TRAPS (Trial on Rivaroxaban in High Risk - FCSA · TRAPS (Trial on Rivaroxaban in High Risk...

TRAPS (Trial on Rivaroxaban in High Risk Patients with AntiPhospholipid Syndrome,

(ClinicalTrials.gov Identifier: NCT02157272)

Background (1)

• Triple positivity (LAC+, aCL+, aβ2GPI+, same isotype) in

APS is associated with thromboembolic events and

severe pregnancy morbidity

• Triple positive APS patients are at high risk of recurrent

thromboembolic events.

Cumulative incidence of thromboembolic events in high risk triple positive APS

patients (n=160)

Pengo V, JTH 2010

Background (2)

• As compared with aspirin, AVK therapy significantly

reduces thromboembolic recurrences, although it might

prove insufficient in some cases.

High risk triple positive APS patients (n=160)

Pengo V, JTH 2010

Background (3)

• The new oral anticoagulant rivaroxaban, an inhibitor of factor Xa, is at least as effective and safe as warfarin in preventing venous and arterial thromboembolism and significantly reduces cerebral bleeding.

• Rivaroxaban does not need laboratory control thus being very much appreciated by the young population of patients with APS. At variance with other new anticoagulants it is administered once daily favoring patients compliance.

A prospective, randomized clinical Trial comparing Rivaroxaban vs warfarin in high risk patients with

AntiPhospholipid Syndrome (TRAPS) European clinical trials database 2013-004575-13

Study Design: Phase III, Randomized, open label, non inferiority, prospective,

multicenter, non-profit.

Primary Objective:

To determine the efficacy and safety of rivaroxaban as compared to

warfarin in the thrombosis prevention of triple aPL-positive APS

patients.

Inclusion criteria

• Age 18-75

• Persistent (at least 12 weeks apart) triple

aPL-positivity

• History of thrombosis (arterial, venous,

and/or biopsy proven microthrombosis) according to Miyakis.

Exclusion criteria (I)

• Creatinine clearance <30 mL/min at the

screening visit (calculated by mean of

Cockroft-Gault formula)

• Current or programmed pregnancy.

• Patients taking interfering medications:

proteases inhibitors (HIV infection) or

systemic antifungal therapy with oral

azole drugs.

Confirmation of triple positivity • To confirm triple positivity for aPL and to

validate the laboratory diagnosis, plasma

from patients of each Center will be

stored and later on retested in a

reference laboratory (Padua Thrombosis

Centre).

Randomization • Rivaroxaban 20mg/qd or rivaroxaban 15mg/qd if creatinine clearance 30-50ml/min. • Warfarin to maintain an INR between 2.0 and 3.0

In patients not on warfarin at the time of randomization low molecular weight heparin until INR value is ≥2.0 will be used. In patients on warfarin at the time of randomization and randomized to rivaroxaban, rivaroxaban is started when INR is below 1.5.

Outcome measure

•The primary end point is cumulative of incident thrombosis (arterial or venous), major bleeding (ISTH) and death

•Thrombosis must be confirmed by appropriate imaging studies.

Statistical Calculations & Analysis •A non-inferiority logrank test with an overall sample size of 535 subjects (267 in the reference group and 268 in the treatment group) achieves a power 80.0% at a 0.05 significance level

•The study lasts for 4 years of which subject accrual (entry) occurs in the first 2 years. •An interim analysis will be carried out after two years from the date in which the first patient was randomized.

TRAPS trial

Study starts: 2015 Study ends: 2019 vittorio.pengo@unipd.it

TRAPS eCRF

Centri con approvazione del rispettivo Comitato Etico

PD01= Padova Cardiologia PD02=Padova Reumatologia BS01=Brescia Reumatologia VI01=Vicenza Ematologia PG01=Perugia Medicina Interna RE01=Reggio Emilia Medicina Interna CA01=Cagliari Medicina Interna CR01=Cremona Centro Trombosi MI01=Milano Gaetano Pini MI02=Milano Policlinico MI03=Milano S.Paolo BE01=Bergamo Trasfusionale RO1=Roma Ematologia LE01=Lecco Immunotrasfusionale FI01=Firenze Medicina Interna

TRAPS

0

5

10

15 BresciaPadova 1Padova 2

VicenzaPerugia

CremonaReggio EmiliaCagliariMilano 2Milano3

Centers

Num

ber

of r

ando

miz

ed p

atie

nts

Centri in attesa di approvazione del Comitato Etico locale

• Pisa1=Patologia Clinica • Pisa2=Immunoallergologia • Torino=Immunomatologia • Roma2=Medicina interna • Roma3:Reumatologia • Alessandria=Emostasi e Trombosi • Bologna=angiologia • Napoli=medicina Interna • Bari/Monopoli=Centro trasfusionale • Foggia=Emostasi e Trombosi • Catanzaro=Emostasi e Trombosi • Palermo=Medicina Interna • Siena=Medicina Interna

Centri Europei

• Parigi 1 • Parigi 2 • Cracovia • Vienna • Saragozza • Madrid • Barcellona • Ginevra • Atene

Organigramma dello studio

• Coordinatore: Vittorio Pengo (Padova)

• Steering Committee: Vittorio Pengo (Padova), Amelia Ruffatti (Padova),

Angela Tincani (Brescia), Pierluigi Meroni (Milano)

• Comitato di aggiudicazione degli eventi: Gualtiero Palareti (Bologna), Paolo Prandoni (Padova)

• Comitato che si occuperà della stesura del manoscritto: Vittorio Pengo (Padova), Alberto Tosetto (Vicenza), Amelia Ruffatti (Padova).

Nomi degli autori nel manoscritto (Authorship)

• 1-5 pazienti randomizzati: 1 co-autore • 6-10 pazienti randomizzati: 1 co-autore più uno in Appendice

(Appendix) indicizzata. • >10 pazienti randomizzati: 2 co-autori più uno in Appendice

(Appendix) indicizzata.

Emendamenti e suggerimenti

• E’ stato approvato un emendamento che estenderà l’età per l’arruolamento dei pazienti fino a 75 anni. (verra inviata notifica a tutti i CE)

• E’ NECESSARIO compilare TUTTI i campi indicati nel format di ciascun paziente in RedCap;

• E’ SUFFICIENTE avere almeno un pregresso test che dimostri la triplice positività del paziente;

• Se il paziente è in Sintrom ed è randomizzato a Warfarin si ricorda che la dose giornaliera di warfarin in mg è approssimativamente doppia di quella del Sintrom.

• Gli eventi avversi seri e quelli che compongono l’end point primario (tromboembolismo, emorragia maggiore e morte) vanno trasmessi al Centro coordinatore con la documentazione necessaria alla aggiudicazione dell’evento.

Lettera ai Centri del 23 settembre

• In accordo con i componenti dello steering committee, si

suggerisce che i pazienti che entrano nello studio

TRAPS ed hanno patologia tromboembolica arteriosa

(stroke/tia, ima etc) debbano essere trattati sia con

l’anticoagulante (warfarin o rivaroxaban) che con

aspirina 100mg/die. Infatti non è chiaro se questi siano

eventi cardio-embolici o aterotrombotici o da vasculite

CARDIOGENIC CEREBRAL ISCHEMIA IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME: SOURCE

OF THROMBI EUROPEAN PROJECT (STEP)

Type and rate of alterations at TEE

A=valvular thickening B=Valvular incompetence C=Mitral prolapse D=Patent foramen ovalis E=vegetations F=echocontrast G=patients with alterations 0

102030405060708090

100

A B C D E F G

Valvular Thickening

Aortic arch plaque