The ENCIRCLE Trial (ENCIRCLE)

SAPIEN M3 System Transcatheter Mitral Valve Replacement Via Transseptal Access

This study will establish the safety and effectiveness of the SAPIEN M3 System in subjects with symptomatic, at least 3+ mitral regurgitation (MR) for whom commercially available surgical or transcatheter treatment options are deemed unsuitable.

Following completion of enrollment, subjects will be eligible for enrollment in the continued access phase of the trial.

Study Overview

• Status: Recruiting
• Conditions: Mitral Regurgitation; Mitral Valve Insufficiency
• Intervention / Treatment: Device: SAPIEN M3 valve and dock

Detailed Description

This is a prospective single-arm, multicenter study.

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Edwards TMTT Clinical Affairs; Phone Number: +1 (949) 250-2500; Email: TMTT_Clinical@edwards.com

Study Locations

• Australia
  • Camperdown, Australia, NSW2050
    • Active, not recruiting
    • Royal Prince Alfred Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • Active, not recruiting
      • The Prince Charles Hospital
• Canada
  • Toronto, Canada, M5B 1W8
    • Recruiting
    • St. Michael's
  • Vancouver, Canada, V6E 1M7
    • Recruiting
    • St. Pauls
  • Quebec
    • Québec, Quebec, Canada, G1V 0A6
      • Recruiting
      • Laval University
• Israel
  • Jerusalem, Israel, 9103102
    • Withdrawn
    • Shaare Zedek Medical Center
  • Petah Tikva, Israel, 4941492
    • Active, not recruiting
    • Rabin Medical Center
  • Ramat Gan, Israel, 5211401
    • Withdrawn
    • Sheba Medical Center
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Active, not recruiting
    • Leiden University Medical Center
  • Rotterdam, Netherlands, 3015 CE
    • Active, not recruiting
    • Rotterdam Erasmus MC
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Active, not recruiting
    • Saint Bartholomew's Medical Center
  • London, United Kingdom, SE1 7EH
    • Active, not recruiting
    • Saint Thomas Hospital
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Active, not recruiting
      • Heart Center Hospital
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Active, not recruiting
      • Banner University Medical Center
    • Phoenix, Arizona, United States, 85013
      • Active, not recruiting
      • Saint Josephs Hospital Medical Center Dignity Health
    • Tucson, Arizona, United States, 85712
      • Withdrawn
      • TMC HealthCare
  • California
    • La Jolla, California, United States, 92037
      • Active, not recruiting
      • Scripps Health
    • Los Angeles, California, United States, 90048
      • Active, not recruiting
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90071
      • Active, not recruiting
      • Kaiser Sunset LA
    • Los Angeles, California, United States, 90017
      • Active, not recruiting
      • Good Samaritan Hospital
    • Orange, California, United States, 92868
      • Withdrawn
      • Saint Joseph Hospital
    • San Francisco, California, United States, 94109
      • Active, not recruiting
      • California Pacific Medical Center
  • Colorado
    • Loveland, Colorado, United States, 80538
      • Active, not recruiting
      • UC Health Northern Colorado (Medical Center of the Rockies)
  • Florida
    • Delray Beach, Florida, United States, 33484
      • Withdrawn
      • Delray Medical Center
    • Gainesville, Florida, United States, 32605
      • Active, not recruiting
      • Cardiac & Vascular Institute Foundation
    • Jacksonville, Florida, United States, 32204
      • Active, not recruiting
      • Ascension St. Vincent's Hospital
    • Naples, Florida, United States, 34102
      • Active, not recruiting
      • Naples Community Hospital
    • Sarasota, Florida, United States, 34239
      • Active, not recruiting
      • Sarasota Memorial Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Active, not recruiting
      • Emory University
    • Atlanta, Georgia, United States, 30309
      • Active, not recruiting
      • Piedmont Healthcare
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Withdrawn
      • Rush University Medical Center
    • Glenview, Illinois, United States, 60026
      • Active, not recruiting
      • NorthShore University Health System
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Withdrawn
      • St. Vincent Heart Center of Indiana
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Active, not recruiting
      • University of Kansas
    • Wichita, Kansas, United States, 67226
      • Active, not recruiting
      • Cardiovascular Research Institute of Kansas (CRIOK)
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Active, not recruiting
      • Our Lady of the Lake Regional Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Active, not recruiting
      • MedStar Union Memorial Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Active, not recruiting
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Withdrawn
      • Brigham & Women's
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Active, not recruiting
      • Henry Ford
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Withdrawn
      • Minneapolis Heart
    • Rochester, Minnesota, United States, 55905
      • Active, not recruiting
      • Mayo Clinic
    • Saint Cloud, Minnesota, United States, 56303
      • Active, not recruiting
      • CentraCare
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Active, not recruiting
      • Saint Luke's Kansas City
  • Montana
    • Missoula, Montana, United States, 59802
      • Withdrawn
      • St. Patrick Hospital
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Active, not recruiting
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Withdrawn
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Active, not recruiting
      • Robert Wood Johnson University Hospital
  • New York
    • Buffalo, New York, United States, 14203
      • Active, not recruiting
      • University of Buffalo
    • New York, New York, United States, 10007
      • Active, not recruiting
      • Weill Cornell Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Withdrawn
      • Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28204
      • Active, not recruiting
      • Novant Health and Vascular Institute
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Active, not recruiting
      • The Christ Hospital
    • Cleveland, Ohio, United States, 44122
      • Active, not recruiting
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43123
      • Active, not recruiting
      • Mount Carmel East Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Active, not recruiting
      • Oklahoma Heart Hospital
    • Tulsa, Oklahoma, United States, 74104
      • Active, not recruiting
      • Oklahoma Heart Institute
  • Pennsylvania
    • Mechanicsburg, Pennsylvania, United States, 17050
      • Active, not recruiting
      • UPMC Heart and Vascular Institute
    • Pittsburgh, Pennsylvania, United States, 15212
      • Withdrawn
      • Alleghany General Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Active, not recruiting
      • Saint Thomas Health
  • Texas
    • Austin, Texas, United States, 78705
      • Active, not recruiting
      • Austin Heart
    • Houston, Texas, United States, 77004
      • Active, not recruiting
      • HCA Houston Healthcare Medical (SCRI)
    • Houston, Texas, United States, 77030
      • Active, not recruiting
      • UT Memorial Hermann
  • Utah
    • Murray, Utah, United States, 84107
      • Active, not recruiting
      • Intermountain Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Active, not recruiting
      • Sentara Norfolk
    • Roanoke, Virginia, United States, 24014
      • Active, not recruiting
      • Carilion Roanoke Memorial Hospital
  • Washington
    • Seattle, Washington, United States, 98195
      • Active, not recruiting
      • University of Washington Seattle
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-3248
      • Withdrawn
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 years of age or older
2. MR ≥ 3+
3. NYHA functional class ≥ II
4. Per the Heart Team, commercially available surgical or transcatheter treatment options are deemed unsuitable due to clinical, anatomic or technical considerations.
5. Subject's heart failure management has been optimized based on subject characteristics and applicable guidelines, and stable for at least 30 days prior to enrollment.
6. The subject or subject's legal representative has been informed of the nature of the study, agrees to its provisions and has provided written informed consent.

Exclusion Criteria:

1. Mitral/cardiac anatomy that would preclude appropriate delivery and deployment of the SAPIEN M3 dock or valve
2. Inappropriate anatomy for femoral introduction and delivery of the SAPIEN M3 dock and valve
3. Presence of any device that will contact or interfere with the SAPIEN M3 System during delivery or after implantation
4. Left ventricular ejection fraction <25%
5. Severe right ventricular dysfunction
6. Need for aortic, tricuspid or pulmonic valve intervention within the next 12 months
7. History of heart transplant
8. Cardiac imaging evidence of intracardiac mass, thrombus or vegetation
9. Active bacterial endocarditis within 180 days of the procedure
10. Hemodynamic instability requiring inotropic or mechanical support within 30 days of the procedure
11. Myocardial infarction within 30 days of the procedure
12. Clinically significant untreated coronary artery disease requiring revascularization
13. Any percutaneous cardiovascular intervention, cardiovascular surgery, or carotid surgery within 30 days of the procedure
14. Stroke or transient ischemic attack within 90 days of the procedure
15. Irreversible, severe pulmonary hypertension
16. Chronic obstructive pulmonary disease requiring home oxygen therapy or chronic outpatient oral steroid use
17. Renal insufficiency or receiving renal replacement therapy
18. Liver disease
19. Planned surgery within the next 12 months
20. Inability to tolerate or a medical condition precluding treatment with antithrombotic therapy, including heparin administration during the procedure
21. Active infection requiring current antibiotic therapy
22. Active SARS-CoV-2 infection (Coronavirus-19 [COVID-19]) or previously diagnosed with COVID-19 with sequelae that could confound endpoint assessments
23. Leukopenia, anemia, thrombocytopenia, history of bleeding diathesis or coagulopathy or hypercoagulable states
24. Refusal of blood products
25. Female who is pregnant or lactating
26. Estimated life expectancy <12 months due to non-cardiac conditions
27. Participating in another investigational drug or device study that has not reached its primary endpoint
28. Subject considered to be part of a vulnerable population

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TMVR - Main Cohort; Subjects for whom commercially available surgical or transcatheter treatment options are deemed unsuitable will have transcatheter mitral valve replacement (TMVR).	Device: SAPIEN M3 valve and dock; During the procedure a SAPIEN M3 dock and a SAPIEN M3 valve will be implanted via transseptal approach.
Experimental: TMVR - Failed TEER Registry; Subjects who have had an attempted but failed transcatheter edge-to-edge repair (TEER) procedure will have TMVR.	Device: SAPIEN M3 valve and dock; During the procedure a SAPIEN M3 dock and a SAPIEN M3 valve will be implanted via transseptal approach.
Experimental: TMVR - MAC Registry; Subjects with mitral annular calcification (MAC) will have TMVR.	Device: SAPIEN M3 valve and dock; During the procedure a SAPIEN M3 dock and a SAPIEN M3 valve will be implanted via transseptal approach.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-hierarchical composite of death and heart failure rehospitalization	Number of subjects with death and/or heart failure rehospitalization	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in NYHA functional class compared to baseline	New York Heart Association (NYHA) functional classification of heart failure is based on how much a patient is limited during physical activity. The rating ranges from I-IV. I = no limitations of physical activity; II = slight limitations of physical activity, ordinary physical activity results in fatigue, palpitation, shortness of breath; III = marked limitations of physical activity, less than ordinary activity causes fatigue, palpitation, or shortness of breath; IV = unable to carry on any physical activity without discomfort, symptoms of heart failure at rest.	1 year
Improvement in KCCQ Overall Score compared to baseline	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. An overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	1 year
Improvement in MR compared to baseline	Number of subjects with improved MR compared to baseline	1 year
Decrease in LVEDVi compared to baseline	Number of subjects with decreased left ventricular end-diastolic volume index (LVEDVi) compared to baseline	1 year

Collaborators and Investigators

• Sponsor: Edwards Lifesciences
• Investigators: Principal Investigator: John Webb, MD, St. Paul's Hospital; Principal Investigator: Mayra Guerrero, MD, Mayo Clinic; Principal Investigator: David Daniels, MD, California Pacific Medical Center

Publications and helpful links

General Publications

• Guerrero ME, Daniels DV, Makkar RR, Thourani VH, Asch FM, Pham M, Muhammad KI, Greenbaum AB, Vasquez A, Oldemeyer JB, Dahle TG, Rihal C, Morse MA, Rodriguez E, O'Neill BP, Russo M, Whisenant B, Yadav P, Yu X, Wang DD, Makar M, Baran DA, Mahoney P, Reddy G, Blanke P, Webb J; ENCIRCLE Trial Executive Committee and Study Investigators. Percutaneous transcatheter valve replacement in individuals with mitral regurgitation unsuitable for surgery or transcatheter edge-to-edge repair: a prospective, multicountry, single-arm trial. Lancet. 2025 Nov 29;406(10519):2541-2550. doi: 10.1016/S0140-6736(25)02073-2. Epub 2025 Oct 27.

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2020
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2031

Study Registration Dates

• First Submitted: November 4, 2019
• First Submitted That Met QC Criteria: November 5, 2019
• First Posted (Actual): November 6, 2019

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 23, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Mitral Valve Insufficiency
• Other Study ID Numbers: 2018-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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