<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03285438</url>
  </required_header>
  <id_info>
    <org_study_id>29BRC17.0125</org_study_id>
    <nct_id>NCT03285438</nct_id>
  </id_info>
  <brief_title>REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism.</brief_title>
  <acronym>RENOVE</acronym>
  <official_title>REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Brest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital of Saint-Etienne</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Brest</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk&#xD;
      factors have a high risk of recurrence after stopping anticoagulation. In these patients,&#xD;
      international guidelines recommend indefinite anticoagulation. However, prolonged use of&#xD;
      warfarin or DOAC at therapeutic dose is associated with a significant risk of bleeding.&#xD;
      Consequently, it has been hypothesized that extended anticoagulation at lower dosage might be&#xD;
      as effective as and safer than full dose of anticoagulation. However, low-dose warfarin (INR&#xD;
      1.5-2) was less effective and not safer than conventional dose warfarin (INR 2-3).&#xD;
&#xD;
      Low dose of DOAC has the potential to validate this hypothesis. In a first randomized trial&#xD;
      comparing full-dose or low-dose apixaban with a placebo during an additional one year of&#xD;
      anticoagulation in patients where physicians were uncertain for prolonging anticoagulation&#xD;
      (&quot;Amplify-extension trial&quot;), low-dose apixaban was more effective than placebo without any&#xD;
      major concern regarding safety and possibly as effective as and safer than full-dose&#xD;
      apixaban; in a second randomized trial comparing full-dose or low-dose rivaroxaban with&#xD;
      aspirin, during an additional one year of anticoagulation in patients where physicians were&#xD;
      uncertain for prolonging anticoagulation (&quot;Einstein-Choice trial&quot;), low-dose rivaroxaban was&#xD;
      more effective than aspirin without any major concern regarding safety and possibly as&#xD;
      effective as and safer than full-dose rivaroxaban. However, these two studies were not&#xD;
      designed and powered to demonstrate non-inferiority on efficacy and superiority on safety of&#xD;
      a reduced dose of DOAC versus a full dose DOAC and the selected population did not have&#xD;
      strong indications for indefinite anticoagulation. Thus, there is currently no evidence to&#xD;
      recommend a reduced dose rather than a full dose of DOAC for extended therapy in patients at&#xD;
      high risk of recurrent VTE. Consequently, a randomized trial comparing low-dose DOAC with&#xD;
      full-dose DOAC therapy in patients at high risk of recurrent VTE is needed and justified.&#xD;
&#xD;
      Main hypothesis:&#xD;
&#xD;
      After VTE at high risk of recurrence initially treated during 6 (-15 days) to 24 (+ 3 months)&#xD;
      uninterrupted months, a reduced dose of DOAC will be non-inferior to a full dose of DOAC in&#xD;
      terms of recurrent VTE during extended anticoagulation phase.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk&#xD;
      factors have a high risk of recurrence after stopping anticoagulation. In the &quot;PADIS-PE&quot;&#xD;
      trial comparing an additional 18 months of warfarin (target international normalized ratio&#xD;
      (INR) from 2 to 3) versus placebo in 371 patients who have completed 6 months of&#xD;
      anticoagulation for a first unprovoked pulmonary embolism, the PADIS-PE trial confirmed that&#xD;
      prolonged warfarin therapy was highly effective for preventing recurrent VTE but that benefit&#xD;
      was lost after stopping anticoagulation. In another trial, similar findings had been reported&#xD;
      using direct oral anticoagulants (DOAC) at therapeutic dose. These results reinforce&#xD;
      international recommendation for indefinite anticoagulation in patients at high risk of&#xD;
      recurrent VTE (unprovoked VTE, recurrent VTE or persistent risk factors).&#xD;
&#xD;
      However, prolonged use of warfarin or DOAC at therapeutic dose is associated with a&#xD;
      significant risk of bleeding. Consequently, it has been hypothesized that extended&#xD;
      anticoagulation at lower dosage might be as effective as and safer than full dose of&#xD;
      anticoagulation. However, low-dose warfarin (INR 1.5-2) was less effective and not safer than&#xD;
      conventional dose warfarin (INR 2-3).&#xD;
&#xD;
      Low dose of DOAC has the potential to validate this hypothesis. First, DOACs have been shown&#xD;
      to be as effective as and safer than warfarin (INR 2-3) during the first 6 months of&#xD;
      anticoagulation after an acute VTE. Second, in a first randomized trial comparing full-dose&#xD;
      or low-dose apixaban with a placebo during an additional one year of anticoagulation in&#xD;
      patients where physicians were uncertain for prolonging anticoagulation (&quot;Amplify-extension&#xD;
      trial&quot;), low-dose apixaban was more effective than placebo without any major concern&#xD;
      regarding safety and possibly as effective as and safer than full-dose apixaban; in a second&#xD;
      randomized trial comparing full-dose or low-dose rivaroxaban with aspirin, during an&#xD;
      additional one year of anticoagulation in patients where physicians were uncertain for&#xD;
      prolonging anticoagulation (&quot;Einstein-Choice trial&quot;), low-dose rivaroxaban was more effective&#xD;
      than aspirin without any major concern regarding safety and possibly as effective as and&#xD;
      safer than full-dose rivaroxaban. However, these two studies were not designed and powered to&#xD;
      demonstrate non-inferiority on efficacy and superiority on safety of a reduced dose of DOAC&#xD;
      versus a full dose DOAC and the selected population did not have strong indications for&#xD;
      indefinite anticoagulation. Thus, there is currently no evidence to recommend a reduced dose&#xD;
      rather than a full dose of DOAC for extended therapy in patients at high risk of recurrent&#xD;
      VTE. Consequently, a randomized trial comparing low-dose DOAC with full-dose DOAC therapy in&#xD;
      patients at high risk of recurrent VTE is needed and justified.&#xD;
&#xD;
      Main hypothesis:&#xD;
&#xD;
      After VTE at high risk of recurrence initially treated during 6 (-15 days) to 24 (+3 months)&#xD;
      uninterrupted months, a reduced dose of DOAC will be non-inferior to a full dose of DOAC in&#xD;
      terms of recurrent VTE during extended anticoagulation phase.&#xD;
&#xD;
      Design&#xD;
&#xD;
      The &quot;RENOVE&quot; trial is designed as an academic, multicenter, open, with blind evaluation&#xD;
      (PROBE), randomized, parallel arm, controlled, trial sponsored by the Brest University&#xD;
      Hospital Center. Patients meeting the inclusion criteria will be randomized at visit 1 (day&#xD;
      0) and allocated to receive:&#xD;
&#xD;
        -  either a reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroaxaban 10 mg once&#xD;
           daily) during a mean follow-up period of 36 months.&#xD;
&#xD;
        -  or a full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily)&#xD;
           during a mean follow-up period of 36 months.&#xD;
&#xD;
      The study is powered to demonstrate the following hypotheses using a three steps hierarchical&#xD;
      analysis:&#xD;
&#xD;
        -  Primary hypothesis: non-inferiority of a reduced dose of DOAC as compared to a full dose&#xD;
           of DOAC on the risk of recurrent VTE;&#xD;
&#xD;
        -  Secondary hypothesis: in case of the confirmation of the previous hypothesis,&#xD;
           superiority of a reduced dose of DOAC on the risk of major or clinically relevant&#xD;
           non-major bleeding.&#xD;
&#xD;
        -  Third hypothesis: in case of the confirmation of the previous hypothesis, superiority of&#xD;
           a reduced dose of DOAC on the risk of the composite of recurrent VTE, major bleeding or&#xD;
           clinically relevant non major bleeding.&#xD;
&#xD;
      Randomization will be centralized and stratified on:&#xD;
&#xD;
        -  Center&#xD;
&#xD;
        -  Type of DOAC&#xD;
&#xD;
        -  antiplatelet agent taking&#xD;
&#xD;
      At visit 1, patients will have a therapeutic education and they will be instructed to call&#xD;
      research team in case of any medical event during the study treatment period. Follow-up&#xD;
      visits will be planned at 3, 6, 12 months and every 6 months until study end (i.e.; after the&#xD;
      last included patient has achieved 12-month of study treatment period).&#xD;
&#xD;
      All critical events will be adjudicated by an independent adjudication committee blinded from&#xD;
      the treatment allocation. A data safety board will be constituted and will meet on a regular&#xD;
      basis. Duration of each patient's participation will be on average 36 months (12 months for&#xD;
      the last included patient) and a total duration of the study is expected for 65 months.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        -  Main Objective&#xD;
&#xD;
           • To demonstrate that a reduced dose of DOAC is non-inferior to a full dose of DOAC for&#xD;
           the risk of recurrent VTE during the during a mean study treatment period of 36 months&#xD;
           in patients with VTE that warrants indefinite anticoagulation and who have been&#xD;
           initially treated for 6 (-15 days) to 24 (+3 months) uninterrupted months.&#xD;
&#xD;
        -  Secondary Objectives&#xD;
&#xD;
           • Key secondary objectives: if the main objective is verified, key secondary objectives&#xD;
           are to demonstrate the superiority of a reduced dose of DOAC over a full dose of DOAC&#xD;
           during a mean study treatment period of 36 months :&#xD;
&#xD;
        -  on the risk of major or CRNMB and, if confirmed,&#xD;
&#xD;
        -  on the composite of recurrent VTE, major bleeding or CRNMB.&#xD;
&#xD;
           • Other secondary objectives:&#xD;
&#xD;
        -  To evaluate the benefit of a reduced dose of DOAC on the risk of major bleeding during a&#xD;
           mean study treatment period of 36 months&#xD;
&#xD;
        -  To evaluate the benefit of a reduced dose of DOAC on the composite outcome of recurrent&#xD;
           VTE and major bleeding during a mean study treatment period of 36 months&#xD;
&#xD;
        -  To determine the impact of a reduced dose of DOAC on deaths of all causes and deaths&#xD;
           related to recurrent VTE or major bleeding during a mean study treatment period of 36&#xD;
           months&#xD;
&#xD;
        -  To evaluate dyspnea and post-thrombotic syndrome (villalta score)(65).&#xD;
&#xD;
        -  To evaluate compliance treatment using the Morisky auto-questionnaire (66,67)&#xD;
&#xD;
        -  To analyse the treatment effect on recurrent VTE and major bleeding and CRNM among&#xD;
           predefined sub-groups (screening for heterogeneity among predefined strata).&#xD;
&#xD;
      Sample size justification&#xD;
&#xD;
      A- Initial hypothesis before starting enrolment in the RENOVE study:&#xD;
&#xD;
      The study is powered to demonstrate the following hypotheses using a three steps hierarchical&#xD;
      analysis:&#xD;
&#xD;
        -  Primary hypothesis: non-inferiority of a reduced dose of DOAC as compared to a full dose&#xD;
           of DOAC on the risk of recurrent VTE. Based on an expected rate of recurrent VTE of&#xD;
           2%/year (4% during the entire study period) in each group and a requirement that the&#xD;
           study would have 90% power to exclude a hazard ratio of 1.7 for the primary outcome with&#xD;
           a reduced dose of DOAC, at a two-sided alpha level of 0.05, 1030 patients need to be&#xD;
           included in each treatment group.&#xD;
&#xD;
        -  Secondary hypothesis: in case of the confirmation of the previous hypothesis,&#xD;
           superiority of a reduced dose of DOAC on the risk of major or clinically relevant&#xD;
           non-major bleeding. Assuming an estimated incidence in the warfarin group of 10% in the&#xD;
           entire study period and a reduction in the relative risk of at least 35% with a reduced&#xD;
           dose of DOAC as compared with a full dose of DOAC, 966 patients in each group for the&#xD;
           study to have 80% power to show the superiority of a reduced dose of DOAC over a full&#xD;
           dose of DOAC, at a two-sided alpha level of 0.05.&#xD;
&#xD;
        -  Third hypothesis: in case of the confirmation of the previous hypothesis, superiority of&#xD;
           a reduced dose of DOAC on the risk of the composite of recurrent VTE, major bleeding or&#xD;
           clinically relevant non major bleeding. Assuming an estimated incidence in the full dose&#xD;
           DOAC group of 14% and 10% in the a reduced dose of DOAC group in the entire study&#xD;
           period, 1029 patients in each group for the study to have 80% power to show the&#xD;
           superiority of a reduced dose of DOAC over a full dose of DOAC, at a two-sided alpha&#xD;
           level of 0.05.&#xD;
&#xD;
      Taking in account 5% of loss to follow-up, a total of 2200 patients are required in order to&#xD;
      be able to confirm these three conditional hypotheses.&#xD;
&#xD;
      All estimates were calculated based on major randomized trials on extended anticoagulation in&#xD;
      VTE patients.&#xD;
&#xD;
      B- New hypothesis based on observed primary endpoint at 2147 included patients:&#xD;
&#xD;
      On February, 12th 2021, 27 recurrent VTE, all adjudicated, occurred on 2147 included&#xD;
      patients, during a mean follow-up of 12 months.&#xD;
&#xD;
        -  From 0 to 12 months, there were 15 recurrent VTE in 2147 patients during this period&#xD;
           (0.7%); and&#xD;
&#xD;
        -  from 12 to 24 months, there were 12 recurrent VTE in 1551 patients during this period&#xD;
           (0.8%).&#xD;
&#xD;
        -  The incidence of recurrence seems to be linear, with 0.75% patients with recurrent VTE&#xD;
           during a mean follow-up of 12 months. Consequently, the expected proportion of recurrent&#xD;
           VTE during 24 months will be 1.5% and not 4% as previously expected before study&#xD;
           started.&#xD;
&#xD;
        -  The scientific committee, blinded of treatment group, decided to increase both the&#xD;
           number of sample size and the follow-up with a new &quot;first&quot; hypothesis on recurrent VTE:&#xD;
&#xD;
        -  New First hypothesis: same non inferiority of a reduced dose of DOAC compared to a full&#xD;
           dose of DOAC on the risk of recurrent VTE. Based on a new expected rate of recurrent VTE&#xD;
           of 3% in each group during the entire study period for the same power (90%) and the same&#xD;
           alpha level (two-side alpha level of 0.05), with a similar hazard ratio non-inferiority&#xD;
           margin, i.e., 1.7, 1387 patients need to be included in each treatment group. Thus, a&#xD;
           total of 2774 patients need to be recruited, which correspond to 574 patients in&#xD;
           addition to 2200. Keeping in mind that the recruitment is 60 patients per months, the&#xD;
           time to recruit 574 additional patients will take 6 months. We will stop the study after&#xD;
           the last included patient has been followed at least 12 months. Thus, the study is&#xD;
           prolonged by 18 additional months (6 to 8 months recruitment + 12-month follow up of the&#xD;
           last patient).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 2, 2017</start_date>
  <completion_date type="Anticipated">October 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The trial is designed as an academic, multicenter, open, with blind evaluation (PROBE), randomized, parallel arm, controlled.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recurrent VTE</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Major and clinically relevant non major bleeding</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The composite of recurrent VTE or major bleeding or non major clinically relevant bleeding</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>The composite of adjudicated recurrent VTE or major bleeding or non major clinically relevant bleeding during the study treatment period will be adjudicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>Mortality of other cause than recurrent VTE or major or clinically relevant non major bleeding during the study treatment period will be adjudicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compliance</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>Treatment compliance will be evaluated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment effect</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>The heterogeneity of the treatment effect on predefined strata will be evaluated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial cardio-vascular events</measure>
    <time_frame>during a mean study treatment period of 36 months</time_frame>
    <description>The arterial cardio-vascular events (myocardial infarction, stroke, cardio-vascular complication other than VTE) will be evaluated</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">2774</enrollment>
  <condition>Venous Thromboembolism</condition>
  <arm_group>
    <arm_group_label>Reduced dose of DOAC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) during a mean follow-up period of 36 months (12 to 65 months)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Full dose of DOAC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily) during a mean follow-up period of 36 months (12 to 65 months).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Reduced dose of DOAC</intervention_name>
    <description>The patient will receive apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily during a mean follow-up period of 36 months (12 to 65 months)</description>
    <arm_group_label>Reduced dose of DOAC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Full dose of DOAC</intervention_name>
    <description>The patient will receive apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily during a mean follow-up period of 36 months (12 to 65 months)</description>
    <arm_group_label>Full dose of DOAC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients &gt;18 years&#xD;
&#xD;
          -  Patients with indications for long-term anticoagulation after VTE (i.e.; symptomatic&#xD;
             PE or proximal DVT) initially treated during 6 (-15 days) to 24 months (+ 3 months) :&#xD;
&#xD;
               -  Patients with multiple episodes of VTE, or&#xD;
&#xD;
               -  Patients with a first episode of unprovoked* VTE&#xD;
&#xD;
               -  Patients with VTE associated with persistent risk factor**, or&#xD;
&#xD;
               -  Patients for whom clinicians feel that indefinite anticoagulation is warranted&#xD;
&#xD;
          -  Social security affiliation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergy to rivaroxaban and apixaban, allergy to any of the excipients&#xD;
&#xD;
          -  Indication for therapeutic dose anticoagulant therapy&#xD;
&#xD;
          -  Unable or refusal to give informed consent&#xD;
&#xD;
          -  Isolated distal DVT&#xD;
&#xD;
          -  HERDOO2 score ≤ 1&#xD;
&#xD;
          -  Indication for anticoagulation other than DVT or PE (e.g.; atrial fibrillation,&#xD;
             mechanic valves…)&#xD;
&#xD;
          -  Treatment with investigational drug in the past 1 month except for patients benefiting&#xD;
             from an anticoagulant at therapeutic doses for the initial pathology&#xD;
&#xD;
          -  Interruption of anticoagulation for 14 days or more before the inclusion&#xD;
&#xD;
          -  Chronic liver disease or chronic hepatitis&#xD;
&#xD;
          -  Patient considered at high risk of bleeding (eg: previous gastro-intestinal tract&#xD;
             bleeding in the past three months, uncontrolled hypertension, etc.)&#xD;
&#xD;
          -  Renal insufficiency with creatinine &lt;25 ml / min on Cockcroft and Gault formula&#xD;
&#xD;
          -  Antiphospholipid syndrome&#xD;
&#xD;
          -  Dual anti-platelet therapy or aspirin at dosage &gt;100 mg per day&#xD;
&#xD;
          -  Concomitant use of a strong inhibitor of cytochrome P-450 3A4 (CYP3A4) (e.g., a&#xD;
             protease inhibitor for human immunodeficiency virus infection or azole-antimycotics&#xD;
             agents ketoconazole, itraconazole, voriconazole, posaconazole) or a CYP3A4 inducer&#xD;
             (e.g., rifampin, carbamazepine, or phenytoin),&#xD;
&#xD;
          -  Active cancer of less than 6 months&#xD;
&#xD;
          -  Active pregnancy or expected pregnancy&#xD;
&#xD;
          -  No effective contraception in women of childbearing age&#xD;
&#xD;
          -  Life expectancy &lt;12 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CHU Amiens-Picardie</name>
      <address>
        <city>Amiens</city>
        <zip>80054</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH d'Arras</name>
      <address>
        <city>Arras</city>
        <zip>62022</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Besançon - Hôpital Jean Minjoz</name>
      <address>
        <city>Besançon</city>
        <zip>25000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Bordeaux</name>
      <address>
        <city>Bordeaux</city>
        <zip>33075</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HIA Brest</name>
      <address>
        <city>Brest</city>
        <zip>29240</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Brest</name>
      <address>
        <city>Brest</city>
        <zip>29609</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique de Clapiers</name>
      <address>
        <city>Castelnau le Lez</city>
        <zip>34170</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HIA Percy</name>
      <address>
        <city>Clamart</city>
        <zip>92141</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cabinet médical</name>
      <address>
        <city>Clapiers</city>
        <zip>34830</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Clermont Ferrand - Hôpital Gabriel Montpied</name>
      <address>
        <city>Clermont-Ferrand</city>
        <zip>63003</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHP Hôpital Louis Mourier</name>
      <address>
        <city>Colombes</city>
        <zip>92700</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Dijon</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Grenoble - Hôpital Nord Michallon</name>
      <address>
        <city>Grenoble</city>
        <zip>38700</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GH Le Havre</name>
      <address>
        <city>Le Havre</city>
        <zip>76290</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Le Mans</name>
      <address>
        <city>Le Mans</city>
        <zip>72 000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges - Hôpital de Dupuytren</name>
      <address>
        <city>Limoges</city>
        <zip>87042</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Morlaix</name>
      <address>
        <city>Morlaix</city>
        <zip>29 672</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chru Nancy</name>
      <address>
        <city>Nancy</city>
        <zip>54511</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Nantes</name>
      <address>
        <city>Nantes</city>
        <zip>44000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Nice - Hôpital Pasteur</name>
      <address>
        <city>Nice</city>
        <zip>06002</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Nîmes</name>
      <address>
        <city>Nîmes</city>
        <zip>30 029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHR Orléans</name>
      <address>
        <city>Orléans</city>
        <zip>45100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital de Cochin</name>
      <address>
        <city>Paris</city>
        <zip>75014</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HEGP</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Paris Nord Val de Seine</name>
      <address>
        <city>Paris</city>
        <zip>75018</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HEGP</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kremlin Bicêtre</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Périgueux</name>
      <address>
        <city>Périgueux</city>
        <zip>24019</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Quimper</name>
      <address>
        <city>Quimper</city>
        <zip>29107</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Rennes - Hôpital Sud</name>
      <address>
        <city>Rennes</city>
        <zip>35203</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de ROUEN</name>
      <address>
        <city>Rouen</city>
        <zip>76000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Saint Brieuc - Hôpital Yves Le Foll</name>
      <address>
        <city>Saint-Brieuc</city>
        <zip>22000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Saint Etienne - Hôpital Nord</name>
      <address>
        <city>Saint-Étienne</city>
        <zip>42055</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Toulon - Hôpital Sainte-Musse</name>
      <address>
        <city>Toulon</city>
        <zip>83056</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HIA Sainte-Anne</name>
      <address>
        <city>Toulon</city>
        <zip>83800</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Toulouse - Hôpital de Rangueil</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Tours - Hôpital Trousseau</name>
      <address>
        <city>Tours</city>
        <zip>37170</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Valenciennes</name>
      <address>
        <city>Valenciennes</city>
        <zip>59 322</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>September 14, 2017</study_first_submitted>
  <study_first_submitted_qc>September 14, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 18, 2017</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Venous Thromboembolism</keyword>
  <keyword>Anticoagulant</keyword>
  <keyword>Direct oral anticoagulant</keyword>
  <keyword>risk of recurrent venous thromboembolism</keyword>
  <keyword>anticoagulant-related bleeding</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thromboembolism</mesh_term>
    <mesh_term>Venous Thromboembolism</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03285438
org study id: 29BRC17.0125
nct id: NCT03285438
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
Patients with unprovoked venous thromboembolism (VTE) or VTE associated with persistent risk
      factors have a high risk of recurrence after stopping anticoagulation. In the "PADIS-PE"
      trial comparing an additional 18 months of warfarin (target international normalized ratio
      (INR) from 2 to 3) versus placebo in 371 patients who have completed 6 months of
      anticoagulation for a first unprovoked pulmonary embolism, the PADIS-PE trial confirmed that
      prolonged warfarin therapy was highly effective for preventing recurrent VTE but that benefit
      was lost after stopping anticoagulation. In another trial, similar findings had been reported
      using direct oral anticoagulants (DOAC) at therapeutic dose. These results reinforce
      international recommendation for indefinite anticoagulation in patients at high risk of
      recurrent VTE (unprovoked VTE, recurrent VTE or persistent risk factors).

      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. First, DOACs have been shown
      to be as effective as and safer than warfarin (INR 2-3) during the first 6 months of
      anticoagulation after an acute VTE. Second, 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.

      Design

      The "RENOVE" trial is designed as an academic, multicenter, open, with blind evaluation
      (PROBE), randomized, parallel arm, controlled, trial sponsored by the Brest University
      Hospital Center. Patients meeting the inclusion criteria will be randomized at visit 1 (day
      0) and allocated to receive:

        -  either a reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroaxaban 10 mg once
           daily) during a mean follow-up period of 36 months.

        -  or a full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily)
           during a mean follow-up period of 36 months.

      The study is powered to demonstrate the following hypotheses using a three steps hierarchical
      analysis:

        -  Primary hypothesis: non-inferiority of a reduced dose of DOAC as compared to a full dose
           of DOAC on the risk of recurrent VTE;

        -  Secondary hypothesis: in case of the confirmation of the previous hypothesis,
           superiority of a reduced dose of DOAC on the risk of major or clinically relevant
           non-major bleeding.

        -  Third hypothesis: in case of the confirmation of the previous hypothesis, superiority of
           a reduced dose of DOAC on the risk of the composite of recurrent VTE, major bleeding or
           clinically relevant non major bleeding.

      Randomization will be centralized and stratified on:

        -  Center

        -  Type of DOAC

        -  antiplatelet agent taking

      At visit 1, patients will have a therapeutic education and they will be instructed to call
      research team in case of any medical event during the study treatment period. Follow-up
      visits will be planned at 3, 6, 12 months and every 6 months until study end (i.e.; after the
      last included patient has achieved 12-month of study treatment period).

      All critical events will be adjudicated by an independent adjudication committee blinded from
      the treatment allocation. A data safety board will be constituted and will meet on a regular
      basis. Duration of each patient's participation will be on average 36 months (12 months for
      the last included patient) and a total duration of the study is expected for 65 months.

      Objectives:

        -  Main Objective

           • To demonstrate that a reduced dose of DOAC is non-inferior to a full dose of DOAC for
           the risk of recurrent VTE during the during a mean study treatment period of 36 months
           in patients with VTE that warrants indefinite anticoagulation and who have been
           initially treated for 6 (-15 days) to 24 (+3 months) uninterrupted months.

        -  Secondary Objectives

           • Key secondary objectives: if the main objective is verified, key secondary objectives
           are to demonstrate the superiority of a reduced dose of DOAC over a full dose of DOAC
           during a mean study treatment period of 36 months :

        -  on the risk of major or CRNMB and, if confirmed,

        -  on the composite of recurrent VTE, major bleeding or CRNMB.

           • Other secondary objectives:

        -  To evaluate the benefit of a reduced dose of DOAC on the risk of major bleeding during a
           mean study treatment period of 36 months

        -  To evaluate the benefit of a reduced dose of DOAC on the composite outcome of recurrent
           VTE and major bleeding during a mean study treatment period of 36 months

        -  To determine the impact of a reduced dose of DOAC on deaths of all causes and deaths
           related to recurrent VTE or major bleeding during a mean study treatment period of 36
           months

        -  To evaluate dyspnea and post-thrombotic syndrome (villalta score)(65).

        -  To evaluate compliance treatment using the Morisky auto-questionnaire (66,67)

        -  To analyse the treatment effect on recurrent VTE and major bleeding and CRNM among
           predefined sub-groups (screening for heterogeneity among predefined strata).

      Sample size justification

      A- Initial hypothesis before starting enrolment in the RENOVE study:

      The study is powered to demonstrate the following hypotheses using a three steps hierarchical
      analysis:

        -  Primary hypothesis: non-inferiority of a reduced dose of DOAC as compared to a full dose
           of DOAC on the risk of recurrent VTE. Based on an expected rate of recurrent VTE of
           2%/year (4% during the entire study period) in each group and a requirement that the
           study would have 90% power to exclude a hazard ratio of 1.7 for the primary outcome with
           a reduced dose of DOAC, at a two-sided alpha level of 0.05, 1030 patients need to be
           included in each treatment group.

        -  Secondary hypothesis: in case of the confirmation of the previous hypothesis,
           superiority of a reduced dose of DOAC on the risk of major or clinically relevant
           non-major bleeding. Assuming an estimated incidence in the warfarin group of 10% in the
           entire study period and a reduction in the relative risk of at least 35% with a reduced
           dose of DOAC as compared with a full dose of DOAC, 966 patients in each group for the
           study to have 80% power to show the superiority of a reduced dose of DOAC over a full
           dose of DOAC, at a two-sided alpha level of 0.05.

        -  Third hypothesis: in case of the confirmation of the previous hypothesis, superiority of
           a reduced dose of DOAC on the risk of the composite of recurrent VTE, major bleeding or
           clinically relevant non major bleeding. Assuming an estimated incidence in the full dose
           DOAC group of 14% and 10% in the a reduced dose of DOAC group in the entire study
           period, 1029 patients in each group for the study to have 80% power to show the
           superiority of a reduced dose of DOAC over a full dose of DOAC, at a two-sided alpha
           level of 0.05.

      Taking in account 5% of loss to follow-up, a total of 2200 patients are required in order to
      be able to confirm these three conditional hypotheses.

      All estimates were calculated based on major randomized trials on extended anticoagulation in
      VTE patients.

      B- New hypothesis based on observed primary endpoint at 2147 included patients:

      On February, 12th 2021, 27 recurrent VTE, all adjudicated, occurred on 2147 included
      patients, during a mean follow-up of 12 months.

        -  From 0 to 12 months, there were 15 recurrent VTE in 2147 patients during this period
           (0.7%); and

        -  from 12 to 24 months, there were 12 recurrent VTE in 1551 patients during this period
           (0.8%).

        -  The incidence of recurrence seems to be linear, with 0.75% patients with recurrent VTE
           during a mean follow-up of 12 months. Consequently, the expected proportion of recurrent
           VTE during 24 months will be 1.5% and not 4% as previously expected before study
           started.

        -  The scientific committee, blinded of treatment group, decided to increase both the
           number of sample size and the follow-up with a new "first" hypothesis on recurrent VTE:

        -  New First hypothesis: same non inferiority of a reduced dose of DOAC compared to a full
           dose of DOAC on the risk of recurrent VTE. Based on a new expected rate of recurrent VTE
           of 3% in each group during the entire study period for the same power (90%) and the same
           alpha level (two-side alpha level of 0.05), with a similar hazard ratio non-inferiority
           margin, i.e., 1.7, 1387 patients need to be included in each treatment group. Thus, a
           total of 2774 patients need to be recruited, which correspond to 574 patients in
           addition to 2200. Keeping in mind that the recruitment is 60 patients per months, the
           time to recruit 574 additional patients will take 6 months. We will stop the study after
           the last included patient has been followed at least 12 months. Thus, the study is
           prolonged by 18 additional months (6 to 8 months recruitment + 12-month follow up of the
           last patient).
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.
primary purpose: Prevention
masking: Single (Outcomes Assessor)
measure: Recurrent VTE
time frame: during a mean study treatment period of 36 months
description: Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.
measure: Major and clinically relevant non major bleeding
time frame: during a mean study treatment period of 36 months
description: 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
measure: The composite of recurrent VTE or major bleeding or non major clinically relevant bleeding
time frame: during a mean study treatment period of 36 months
description: The composite of adjudicated recurrent VTE or major bleeding or non major clinically relevant bleeding during the study treatment period will be adjudicated
measure: Mortality
time frame: during a mean study treatment period of 36 months
description: Mortality of other cause than recurrent VTE or major or clinically relevant non major bleeding during the study treatment period will be adjudicated
measure: Compliance
time frame: during a mean study treatment period of 36 months
description: Treatment compliance will be evaluated
measure: Treatment effect
time frame: during a mean study treatment period of 36 months
description: The heterogeneity of the treatment effect on predefined strata will be evaluated
measure: Arterial cardio-vascular events
time frame: during a mean study treatment period of 36 months
description: The arterial cardio-vascular events (myocardial infarction, stroke, cardio-vascular complication other than VTE) will be evaluated
arm group label: Reduced dose of DOAC
arm group type: Experimental
description: A reduced dose of DOAC (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) during a mean follow-up period of 36 months (12 to 65 months)
arm group label: Full dose of DOAC
arm group type: Active Comparator
description: A full dose of DOAC (Apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily) during a mean follow-up period of 36 months (12 to 65 months).
intervention type: Drug
intervention name: Reduced dose of DOAC
description: The patient will receive apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily during a mean follow-up period of 36 months (12 to 65 months)
arm group label: Reduced dose of DOAC
intervention type: Drug
intervention name: Full dose of DOAC
description: The patient will receive apixaban 5 mg twice daily or Rivaroxaban 20 mg once daily during a mean follow-up period of 36 months (12 to 65 months)
arm group label: Full dose of DOAC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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country: France
responsible party type: Sponsor
mesh term: Thromboembolism
mesh term: Venous Thromboembolism
sharing ipd: No