Venous ThromboembolismPhase 3RENOVENCT03285438
REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism.
A Phase 3 study testing Reduced dose of DOAC and Full dose of DOAC in people with Venous Thromboembolism, run by University Hospital, Brest at 39 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Venous Thromboembolism
- What is being tested?
- Reduced dose of DOAC and Full dose of DOAC
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,774 participants
- Where
- 39 sitesFrance
- Study dates
- 2 Nov 2017to 8 Nov 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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…)
Show all 18Show fewer
- 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
Trial locations and contacts
39 sites in 1 country.
39 sites in 1 country
France39 sites
CHU Amiens-Picardie
Amiens, 80054
CHU Angers
Angers
CH d'Arras
Arras, 62022
CHU de Besançon - Hôpital Jean Minjoz
Besançon, 25000
CH Bordeaux
Bordeaux, 33075
HIA Brest
Brest, 29240
CHRU de Brest
Brest, 29609
Clinique de Clapiers
Castelnau-le-Lez, 34170
HIA Percy
Clamart, 92141
Cabinet médical
Clapiers, 34830
CHU de Clermont Ferrand - Hôpital Gabriel Montpied
Clermont-Ferrand, 63003
APHP Hôpital Louis Mourier
Colombes, 92700
CHU de Dijon
Dijon, 21079
CHU de Grenoble - Hôpital Nord Michallon
Grenoble, 38700
GH Le Havre
Le Havre, 76290
CH Le Mans
Le Mans, 72 000
CHU de Limoges - Hôpital de Dupuytren
Limoges, 87042
CH Morlaix
Morlaix, 29 672
Chru Nancy
Nancy, 54511
CHU de Nantes
Nantes, 44000
CHU de Nice - Hôpital Pasteur
Nice, 06002
CHU Nîmes
Nîmes, 30 029
CHR Orléans
Orléans, 45100
Hôpital de Cochin
Paris, 75014
HEGP
Paris, 75015
CHU Paris Nord Val de Seine
Paris, 75018
HEGP
Paris
Kremlin Bicêtre
Paris
CH de Périgueux
Périgueux, 24019
CH de Quimper
Quimper, 29107
CHU de Rennes - Hôpital Sud
Rennes, 35203
CHU de ROUEN
Rouen, 76000
CH de Saint Brieuc - Hôpital Yves Le Foll
Saint-Brieuc, 22000
CHU de Saint Etienne - Hôpital Nord
Saint-Etienne, 42055
CH de Toulon - Hôpital Sainte-Musse
Toulon, 83056
HIA Sainte-Anne
Toulon, 83800
CHU de Toulouse - Hôpital de Rangueil
Toulouse, 31059
CHU de Tours - Hôpital Trousseau
Tours, 37170
CH Valenciennes
Valenciennes, 59 322
About this study
Official title: REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
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.
Read more
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.
Read the detailed description
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 Girerd auto-questionnaire
- 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).
- Conditions
- Venous Thromboembolism
- Being tested
- Reduced dose of DOAC, Full dose of DOAC
- Keywords
- Venous Thromboembolism, Anticoagulant, Direct oral anticoagulant, risk of recurrent venous thromboembolism, anticoagulant-related bleeding
- Medical subject headings
- Venous Thromboembolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Reduced dose of DOACDrug
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)
Full dose of DOACDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| Reduced dose of DOAC | Experimental | 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) Receives: Drug: Reduced dose of DOAC |
| Full dose of DOAC | Active comparator | 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). Receives: Drug: Full dose of DOAC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recurrent VTE
Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.
Measured: during a mean study treatment period of 36 months
Secondary outcomes (6)
Major and clinically relevant non major bleeding
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
Measured: during a mean study treatment period of 36 months
The composite of recurrent VTE or major bleeding or non major clinically relevant bleeding
The composite of adjudicated recurrent VTE or major bleeding or non major clinically relevant bleeding during the study treatment period will be adjudicated
Measured: during a mean study treatment period of 36 months
Mortality
Mortality of other cause than recurrent VTE or major or clinically relevant non major bleeding during the study treatment period will be adjudicated
Measured: during a mean study treatment period of 36 months
Compliance
Treatment compliance will be evaluated
Measured: during a mean study treatment period of 36 months
Treatment effect
The heterogeneity of the treatment effect on predefined strata will be evaluated
Measured: during a mean study treatment period of 36 months
Arterial cardio-vascular events
The arterial cardio-vascular events (myocardial infarction, stroke, cardio-vascular complication other than VTE) will be evaluated
Measured: during a mean study treatment period of 36 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Sep 2017
- Study start2 Nov 2017
- Primary completion8 Nov 2023
- Study completion8 Nov 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Venous ThromboembolismStudies of the same condition, open and under way.
- More trials run by University Hospital, BrestThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The trial is designed as an academic, multicenter, open, with blind evaluation (PROBE), randomized, parallel arm, controlled.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 2,774 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Brest
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital of Saint-Etienne
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03285438
- Sponsor's protocol ID
- 29BRC17.0125
- Acronym
- RENOVE
- Status last verified
- Dec 2023
- First submitted
- 14 Sep 2017
- Last updated
- 28 Dec 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Couturaud F, Schmidt J, Sanchez O, Ballerie A, Sevestre MA, Meneveau N, Bertoletti L, Connault J, Benhamou Y, Constans J, Quemeneur T, Lapebie FX, Pernod G, Picart G, Elias A, Doutrelon C, Neveux C, Khider L, Roy PM, Zuily S, Falvo N, Lacroix P, Emmerich J, Mahe I, Boileau J, Yaici A, Le Jeune S, Stephan D, Plissonneau-Duquene P, Ray V, des Deserts MD, Belhadj-Chaidi R, Lamia B, Gruel Y, Presles E, Girard P, Tromeur C, Moustafa F, Rothstein V, Lacut K, Melac S, Barillot S, Mismetti P, Laporte S, Mottier D, Meyer G, Leroyer C; RENOVE Investigators. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. Lancet. 2025 Mar 1;405(10480):725-735. doi: 10.1016/S0140-6736(24)02842-3.
PubMed 40023651
Study at a glance
From the registry record, last updated by the sponsor on 28 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- REduced Dose Versus Full-dose of Direct Oral Anticoagulant After uNprOvoked Venous thromboEmbolism. The RENOVE Open-label, Randomized, Controlled Trial.
- ClinicalTrials.gov ID
- NCT03285438
- Acronym / sponsor ID
- RENOVE / 29BRC17.0125
- Conditions
- Venous Thromboembolism
- Keywords
- Venous Thromboembolism, Anticoagulant, Direct oral anticoagulant, risk of recurrent venous thromboembolism, anticoagulant-related bleeding
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2,774 participants (actual)
- Lead sponsor
- University Hospital, BrestUniversity, hospital or other
- Collaborators
- University Hospital of Saint-Etienne
- Study start
- 2 Nov 2017 (actual)
- Primary completion
- 8 Nov 2023 (actual)
- Study completion
- 8 Nov 2023 (actual)
- First posted
- 18 Sep 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 Girerd auto-questionnaire
- 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).
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- The trial is designed as an academic, multicenter, open, with blind evaluation (PROBE), randomized, parallel arm, controlled.
| Arm | Type | Receives |
|---|---|---|
| Reduced dose of DOAC | Experimental | Drug: Reduced dose of DOACA 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) |
| Full dose of DOAC | Active comparator | Drug: Full dose of DOACA 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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) :
- Social security affiliation.
Key exclusion criteria (18 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Reduced dose of DOACThe 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) | Drug | Reduced dose of DOAC |
| Full dose of DOACThe 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) | Drug | Full dose of DOAC |
Primary outcome
Recurrent VTE
Time frame: during a mean study treatment period of 36 months
Adjudicated symptomatic objectively confirmed recurrent VTE (non fatal or fatal VTE) during the study treatment period.
6 secondary outcomes
Major and clinically relevant non major bleeding
Time frame: during a mean study treatment period of 36 months
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
Mortality
Time frame: during a mean study treatment period of 36 months
Compliance
Time frame: during a mean study treatment period of 36 months
Treatment effect
Time frame: during a mean study treatment period of 36 months
Arterial cardio-vascular events
Time frame: during a mean study treatment period of 36 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Dec 2023.
- Derived from this study: PubMed 40023651Couturaud F, Schmidt J, Sanchez O, Ballerie A, Sevestre MA, Meneveau N, Bertoletti L, Connault J, Benhamou Y, Constans J, Quemeneur T, Lapebie FX, Pernod G, Picart G, Elias A, Doutrelon C, Neveux C, Khider L, Roy PM, Zuily S, Falvo N, Lacroix P, Emmerich J, Mahe I, Boileau J, Yaici A, Le Jeune S, Stephan D, Plissonneau-Duquene P, Ray V, des Deserts MD, Belhadj-Chaidi R, Lamia B, Gruel Y, Presles E, Girard P, Tromeur C, Moustafa F, Rothstein V, Lacut K, Melac S, Barillot S, Mismetti P, Laporte S, Mottier D, Meyer G, Leroyer C; RENOVE Investigators. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. Lancet. 2025 Mar 1;405(10480):725-735. doi: 10.1016/S0140-6736(24)02842-3.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
39 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Reduced dose of DOAC and Full dose of DOAC in people with Venous Thromboembolism, run by University Hospital, Brest at 39 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 39 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recurrent VTE (time frame: during a mean study treatment period of 36 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03285438, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Dec 2023.