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    Clinical Trial Results:
    Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban: Prospective Management Trial (HoT-PE)

    Summary
    EudraCT number
    		 2013-001657-28
    Trial protocol
    		 DE   PT   FI   ES   NL   GR   IT  
    Global end of trial date
    26 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2021
    First version publication date
    29 Nov 2021
    Other versions
    Summary report(s)
    		 HoT-PE_Report Synopsis_2020-07-09

    Trial information

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    Trial identification
    Sponsor protocol code
    CTHC002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Medical Center of the Johannes Gutenberg University Mainz
    Sponsor organisation address
    Langenbeckstrasse 1, Mainz, Germany, 55131
    Public contact
    Prof. Dr. S. Konstantinides, University Medical Center of the Johannes Gutenberg University Mainz, +49 6131 17-8382, stavros.konstantinides@unimedizin-mainz.de
    Scientific contact
    Prof. Dr. S. Konstantinides, University Medical Center of the Johannes Gutenberg University Mainz, +49 6131 17-8382, stavros.konstantinides@unimedizin-mainz.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether early discharge and out-of-hospital treatment of patients with low-risk acute PE (as defined by the inclusion and exclusion criteria) with the new oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe.
    Protection of trial subjects
    N/A
    Background therapy
    		 This is a single-arm trial
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    27 May 2014
    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
    Netherlands: 16
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Finland: 28
    Country: Number of subjects enrolled
    Germany: 339
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Italy: 135
    Worldwide total number of subjects
    576
    EEA total number of subjects
    576
    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)
    359
    From 65 to 84 years
    206
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 Date of first enrolment: 27.05.2014 Date of last enrolment: 27.11.2018

    Pre-assignment
    Screening details
    		 2,854 patients diagnosed with acute PE were screened for enrolment at 49 centres in 7 European countries.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment arm
    Arm description
    		 This is a single-arm trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Substance name: Rivaroxaban
    Investigational medicinal product code
    ATC code: B01AF01
    Other name
    Brand name: Xarelto
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 15 mg rivaroxaban twice daily for the first 3 weeks, followed by 20 mg once daily for the duration of the study, but for no less than 3 months.

    Number of subjects in period 1
    		Treatment arm
    Started
    576
    Completed
    554
    Not completed
    22
         Adverse event, serious fatal
    3
         Physician decision
    5
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    4
         Excluded medication
    1
         Adminisitrative/regulatory reasons
    1
         Lost to follow-up
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 576 576
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 359 359
        From 65-84 years
    		 206 206
        85 years and over
    		 11 11
    Gender categorical
    Units: Subjects
        Female
    		 266 266
        Male
    		 310 310
    Subject analysis sets

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients, who received at least one dose of study drug and fulfilled the protocol requirements for early discharge from the hospital.

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who signed the informed consent.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients, who received at least one dose of study drug.

    Subject analysis sets values
    		 Per-protocol population Intention-to-treat population Safety population
    Number of subjects
    547
    576
    569
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    341
    359
    355
        From 65-84 years
    197
    206
    203
        85 years and over
    9
    11
    11
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    251
    266
    263
        Male
    296
    310
    306

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    		 This is a single-arm trial.

    Subject analysis set title
    Per-protocol population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients, who received at least one dose of study drug and fulfilled the protocol requirements for early discharge from the hospital.

    Subject analysis set title
    Intention-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who signed the informed consent.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients, who received at least one dose of study drug.

    Primary: Symptomatic recurrent venous thromboembolism, or pulmonary embolism-related death

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    End point title
    		 Symptomatic recurrent venous thromboembolism, or pulmonary embolism-related death
    End point description
    The primary efficacy outcome was symptomatic recurrent venous thromboembolism, or pulmonary embolism-related death within three months of enrolment.
    End point type
    Primary
    End point timeframe
    Within 3 months of enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: Deaths
    3
    3
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    The null hypothesis (H0) that p ≥ 0.03 (where p=probability for recurrent VTE or death within 3 months) was tested against the alternative hypothesis (H1) that p < 0.03, using a binomial test (2-stage adaptive design based on an O’Brien Fleming design).
    Comparison groups
    Treatment arm v Intention-to-treat population
    Number of subjects included in analysis
    1152
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≥ 0.03
    Method
    		 Binomial test (O’Brien Fleming design)
    Confidence interval

    Secondary: All-cause mortality within 7 days

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    End point title
    		 All-cause mortality within 7 days
    End point description
    End point type
    Secondary
    End point timeframe
    Within 7 days of enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: Deaths
    0
    0
    No statistical analyses for this end point

    Secondary: All-cause mortality within 3 weeks

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    End point title
    		 All-cause mortality within 3 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Within 3 weeks from enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: Deaths
    0
    0
    No statistical analyses for this end point

    Secondary: All-cause mortality within 3 months

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    End point title
    		 All-cause mortality within 3 months
    End point description
    End point type
    Secondary
    End point timeframe
    Within 3 months from enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: Deaths
    3
    3
    No statistical analyses for this end point

    Secondary: Overall duration of hospital stay within 3 months

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    End point title
    		 Overall duration of hospital stay within 3 months
    End point description
    Duration of hospital stay due to index event and repeated hospitalizations due to PE [index or recurrent event] or to a bleeding event) within 3 months
    End point type
    Secondary
    End point timeframe
    Within 3 months from enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: days
    927
    927
    No statistical analyses for this end point

    Secondary: Rehospitalization due to PE or to a bleeding event

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    End point title
    		 Rehospitalization due to PE or to a bleeding event
    End point description
    Rehospitalization due to index or recurrent PE or to a bleeding event
    End point type
    Secondary
    End point timeframe
    Within 3 months of hospitailzation
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: hospitalizations
    19
    19
    No statistical analyses for this end point

    Secondary: Generic quality of life

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    End point title
    		 Generic quality of life
    End point description
    Data on generic quality of life (QoL) were collected by use of the EQ-5D-5L questionnaires.
    End point type
    Secondary
    End point timeframe
    At baseline
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    473
    473
    Units: EQ-5D-5L score
        number (not applicable)
    0.82
    0.82
    No statistical analyses for this end point

    Secondary: Treatment satisfaction

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    End point title
    		 Treatment satisfaction
    End point description
    Treatment satisfaction was analysed by the Anti-Clot Treatment Scale (ACTS).
    End point type
    Secondary
    End point timeframe
    At 3 weeks
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    421
    421
    Units: ACTS burden score
        number (not applicable)
    40.5
    40.5
    No statistical analyses for this end point

    Secondary: All-cause mortality at one year

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    End point title
    		 All-cause mortality at one year
    End point description
    End point type
    Secondary
    End point timeframe
    Within 1 year of enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    576
    576
    Units: Deaths
    5
    5
    No statistical analyses for this end point

    Secondary: Treatment satisfaction

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    End point title
    		 Treatment satisfaction
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 months after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    421
    421
    Units: ACTS burden scale
        number (not applicable)
    42.5
    42.5
    No statistical analyses for this end point

    Secondary: Generic quality of life

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    End point title
    		 Generic quality of life
    End point description
    End point type
    Secondary
    End point timeframe
    At 1 week after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    473
    473
    Units: EQ-5D-5L score
        number (not applicable)
    0.86
    0.86
    No statistical analyses for this end point

    Secondary: Generic quality of life

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    End point title
    		 Generic quality of life
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 months after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    473
    473
    Units: EQ-5D-5L score
        number (not applicable)
    0.91
    0.91
    No statistical analyses for this end point

    Secondary: Generic quality of life

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    End point title
    		 Generic quality of life
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 weeks after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    473
    473
    Units: EQ-5D-5L score
        number (not applicable)
    0.89
    0.89
    No statistical analyses for this end point

    Secondary: Disease-specific quality of life (QoL)

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    End point title
    		 Disease-specific quality of life (QoL)
    End point description
    End point type
    Secondary
    End point timeframe
    At baseline
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    425
    425
    Units: PEmb-QoL score
        number (not applicable)
    37.0
    37.0
    No statistical analyses for this end point

    Secondary: Disease-specific quality of life (QoL)

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    End point title
    		 Disease-specific quality of life (QoL)
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 weeks after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    425
    425
    Units: PEmb-QoL score
        number (not applicable)
    28.9
    28.9
    No statistical analyses for this end point

    Secondary: Disease-specific quality of life (QoL)

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    End point title
    		 Disease-specific quality of life (QoL)
    End point description
    End point type
    Secondary
    End point timeframe
    At 3 months after enrolment
    End point values
    		 Treatment arm Intention-to-treat population
    Number of subjects analysed
    425
    425
    Units: PEmb-QoL score
        number (not applicable)
    19.9
    19.9
    No statistical analyses for this end point

    Other pre-specified: Major bleeding

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    End point title
    		 Major bleeding
    End point description
    The safety outcomes included major bleeding (defined by the criteria of the International Society on Thrombosis and Haemostasis, ISTH).
    End point type
    Other pre-specified
    End point timeframe
    Within 3 months of enrolment
    End point values
    		 Treatment arm Safety population
    Number of subjects analysed
    569
    569
    Units: Bleedings
    6
    6
    No statistical analyses for this end point

    Other pre-specified: Clinically relevant non-major bleeding

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    End point title
    		 Clinically relevant non-major bleeding
    End point description
    Clinically relevant non-major bleeding as defined by the criteria of the International Society on Thrombosis and Haemostasis
    End point type
    Other pre-specified
    End point timeframe
    Within 3 months of enrolment
    End point values
    		 Treatment arm Safety population
    Number of subjects analysed
    569
    569
    Units: Bleedings
    30
    30
    No statistical analyses for this end point

    Other pre-specified: Serious adverse events (SAEs)

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    End point title
    		 Serious adverse events (SAEs)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Within 3 months of enrolment
    End point values
    		 Treatment arm Safety population
    Number of subjects analysed
    576
    569
    Units: events
    68
    68
    Statistical analysis title
    		 Safety outcome analysis
    Statistical analysis description
    Safety analysis was conducted in the safety population, including all patients who received at least one dose of study drug. Absolute (N) and relative (%) frequencies and Kaplan-Meier curves including a table with the number of patients under risk were calculated.
    Comparison groups
    Treatment arm v Safety population
    Number of subjects included in analysis
    1145
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Binomial test (1-sided)
    Parameter type
    		 absolute risk
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [1] - The primary efficacy endpoint (symptomatic recurrent venous thromboembolism [VTE] or death related to pulmonary embolism within 3 months after enrolment) is a safety endpoint, therefore the corresponding test from the main analysis is reported here.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the subject has signed the informed consent document up to 3 months after enrolment (Visit 4)
    Adverse event reporting additional description
    If the investigator detects a serious adverse event in a trial subject after the end of the period of observation, and considers the event possibly related to the prior trial, he should contact the Sponsor to determine how the adverse event should be documented and reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 All patients, who received at least one dose of study medication.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 569 (12.30%)
         number of deaths (all causes)
    14
         number of deaths resulting from adverse events
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mesothelioma
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oesophageal neoplasm
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Removal of external fixation
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Chest discomfort
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    5 / 569 (0.88%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 569 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute stress disorder
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Echocardiogram abnormal
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ultrasound pancreas abnormal
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram change
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Coronary artery disorders NEC
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Demyelinating polyneuropathy
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Intervertebral discitis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus mononucleosis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 569 (1.41%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Bacteraemia
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 569 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 569 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    220 / 569 (38.66%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    6 / 569 (1.05%)
         occurrences all number
    6
    Vascular disorders
    Haematoma
         subjects affected / exposed
    11 / 569 (1.93%)
         occurrences all number
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 569 (1.41%)
         occurrences all number
    11
    Dizziness
         subjects affected / exposed
    6 / 569 (1.05%)
         occurrences all number
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 569 (1.41%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    16 / 569 (2.81%)
         occurrences all number
    22
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    9 / 569 (1.58%)
         occurrences all number
    10
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    10 / 569 (1.76%)
         occurrences all number
    10
    Gingival bleeding
         subjects affected / exposed
    38 / 569 (6.68%)
         occurrences all number
    38
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    14 / 569 (2.46%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    15 / 569 (2.64%)
         occurrences all number
    15
    Haemoptysis
         subjects affected / exposed
    9 / 569 (1.58%)
         occurrences all number
    9
    Epistaxis
         subjects affected / exposed
    36 / 569 (6.33%)
         occurrences all number
    46
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    9 / 569 (1.58%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 569 (1.23%)
         occurrences all number
    7
    Pain in extremity
         subjects affected / exposed
    11 / 569 (1.93%)
         occurrences all number
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 569 (1.23%)
         occurrences all number
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2013
    Inclusion Criterion no. 4: Acceptable method of contraception for fertile women updated to not recommend the use of hormone-based contraceptives and to request the performance of a pregnancy test in case menstruation is delayed during therapy. Reason: hormonal contraception is not suitable for women with a history of DVT / PE Inclusion Criteria - Additional Criterion no. 6: Absence of right ventricular (RV) enlargement or dysfunction, and of free floating thrombi in the right atrium or right ventricle, detected by echocardiography or on computed tomography. [with definitions] Exclusion Criteria – Removal of Criterion no. 6: Right ventricular (RV) enlargement or dysfunction, or free floating thrombi in the right atrium or right ventricle, detected by echocardiography or on computed tomography. Reason: To emphasize that right ventricular function must be properly assessed by either CT or echocardiography Exclusion Criterion no. 14: specified that GFR should be calculated by the MDRD formula Reason: To assure that the calculation of GFR is done in the same manner across all study sites Change of procedures for collecting data gathered with patient questionnaires Reason: A more safe and streamlined process has been agreed upon to assure that this data is being collected.
    24 Jun 2014
    Trial Schedule, Visit 2: Time window re-specified to say Day 7-11 Reason: To allow for scheduling of telephone interviews around weekends and bank holidays 3.6.2 Exclusion criterion no. 6: Rewording of text on limits for pre-treatment of index episode with anticoagulants 3.6.2 Exclusion criterion no. 7: Rewording of text on concurrent anticoagulation treatment for previous indications Reason: Previous text was confusing, partly incorrect and difficult to interpret at study sites. 4.1.4 Dosage Schedule, 1st Para.: Rewording of text to align with the changes in Excl. Criteria 6 and 7
    09 Nov 2015
    Number of sites has been changed to 40-50 not only in Germany but in Europe. Reason: The recruitment rate in Germany remain very stable, indicating that an increase in recruitment rate is not possible among German sites. Trial Schedule: - The Computer Assisted Telephone Interview (CATI) is done with patients recruited at German sites only. In other countries, a structured telephone call to the patients will be made by the respective study group. Reason: An operational computerized system is not available in the foreseen non-German countries. The contact with patients will be ensured by phone calls by the site’s study team - Utilization of health care resources will be assesed in German patients only. Reason: There is no good model available to compare or co-analyze health costs across national health care systems. Duration of the trial has been changed from 28 to 60 months. Reason: A lower than anticipated recruitment rate Inclusion Criterion 6: Absence of right ventricular (RV) enlargement or dysfunction, and of free floating thrombi in the right atrium or right ventricle on echocardiography or computed tomography. In the amendment, RV dysfunction is absent on echocardiography when both criteria listed below are met: - Right/left ventricular end-diastolic diameter ratio < 0.9 (apical or subcostal 4-chamber view) - No paradoxical motion of the interventricular septum. The remaining echocardiographic criteria have been deleted. Reason: Based on updated Recommendations for Cardiac Chamber Quantification in Adults by the American Society of Echocardiography and the European Society of Cardiovascular Imaging in 2015, all outdated or controversial criteria of RV dysfunction were deleted and only the “simple” criterion, validated in the most recent pulmonary embolism trials , i.e. right/left ventricular end-diastolic diameter ratio < 0.9, is kept.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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