatran etexilate
    Reporting group description
    Participants were orally treated with Dabigatran etexilate 150 milligram (mg) capsule twice daily for 24 weeks.

    Serious adverse events
    Warfarin Dabigatran etexilate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 60 (10.00%)
    8 / 60 (13.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio fluctuation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningioma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Evans syndrome
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haematoma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe fever with thrombocytopenia syndrome
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Warfarin Dabigatran etexilate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 60 (28.33%)
    21 / 60 (35.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 60 (0.00%)
    5 / 60 (8.33%)
         occurrences all number
    0
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 60 (13.33%)
    10 / 60 (16.67%)
         occurrences all number
    9
    12
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 60 (3.33%)
         occurrences all number
    4
    2
    Insomnia
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 60 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    2
    4
    Dyspepsia
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2017
    The number of planned patients was changed from a total of 180 to 120 (and from 90 to 60 patients planned in each treatment arm). The anticipated drop-out rate was changed from 15-20% to 10%, resulting in an estimated 108 evaluable patients (54 per treatment arm). It was clarified that all women of childbearing potential (WOCBP) should perform a pregnancy test every 4 weeks. A list of acceptable contraception methods was added and tubal ligation was removed from the list of procedures to render a woman not of childbearing potential. It was also specified that WOCBP should use effective methods of birth control from the moment of signing informed consent for the trial until completion of the follow-up visit (Visit 6). It was clarified that the primary objective did not require 24 weeks of treatment. The set up of the adjudication committee (AC) was performed by BI and not by a third party. A caution statement was added regarding treatment with warfarin in patients with known protein C or protein S deficiency. The requirements for confirmation of DVT, PE and splanchnic vein thrombosis were changed to require images and/or reports (instead of both) to be provided to the AC. An additional patient population, Screened Set (SCR), was defined, i.e. All patients who signed informed consent and completed at least some screening procedures. The list of documents and images that would be made available for adjudication purposes was removed.

    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.
    Full analysis set (FAS): All patients randomised were analysed in the treatment group to which they were randomised regardless of whether they took study medication. This followed the intent-to-treat principle.
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