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XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis (XENITH)

Primary Purpose

Pulmonary Embolism, Venous Thrombosis

Status
Terminated
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
rivaroxaban
warfarin
Sponsored by
Susan Smyth
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Embolism focused on measuring Rivaroxaban, CDT (Catheter directed thrombolysis), PE (pulmonary embolism), NETs, factor Xa

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Provisions of informed consent prior to any study specific procedure
  • Diagnosis of acute PE
  • Evidence of RV strain as defined by one of the following:
  • 1. an RV-to-LV diameter ratio>0.9
  • 2. elevated troponin
  • 3. elevated BNP
  • Plan for CDT for PE.

Exclusion Criteria:

  • Arterial hypotension and cardiogenic shock at the time of enrollment. Arterial hypotension defined as a systolic arterial pressure <90mm Hg or a drop in systolic arterial pressure of at least 40 mm Hg for at least 15 minutes with tissue hypoperfusion and/or hypoxia)
  • Hypersensitivity or other reaction to rivaroxaban
  • Other indication for VKA than PE
  • Creatinine clearance <30 ml/min
  • Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALT > 3 x ULN
  • Life expectancy <3 months

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    rivaroxaban

    heparin-warfarin

    Arm Description

    For the first 3 weeks, patients will receive rivaroxaban 15mg twice-daily; thereafter they will take rivaroxaban 20mg once-daily as per the drug label. Rivaroxaban will be initiated immediately following completion of alterplase infusion, and heparin will be discontinued at the time of rivaroxaban administration.

    Unfractioned heparin (UFH), following hospital protocol to achieve a target PTT or enoxaparin, 1.0mg/kg twice-daily, for a minimal duration of treatment of 5 days. Warfarin may be started on the night after CDT. UFH or enoxaparin should continue until the INR is >= 2.0 on two consecutive measurements at least 24 hours apart with an advised overlap with VKA for 4 to 5 days. VKA dosages will be adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0).

    Outcomes

    Primary Outcome Measures

    Change in Markers of NETosis at 12h Compared to Baseline
    Change in Markers of NETosis at 12h Compared to Baseline
    Change in Markers of NETosis at 24h Compared to Baseline
    Values will be reported in comparison to baseline in the two treatment groups.
    Change in Markers of NETosis at 48h Compared to Baseline
    Values will be reported in comparison to baseline in the two treatment groups.
    Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline
    Change in Markers of NETosis at 5 days (or day of hospital discharge) Compared to Baseline. Values will be reported in comparison to baseline in the two treatment groups.
    Change in Markers of NETosis at 30 Days Compared to Baseline
    Values will be reported in comparison to baseline in the two treatment groups.

    Secondary Outcome Measures

    Full Information

    First Posted
    June 17, 2015
    Last Updated
    August 30, 2018
    Sponsor
    Susan Smyth
    Collaborators
    Janssen Scientific Affairs, LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02506985
    Brief Title
    XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis
    Acronym
    XENITH
    Official Title
    XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2018
    Overall Recruitment Status
    Terminated
    Study Start Date
    July 2015 (undefined)
    Primary Completion Date
    June 29, 2016 (Actual)
    Study Completion Date
    June 29, 2016 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor-Investigator
    Name of the Sponsor
    Susan Smyth
    Collaborators
    Janssen Scientific Affairs, LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The trial is an open-label, randomized, trial examining novel biomarkers of thrombosis in patients managed with rivaroxaban vs. standard care following treatment of pulmonary embolism (PE) with catheter-guided alteplase. Patients >18 years old who present with PE and are managed with catheter-guided alteplase will be screened for study inclusion. Patient's meeting inclusion/exclusion criteria will undergo informed consent. Immediately following completion of alteplase infusion, patients will be randomized to receipt of rivaroxaban 15 mg oral bid for 21 days followed by 20mg oral daily or continuation on unfractioned heparin or low-molecular weight heparin with initiation of warfarin adjusted to INR of 2-3. Blood samples will be taken within 2 hours of CDT completion prior to receipt of study treatment (study day 1), at 8h-12h, 24h, 48h, 5d (or prior to hospital discharge), and at 30 day follow-up. Clinical endpoints, including bleeding, evidence of thrombosis progression, and death will be tracked during index hospitalization and at follow-up 30 days post-discharge.
    Detailed Description
    Catheter-guided alteplase has a growing role in the management of acute pulmonary embolism (PE). Following a 12-24 hour alteplase infusion (for bilateral or unilateral PE, respectively) patients are routinely managed with therapeutic unfractionated heparin (UFH) as a bridge to chronic warfarin therapy. It is our desire to study the effects of rivaroxaban vs. standard care following catheter-guided alteplase thrombolytic therapy (CDT) in patients with acute pulmonary embolism. Use of rivaroxaban may offer several important advantages compared to standard therapy in this setting. Among these is the potential for rivaroxaban to improve novel biomarkers of thrombosis including inhibition neutrophil extracellular traps (NETs), tissue factor-positive microparticles, and markers of inflammation. Neutrophil release of extracellular DNA may provide a scaffold upon which venous thrombosis propagates. NETs are associated with thrombus organization. Their dissolution may facilitate thrombolysis. Circulating DNA, a surrogate marker for NETs, is elevated 2-3 fold in patients with venous thromboembolism (VTE) and correlates strongly with plasma myeloperoxidase (MPO), an inflammatory marker of neutrophil and monocyte activation. The investigators have previously demonstrated that heparin can trigger MPO release from leukocytes. Thus, it is resonable to speculate that anti-Xa therapy may reduce inflammation, MPO, and NET levels in circulation. Further, the investigators have observed that catheter-directed thrombolysis may increase length of stay (time frame = 8 hours to 30 days following administration of study drugs) and the investigators would also propose treatment with rivaroxaban may balance this by eliminating a "bridging" period.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Pulmonary Embolism, Venous Thrombosis
    Keywords
    Rivaroxaban, CDT (Catheter directed thrombolysis), PE (pulmonary embolism), NETs, factor Xa

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    10 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    rivaroxaban
    Arm Type
    Experimental
    Arm Description
    For the first 3 weeks, patients will receive rivaroxaban 15mg twice-daily; thereafter they will take rivaroxaban 20mg once-daily as per the drug label. Rivaroxaban will be initiated immediately following completion of alterplase infusion, and heparin will be discontinued at the time of rivaroxaban administration.
    Arm Title
    heparin-warfarin
    Arm Type
    Experimental
    Arm Description
    Unfractioned heparin (UFH), following hospital protocol to achieve a target PTT or enoxaparin, 1.0mg/kg twice-daily, for a minimal duration of treatment of 5 days. Warfarin may be started on the night after CDT. UFH or enoxaparin should continue until the INR is >= 2.0 on two consecutive measurements at least 24 hours apart with an advised overlap with VKA for 4 to 5 days. VKA dosages will be adjusted to maintain the INR within the therapeutic range (target 2.5, range 2.0 - 3.0).
    Intervention Type
    Drug
    Intervention Name(s)
    rivaroxaban
    Other Intervention Name(s)
    Xarelto
    Intervention Description
    Immediately following completion of alteplase infusion, patients will receive rivaroxaban 15 mg oral bid for 21 days followed by 20 mg oral daily.
    Intervention Type
    Drug
    Intervention Name(s)
    warfarin
    Other Intervention Name(s)
    Coumadin
    Intervention Description
    Immediately following completion of alteplase infusion, patients will continue on unfractionated heparin or low-molecular weight heparin with initiation of warfarin adjusted to INR of 2-3.
    Primary Outcome Measure Information:
    Title
    Change in Markers of NETosis at 12h Compared to Baseline
    Description
    Change in Markers of NETosis at 12h Compared to Baseline
    Time Frame
    12h
    Title
    Change in Markers of NETosis at 24h Compared to Baseline
    Description
    Values will be reported in comparison to baseline in the two treatment groups.
    Time Frame
    24h
    Title
    Change in Markers of NETosis at 48h Compared to Baseline
    Description
    Values will be reported in comparison to baseline in the two treatment groups.
    Time Frame
    48h
    Title
    Change in Markers of NETosis at 5 Days (or Day of Hospital Discharge) Compared to Baseline
    Description
    Change in Markers of NETosis at 5 days (or day of hospital discharge) Compared to Baseline. Values will be reported in comparison to baseline in the two treatment groups.
    Time Frame
    5 days (or day of hospital discharge)
    Title
    Change in Markers of NETosis at 30 Days Compared to Baseline
    Description
    Values will be reported in comparison to baseline in the two treatment groups.
    Time Frame
    30 days

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Provisions of informed consent prior to any study specific procedure Diagnosis of acute PE Evidence of RV strain as defined by one of the following: 1. an RV-to-LV diameter ratio>0.9 2. elevated troponin 3. elevated BNP Plan for CDT for PE. Exclusion Criteria: Arterial hypotension and cardiogenic shock at the time of enrollment. Arterial hypotension defined as a systolic arterial pressure <90mm Hg or a drop in systolic arterial pressure of at least 40 mm Hg for at least 15 minutes with tissue hypoperfusion and/or hypoxia) Hypersensitivity or other reaction to rivaroxaban Other indication for VKA than PE Creatinine clearance <30 ml/min Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALT > 3 x ULN Life expectancy <3 months
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Susan S Smyth, MD PhD
    Organizational Affiliation
    University of Kentucky
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    18574041
    Citation
    Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008 Jul 1;112(1):19-27. doi: 10.1182/blood-2008-01-077909.
    Results Reference
    background
    PubMed Identifier
    16410357
    Citation
    Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):903-8. doi: 10.1073/pnas.0507195103. Epub 2006 Jan 12.
    Results Reference
    background
    PubMed Identifier
    22968458
    Citation
    Smith SA, Choi SH, Collins JN, Travers RJ, Cooley BC, Morrissey JH. Inhibition of polyphosphate as a novel strategy for preventing thrombosis and inflammation. Blood. 2012 Dec 20;120(26):5103-10. doi: 10.1182/blood-2012-07-444935. Epub 2012 Sep 11.
    Results Reference
    background
    PubMed Identifier
    15561697
    Citation
    Lopez JA, Kearon C, Lee AY. Deep venous thrombosis. Hematology Am Soc Hematol Educ Program. 2004:439-56. doi: 10.1182/asheducation-2004.1.439.
    Results Reference
    background
    PubMed Identifier
    19265029
    Citation
    Zhou J, May L, Liao P, Gross PL, Weitz JI. Inferior vena cava ligation rapidly induces tissue factor expression and venous thrombosis in rats. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):863-9. doi: 10.1161/ATVBAHA.109.185678. Epub 2009 Mar 5.
    Results Reference
    background
    PubMed Identifier
    17393020
    Citation
    Bugert P, Pabinger I, Stamer K, Vormittag R, Skeate RC, Wahi MM, Panzer S. The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154. Thromb Haemost. 2007 Apr;97(4):573-80.
    Results Reference
    background
    PubMed Identifier
    22451716
    Citation
    von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012 Apr 9;209(4):819-35. doi: 10.1084/jem.20112322. Epub 2012 Mar 26.
    Results Reference
    background
    PubMed Identifier
    19962723
    Citation
    Ramacciotti E, Myers DD Jr, Wrobleski SK, Deatrick KB, Londy FJ, Rectenwald JE, Henke PK, Schaub RG, Wakefield TW. P-selectin/ PSGL-1 inhibitors versus enoxaparin in the resolution of venous thrombosis: a meta-analysis. Thromb Res. 2010 Apr;125(4):e138-42. doi: 10.1016/j.thromres.2009.10.022. Epub 2009 Dec 4.
    Results Reference
    background
    PubMed Identifier
    22652600
    Citation
    Fuchs TA, Brill A, Wagner DD. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1777-83. doi: 10.1161/ATVBAHA.111.242859. Epub 2012 May 31.
    Results Reference
    background
    PubMed Identifier
    20798043
    Citation
    Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15880-5. doi: 10.1073/pnas.1005743107. Epub 2010 Aug 23.
    Results Reference
    background
    PubMed Identifier
    22044575
    Citation
    Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012 Jan;10(1):136-44. doi: 10.1111/j.1538-7836.2011.04544.x.
    Results Reference
    background
    PubMed Identifier
    23293023
    Citation
    Longstaff C, Varju I, Sotonyi P, Szabo L, Krumrey M, Hoell A, Bota A, Varga Z, Komorowicz E, Kolev K. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013 Mar 8;288(10):6946-56. doi: 10.1074/jbc.M112.404301. Epub 2013 Jan 4.
    Results Reference
    background
    PubMed Identifier
    24102472
    Citation
    Bain J, Oyler DR, Smyth SS, Macaulay TE. Pathophysiology and pharmacologic treatment of venous thromboembolism. Curr Drug Targets. 2014 Feb;15(2):199-209. doi: 10.2174/13894501113146660226.
    Results Reference
    background
    PubMed Identifier
    24226805
    Citation
    Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.
    Results Reference
    background

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    XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis

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