Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03285438 |
| Other study ID # |
29BRC17.0125 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
November 2, 2017 |
| Est. completion date |
November 8, 2023 |
Study information
| Verified date |
December 2023 |
| Source |
University Hospital, Brest |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical 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. 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.
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).
