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Non-major Orthopaedic SurgeryPhase 3PRONOMOSNCT02401594

PROphylaxis in NOn Major Orthopaedic Surgery

A Phase 3 study testing Rivaroxaban and Enoxaparin in people with Non-major Orthopaedic Surgery, run by Centre Hospitalier Universitaire de Saint Etienne at 38 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

PRONOMOS is an international multicentre, interventional, parallel, randomised, double-blind non-inferiority study comparing rivaroxaban 10mg od to an active comparator, enoxaparin 4000 UI od in 4040 valid subjects requiring orthopaedic surgery (except low risk such material removal foot surgery or hallux valgus… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Non-major Orthopaedic Surgery
What is being tested?
Rivaroxaban and Enoxaparin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3,608 participants
Where
38 sitesFrance
Study dates
8 Dec 2015to 16 Apr 2018
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

  • Signed and dated informed consent form,
  • Age ≥ 18 years,
  • Hospitalised for non-major orthopaedic surgery and requiring thromboprophylaxis according to the investigator's judgement on VTE risk such Achilles' repair, hip (except femoral neck and trochanteric fracture), knee, tibial plateau, femur (non femoral head), tibial and ankle fractures and tibial osteotomy, tibial transposition, arthrodesis of leg articulation, ligament repair of the knee or the ankle or any elective orthopaedic limb surgery requiring thromboprophylaxis).

Who cannot join

  • Major orthopaedic surgery Hip and Knee replacement, femoral neck and trochanteric fractures, spine surgery,
  • Low risk surgery without patient VTE risk: foot surgery (Hallux Valgus), material removal,
  • Delay between hospitalisation and randomisation greater than two days,
  • Women of childbearing potential not using a reliable contraceptive method throughout the study period (a list of reliable contraceptive methods is provided in the accompanying SPM),
  • Women pregnant or breast-feeding during the study period,
  • Body weight less than 50 kg (to avoid bleeding over risk) or over 120 kg,
Show all 19Show fewer
  • Long term treatment with VKA therapy or NOAC,
  • Concomitant treatment with clopidogrel, prasugrel and ticagrelor,
  • Platelet count < 100 Giga/L,
  • Documented history of acquired or inherited bleeding disorder (e.g., von Willebrand's disease),
  • Severe renal failure with calculated creatinine clearance (Cockcroft Formula) < 30 mL/min,
  • Severe hepatic insufficiency with prothrombin time < 60% or liver impairment associated with coagulation disorders,
  • History of thrombocytopenia,
  • Any other current significant medical condition that might interfere with treatment evaluation according to the investigator's judgement,
  • Known hypersensitivity or other severe reaction to any component of the investigational medicinal product(s),
  • Participation in another clinical study involving an investigational medicinal product within 30 days prior to inclusion or concomitantly with this study,
  • Active bleeding or contraindication to anticoagulant therapy
  • Chronic alcoholic intoxication,
  • Anticipated poor compliance of subject with study procedures

Trial locations and contacts

38 sites in 1 country.

38 sites in 1 country

France38 sites

  • CHU AMIENS Picardie

    Amiens, 80054

  • CHU Angers

    Angers, 49933

  • Clinique Générale d'ANNECY

    Annecy, 74000

  • CHU BESANCON- Hôpital Jean Minjoz

    Besançon, 25030

  • Hopital Ambroise Pare

    Boulogne-Billancourt, 92100

  • Médipôle de Savoie

    Challes-les-Eaux, 73190

  • Clinique Léonard de Vinci

    Chambray-lès-Tours, 37170

  • CHU de Dijon- Bocage

    Dijon, 21079

  • Hôpitaux Universitaires de Strasbourg C.C.O.M

    Illkirch-Graffenstaden, 67403

  • CHU de Grenoble 6 Hôpital Michallon

    La Tronche, 38700

  • Chu Kremlin Bicetre

    Le Kremlin-Bicêtre, 94275

  • CHRU Lille -Hôpital Roger Sallengro

    Lille

  • CHU Dupuytren

    Limoges, 87042

  • Ch Lyon Sud Pierre Benite

    Lyon

  • Ch Les Chanaux

    Mâcon, 71000

  • Chu Marseille La Timone

    Marseille, 13385

  • CHU de MONTPELLIER - Lapeyronnie

    Montpellier, 34000

  • CHRU NANTES - Hôtel Dieu

    Nantes, 44093

  • CHU Carémeau

    Nîmes, 30000

  • Clinique ARAGO

    Paris, 75014

  • GH Paris Saint-Joseph

    Paris, 75014

  • Hopital Cochin

    Paris, 75014

  • Hopital Europeen Georges POMPIDOU

    Paris, 75015

  • Ch Paris Pitie Salpetriere

    Paris

  • Ch Saint Louis-Lariboisiere

    Paris

  • CHU Bordeaux

    Pessac, 33604

  • Polyclynique de Poitiers

    Poitiers, 86000

  • CHU de Reims - Hôpital MAsion Blanche

    Reims, 51000

  • Hôpital Robert Debré

    Reims, 51092

  • CHU de Rennes - Hôpital Pontchaillou

    Rennes

  • CHU de Rouen

    Rouen, 76000

  • CHU de SAINT-ETIENNE

    Saint-Etienne, 42000

  • Clinique de la Mutualiste

    Saint-Etienne, 42013

  • Chp Saint Gregoire

    Saint-Grégoire, 35760

  • Polyclinique Du Parc

    Saint-Saulve, 59880

  • CHRU de Strasbourg- Hôpital Hautepierre

    Strasbourg

  • Clinique Médipôle

    Toulouse, 31036

  • CHU Toulouse - Hôpital Pierre-Paul Riquet

    Toulouse, 31059

Other trials in France

About this study

Official title: A Multicentre, Randomised, Double-blind, Controlled, Phase IIIb Study to Assess the Efficacy and Safety of Rivaroxaban 10mg od Versus Enoxaparin 4000 UI for VTE PROphylaxis in NOn Major Orthopaedic Surgery

PRONOMOS is an international multicentre, interventional, parallel, randomised, double-blind non-inferiority study comparing rivaroxaban 10mg od to an active comparator, enoxaparin 4000 UI od in 4040 valid subjects requiring orthopaedic surgery (except low risk such material removal foot surgery or hallux valgus without patient risk factor [6], and major orthopaedic surgeries for femoral neck and trochanteric fractures, THR, TKR)

Pre-randomization treatment with LMWH anticoagulant is allowed for a maximum duration of 24 hours. However, only a single pre-randomization dose of LMWH is allowed. After randomization, patients allocated to the rivaroxaban arm will receive rivaroxaban 10 mg once-daily started 6-10 hours provided haemostasis has been established after surgery or 24h hours after LMWH injection if needed for the intended treatment duration of 2 to 12 weeks based on medical judgment (according to immobilization). Patients allocated to the comparator arm will receive enoxaparin once daily for the same intended treatment duration. All patients will have a 30-day observational period after cessation of treatment.

Read the detailed description

Major orthopedic surgery (hip, knee replacements and hip fracture) represents only a small part of all orthopaedic surgery procedures. Procedures for trauma patients and orthopaedic lower limb surgery without trauma are much more frequent (tibia osteotomy, arthrodesis, ligament repair….).

The incidence of trauma patients requiring surgery and prolonged immobilisation is rising, mainly because of the increasing popularity of recreational sports. However, the epidemiology and prevention of VTE after such injuries have been poorly studied. The combination of limb surgery with or without trauma in orthopaedic surgery is responsible for an increase in venous thromboembolism (VTE). Usually, surgery of lower limb is considered as moderate or high risk for DVT with different duration related to immobilisation. For instance tibia osteotomy is at very high risk during at least 6 weeks and knee arthroscopy for ligament repair is at moderate risk during 10 days. However LMWH is recommended in both surgeries. Non-major orthopaedic surgery represents a major additional risk factor by itself; therefore such patients undergoing surgery deserve to receive VTE prophylaxis.

Rivaroxaban is a new oral anticoagulant developing a potent anti-Xa activity. In major orthopaedic surgery, it has shown to be more effective and as safe as LMWH (Enoxaparin 4000 IU once daily) in THR and TKR patients (RECORD program). Up to now, pending the limited number of surgical settings in which it has been developed in orthopaedic surgery, it is only approved for the prevention of venous thromboembolism (VTE) in THR and TKR procedures, which represent only 20% of all orthopaedic interventions. Non-major elective lower limb surgery and traumatology population is younger as compared to prosthetic orthopaedic surgery patients. Fewer VTE and cardiovascular events are to be feared. These patients receive quite often injectable thromboprophylaxis for a total duration lying between approximately 6 weeks to 3 months. In the one hand, the risk of major bleeding is low in this younger population. On the other hand, compliance and cost should be in favour of Rivaroxaban, because no injection and no platelets counts are needed.

The results of Xamos descriptive sub-analysis in non-elective (fracture related) orthopaedic surgery are consistent with the overall results of Xamos and are in favour of further investigations in this area. In this small subset of patients (n=790), the incidence of symptomatic thromboembolic events observed was low in patients treated with Xarelto and the overall frequency of treatment emergent major bleedings was low in both groups and serious adverse events occurred less frequently in patients treated with Xarelto. Therefore, collection of clinical data in this population is needed and awaited by many orthopaedic surgeons and anaesthetists in charge of VTE prophylaxis.

The population with femoral neck and trochanteric fracture is a specific one with different characteristics, elderly, frail and with a higher bleeding risk. This population will be excluded.

Being tested
Rivaroxaban, Enoxaparin
Keywords
Non-major orthopaedic surgery, deep vein thrombosis
Medical subject headings
Venous Thrombosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RivaroxabanDrug

    Also called Group 1:

    10 mg once daily of Rivaroxaban active substance (10 mg tablet) plus a placebo syringe of enoxaparin 4000 UI once daily

  • EnoxaparinDrug

    Also called Group 2:

    A syringe of enoxaparin active substance 4000 UI once daily plus a placebo tablet of Rivaroxaban 10 mg.

Study groups in NCT02401594
Study groupRoleWhat they receive
Group 1: Rivaroxaban treatmentExperimentalRivaroxaban active substance plus a placebo of enoxaparin
Receives: Drug: Rivaroxaban
Grouyp 2: Enoxaparine treatmentActive comparatorEnoxaparin active substance plus a placebo tablet of Rivaroxaban
Receives: Drug: Enoxaparin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Major VTE

    composite of proximal DVT (asymptomatic and symptomatic) assessed by ultrasonography, symptomatic events (distal and proximal DVT, PE) and VTE related deaths.

    The treatment period ranges from 15 days to 3 months depending on the type of surgery

    Measured: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).

Secondary outcomes (4)

  1. Major bleeding

    bleeding event that meets at least one of the following criteria [5]:

    • fatal bleeding;
    • critical bleeding (intracranial, intraocular, intraspinal, pericardial, retroperitoneal);
    • clinically overt bleeding (at surgical or extrasurgical site) associated with a decrease in the haemoglobin level of more than 2 g/dL (20 g/l; 1.24 mmol/L) compared with the pre-randomization level;
    • clinically overt bleeding (at surgical or extrasurgical site) leading to transfusion of two or more units of whole blood or packed cells;
    • bleeding located at the surgical site and leading to re-operation or to any unusual medical intervention or procedure for relief (e.g. draining or puncture of an haematoma at the surgical site, transfer to an ICU or emergency room) The treatment period ranges from 15 days to 3 months depending on the type of surgery

    Measured: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).

  2. Clinically relevant non-major bleeding

    overt bleeding not meeting the criteria for major bleeding and corresponds to any bleeding necessitating medical intervention or a specific, unscheduled consultation or treatment discontinuation, or resulting in a deterioration of the subject's quality of life. Some examples of clinically significant bleeding are given below:

    • Epistaxis that lasts more than five minutes or recurrent or necessitates packing,
    • Spontaneous macroscopic haematuria or haematuria lasting more than 24 hours after instrumentation,
    • Gastrointestinal haemorrhage (melena or rectorrhagia),
    • Haemoptysis,
    • Subcutaneous haematoma > 100 cm². The treatment period ranges from 15 days to 3 months depending on the type of surgery

    Measured: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..

  3. Overt thrombocytopenia

    platelet count <100 giga/L or fall ≥ 50% of the platelet count as compared with the first post-operative count which will be done as local lab for all centres The treatment period ranges from 15 days to 3 months depending on the type of surgery

    Measured: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..

  4. Mortality

    All cause mortality The treatment period ranges from 15 days to 3 months depending on the type of surgery

    Measured: From date of randomization until the date of the end of the treatment period (up to 3 months maximum)..

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Mar 2015 (estimated)
  2. Study start8 Dec 2015
  3. Primary completion11 Apr 2018
  4. Study completion16 Apr 2018

Why it stopped: Remaining outdated treatments and additional costs too high for new manufacturing

Resources

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
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
3,608 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02401594
Sponsor's protocol ID
1408143
Other IDs
2015-000981-70, 2015
Acronym
PRONOMOS
Status last verified
Dec 2018
First submitted
6 Mar 2015
Last updated
7 Dec 2018
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Samama CM, Laporte S, Rosencher N, Girard P, Llau J, Mouret P, Fisher W, Martinez-Martin J, Duverger D, Deygas B, Presles E, Cucherat M, Mismetti P; PRONOMOS Investigators. Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery. N Engl J Med. 2020 May 14;382(20):1916-1925. doi: 10.1056/NEJMoa1913808. Epub 2020 Mar 29.

    PubMed 32223113

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Rivaroxaban and Enoxaparin in people with Non-major Orthopaedic Surgery, run by Centre Hospitalier Universitaire de Saint Etienne at 38 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 3 inclusion and 19 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 7 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 38 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: Remaining outdated treatments and additional costs too high for new manufacturing). 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?

Major VTE (time frame: From date of randomization until the date of the end of the treatment period (up to 3 months maximum).). 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 NCT02401594, 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 7 Dec 2018; AzTrials last refreshed its copy on 2 Nov 2026.

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