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Trial record 1 of 1 for:    NCT03285438​
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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 : January 2, 2020
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

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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
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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
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Sponsors and Collaborators
University Hospital, Brest
University Hospital of Saint-Etienne
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Responsible Party: University Hospital, Brest
ClinicalTrials.gov Identifier: NCT03285438    
Other Study ID Numbers: 29BRC17.0125 RENOVE
First Posted: September 18, 2017    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Thromboembolism
Venous Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases