A Pilot Study on Edoxaban for the Resolution of Left Atrial Thrombosis in Patients With Non-valvular Atrial Fibrillation

Isolated reports have indicated that complete Left Atrial or Left Atrial Appendage thrombus resolution may be achieved also with use of oral Factor Xa inhibitors, which have demonstrated the same efficacy but a better safety profile compared to warfarin.

The aim of this open-label pilot study is to investigate the percentage of Left Atrial /Left Atrial Appendage thrombus resolution with edoxaban therapy in patients with non-valvular atrial fibrillation. The subordinated aim is the design a larger and longer study to compare edoxaban and warfarin in the same patient population.

With the exception of few case reports, there are no data in the same patient population referred to antithrombotic treatments other than vitamin K antagonists.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Edoxaban

Detailed Description

This is a non-controlled, open-label, 4 weeks pilot study.

As the main goal of this exploratory study is the estimation of the magnitude of the Left Atrial /Left Atrial Appendage thrombus resolution with edoxaban, no control group with vitamin K antagonists has been considered, providing that, for the purpose of this study, the magnitude of the response of warfarin is satisfactory defined.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Caserta, Italy, 81100
    • AORN S.ANNA e S.SEBASTIANO
  • Chieti, Italy, 66013
    • Università degli Studi G. D'Annunzio
  • Napoli, Italy, 80131
    • Ospedale P. Monaldi
  • Padova, Italy, 35128
    • Policlinico AO di Padova
  • Roma, Italy, 00128
    • Policlinico Universitario Campus Bio-Medico
  • Ascoli Piceno
    • San Benedetto Del Tronto, Ascoli Piceno, Italy, 63074
      • Ospedale Madonna del Soccorso
  • Bari
    • Acquaviva delle Fonti, Bari, Italy, 70021
      • Ospedale Generale Regionale "F. Miulli"
  • Napoli
    • Pozzuoli, Napoli, Italy, 80078
      • Presidio Ospedaliero S. Maria Delle Grazie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients with all the following criteria will be eligible for inclusion in the study protocol:

1. Signed written informed consent.
2. Males and females ≥ 18 years of age.
3. Female subjects must be post-menopausal (for at least 2 years), surgically sterile, abstinent, or, if sexually active, be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study; and, for those of childbearing potential, have a negative serum β-human chorionic gonadotropin pregnancy test at screening.
4. Atrial fibrillation (AF) must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before enrolment.

5. Subjects with newly diagnosed atrial fibrillation are eligible provided that:

   • -there is evidence that the atrial fibrillation is non-valvular:
   • -there is ECG evidence on 2 occasions 24 hours apart demonstrating atrial fibrillation.
6. Left Atrial or Left Atrial Appendage thrombosis documented by trans-esophageal echocardiography (TEE)
7. Cardiac failure, Hypertension, Age (x2 ), Diabetes, Stroke (x 2) risk index-VASC score >1.

Exclusion Criteria:

Patients with all the following criteria will not be eligible for inclusion in the study protocol:

1. Hemodynamically significant mitral valve stenosis.
2. Prosthetic heart mechanical or biological valve (annuloplasty with or without prosthetic ring, commissurotomy and/or valvuloplasty are permitted).
3. Transient atrial fibrillation caused by a reversible disorder (e.g., thyrotoxicosis, pulmonary embolism, recent surgery or myocardial infarction).
4. Known presence of atrial myxoma.
5. Left ventricular thrombus.
6. Active endocarditis.
7. Active internal bleeding.

8. History of condition associated with increased bleeding risk including, but not limited to:

   • major surgical procedure or trauma within 30 days;
   • clinically significant gastrointestinal bleeding within 6 months;
   • previous intracranial, intraocular, spinal, atraumatic intra-articular bleeding;
   • chronic haemorrhagic disorder;
   • Any neoplasm, including intracranial neoplasm,
   • arteriovenous malformation or aneurysm.
9. Platelet count <90,000/μL at the screening visit.
10. Sustained uncontrolled hypertension: Systolic Blood Pressure ≥180 mmHg or Diastolic Blood Pressure ≥100 mmHg.
11. Severe, disabling stroke (modified Rankin score of 4 to 5, inclusive within 3 months or any stroke < 14 days).
12. Transient ischemic attack within 3 days.
13. Any oral anticoagulant therapy at the time of the baseline visit.

14. Treatment with:

    • aspirin >160 mg daily;
    • aspirin plus a thienopyridine within 5 days;
    • intravenous antiplatelets within 5 days;
    • fibrinolytics within 10 days.
15. Anticipated need for therapy with a non-steroidal anti-inflammatory drug in the next 4 weeks.
16. Treatment with a strong inducer of cytochrome P450 and P glycoprotein, such as ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, lopinavir, telaprevir, indinavir, conivaptan, clarithromycin or planned treatment during the study.
17. Other indication for anticoagulant therapy.
18. Hypersensitivity or intolerance to the study drug, including excipients.
19. Women of childbearing potential who do not want adopt a contraceptive method during the study period and the following 4 weeks.
20. Breast-feeding women during the study period and the following 4 weeks.
21. Anemia (hemoglobin <10 g/dL) at the screening visit.
22. Known significant liver disease (e.g., acute clinical hepatitis, chronic active hepatitis, cirrhosis), or Alanine aminotransferase or Aspartate aminotransferase >2 x Upper Level of Normal or total bilirubin >1.5 x Upper Level of Normal.
23. Patients with moderate or severe renal impairment (CrCL <50 mL/min) or patients with end stage renal disease (CrCL < 15 mL/min) or on dialysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Edoxaban; Used for Treatment. All patients will receive edoxaban 60 mg once a day, with open-label design, for 4 weeks. Edoxaban daily dose will be reduced to 30 mg/day in case of: body weight ≤60 kg, or concomitant therapy with verapamil/quinidine/dronedarone.	Drug: Edoxaban; Edoxaban 60 mg once a day for 4 weeks. Edoxaban 30 mg/day in patients with body weight ≤60 kg, or with concomitant therapy with verapamil/quinidine/dronedarone.; Other Names: Lixiana

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of patients with complete thrombus resolution by TEE, evaluated with the following Probe angulations: 0°, 45°-to-60°, 90°.	Only a descriptive statistical analysis will be performed.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute variation of thrombus area by TEE evaluation (Probe angulations: 0°, 45-to-60°, 90°)	Only a descriptive statistical analysis will be performed.	4 weeks
Percent variation of thrombus area by TEE evaluation (Probe angulations: 0°, 45-to-60°, 90°)	Only a descriptive statistical analysis will be performed.	4 weeks
Time to electrical cardioversion (when applicable).	Only a descriptive statistical analysis will be performed.	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety analysis - Percentage of bleeding events (telephone assessment)	Only a descriptive statistical analysis will be performed.	4 weeks and 8 weeks
Safety analysis - Percentage of any stroke or peripheral embolism (telephone assessment)	Only a descriptive statistical analysis will be performed.	4 weeks and 8 weeks
Safety analysis - Percentage of any other safety related events (deaths, Serious Adverse Events and Adverse Events).	Only a descriptive statistical analysis will be performed.	4 weeks and 8 weeks

Collaborators and Investigators

• Sponsor: Raffaele De Caterina
• Collaborators: Hippocrates Research
• Investigators: Principal Investigator: Raffaele De Caterina, Università degli Studi G. d'Annunzio Chieti

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): April 30, 2021

Study Registration Dates

• First Submitted: March 15, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 5, 2018

Study Record Updates

• Last Update Posted (Actual): May 4, 2021
• Last Update Submitted That Met QC Criteria: May 1, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Atrial Fibrillation; Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban
• Other Study ID Numbers: EDO-SP-01-2015; 2015-004847-37 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No