Rivaroxaban for Patients With Antiphospholipid Syndrome

Rivaroxaban Versus Acenocumarol for Secondary Thromboprophylaxis in Patients With Antiphospholipid Syndrome: a Randomized, Prospective, Phase III Study. Analysis of Stratification Prognostic Factors

Long-term anticoagulation is widely used for secondary thromboprophylaxis in the antiphospholipid syndrome (APS) due to the high risk of recurrent events. Currently anticoagulation with vitamin K antagonists (VKAs) is the standard of care but have unpredictable pharmacodynamic properties that requiere monitoring for dose adjustment. Rivaroxaban, an orally active direct factor Xa inhibitor, has been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism and non valvular atrial fibrillation in major RCTs. No studies had been published in APS.The aim of the study is to investigate the efficacy and safety of rivaroxaban in preventing recurrent thrombosis in patients with APS compared with acenocoumarol

Study Overview

• Status: Completed
• Conditions: Antiphospholipid Syndrome
• Intervention / Treatment: Drug: Rivaroxaban; Drug: acenocumarol

Detailed Description

This is a phase 3 randomized, multicenter, non-inferiority open-label RCT. 190 eligible APS patients with arterial or venous thrombotic history receiving acenocoumarol will be stratified according the presence of SLE and venous/arterial thrombotic history and randomized (1:1) either to continue vitamin K antagonists (standard of care, normalized ratio (INR) 2-3 or 2.5 to 3.5 in those with recurrent thrombotic episodes) or to switch to rivaroxaban (20 mg/day). The primary efficacy outcome is the development of any thrombotic event during the study period. Secondary efficacy outcomes include time to thrombosis, type of thrombosis (arterial or venous), overall causes of death, evaluation of a prognostic biomarker panel of recurrent thrombosis. The primary safety outcome will be major bleeding. Secondary safety outcomes include any adverse event and minor bleeding.

• Study Type: Interventional
• Enrollment (Actual): 190
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Vall D'Hebron University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with thrombotic antiphsopholipd syndrome
• Treated with acenocumarol for a minimum period of 6 months
• Positivity for Lupus anticoagulant and/or anti-cardiolipin or anti-B2GPI antibodies IgG or IgM≥40

Exclusion Criteria:

• Major haemorrhage (cerebral or gastrointestinal) within the previous 6 months
• Neurosurgery within the previous 4 weeks
• Any surgery within the previous 10 days
• Active peptic ulcus
• ALT or GPT >120 UI/mL non-lupus related in the previous 30 days
• Platelets <30x10E9 in the previous 30 days
• Recent diagnosed malignancy
• Any criteria listed in the summary of the produt characterisitcs (SPC)
• Renal disease with a creatinine clearance <30 mL/min or with a known uncontrolled renal disease
• Concomitant administration of drugs that could interfere with CYP3A4

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: rivaroxaban; Rivaroxaban 20 mg per day	Drug: Rivaroxaban; Rivaroxaban will be started at 20 mg/day. Dose will be adjusted according to Cr Clearance. Cr Clearance 30-49 ml/min will receive 15 mg/day.; Other Names: XARELTO
Active Comparator: acenocumarol; INR adjusted dose	Drug: acenocumarol; Doses will be adjusted according to INR; Other Names: SINTROM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Developement of a new thrombotic event (arterial or venous), confirmed by appropiate imaging studies	Stroke or transient ischemic attack, myocardial infarction, peripheral arterial thrombosis, cerebral vein thrombosis, deep-vein thrombosis, or pulmonary embolism) that was confirmed by adjudication	36 months
Incidence of major bleeding	Major bleeding is defined as clinically overt bleeding associated with any of the following: fatal bleeding causing death, involvement of a critical anatomic site (intracranial, spinal, intraocular, pericardial, articular, retroperitoneal, or intramuscular with compartment syndrome) or need for surgery or angiographic intervention to stop haemorrhage, fall in haemoglobin concentration of at least 20 g/L in 24 hours, and/or requiring non-planned transfusion of ≥2 units of packed red blood cells or whole blood	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of any treatment-Emergent Adverse events	i) all adverse events; ii) serious adverse events (SAE); iii) all bleeding events; iv) overall causes of death	36 months
Death due to thrombotic events	Death as result of a thrombotic event	36 months
Time to the first thrombotic event	Time (months) from the treatment onset up to the thrombotic event	36 months
Location of thrombotic events	Location (arterial or venous) whenre the thrombotic event occurred	36 months
Evaluation of a prognostic biomarker panel	Measuremnt of D-dimer, P-selectine and Von-willebrand factor	36 months

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Investigators: Principal Investigator: Josefina Cortes, MD,pHD, Vall d'Hebron Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2013
• Primary Completion (Actual): December 31, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: October 3, 2016
• First Submitted That Met QC Criteria: October 5, 2016
• First Posted (Estimate): October 6, 2016

Study Record Updates

• Last Update Posted (Actual): May 11, 2018
• Last Update Submitted That Met QC Criteria: May 4, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Disease; Syndrome; Antiphospholipid Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: 2010-019764-36

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided