XENITH: Rivaroxaban for Pulmonary Embolism Managed With Catheter Directed Thrombolysis

NCT02506985 | Terminated Phase 4 Results

• 1 other identifier: 15-0275-F6A
• Study Type: interventional
• Target: 10
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Pulmonary Embolism; Venous Thrombosis

Keywords

Rivaroxaban; CDT (Catheter directed thrombolysis); PE (pulmonary embolism); NETs; factor Xa

Outcome Measures

Primary Outcomes (5)

• Change in Markers of NETosis at 12h Compared to Baseline

  Change in Markers of NETosis at 12h Compared to Baseline

  12h

• Change in Markers of NETosis at 24h Compared to Baseline

  Values will be reported in comparison to baseline in the two treatment groups.

  24h

• Change in Markers of NETosis at 48h Compared to Baseline

  Values will be reported in comparison to baseline in the two treatment groups.

  48h

• 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.

  5 days (or day of hospital discharge)

• Change in Markers of NETosis at 30 Days Compared to Baseline

  Values will be reported in comparison to baseline in the two treatment groups.

  30 days

Study Arms (2)

rivaroxaban

EXPERIMENTAL

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.

Drug: rivaroxaban

heparin-warfarin

EXPERIMENTAL

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).

Drug: warfarin

Interventions

rivaroxaban DRUG

Immediately following completion of alteplase infusion, patients will receive rivaroxaban 15 mg oral bid for 21 days followed by 20 mg oral daily.

Also known as: Xarelto

rivaroxaban

warfarin DRUG

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.

Also known as: Coumadin

heparin-warfarin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• \. an RV-to-LV diameter ratio\>0.9
• \. elevated troponin
• \. elevated BNP
• Plan for CDT for PE.

You may not qualify if:

• 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

Sponsors & Collaborators

• Susan Smyth: lead
• Janssen Scientific Affairs, LLC: collaborator

Related Publications (14)

• 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.

  PMID: 18574041 BACKGROUND

• 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.

  PMID: 16410357 BACKGROUND

• 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.

  PMID: 22968458 BACKGROUND

• 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.

  PMID: 15561697 BACKGROUND

• 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.

  PMID: 19265029 BACKGROUND

• 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.

  PMID: 17393020 BACKGROUND

• 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.

  PMID: 22451716 BACKGROUND

• 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.

  PMID: 19962723 BACKGROUND

• 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.

  PMID: 22652600 BACKGROUND

• 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.

  PMID: 20798043 BACKGROUND

• 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.

  PMID: 22044575 BACKGROUND

• 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.

  PMID: 23293023 BACKGROUND

• 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.

  PMID: 24102472 BACKGROUND

• 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.

  PMID: 24226805 BACKGROUND

MeSH Terms

Conditions

Pulmonary Embolism; Venous Thrombosis; Focal cortical dysplasia of Taylor

Interventions

Rivaroxaban; Warfarin

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Thrombosis

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Susan Smyth
• Organization: University of Kentucky

susansmyth@uky.edu

859-323-2274

Study Officials

• Susan S Smyth, MD PhD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: June 17, 2015
• First Posted: July 23, 2015
• Study Start: July 1, 2015
• Primary Completion: June 29, 2016
• Study Completion: June 29, 2016
• Last Updated: September 27, 2018
• Results First Posted: September 27, 2018

Record last verified: 2018-08