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Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants (VERDICT)

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ClinicalTrials.gov Identifier: NCT02664155
Recruitment Status : Recruiting
First Posted : January 26, 2016
Last Update Posted : February 14, 2018
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Saint Etienne

Brief Summary:

In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented and patients with severe renal insufficiency not at all. So no dose reduction was considered.

Surprisingly, DOAs have been approved for VTE treatment in moderate and severe renally impaired patients. There is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency.

We plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.


Condition or disease Intervention/treatment Phase
Renal Insufficiency Drug: Apixaban Drug: Rivaroxaban Drug: Heparin Drug: VKA Phase 3

Detailed Description:

In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. These patients represent more than 20% of the VTE population in clinical practice. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented (<10%) and patients with severe renal insufficiency not at all. So no dose reduction was considered.

The new DOAs have also been developed for stroke prevention in atrial fibrillation (SPAF). Patients including in AF trials are generally older and more prone to present renal impairment (>20%) than in VTE trials. So a reduced dose of DOAs was evaluated and shown to be at least as effective as, and safer than VKA in the subgroup of patients with moderate renal insufficiency (creatinine clearance between 30 to 50 ml/min).

Surprisingly, DOAs have been approved for VTE treatment and SPAF in moderate and severe renally impaired patients (creatinine clearance between 15 to 30 mL/min). Moreover, patients have to receive a reduced dose of DOAs for SPAF but a full dose of DOAs for VTE that could be associated with an increased bleeding risk, as suggested by some subgroup analyses. So, there, there is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency (creatinine clearance between 15 to 50 mL/min).

Apixaban and rivaroxaban appear to be the best candidates since:

  • both are approved in France in VTE patients
  • they have mixed pathway of elimination (hepatic and renal)
  • they have several other pharmacological similarities and they respective clinical trials have shown similar efficacy and safety profiles when compared with SOC for VTE treatment.
  • they do not need to be preceded by initial parenteral heparins on the contrary to dabigatran and edoxaban. This allows evaluating the impact of DOAs in renally impaired patients independently from the initial heparins effect
  • a reduced dose regimen is available and approved in AF
  • the evaluation of 2 DAOs allows evaluating the concept of this new class in renally impaired VTE patients independently from the pharmaceutical companies.

Finally we plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
Actual Study Start Date : October 19, 2016
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners
U.S. FDA Resources

Arm Intervention/treatment
Experimental: DOA : Direct Oral Anticoagulants

The experimental group receiving DOA regimens: patients will be secondarily randomly assigned within DOAs group between:

  • Apixaban (Eliquis® tablet) 10 mg bid for 7 days then 2.5 mg bid for 3 months
  • Rivaroxaban (Xarelto® tablet) 15 mg bid for 21 days then 15 mg od for 3 months.
Drug: Apixaban
Direct Oral Anticoagulant
Other Name: Eliquis®
Drug: Rivaroxaban
Direct Oral Anticoagulant
Other Name: Xarelto®
Active Comparator: SOC : Standard Of Care
The control group receiving the standard of care (SOC), i.e. heparins/VKA regimen. Patients will receive the current recommended therapy: subcutaneous or intravenous UFH/VKA in case of severe renal insufficiency and subcutaneous LMWH/VKA in case of moderate renal insufficiency for at least 5 days. VKA will begin concomitantly and continue for 3 months.
Drug: Heparin
Standard Of Care
Drug: VKA
Standard Of Care
Other Name: vitamin K antagonists



Primary Outcome Measures :
  1. Non inferiority of reduced doses of DOAs [ Time Frame: Month 3 ]
    To demonstrate that reduced doses of DOAs (rivaroxaban or apixaban) are non-inferior to standard of care (heparins/VKA) on the net clinical benefit (recurrent VTE and major bleeding) in renally impaired patients suffering from an acute VTE.


Secondary Outcome Measures :
  1. Bleeding events [ Time Frame: Month 3 ]
    To demonstrate the non--inferiority of reduced dose of DOAs on the risk of major bleedings.

  2. Venous Thromboembolism (VTE) events [ Time Frame: Month 3 ]
    To demonstrate the non--inferiority of reduced dose of DOAs on the risk of recurrent VTE.



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with a moderate renal insufficiency defined by a creatinine clearance between 30 to 50 ml/min (Cockcroft and Gault formulae) or a severe renal insufficiency (between 15 to 29 ml/min)
  • Patients with acute objectively confirmed symptomatic proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (with or without deep-vein thrombosis), planned to be treated for at least 3 months
  • Patients >18 years
  • Life expectancy more than 3 months
  • Social security affiliation
  • Signed informed consent

Exclusion Criteria:

  • Indication for anticoagulants other than VTE
  • Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg
  • Anticoagulation for more than 72 hours prior to randomization
  • Chronic liver disease or chronic hepatitis
  • Patient at high risk of bleeding
  • Creatinine clearance <15 ml/min or end stage renal disease or indication for extra-renal dialysis
  • Need for concomitant anti-platelet therapy other than aspirin 75-325 mg per day. However concomitant treatment with aspirin is discouraged in this population at bleeding risk.
  • Concomitant use of a strong inhibitor of cytochrome P-450 3A4 (CYP3A4) (e.g., a protease inhibitor for human immunodeficiency virus infection or azole-antimycotics agents ketoconazole, itraconazole, voriconazole, posaconazole) or a CYP3A4 inducer (e.g., rifampin, carbamazepine, or phenytoin),
  • Active pregnancy or expected pregnancy or no effective contraception
  • Any contraindication listed in the local labeling of UFH, LMWH or VKA or oral anticoagulant.
  • Cancer-associated VTE requiring long-term treatment with LMWH
  • Life expectancy of less than 3 months.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02664155


Contacts
Contact: MISMETTI Patrick, MD 04 77 12 02 85 ext +33 patrick.mismetti@chu-st-etienne.fr
Contact: LABRUYERE Carine, CRA carine.labruyere@chu-st-etienne.fr

Locations
France
CH ARRAS Recruiting
Arras, Boulevard Georges Besnier, France, 62022
Contact: Sandro AQUILANTI, MD         
Principal Investigator: Sandro AQUILANTI, MD         
Sub-Investigator: Jonathan GREBET, MD         
Sub-Investigator: Abed RIFAI, MD         
Chu Tours Recruiting
Tours, Hôpital Trousseau, France, 37550
Contact: Denis ANGOULVANT, MD PhD         
Principal Investigator: Denis ANGOULVANT, MD PhD         
Sub-Investigator: Christophe SAINT ETIENNE, MD         
CH d'Agen-Nérac Not yet recruiting
Agen, France
Contact: Albert TRINH-DUC, MD         
Principal Investigator: Albert TRINH-DUC, MD         
Chu Amiens Recruiting
Amiens 1, France, 80054
Contact: Marie-Antoinette SEVESTRE-PIETRI, MD PhD         
Principal Investigator: Marie-Antoinette SEVESTRE-PIETRI, MD PhD         
Chu Angers Recruiting
Angers 9, France, 49933
Contact: Pierre-Marie ROY, MD         
Principal Investigator: Pierre-Marie ROY, MD PhD         
Sub-Investigator: Thomas MOUMNEH, MD         
Sub-Investigator: Vincent AZZOLA, MD         
CH Besançon Recruiting
Besancon, France, 25030
Contact: Nicolas MENNEVEAU, MD PhD         
Principal Investigator: Nicolas MENNEVEAU, MD PhD         
Sub-Investigator: Bruno GENET, MD         
CHU de Bordeaux Not yet recruiting
Bordeaux, France
Contact: Joël CONSTANS, MD         
Principal Investigator: Joël CONSTANS, MD         
Sub-Investigator: Sophie SKOPINSKI, MD         
CHU La Cavale Blanche Brest Recruiting
Brest, France, 29200
Contact: Francis COUTURAUD, MD PhD         
Principal Investigator: Francis COUTURAUD, MD PhD         
Sub-Investigator: Norbert ANDRE, MD         
Sub-Investigator: Nolwenn ASTRUC, MD         
Sub-Investigator: Aude BARNIER, MD         
Sub-Investigator: Amélie BAZIRE, MD         
Sub-Investigator: Claire DE MOREUIL, MD         
Sub-Investigator: Luc DE SAINT-MARTIN, MD         
Sub-Investigator: Aurélien DELLUC, MD         
Sub-Investigator: Dominique MOTTIER, MD PhD         
Sub-Investigator: Cécile TROMEUR, MD         
Sub-Investigator: Emmanuelle GOURVIL, MD         
Sub-Investigator: Christophe LEROYER, MD         
HIA de Brest Not yet recruiting
Brest, France
Contact: Gwénolé ROHEL, MD         
Principal Investigator: Gwénolé ROHEL, MD         
Sub-Investigator: Emilie RIVIERE, MD         
Sub-Investigator: Marc DANGUY DES DESERTS, MD         
CHU Castelnau-le-Lez Recruiting
Castelnau Le Lez, France, 34170
Contact: Dominique BRISOT, MD         
Principal Investigator: Dominique BRISOT, MD         
Chu Clermont-Ferrand Recruiting
Clermont-Ferrand, France, 63003
Contact: Jeannot SCHMIDT, MD PhD         
Principal Investigator: Jeannot SCHMIDT, MD PhD         
Sub-Investigator: Géraldine GIROUD, MD         
Sub-Investigator: Thierry MATHEVON, MD         
Sub-Investigator: Nicolas DUBLANCHET, MD         
Sub-Investigator: Simone HEUSER, MD         
Sub-Investigator: Nadine BREUIL, MD         
Sub-Investigator: Mohamed HADJ-ABDELKADER, MD         
CHU Dijon Recruiting
Dijon, France, 21034
Contact: Nicolas FALVO, MD         
Principal Investigator: Nicolas FALVO, MD         
Hôpital La Tronche Grenoble Not yet recruiting
Grenoble 9, France, 38043
Contact: Gilles PERNOD, MD PhD         
Principal Investigator: Gilles PERNOD, MD PhD         
Hôpital Charles Foix - APHP Ivry sur Seine Recruiting
Ivry sur Seine, France, 94200
Contact: Eric PAUTAS, MD PhD         
Principal Investigator: Eric PAUTAS, MD PhD         
Chu Limoges Recruiting
Limoges, France, 87000
Contact: Philippe LACROIX, MD PhD         
Principal Investigator: Philippe LACROIX, MD PhD         
CHU Lyon Not yet recruiting
Lyon, France, 69000
Contact: Claire GRANGE, MD         
Principal Investigator: Claire GRANGE, MD         
HCL - Hôpital Edouard Herriot Not yet recruiting
Lyon, France
Contact: Hélène DESMURS-CLAVEL, MD         
Principal Investigator: Hélène DESMURS-CLAVEL, MD         
Sub-Investigator: Cécile Audrey DUREL, MD         
Sub-Investigator: Magali AUBINEAU, MD         
Chu Montpellier Not yet recruiting
Montpellier 5, France, 34295
Contact: Isabelle QUERE, MD PhD         
Principal Investigator: Isabelle QUERE, MD PhD         
CHU de Nantes Not yet recruiting
Nantes, France
Contact: Dominique EL KOURI, MD         
Principal Investigator: Dominique EL KOURI, MD         
CHU Nice Not yet recruiting
Nice, France, 06003
Contact: Emile FERRARI, MD PhD         
Principal Investigator: Emile FERRARI, MD PhD         
HEGP - APHP Paris Recruiting
Paris, France, 75000
Contact: Guy MEYER, MD PhD         
Principal Investigator: Guy MEYER, MD PhD         
Sub-Investigator: Jonathan MAREY, MD         
Hôpital Louis Mourier- APHP Paris Recruiting
Paris, France, 75000
Contact: Isabelle MAHE, MD PhD         
Principal Investigator: Isabelle MAHE, MD PhD         
Sub-Investigator: Caroline FOURGEAUD, MD         
Sub-Investigator: Maxime DELRUE, MD         
CHU de Rouen Not yet recruiting
Rouen, France
Contact: Ygal BENHAMOU, MD         
Principal Investigator: Ygal BENHAMOU, MD         
Chu Saint Etienne Recruiting
Saint Etienne, France, 42055
Contact: Patrick MISMETTI, MD PhD    04 77 12 02 85 ext +33    patrick.mismetti@chu-st-etienne.fr   
Principal Investigator: Patrick MISMETTI, MD PhD         
Sub-Investigator: Laurent BERTOLETTI, MD PhD         
Sub-Investigator: Sandrine ACCASSAT, MD         
Sub-Investigator: Nathalie MOULIN, MD         
Sub-Investigator: Cécile DUVILLARD, MD         
Sub-Investigator: Elodie DE MAGALHES, MD         
Sub-Investigator: Andréa BUCHMULLER-CORDIER, MD         
Chu Strasbourg Recruiting
Strasbourg, France, 67091
Contact: Dominique STEPHAN, MD PhD         
Principal Investigator: Dominique STEPHAN, MD PhD         
Sub-Investigator: Elena-Mihaela CORDEANU, MD         
Sub-Investigator: Sébastien GAERTNER, MD         
Sub-Investigator: Anne-Marie FALLER, MD         
CH Toulon Recruiting
Toulon, France, 83056
Contact: Antoine ELIAS, MD PhD         
Principal Investigator: Antoine ELIAS, MD PhD         
Sub-Investigator: Richard COLIN, MD         
Sub-Investigator: Jean-Noël POGGI, MD         
Sub-Investigator: Marie ELIAS, MD         
HIA de Toulon Not yet recruiting
Toulon, France
Contact: Nicolas PALEIRON, MD         
Principal Investigator: Nicolas PALEIRON, MD         
CHU Toulouse Not yet recruiting
Toulouse 9, France, 31059
Contact: Alessandra BURA-RIVIERE, MD         
Principal Investigator: Alessandra BURA-RIVIERE, MD         
Sponsors and Collaborators
Centre Hospitalier Universitaire de Saint Etienne
Ministry of Health, France
Investigators
Principal Investigator: MISMETTI Patrick, MD CHU SAINT ETIENNE

Responsible Party: Centre Hospitalier Universitaire de Saint Etienne
ClinicalTrials.gov Identifier: NCT02664155     History of Changes
Other Study ID Numbers: 1508189
2016-000858-35 ( EudraCT Number )
First Posted: January 26, 2016    Key Record Dates
Last Update Posted: February 14, 2018
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Centre Hospitalier Universitaire de Saint Etienne:
Renal insufficiency
Direct oral anticoagulants (DOA)
Deep Vein Thrombosis (DVT)
Pulmonary Embolism (PE)
Venous Thromboembolism (VTE)
Heparins

Additional relevant MeSH terms:
Thromboembolism
Venous Thromboembolism
Renal Insufficiency
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Kidney Diseases
Urologic Diseases
Calcium heparin
Apixaban
Heparin
Rivaroxaban
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors