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REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. (RENOVE)

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ClinicalTrials.gov Identifier: NCT03285438
Recruitment Status : Recruiting
First Posted : September 18, 2017
Last Update Posted : August 23, 2018
Sponsor:
Collaborator:
University Hospital of Saint-Etienne
Information provided by (Responsible Party):
University Hospital, Brest

Brief Summary:

Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk factors have a high risk of recurrence after stopping anticoagulation. In these patients, international guidelines recommend indefinite anticoagulation. However, prolonged use of warfarin or DOAC at therapeutic dose is associated with a significant risk of bleeding. Consequently, it has been hypothesized that extended anticoagulation at lower dosage might be as effective as and safer than full dose of anticoagulation. However, low-dose warfarin (INR 1.5-2) was less effective and not safer than conventional dose warfarin (INR 2-3).

Low dose of DOAC has the potential to validate this hypothesis. In a first randomized trial comparing full-dose or low-dose apixaban with a placebo during an additional one year of anticoagulation in patients where physicians were uncertain for prolonging anticoagulation ("Amplify-extension trial"), low-dose apixaban was more effective than placebo without any major concern regarding safety and possibly as effective as and safer than full-dose apixaban; in a second randomized trial comparing full-dose or low-dose rivaroxaban with aspirin, during an additional one year of anticoagulation in patients where physicians were uncertain for prolonging anticoagulation ("Einstein-Choice trial"), low-dose rivaroxaban was more effective than aspirin without any major concern regarding safety and possibly as effective as and safer than full-dose rivaroxaban. However, these two studies were not designed and powered to demonstrate non-inferiority on efficacy and superiority on safety of a reduced dose of DOAC versus a full dose DOAC and the selected population did not have strong indications for indefinite anticoagulation. Thus, there is currently no evidence to recommend a reduced dose rather than a full dose of DOAC for extended therapy in patients at high risk of recurrent VTE. Consequently, a randomized trial comparing low-dose DOAC with full-dose DOAC therapy in patients at high risk of recurrent VTE is needed and justified.

Main hypothesis:

After VTE at high risk of recurrence initially treated during 6 (-15 days) to 24 (+ 3 months) uninterrupted months, a reduced dose of DOAC will be non-inferior to a full dose of DOAC in terms of recurrent VTE during extended anticoagulation phase.


Condition or disease Intervention/treatment Phase
Venous Thromboembolism Drug: Reduced dose of DOAC Drug: Full dose of DOAC Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The trial is designed as an academic, multicenter, open, with blind evaluation (PROBE), randomized, parallel arm, controlled.
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
Actual Study Start Date : October 16, 2017
Estimated Primary Completion Date : October 9, 2022
Estimated Study Completion Date : October 9, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Experimental: Reduced dose of DOAC
A reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) during a mean follow-up period of 24 months (12 to 48 months)
Drug: Reduced dose of DOAC
The patient will receive apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily during a mean follow-up period of 24 months (12 to 48 months)

Active Comparator: Full dose of DOAC
A full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily) during a mean follow-up period of 24 months (12 to 48 months).
Drug: Full dose of DOAC
The patient will receive apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily during a mean follow-up period of 24 months (12 to 48 months)




Primary Outcome Measures :
  1. Recurrent VTE [ Time Frame: during a mean study treatment period of 24 months ]
    Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.


Secondary Outcome Measures :
  1. Major and clinically relevant non major bleeding [ Time Frame: during a mean study treatment period of 24 months ]
    Adjudicated major bleeding (as defined by the criteria of the International Society of Thrombosis and Haemostasis) or clinically relevant non major bleeding during the study treatment period

  2. The composite of recurrent VTE or major bleeding or non major clinically relevant bleeding [ Time Frame: during a mean study treatment period of 24 months ]
    The composite of adjudicated recurrent VTE or major bleeding or non major clinically relevant bleeding during the study treatment period will be adjudicated

  3. Mortality [ Time Frame: during a mean study treatment period of 24 months ]
    Mortality of other cause than recurrent VTE or major or clinically relevant non major bleeding during the study treatment period will be adjudicated

  4. Compliance [ Time Frame: during a mean study treatment period of 24 months ]
    Treatment compliance will be evaluated

  5. Treatment effect [ Time Frame: during a mean study treatment period of 24 months ]
    The heterogeneity of the treatment effect on predefined strata will be evaluated

  6. Arterial cardio-vascular events [ Time Frame: during a mean study treatment period of 24 months ]
    The arterial cardio-vascular events (myocardial infarction, stroke, cardio-vascular complication other than VTE) will be evaluated



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

Inclusion Criteria:

  • Patients >18 years
  • Patients with indications for long-term anticoagulation after VTE (i.e.; symptomatic PE or proximal DVT) initially treated during 6 (-15 days) to 24 months (+ 3 months) :

    • Patients with multiple episodes of VTE, or
    • Patients with a first episode of unprovoked* VTE
    • Patients with VTE associated with persistent risk factor**, or
    • Patients for whom clinicians feel that indefinite anticoagulation is warranted
  • Social security affiliation.

Exclusion Criteria:

  • Known allergy to rivaroxaban and apixaban, allergy to any of the excipients
  • Indication for therapeutic dose anticoagulant therapy
  • Unable or refusal to give informed consent
  • Isolated distal DVT
  • HERDOO2 score ≤ 1
  • Indication for anticoagulation other than DVT or PE (e.g.; atrial fibrillation, mechanic valves…)
  • Treatment with investigational drug in the past 1 month except for patients benefiting from an anticoagulant at therapeutic doses for the initial pathology
  • Interruption of anticoagulation for 14 days or more before the inclusion
  • Chronic liver disease or chronic hepatitis
  • Patient considered at high risk of bleeding (eg: previous gastro-intestinal tract bleeding in the past three months, uncontrolled hypertension, etc.)
  • Renal insufficiency with creatinine <25 ml / min on Cockcroft and Gault formula
  • Antiphospholipid syndrome
  • Dual anti-platelet therapy or aspirin at dosage >100 mg per day
  • 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 cancer of less than 6 months
  • Active pregnancy or expected pregnancy
  • No effective contraception in women of childbearing age
  • Life expectancy <12 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): NCT03285438


Contacts
Contact: Francis COUTURAUD, PhD 2 98 34 73 48 ext +33 francis.couturaud@chu-brest.fr
Contact: Sophie BARILLOT sophie.barillot@chu-brest.fr

Locations
France
CHU Amiens-Picardie Recruiting
Amiens, France, 80054
Contact: Marie-Antoinette SEVESTRE PIETRI, PH       sevestre.marie-antoinette@chu-amiens.fr   
CHU Angers Recruiting
Angers, France
Contact: Pierre-Marie ROY, PUPH       PMRoy@chu-angers.fr   
CH d'Arras Not yet recruiting
Arras, France, 62022
Contact: Sandro AQUILANTI, PH       saquilanti@nordnet.fr   
CHU de Besançon - Hôpital Jean Minjoz Recruiting
Besançon, France, 25000
Contact: Nicolas MENEVEAU, PH       nicolas.meneveau@univ-fcomte.fr   
CH Bordeaux Recruiting
Bordeaux, France, 33075
Contact: Joël CONSTANS, PUPH       joel.constans@chu-bordeaux.fr   
Sub-Investigator: Sophie SKOPINSKI, PH         
HIA Brest Recruiting
Brest, France, 29240
Contact: Gwénolé ROHEL         
CHRU de Brest Recruiting
Brest, France, 29609
Contact: Francis COUTURUAD, PhD       francis.couturaud@chu-brest.fr   
Contact: Sophie BARILLOT       sophie.barillot@chu-brest.fr   
Clinique de Clapiers Recruiting
Castelnau le Lez, France, 34170
Contact: Dominique BRISOT         
Principal Investigator: Dominique BRISOT         
HIA Percy Not yet recruiting
Clamart, France, 92141
Contact: Caroline DOUTRELON         
Principal Investigator: Caroline DOUTRELON         
Cabinet médical Recruiting
Clapiers, France, 34830
Contact: Dominique Brisot         
CHU de Clermont Ferrand - Hôpital Gabriel Montpied Recruiting
Clermont-Ferrand, France, 63003
Contact: Jeannot SCHMIDT, PUPH       jschmidt@chu-clermontferrand.fr   
APHP Hôpital Louis Mourier Recruiting
Colombes, France, 92700
Contact: Isabelle MAHE, PH       isabelle.mahe@lmr.aphp.fr   
CHU de Dijon Recruiting
Dijon, France, 21079
Contact: Nicolas FALVO, PH       nicolas.falvo@chu-dijon.fr   
CHU de Grenoble - Hôpital Nord Michallon Recruiting
Grenoble, France, 38700
Contact: Gilles PERNOD, PUPH       Gpernod@chu-grenoble.fr   
GH Le Havre Not yet recruiting
Le Havre, France, 76290
Contact: L BOUCHRA    02 32 73 31 95    bouchra.lamia@ch-havre.fr   
Principal Investigator: Lamia BOUCHRA         
CH Le Mans Not yet recruiting
Le Mans, France, 72 000
Contact: Claire NEVEUX    02 43 43 43 43    cneveu@ch-lemans.fr   
Principal Investigator: Claire NEVEUX         
CHU de Limoges - Hôpital de Dupuytren Not yet recruiting
Limoges, France, 87042
Contact: Philippe LACROIX, PH       philippe.lacroix@unilim.fr   
CH Morlaix Recruiting
Morlaix, France, 29 672
Contact: Julien BOILEAU    02 98 62 61 60    jboileau@ch-morlaix.fr   
Principal Investigator: Julien BOILEAU         
Chru Nancy Not yet recruiting
Nancy, France, 54511
Contact: Stéphane ZUILY, PhD       s.zuily@chru-nancy.fr   
CHU de Nantes Recruiting
Nantes, France, 44000
Contact: Pierre POTTIER, PH       pierre.pottier@univ-nantes.fr   
CHU de Nice - Hôpital Pasteur Not yet recruiting
Nice, France, 06002
Contact: Emilie FERRARI, PUPH       emile.ferrari@chu-nice.fr   
CHU Nîmes Recruiting
Nîmes, France, 30 029
Contact: Valérie RAY    04 66 68 30 30    valerie.RAY@chu-nimes.fr   
Principal Investigator: Valérie RAY         
CHR Orléans Recruiting
Orléans, France, 45100
Contact: Azzedine YAICI, PH       azzedine.yaici@chr-orleans.fr   
Hôpital de Cochin Recruiting
Paris, France, 75014
Contact: Claire LEJEUNNE, PUPH       claire.le-jeunne@htd.aphp.fr   
HEGP Recruiting
Paris, France, 75015
Contact: Guy MEYER, PUPH       guy.meyer@egp.aphp.fr   
Sub-Investigator: Olivier SANCHEZ, PUPH         
CHU Paris Nord Val de Seine Not yet recruiting
Paris, France, 75018
Contact: Bruno CRESTANI, PUPH       bruno.crestani@bch.aphp.fr   
HEGP Recruiting
Paris, France
Contact: Emmanuel MESSAS       emmanuel.messas@egp.aphp.fr   
Kremlin Bicêtre Recruiting
Paris, France
Contact: Flroence PARENT, PH       florence.parent@bct.aphp.fr   
CH de Périgueux Not yet recruiting
Périgueux, France, 24019
Contact: Alain MOUKARZEL         
Principal Investigator: Alain MOUKARZEL         
CH de Quimper Recruiting
Quimper, France, 29107
Contact: Brigitte PAN-PETESCH, PH       brigitte.pan-petesch@chu-brest.fr   
CHU de Rennes - Hôpital Sud Recruiting
Rennes, France, 35203
Contact: Patrick JEGO       patrick.jego@chu-rennes.fr   
CHU de ROUEN Recruiting
Rouen, France, 76000
Contact: Ygal BENHAMOU, PH       ygal.benhamou@chu-rouen.fr   
CH de Saint Brieuc - Hôpital Yves Le Foll Recruiting
Saint-Brieuc, France, 22000
Contact: Elisabeth DUHAMEL, PH       elisabeth.duhamel@ch-stbrieuc.fr   
CHU de Saint Etienne - Hôpital Nord Recruiting
Saint-Étienne, France, 42055
Contact: Laurent BERTOLETTI, PUPH       laurent.bertoletti@chu-st-etienne.fr   
Sub-Investigator: Patrick MISMETTI, PUPH         
CH de Toulon - Hôpital Sainte-Musse Recruiting
Toulon, France, 83056
Contact: Antoine ELIAS, PUPH       antoine.elias@ch-toulon.fr   
HIA Sainte-Anne Not yet recruiting
Toulon, France, 83800
Contact: Hélène BARAZZUTTI    04 83 16 25 13    helene.barazzutti@gmail.com   
Principal Investigator: Hélène BARAZZUTTI         
CHU de Toulouse - Hôpital de Rangueil Recruiting
Toulouse, France, 31059
Contact: François-Xavier LAPEBIE, PH       lapebie.fx@chu-toulouse.fr   
Sub-Investigator: Alessandra BURA RIVIERE, PUPH         
CHU de Tours - Hôpital Trousseau Not yet recruiting
Tours, France, 37170
Contact: Yves Gruel, PUPH       gruel@med.univ-tours.fr   
Sub-Investigator: Denis ANGOULVANT         
CH Valenciennes Not yet recruiting
Valenciennes, France, 59 322
Contact: Thomas QUEMENEUR    03 27 14 30 89    quemeneur-t@ch-valenciennes.fr   
Principal Investigator: Thomas QUEMENEUR         
Sponsors and Collaborators
University Hospital, Brest
University Hospital of Saint-Etienne

Responsible Party: University Hospital, Brest
ClinicalTrials.gov Identifier: NCT03285438     History of Changes
Other Study ID Numbers: 29BRC17.0125 RENOVE
First Posted: September 18, 2017    Key Record Dates
Last Update Posted: August 23, 2018
Last Verified: August 2018
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 University Hospital, Brest:
Venous Thromboembolism
Anticoagulant
Direct oral anticoagulant
risk of recurrent venous thromboembolism
anticoagulant-related bleeding

Additional relevant MeSH terms:
Embolism and Thrombosis
Thromboembolism
Venous Thromboembolism
Vascular Diseases
Cardiovascular Diseases
Rivaroxaban
Apixaban
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action