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    Clinical Trial Results:
    Rivaroxaban in Antiphospholipid Syndrome (RAPS). A prospective randomised controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.

    Summary
    EudraCT number
    		 2012-002345-38
    Trial protocol
    		 GB  
    Global end of trial date
    08 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2018
    First version publication date
    26 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0033/CTU/IMM/001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN68222801
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    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 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether the anticoagulant effects of rivaroxaban (established for the treatment and secondary prevention of venous thromboembolism) are not inferior to those of warfarin in patients with antiphospholipid syndrome, with or without systemic lupus erythematosus (SLE). This was measured by comparing the percentage change in endogenous thrombin potential (ETP), assessed by thrombin generation, from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by Commission Directive 2005/28/EC with the implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Protocol pre-defined reasons for discontinuation of trial medication: unacceptable toxicity; unacceptable SAE; pregnancy. Protocol pre-defined reasons for possible discontinuation of trial medication: SAE; thrombotic event; any change in the patient’s condition that justifies the discontinuation of treatment in the clinician’s opinion (included needing any drug specified in the exclusion criteria). All participants could choose to discontinue trial treatment at any time, without giving a reason, without penalty or loss of benefits to which they would otherwise be entitled. Protocol pre-defined dose modifications were in place for patients with renal impairment – the dose of rivaroxaban could be modified if creatinine clearance decreased. Procedures were in place for treatment with rivaroxaban to be temporarily stopped if a patient had a bleeding event or needed bridging anticoagulation for a procedure (routine or emergency). Investigation and treatment of adverse events (including bleeding) were as per NHS standard of care. All participants were asked to attend hospital and contact their trial site immediately if they experienced symptoms suggestive of recurrent thrombosis, VTE or arterial, and in the event of severe or persistent bleeding. Participants randomised to rivaroxaban were supplied with the contact details for a healthcare professional to gain information on what to do about rivaroxaban in the event of bleeding.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2013
    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: 116
    Worldwide total number of subjects
    116
    EEA total number of subjects
    116
    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)
    96
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in two hospitals in England with randomisations from 05 June 2013 to 11 November 2014. Participants were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without SLE).

    Pre-assignment
    Screening details
    		 Inclusion: Patients with APS, with or without SLE, who were taking warfarin for a minimum of 3mths since last VTE (whilst not on anticoagulation or recurrent episode(s) which occurred whilst off anticoagulation or on sub-therapeutic anticoagulant therapy), with a target INR of 2.5 (range 2.0 – 3.0). Female patients using adequate contraception.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial was open label to ensure optimum warfarin dosing. An unblinded study was additionally necessary as should patients have experienced bleeding, it would have been important to know immediately whether they were on warfarin or rivaroxaban as the management of bleeding events differs.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Warfarin
    Arm description
    		 Warfarin prescribed and dispensed in accordance with national guidance (National Patient Safety Agency Safer Practice Notice 18 [1], and British Committee for Standards in Haematology guidelines [2]) with anticoagulant monitoring undertaken by patient's usual anticoagulation clinic. [1] National Patient Safety Agency Safer Practice Notice 18, https://www.sps.nhs.uk/articles/npsa-alert-actions-that-can-make-oral-anticoagulant-therapy-safer-2007/ [2] Keeling D, et al. British Committee for Standards in Haematology (BCSH) - Guidelines for General Haematology, Haemostasis and Thrombosis. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011; 154: 311–324.
    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
    Standard-intensity warfarin (target international normalised ratio [INR] 2.5, range 2.0-3.0) was prescribed and dispensed in accordance with national guidance (National Patient Safety Agency Safer Practice Notice 18 [1], and British Committee for Standards in Haematology Guidelines [2]) [1] National Patient Safety Agency Safer Practice Notice 18, https://www.sps.nhs.uk/articles/npsa-alert-actions-that-can-make-oral-anticoagulant-therapy-safer-2007/ [2] Keeling D, et al. British Committee for Standards in Haematology (BCSH) - Guidelines for General Haematology, Haemostasis and Thrombosis. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011; 154: 311–324.

    Arm title
    		 Rivaroxaban
    Arm description
    		 Fixed-dose (20mg once daily; full dosage administration details below) of the anticoagulant drug Rivaroxaban.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients with creatinine clearance ≥ 50 mL/min were instructed to take a 20mg tablet orally once daily in the morning, with food to maximise absorption, for six months. Patients with moderate renal impairment (creatinine clearance of 30 – 49 mL/min) were prescribed either one 20mg tablet or one 15mg tablet to be taken orally once daily in the morning, with food, for six months depending on local clinical care and following the Summary of Product Characteristics (SPC) [1]. If the patient was prescribed 15mg and subsequent testing showed that the patient’s creatinine clearance was ≥50 mL/min, the patient’s dose of rivaroxaban was recommended to be increased to one 20mg tablet once daily in the morning depending on local clinical care and following the SPC. [1] 15mg and 20mg rivaroxaban (Xarelto) SPC Bayer plc (Date of last revision November 2013) obtained from the Medicines Compendium (www.medicines.org.uk)).

    Number of subjects in period 1
    		Warfarin Rivaroxaban
    Started
    59
    57
    Completed
    55
    56
    Not completed
    4
    1
         Adverse event, non-fatal
    -
    1
         Withdrawal
    2
    -
         Lost to follow-up
    1
    -
         Died
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Warfarin
    Reporting group description
    		 Warfarin prescribed and dispensed in accordance with national guidance (National Patient Safety Agency Safer Practice Notice 18 [1], and British Committee for Standards in Haematology guidelines [2]) with anticoagulant monitoring undertaken by patient's usual anticoagulation clinic. [1] National Patient Safety Agency Safer Practice Notice 18, https://www.sps.nhs.uk/articles/npsa-alert-actions-that-can-make-oral-anticoagulant-therapy-safer-2007/ [2] Keeling D, et al. British Committee for Standards in Haematology (BCSH) - Guidelines for General Haematology, Haemostasis and Thrombosis. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011; 154: 311–324.

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Fixed-dose (20mg once daily; full dosage administration details below) of the anticoagulant drug Rivaroxaban.

    Reporting group values
    		 Warfarin Rivaroxaban Total
    Number of subjects
    		 59 57 116
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ( 14 ) 47 ( 17 ) -
    Gender categorical
    Units: Subjects
        Female
    		 42 42 84
        Male
    		 17 15 32
    Stratification variable - Systemic lupus erythematosus (SLE)
    Units: Subjects
        Yes
    		 11 11 22
        No
    		 48 46 94
    Stratification variable - site
    Site of patient recruitment and treatment.
    Units: Subjects
        University College London Hospital
    		 25 23 48
        Guy's and St Thomas' Hospitals
    		 34 34 68
    Rivaroxaban dose
    Units: Subjects
        20mg
    		 0 55 55
        15mg
    		 0 2 2
        N/A
    		 59 0 59
    Thrombotic event with no or subtherapeutic anticoagulation
    Units: Subjects
        Deep vein thrombosis
    		 37 32 69
        Pulmonary embolism
    		 22 25 47
    Previous bleeding events while taking anticoagulation
    Units: Subjects
        Major
    		 0 0 0
        Clinically relevant
    		 4 0 4
        N/A
    		 55 57 112
    aPL (Miyakis categories)
    Units: Subjects
        I (excluding triple-positive aPL)
    		 19 16 35
        I (including triple-positive aPL)
    		 12 7 19
        IIa
    		 23 30 53
        IIb
    		 1 3 4
        IIc
    		 4 1 5
    Raised in-vivo coagulation activation markers - prothrombin fragment 1.2
    Units: Subjects
        Yes
    		 1 0 1
        No
    		 58 57 115
    Raised in-vivo coagulation activation markers - Thrombin-antithrombin complex
    Units: Subjects
        Yes
    		 2 2 4
        No
    		 57 55 112
    Raised in-vivo coagulation activation markers - D-dimer
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 55 54 109
    Raised in-vivo coagulation activation markers - Any marker
    Units: Subjects
        Yes
    		 6 5 11
        No
    		 53 52 105
    Laboratory data - Haemoglobin
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: g/L
        geometric mean (standard deviation)
    		 137 ( 1.04 ) 130 ( 1.06 ) -
    Laboratory data - platelet count
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: *10(^9)/L
        geometric mean (standard deviation)
    		 220 ( 1.14 ) 222 ( 1.14 ) -
    Laboratory data - International normalised ratio
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: ratio
        geometric mean (standard deviation)
    		 2.7 ( 1.17 ) 2.8 ( 1.10 ) -
    Laboratory data - Creatinine clearance
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: mL/min
        geometric mean (standard deviation)
    		 95 ( 1.15 ) 92 ( 1.15 ) -
    Laboratory data - Alanine aminotransferase
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: IU/L
        geometric mean (standard deviation)
    		 20 ( 1.25 ) 21 ( 1.22 ) -
    Thrombin generation - ETP
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: nmol/L per min
        geometric mean (standard deviation)
    		 542 ( 1.28 ) 555 ( 1.2 ) -
    Thrombin generation - Peak thrombin generation
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: nmol/L
        geometric mean (standard deviation)
    		 79.9 ( 1.42 ) 93.8 ( 1.34 ) -
    In-vivo coagulation activation markers - prothrombin fragment 1.2
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: pmol/L
        geometric mean (standard deviation)
    		 43.1 ( 1.27 ) 43.3 ( 1.24 ) -
    In-vivo coagulation activation markers - Thrombin-antithrombin complex
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: ug/L
        geometric mean (standard deviation)
    		 2.7 ( 1.10 ) 2.9 ( 1.29 ) -
    Percentage of time in therapeutic range while taking warfarin
    Units: percentage
        arithmetic mean (standard deviation)
    		 53 ( 24 ) 64 ( 28 ) -
    EQ-5D-5L Quality of life scores - Health utility
    Units: score
        arithmetic mean (standard deviation)
    		 0.79 ( 0.24 ) 0.83 ( 0.21 ) -
    EQ-5D-5L Quality of life scores - Health state: VAS
    Units: score
        arithmetic mean (standard deviation)
    		 75 ( 20 ) 81 ( 16 ) -
    Thrombin generation - Lag time
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: min
        geometric mean (standard deviation)
    		 7.6 ( 1.27 ) 7.3 ( 1.23 ) -
    Thrombin generation - time to peak thrombin generation
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: min
        geometric mean (standard deviation)
    		 11.7 ( 1.24 ) 10.8 ( 1.19 ) -
    In-vivo coagulation activation markers - D-dimer
    Units: mg/L Fibrinogen equivalent units (FEU)
        median (inter-quartile range (Q1-Q3))
    		 0.19 (0.19 to 0.22) 0.19 (0.19 to 0.25) -

    End points

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    End points reporting groups
    Reporting group title
    Warfarin
    Reporting group description
    		 Warfarin prescribed and dispensed in accordance with national guidance (National Patient Safety Agency Safer Practice Notice 18 [1], and British Committee for Standards in Haematology guidelines [2]) with anticoagulant monitoring undertaken by patient's usual anticoagulation clinic. [1] National Patient Safety Agency Safer Practice Notice 18, https://www.sps.nhs.uk/articles/npsa-alert-actions-that-can-make-oral-anticoagulant-therapy-safer-2007/ [2] Keeling D, et al. British Committee for Standards in Haematology (BCSH) - Guidelines for General Haematology, Haemostasis and Thrombosis. Guidelines on oral anticoagulation with warfarin – fourth edition. Br J Haematol 2011; 154: 311–324.

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Fixed-dose (20mg once daily; full dosage administration details below) of the anticoagulant drug Rivaroxaban.

    Primary: ETP at day 42

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    End point title
    		 ETP at day 42
    End point description
    End point type
    Primary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    56
    54
    Units: nmol/L per min
        geometric mean (confidence interval 95%)
    548 (484 to 621)
    1086 (957 to 1233)
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-ETP between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-ETP. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean ETP between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 2.4

    Secondary: Lag time at day 42

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    End point title
    		 Lag time at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    57
    53
    Units: min
        geometric mean (confidence interval 95%)
    7.3 (6.7 to 8.0)
    8.9 (8.1 to 9.8)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-lag time between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-lag time. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean lag time between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0052
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.4

    Secondary: Time to peak thrombin generation at day 42

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    End point title
    		 Time to peak thrombin generation at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    54
    Units: min
        geometric mean (confidence interval 95%)
    11.2 (10.3 to 12.1)
    19.2 (17.7 to 20.9)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-time to peak thrombin generation between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-time to peak thrombin. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean time to peak between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 1.9

    Secondary: Peak thrombin generation at day 42

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    End point title
    		 Peak thrombin generation at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    56
    54
    Units: nmol/L
        geometric mean (confidence interval 95%)
    85.7 (72.3 to 101.5)
    55.6 (46.8 to 66.1)
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Rivaroxaban v Warfarin
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.00061
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.8
    Notes
    [1] - Linear regression was used to estimate the difference in log-peak thrombin generation between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-peak thrombin. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean peak thrombin between the treatment arms (after adjustment for baseline values).

    Secondary: Prothrombin fragment 1.2 at day 42

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    End point title
    		 Prothrombin fragment 1.2 at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: pmol/L
        geometric mean (confidence interval 95%)
    45.6 (40.1 to 52.0)
    93.6 (82.1 to 106.9)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-prothrombin fragment between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline prothrombin values. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean ETP between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Rivaroxaban v Warfarin
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 2.5

    Secondary: Thrombin–antithrombin complex at day 42

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    End point title
    		 Thrombin–antithrombin complex at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: ug/L
        geometric mean (confidence interval 95%)
    2.6 (2.5 to 2.8)
    2.4 (2.3 to 2.6)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-thrombin-antithrombin between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-thrombin-antithrombin. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean thrombin-antithrombin between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.14
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1

    Secondary: D-dimer at day 42

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    End point title
    		 D-dimer at day 42
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: mg/L FEU
        geometric mean (confidence interval 95%)
    0.19 (0.19 to 0.2)
    0.19 (0.19 to 0.23)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression was used to estimate the difference in log-D-dimer between the two treatments (rivaroxaban - warfarin) at day 42 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline log-D-dimer. Results were then exponentiated to produce a ratio representing the difference in (geometric) mean D-dimer between the treatment arms (after adjustment for baseline values).
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Raised concentrations at day 42 (and also raised at baseline): prothrombin fragment 1.2 (pmol/L)

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    End point title
    		 Raised concentrations at day 42 (and also raised at baseline): prothrombin fragment 1.2 (pmol/L)
    End point description
    Count of patients with raised concentrations at day 42 of follow-up, and count of those patients who also had raised concentrations at baseline.
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: Number of patients
        Day 42
    0
    2
        Baseline and day 42
    0
    0
    No statistical analyses for this end point

    Secondary: Raised concentrations at day 42 (and also raised at baseline): Thrombin-antithrombin complex (ug/L)

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    End point title
    		 Raised concentrations at day 42 (and also raised at baseline): Thrombin-antithrombin complex (ug/L)
    End point description
    Count of patients with raised concentrations at day 42 of follow-up, and count of those patients who also had raised concentrations at baseline.
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: Number of patients
        Day 42
    3
    0
        Baseline and day 42
    1
    0
    No statistical analyses for this end point

    Secondary: Raised concentrations at day 42 (and also raised at baseline): D-dimer (mg/L FEU)

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    End point title
    		 Raised concentrations at day 42 (and also raised at baseline): D-dimer (mg/L FEU)
    End point description
    Count of patients with raised concentrations at day 42 of follow-up, and count of those patients who also had raised concentrations at baseline.
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: Number of patients
        Day 42
    4
    2
        Baseline and day 42
    1
    1
    No statistical analyses for this end point

    Secondary: Raised concentrations at day 42 (and also raised at baseline): Any marker

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    End point title
    		 Raised concentrations at day 42 (and also raised at baseline): Any marker
    End point description
    Count of patients with raised concentrations at day 42 of follow-up, and count of those patients who also had raised concentrations at baseline.
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    58
    57
    Units: Number of patients
        Day 42
    6
    3
        Day 42 and also baseline
    2
    1
    No statistical analyses for this end point

    Secondary: Adherence at day 42: peak rivaroxaban concentration in plasma

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    End point title
    		 Adherence at day 42: peak rivaroxaban concentration in plasma [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not relevant for the Warfarin arm.
    End point values
    		 Rivaroxaban
    Number of subjects analysed
    57
    Units: ug/L
        median (inter-quartile range (Q1-Q3))
    162 (101 to 245)
    No statistical analyses for this end point

    Secondary: Adherence at day 42: Factor X amidolytic

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    End point title
    		 Adherence at day 42: Factor X amidolytic [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not relevant for the Rivaroxaban arm.
    End point values
    		 Warfarin
    Number of subjects analysed
    58
    Units: IU/dL
        geometric mean (confidence interval 95%)
    25.3 (23.5 to 27.3)
    No statistical analyses for this end point

    Secondary: Adherence at day 42: international normalised ratio

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    End point title
    		 Adherence at day 42: international normalised ratio [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 42nd day after the baseline assessment at time of randomisation.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not relevant for the Rivaroxaban arm.
    End point values
    		 Warfarin
    Number of subjects analysed
    58
    Units: ratio
        geometric mean (confidence interval 95%)
    2.7 (2.6 to 2.9)
    No statistical analyses for this end point

    Secondary: Time between baseline and day 180 in therapeutic range

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    End point title
    		 Time between baseline and day 180 in therapeutic range [5]
    End point description
    Percentage of the time between baseline and 180th day of follow-up during which the patient was in the therapeutic range for Warfarin.
    End point type
    Secondary
    End point timeframe
    Between baseline and 180th day after the baseline assessment.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not relevant for the Rivaroxaban arm.
    End point values
    		 Warfarin
    Number of subjects analysed
    56
    Units: percentage
        arithmetic mean (standard deviation)
    55 ( 23 )
    No statistical analyses for this end point

    Secondary: EQ-5D-5L quality of life scores at day 180: Health Utility

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    End point title
    		 EQ-5D-5L quality of life scores at day 180: Health Utility
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 180th day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    55
    56
    Units: EQ-5D-5L health utility score
        arithmetic mean (standard error)
    0.78 ( 0.02 )
    0.82 ( 0.02 )
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Regression was used to estimate the difference in mean EQ-5D-5L Health utility between the two treatments (rivaroxaban - warfarin) at day 180 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline EQ-5D-5L Health utility.
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.09

    Secondary: EQ-5D-5L quality of life scores at day 180: Health state Visual Analogue Scale (VAS)

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    End point title
    		 EQ-5D-5L quality of life scores at day 180: Health state Visual Analogue Scale (VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 180th day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    55
    56
    Units: EQ-5D-5L Health state VAS score
        arithmetic mean (standard error)
    73 ( 1.8 )
    80 ( 1.8 )
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Regression was used to estimate the difference in mean EQ-5D-5L Health state: VAS between the two treatments (rivaroxaban - warfarin) at day 180 together with a two-sided 95% confidence interval, adjusting for the stratification variables (site and patient type) and also baseline EQ-5D-5L Health state: VAS.
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 11.5

    Secondary: New thrombotic events at day 210

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    End point title
    		 New thrombotic events at day 210
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 210th day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    55
    57
    Units: Number of patients
        Deep vein thrombosis
    0
    0
        Pulmonary embolism
    0
    0
        Arterial thrombosis
    0
    0
        Other
    0
    0
        Any combination
    0
    0
    No statistical analyses for this end point

    Secondary: Bleeding events at day 210

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    End point title
    		 Bleeding events at day 210
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 210th day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    55
    57
    Units: Number of events
        Major
    0
    0
        Clinically relevant
    2
    3
        Minor
    8
    10
        Unclassified, insufficient information
    0
    1
    Statistical analysis title
    		 Secondary - clinically relevant bleeds comparison
    Statistical analysis description
    A test for the difference between two proportions based on the normal approximation to the binomial distribution was used to estimate the difference in percentage of bleeds between the two treatments (rivaroxaban - warfarin) at day 210 together with a two-sided 95% confidence interval.
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference between percentages
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 9.3
    Statistical analysis title
    		 Secondary - minor bleeds comparison
    Statistical analysis description
    A test for the difference between two proportions based on the normal approximation to the binomial distribution was used to estimate the difference in percentage of bleeds between the two treatments (rivaroxaban - warfarin) at day 210 together with a two-sided 95% confidence interval.
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference between percentages
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 16.5
    Statistical analysis title
    		 Secondary - unclassified bleeds comparison
    Statistical analysis description
    A test for the difference between two proportions based on the normal approximation to the binomial distribution was used to estimate the difference in percentage of bleeds between the two treatments (rivaroxaban - warfarin) at day 210 together with a two-sided 95% confidence interval.
    Comparison groups
    Warfarin v Rivaroxaban
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference between percentages
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 5.3

    Secondary: Site of bleed

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    End point title
    		 Site of bleed
    End point description
    End point type
    Secondary
    End point timeframe
    Measurement at 210th day after the baseline assessment at time of randomisation.
    End point values
    		 Warfarin Rivaroxaban
    Number of subjects analysed
    55
    54
    Units: Number of patients
        Intracranial
    0
    1
        Skin (bruise)
    0
    3
        Oral
    1
    0
        Nasal
    3
    5
        Vaginal
    0
    1
        Rectal
    3
    0
        Lower ureteric
    0
    1
        Other
    7
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Measurement at 210th day after the baseline assessment at time of randomisation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Warfarin
    Reporting group description
    		 Warfarin prescribed and dispensed in accodrance with national guidance (National Patient Safety Agency Safer Practice notice 18, and British Committee for Standards in Haematology guidelines) with anticoagulant monitoring undertaken by patient's usual anticogulation clinic.

    Reporting group title
    Rivaroxaban
    Reporting group description
    		 Fixed-dose (15mg or 20mg once daily) of the antioagulant drug Rivaroxaban.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Adverse events were not reported for this trial, however a number was required for this field so we used the number 0 for both arms. We expect there were many adverse events in each arm. They were recorded in patient notes and used to modify NHS care, but, as per the protocol, they were not reported to sponsor unless an investigator judged they were due to the drug not working.
    Serious adverse events
    		 Warfarin Rivaroxaban
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 57 (7.02%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma metastatic
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intercranial hemorrhage
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhoidal hemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 57 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    abdominal pain, vomiting, arthralgia, and myalgia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Warfarin Rivaroxaban
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 57 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2013
    Protocol updated to v4.0 to include the following; the change in the SPC to SPC Mercury Pharma Group Limited 18 Sep 2012; widening of exclusion criteria to include refusal to consent to the site informing the healthcare professional responsible for anticoagulation care and those on St. John’s Wort; change to inclusion criteria for treatment with warfarin now for a 3 month period not 6; arm B widened for patients with moderate renal impairment to incorporate a 20mg OD or 15mg OD depending on local clinical care or following the SPC; visit 1 time-points changed from ±12 days to ideally -12days +14 days and all others from ideally ±21 days to ideally ±14 days; stopping of warfarin in patients randomised to rivaroxaban changed to on the day of conversion not the day of randomisation; the stopping of rivaroxaban being based on clinical judgment; in case any medications not permitted need to be prescribed the participant is to change to appropriate anticoagulation not ‘revert back to warfarin’; Appendix C: Sections 2 and 3 made more generic as these details are covered in a SOP; clarifications throughout.
    24 Oct 2014
    Protocol updated to v5.0 to include the following: addition of in vivo coagulation activation markers to secondary outcome measures; reduction in the number randomised from 156 to 116; increase in recruitment period from 10 to 18 months and overall planned duration from 24 to 44 months; removal of measurement of abdominal circumference at screening and visit 3; classification of thrombotic events will be done by the PI not the Independent Adjudication Committee; additional exclusion criterion of patients on dronedarone; clarifications throughout.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27570089
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