Renal InsufficiencyPhase 3VERDICTNCT02664155
Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
A Phase 3 study testing Apixaban, Rivaroxaban and Heparin in people with Renal Insufficiency, run by Centre Hospitalier Universitaire de Saint Etienne at 31 sites in France.
Trial summary
In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Insufficiency
- What is being tested?
- Apixaban, Rivaroxaban and Heparin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 203 participants
- Where
- 31 sitesFrance
- Study dates
- 19 Oct 2016to 30 May 2022
- 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 with a moderate renal insufficiency defined by a creatinine clearance between 30 to 50 ml/min (Cockcroft and Gault formulae) or a severe renal insufficiency (between 15 to 29 ml/min)
- Patients with acute objectively confirmed symptomatic proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (with or without deep-vein thrombosis), planned to be treated for at least 3 months
- Patients >18 years
- Life expectancy more than 3 months
- Social security affiliation
- Signed informed consent
Who cannot join
- Indication for anticoagulants other than VTE
- Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg
- Anticoagulation for more than 72 hours prior to randomization
- Chronic liver disease or chronic hepatitis
- Patient at high risk of bleeding
- Creatinine clearance <15 ml/min or end stage renal disease or indication for extra-renal dialysis
Show all 12Show fewer
- Need for concomitant anti-platelet therapy other than aspirin 75-325 mg per day. However concomitant treatment with aspirin is discouraged in this population at bleeding risk.
- 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 pregnancy or expected pregnancy or no effective contraception
- Any contraindication listed in the local labeling of UFH, LMWH or VKA or oral anticoagulant.
- Cancer-associated VTE requiring long-term treatment with LMWH
- Life expectancy of less than 3 months.
Trial locations and contacts
31 sites in 1 country.
31 sites in 1 country
France31 sites
CH d'Agen-Nérac
Agen
Chu Amiens
Amiens, 80054
Chu Angers
Angers, 49933
CH ARRAS
Arras, Boulevard Georges Besnier, 62022
CH Besançon
Besançon, 25030
CHU de Bordeaux
Bordeaux
CHU La Cavale Blanche Brest
Brest, 29200
HIA de Brest
Brest
CHU Castelnau-le-Lez
Castelnau-le-Lez, 34170
CH Louis Pasteur - Chartres
Chartres
Chu Clermont-Ferrand
Clermont-Ferrand, 63003
CHU Dijon
Dijon, 21034
Hôpital La Tronche Grenoble
Grenoble, 38043
Hôpital Charles Foix - APHP Ivry sur Seine
Ivry-sur-Seine, 94200
Chu Limoges
Limoges, 87000
CHU Lyon
Lyon, 69000
HCL - Hôpital Edouard Herriot
Lyon
Chu Montpellier
Montpellier, 34295
CHU de Nantes - Hôpital Bellier
Nantes
CHU de Nantes - Hôpital Hôtel Dieu
Nantes
CHU Nice
Nice, 06003
HEGP - APHP Paris
Paris, 75000
Hôpital Louis Mourier- APHP Paris
Paris, 75000
CHU de Rouen
Rouen
Chu Saint Etienne
Saint-Etienne, 42055
Chu Strasbourg
Strasbourg, 67091
CH Toulon
Toulon, 83056
HIA de Toulon
Toulon
CHU Toulouse
Toulouse, 31059
Chu Tours
Tours, Hôpital Trousseau, 37550
CH de Valenciennes
Valenciennes
About this study
In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented and patients with severe renal insufficiency not at all. So no dose reduction was considered.
Surprisingly, DOAs have been approved for VTE treatment in moderate and severe renally impaired patients. There is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency.
We plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.
Read the detailed description
In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. These patients represent more than 20% of the VTE population in clinical practice. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented (<10%) and patients with severe renal insufficiency not at all. So no dose reduction was considered.
The new DOAs have also been developed for stroke prevention in atrial fibrillation (SPAF). Patients including in AF trials are generally older and more prone to present renal impairment (>20%) than in VTE trials. So a reduced dose of DOAs was evaluated and shown to be at least as effective as, and safer than VKA in the subgroup of patients with moderate renal insufficiency (creatinine clearance between 30 to 50 ml/min).
Surprisingly, DOAs have been approved for VTE treatment and SPAF in moderate and severe renally impaired patients (creatinine clearance between 15 to 30 mL/min). Moreover, patients have to receive a reduced dose of DOAs for SPAF but a full dose of DOAs for VTE that could be associated with an increased bleeding risk, as suggested by some subgroup analyses. So, there, there is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency (creatinine clearance between 15 to 50 mL/min).
Apixaban and rivaroxaban appear to be the best candidates since:
- both are approved in France in VTE patients
- they have mixed pathway of elimination (hepatic and renal)
- they have several other pharmacological similarities and they respective clinical trials have shown similar efficacy and safety profiles when compared with SOC for VTE treatment.
- they do not need to be preceded by initial parenteral heparins on the contrary to dabigatran and edoxaban. This allows evaluating the impact of DOAs in renally impaired patients independently from the initial heparins effect
- a reduced dose regimen is available and approved in AF
- the evaluation of 2 DAOs allows evaluating the concept of this new class in renally impaired VTE patients independently from the pharmaceutical companies.
Finally we plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.
- Conditions
- Renal Insufficiency
- Being tested
- Apixaban, Rivaroxaban, Heparin, VKA
- Keywords
- Renal insufficiency, Direct oral anticoagulants (DOA), Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Venous Thromboembolism (VTE), Heparins
- Medical subject headings
- Renal Insufficiency, Venous Thrombosis, Pulmonary Embolism, Venous Thromboembolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ApixabanDrug
Also called Eliquis®
Direct Oral Anticoagulant
RivaroxabanDrug
Also called Xarelto®
Direct Oral Anticoagulant
HeparinDrug
Standard Of Care
VKADrug
Also called vitamin K antagonists
Standard Of Care
| Study group | Role | What they receive |
|---|---|---|
| DOA : Direct Oral Anticoagulants | Experimental | The experimental group receiving DOA regimens: patients will be secondarily randomly assigned within DOAs group between:
* Apixaban (Eliquis® tablet) 10 mg bid for 7 days then 2.5 mg bid for 3 months
* Rivaroxaban (Xarelto® tablet) 15 mg bid for 21 days then 15 mg od for 3 months. Receives: Drug: Apixaban; Drug: Rivaroxaban |
| SOC : Standard Of Care | Active comparator | The control group receiving the standard of care (SOC), i.e. heparins/VKA regimen. Patients will receive the current recommended therapy: subcutaneous or intravenous UFH/VKA in case of severe renal insufficiency and subcutaneous LMWH/VKA in case of moderate renal insufficiency for at least 5 days. VKA will begin concomitantly and continue for 3 months. Receives: Drug: Heparin; Drug: VKA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Non inferiority of reduced doses of DOAs
To demonstrate that reduced doses of DOAs (rivaroxaban or apixaban) are non-inferior to standard of care (heparins/VKA) on the net clinical benefit (recurrent VTE and major bleeding) in renally impaired patients suffering from an acute VTE.
Measured: Month 3
Secondary outcomes (2)
Bleeding events
To demonstrate the non--inferiority of reduced dose of DOAs on the risk of major bleedings.
Measured: Month 3
Venous Thromboembolism (VTE) events
To demonstrate the non--inferiority of reduced dose of DOAs on the risk of recurrent VTE.
Measured: Month 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2016 (estimated)
- Study start19 Oct 2016
- Primary completion30 Nov 2021
- Study completion30 May 2022
Why it stopped: recruiting difficulties
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 Renal InsufficiencyStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire de Saint EtienneThe 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
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Health, France
- Responsible party
- Sponsor
- Investigators
- MISMETTI Patrick, MD, Principal investigator, Centre Hospitalier Universitaire de Saint Etienne
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02664155
- Sponsor's protocol ID
- 1508189
- Other IDs
- 2016-000858-35, 2016
- Acronym
- VERDICT
- Status last verified
- Oct 2022
- First submitted
- 22 Jan 2016
- Last updated
- 19 Oct 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Wetmore JB, Herzog CA, Yan H, Reyes JL, Weinhandl ED, Roetker NS. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. Clin J Am Soc Nephrol. 2022 May;17(5):693-702. doi: 10.2215/CJN.14021021. Epub 2022 Apr 25.
PubMed 35470214
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Venous Thromboembolism in Renally Impaired Patients and Direct Oral Anticoagulants
- ClinicalTrials.gov ID
- NCT02664155
- Acronym / sponsor ID
- VERDICT / 1508189
- Conditions
- Renal Insufficiency
- Keywords
- Renal insufficiency, Direct oral anticoagulants (DOA), Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Venous Thromboembolism (VTE), Heparins
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: recruiting difficulties
- Enrolment
- 203 participants (actual)
- Lead sponsor
- Centre Hospitalier Universitaire de Saint EtienneUniversity, hospital or other
- Collaborators
- Ministry of Health, France
- Study start
- 19 Oct 2016 (actual)
- Primary completion
- 30 Nov 2021 (actual)
- Study completion
- 30 May 2022 (actual)
- First posted
- 26 Jan 2016 (estimated)
- 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.
In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented and patients with severe renal insufficiency not at all. So no dose reduction was considered.
Surprisingly, DOAs have been approved for VTE treatment in moderate and severe renally impaired patients. There is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency.
We plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.
Detailed description
In renally impaired patients with acute venous thromboembolism (VTE), standard-of-care (SOC) anticoagulation, i.e. heparins-vitamin K antagonists (VKA), at therapeutic dosage is associated with an increased risk of thromboembolic and bleeding complications compared to patients with normal renal function. These patients represent more than 20% of the VTE population in clinical practice. Direct oral anticoagulants (DOAs) have been shown to be at least as effective and safe as SOC in VTE treatment. But in the clinical trials, moderate renally impaired patients were poorly represented (<10%) and patients with severe renal insufficiency not at all. So no dose reduction was considered.
The new DOAs have also been developed for stroke prevention in atrial fibrillation (SPAF). Patients including in AF trials are generally older and more prone to present renal impairment (>20%) than in VTE trials. So a reduced dose of DOAs was evaluated and shown to be at least as effective as, and safer than VKA in the subgroup of patients with moderate renal insufficiency (creatinine clearance between 30 to 50 ml/min).
Surprisingly, DOAs have been approved for VTE treatment and SPAF in moderate and severe renally impaired patients (creatinine clearance between 15 to 30 mL/min). Moreover, patients have to receive a reduced dose of DOAs for SPAF but a full dose of DOAs for VTE that could be associated with an increased bleeding risk, as suggested by some subgroup analyses. So, there, there is need to evaluate a reduced dose of DOAs for VTE treatment in patients with moderate and severe renal insufficiency (creatinine clearance between 15 to 50 mL/min).
Apixaban and rivaroxaban appear to be the best candidates since:
- both are approved in France in VTE patients
- they have mixed pathway of elimination (hepatic and renal)
- they have several other pharmacological similarities and they respective clinical trials have shown similar efficacy and safety profiles when compared with SOC for VTE treatment.
- they do not need to be preceded by initial parenteral heparins on the contrary to dabigatran and edoxaban. This allows evaluating the impact of DOAs in renally impaired patients independently from the initial heparins effect
- a reduced dose regimen is available and approved in AF
- the evaluation of 2 DAOs allows evaluating the concept of this new class in renally impaired VTE patients independently from the pharmaceutical companies.
Finally we plan to evaluate reduced doses of 2 DOAs (apixaban, rivaroxaban) compared to SOC in VTE patients with moderate or severe renal insufficiency in terms of net clinical benefit (recurrent VTE and major bleeding) at 3 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| DOA : Direct Oral Anticoagulants | Experimental | Drug: Apixaban, Drug: RivaroxabanThe experimental group receiving DOA regimens: patients will be secondarily randomly assigned within DOAs group between: * Apixaban (Eliquis® tablet) 10 mg bid for 7 days then 2.5 mg bid for 3 months * Rivaroxaban (Xarelto® tablet) 15 mg bid for 21 days then 15 mg od for 3 months. |
| SOC : Standard Of Care | Active comparator | Drug: Heparin, Drug: VKAThe control group receiving the standard of care (SOC), i.e. heparins/VKA regimen. Patients will receive the current recommended therapy: subcutaneous or intravenous UFH/VKA in case of severe renal insufficiency and subcutaneous LMWH/VKA in case of moderate renal insufficiency for at least 5 days. VKA will begin concomitantly and continue for 3 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Patients with a moderate renal insufficiency defined by a creatinine clearance between 30 to 50 ml/min (Cockcroft and Gault formulae) or a severe renal insufficiency (between 15 to 29 ml/min)
- Patients with acute objectively confirmed symptomatic proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (with or without deep-vein thrombosis), planned to be treated for at least 3 months
- Patients >18 years
- Life expectancy more than 3 months
- Social security affiliation
Key exclusion criteria (12 listed)
- Indication for anticoagulants other than VTE
- Active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg
- Anticoagulation for more than 72 hours prior to randomization
- Chronic liver disease or chronic hepatitis
- Patient at high risk of bleeding
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 |
|---|---|---|
| ApixabanAlso: Eliquis®Direct Oral Anticoagulant | Drug | DOA : Direct Oral Anticoagulants |
| RivaroxabanAlso: Xarelto®Direct Oral Anticoagulant | Drug | DOA : Direct Oral Anticoagulants |
| HeparinStandard Of Care | Drug | SOC : Standard Of Care |
| VKAAlso: vitamin K antagonistsStandard Of Care | Drug | SOC : Standard Of Care |
Primary outcome
Non inferiority of reduced doses of DOAs
Time frame: Month 3
To demonstrate that reduced doses of DOAs (rivaroxaban or apixaban) are non-inferior to standard of care (heparins/VKA) on the net clinical benefit (recurrent VTE and major bleeding) in renally impaired patients suffering from an acute VTE.
2 secondary outcomes
Bleeding events
Time frame: Month 3
Venous Thromboembolism (VTE) events
Time frame: Month 3
Results and safety
The study was stopped early (reason given: recruiting difficulties). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2022.
- Derived from this study: PubMed 35470214Wetmore JB, Herzog CA, Yan H, Reyes JL, Weinhandl ED, Roetker NS. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. Clin J Am Soc Nephrol. 2022 May;17(5):693-702. doi: 10.2215/CJN.14021021. Epub 2022 Apr 25.
- 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.
MISMETTI Patrick, MD principal investigator
Centre Hospitalier Universitaire de Saint Etienne
31 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 Apixaban, Rivaroxaban and Heparin in people with Renal Insufficiency, run by Centre Hospitalier Universitaire de Saint Etienne at 31 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 6 inclusion and 12 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: stopped early, as of the sponsor's last update on 19 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 31 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 was stopped early (reason given: recruiting difficulties). Results are not available in the source record.
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?
Non inferiority of reduced doses of DOAs (time frame: Month 3). 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 NCT02664155, 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 19 Oct 2022.