The MITRAL II Pivotal Trial (Mitral Implantation of TRAnscatheter vaLves).

Mitral Regurgitation Clinical Trial

— MITRAL-II  

Official title:

The Safety and Effectiveness of the Edwards SAPIEN 3, SAPIEN 3 Ultra, and SAPIEN 3 Ultra RESILIA (SAPIEN 3/Ultra/RESILIA) Valve in Patients With Symptomatic Severe Calcific Mitral Valve Disease With Severe Mitral Annular Calcification Who Are Not Candidates for Standard Mitral Valve Surgery.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04408430
• Other study ID #: 20-002438
• Status: Recruiting
• Phase: N/A
• Start date: March 8, 2021
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: Mayo Clinic
• Contact: Tatiana Kaptzan, Ph. D.
• Phone: 507-284-1610
• Email: kaptzan.tatiana[@]mayo.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A prospective multicenter study enrolling high surgical risk patients with severe mitral annular calcification (MAC) and symptomatic mitral valve dysfunction (severe stenosis, ≥ moderate to severe regurgitation, or mixed ≥ moderate stenosis and ≥ regurgitation). There are 2 Arms in this study: 1) "Transseptal (TS) Valve-in-MAC" (ViMAC) Arm, and 2) Natural History of Disease Registry (NHDR) for patients treated with medical treatment only (which includes patients who meet inclusion criteria but can't be treated with transeptal ViMAC due to the presence of anatomical exclusion criteria or other exclusion criteria) and have not had other procedures that may impact outcomes (i.e., alcohol septal ablation or radiofrequency ablation). The study also includes a Registry of Permanently Unassigned" for subjects who undergo preemptive septal ablation procedures (alcohol or radiofrequency) in anticipation of continuing onto ViMAC arm, but are not accepted in the ViMAC Study arm or the patient chooses not to undergo ViMAC procedure.

Description:

STUDY OBJECTIVE

The purpose of this study is to establish the safety and effectiveness of the Edwards SAPIEN 3, SAPIEN 3 Ultra and SAPIEN 3 Ultra RESILIA (SAPIEN 3/Ultra/RESILIA) valves with Commander delivery system in patients with severe mitral annular calcification and symptomatic mitral valve dysfunction who are not candidates for standard mitral valve surgery.

STUDY DESIGN

A prospective multicenter study enrolling high surgical risk patients with severe mitral annular calcification (MAC) and symptomatic mitral valve dysfunction (severe stenosis, ≥ moderate to severe regurgitation, or mixed ≥ moderate stenosis and ≥ regurgitation). There are 2 arms in this study: 1) "Transseptal (TS) Valve-in-MAC (ViMAC)" arm, 2) Natural History of Disease Registry (NHDR). Patients treated with medical treatment only (which will include patients who meet inclusion criteria but can't be treated with transseptal ViMAC due to the presence of anatomical exclusion criteria or other exclusion criteria) and have not had other procedures that may impact outcomes (i.e. alcohol septal ablation, radiofrequency ablation).

Enrollment Enrollment will consist of 110 patients in the treatment arm (transseptal ViMAC) and up to 100 in the medically treated arm).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 210
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

All Candidates must meet the following criteria:

1. - 18 years of age or older

2. -Severe mitral annular calcification with symptomatic mitral valve dysfunction including severe mitral stenosis defined as mitral valve area (MVA) of =1.5 cm2, or = moderate to severe mitral regurgitation, or mixed = moderated stenosis and = moderate regurgitation. For this study, the severity of mitral regurgitation will be graded according to the 2017 American Society of Echocardiography Guidelines: None, Trivial, Mild 1(+), Moderate 2(+), Moderate to severe 3(+), and severe 4(+).

3. - NYHA Functional Class =II.

4. The heart team agrees that valve implantation will likely benefit the patient.

5. High or prohibitive risk for standard mitral valve surgery as determined by the heart team (at least one site cardiac surgeon must personally examine the subject to determine operative risk in patients presented for inclusion to ViMAC arm). NOTE: Patients not interested in mitral intervention or who are being considered for inclusion in the Natural History of Disease Registry are not required to be evaluated in person by a surgeon.)

6. The study patient has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.

7. The study patient agrees to comply with all required post-procedure follow-up visits including annual visits through 5 years.

Exclusion Criteria for ViMAC subjects (does not apply to the Natural History of Disease Registry):

1. - The heart team considers the patient is a surgical candidate.

2. - Mitral annulus is not severely calcified.

3. - Myocardial infarction requiring revascularization within 30 days from procedure.

4. - Clinically significant untreated coronary artery disease requiring revascularization.

5. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease). Implantation of a permanent pacemaker is not exclusionary.

6. Any patient with a balloon valvuloplasty (BMV) within 30 days of the procedure (unless BMV is a bridge to ViMAC procedure after a qualifying Echo).

7. Severe symptomatic tricuspid regurgitation (hepatic dysfunction, ascites, edema not controlled with diuretics) requiring surgery.

8. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Platelets < 50,000 cell/mL), history of coagulopathy or hypercoagulable state.

9. Hypertrophic obstructive cardiomyopathy (HOCM) with mean LVOT gradient of =20 mm Hg at rest or =50 mmHg with Valsalva.

10. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening evaluation.

11. Need for emergency surgery for any reason.

12. Severe left ventricular dysfunction with LVEF < 20%.

13. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.

14. Active upper GI bleeding within 90 days prior to procedure.

15. A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure.

16. Cardiac anatomy that would preclude appropriate delivery and deployment of an Edwards SAPIEN 3/Ultra/RESILIA valve in MAC via transseptal access, including but not limited to:

• Native neo mitral annulus size < 275 mm2 or > 810 mm2 as measured by CT scan.

• Significant risk of LVOT obstruction or valve embolization as assessed by CT core lab

17. Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack (TIA) within 90 days of the procedure.

18. Estimated life expectancy <12 months due to non-cardiac conditions.

19. Expectation that patient will not improve despite treatment of mitral valve dysfunction.

20. Active bacterial endocarditis within 180 days of procedure.

21. - Severe right ventricular dysfunction as assessed by Echo core lab

22. - Active infection requiring antibiotic therapy (subject may be a candidate after 2 weeks of antibiotic discontinuation.

23. - Female who is pregnant or lactating.

24. - Participating in another investigational device study.

25. - Aortic valve disease requiring intervention. If aortic valve intervention is required, the AVR procedure should be performed first and if the patient remains symptomatic after AVR, may be presented for consideration for inclusion in this trial.

26. - Severe fixed pulmonary hypertension (PASP =70 mmHg and more than 2/3 of the systemic systolic blood pressure).

27. - Severe chronic obstructive pulmonary disease requiring continuous home oxygen.

28. - The patient refuses mitral valve intervention

29. - Recent symptomatic COVID-19 infection with residual symptoms that may affect the outcomes of this trial.

Related Conditions & MeSH terms

• Calcinosis
• Heart Valve Diseases
• Mitral Annular Calcification
• Mitral Regurgitation
• Mitral Stenosis
• Mitral Valve Disease
• Mitral Valve Insufficiency
• Mitral Valve Stenosis

Intervention

Device:
• Transseptal ViMAC
Transseptal TMVR using balloon-expandable aortic transcatheter valves.

Locations

Country	Name	City	State
United States	Piedmont Healthcare	Atlanta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Sutter Health	Burlingame	California
United States	Northwestern University Medical School	Chicago	Illinois
United States	Henry Ford Health System	Detroit	Michigan
United States	Uchealth Heart & Vascular Clinic Harmony Campus	Fort Collins	Colorado
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Intermountain Medical Center	Murray	Utah
United States	Columbia University Medical Center/NYPH	New York	New York
United States	The Sentara Heart Valve and Structural Disease Center	Norfolk	Virginia
United States	Banner - University Medicine Cardiology Clinic	Phoenix	Arizona
United States	Baylor Scott and White - The Heart Hospital - Plano	Plano	Texas
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Pima Heart & Vascular	Tucson	Arizona
United States	Oklahoma Heart Institute Utica Office	Tulsa	Oklahoma
United States	Medstar Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Mayra Guerrero

Country where clinical trial is conducted

United States, 

References & Publications (6)

Guerrero M, Greenbaum A, O'Neill W. First in human percutaneous implantation of a balloon expandable transcatheter heart valve in a severely stenosed native mitral valve. Catheter Cardiovasc Interv. 2014 Jun 1;83(7):E287-91. doi: 10.1002/ccd.25441. Epub 2014 Mar 14. — View Citation

Guerrero M, Urena M, Himbert D, Wang DD, Eleid M, Kodali S, George I, Chakravarty T, Mathur M, Holzhey D, Pershad A, Fang HK, O'Hair D, Jones N, Mahadevan VS, Dumonteil N, Rodes-Cabau J, Piazza N, Ferrari E, Ciaburri D, Nejjari M, DeLago A, Sorajja P, Zah — View Citation

Guerrero M, Urena M, Pursnani A, Wang DD, Vahanian A, O'Neill W, Feldman T, Himbert D. Balloon expandable transcatheter heart valves for native mitral valve disease with severe mitral annular calcification. J Cardiovasc Surg (Torino). 2016 Jun;57(3):401-9. — View Citation

Guerrero M, Wang DD, Himbert D, Urena M, Pursnani A, Kaddissi G, Iyer V, Salinger M, Chakravarty T, Greenbaum A, Makkar R, Vahanian A, Feldman T, O'Neill W. Short-term results of alcohol septal ablation as a bail-out strategy to treat severe left ventricular outflow tract obstruction after transcatheter mitral valve replacement in patients with severe mitral annular calcification. Catheter Cardiovasc Interv. 2017 Dec 1;90(7):1220-1226. doi: 10.1002/ccd.26975. Epub 2017 Mar 7. — View Citation

Guerrero M, Wang DD, O'Neill W. Percutaneous alcohol septal ablation to acutely reduce left ventricular outflow tract obstruction induced by transcatheter mitral valve replacement. Catheter Cardiovasc Interv. 2016 Nov 15;88(6):E191-E197. doi: 10.1002/ccd.26649. Epub 2016 Jul 5. — View Citation

Russell HM, Guerrero ME, Salinger MH, Manzuk MA, Pursnani AK, Wang D, Nemeh H, Sakhuja R, Melnitchouk S, Pershad A, Fang HK, Said SM, Kauten J, Tang GHL, Aldea G, Feldman TE, Bapat VN, George IM. Open Atrial Transcatheter Mitral Valve Replacement in Patients With Mitral Annular Calcification. J Am Coll Cardiol. 2018 Sep 25;72(13):1437-1448. doi: 10.1016/j.jacc.2018.07.033. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Additional Endpoint: Technical Success	• Technical success at exit from the cath lab.; Defined as: Successful vascular access, delivery and retrieval of the transcatheter valve delivery system.; Deployment of a single valve.; Correct position of transcatheter valve in the mitral annulus.; Adequate performance of the prosthetic heart valve (MVA > 1.5 cm2) without residual mitral regurgitation grade =2 (+).; No need for additional surgery or re-intervention (includes drainage of pericardial effusion).; The patient leaves the cath lab alive.	Immediately after the intervention procedure.
Other	Additional Endpoint: Procedural Success	• Procedural Success at 30 days.; Defined as: Device success at 30 days.; No device/procedure related SAE's including: death, stroke, MI or coronary ischemia requiring PCI or CABG, stage 2 or 3 AKI including dialysis, life threatening bleeding, major vascular or access complications (arterial, venous, or TA - any event requiring additional unplanned surgical or transcatheter intervention), pericardial effusion or tamponade requiring drainage, severe hypotension, heart failure or respiratory failure requiring intravenous pressors or invasive or mechanical treatments such as ultrafiltration or hemodynamic assist devices including intra-aortic balloon pump or left ventricular assist device, or prolonged intubation for =48 hrs, or any valve-related dysfunction, migration, thrombosis, or other complication requiring surgery or repeat intervention.	30 days
Other	Additional Endpoint: Device Success	Device success is defined as: Stroke free survival with original valve in place.; No need for additional surgery or re-intervention related to the procedure, access or to the replacement valve.; Proper placement and intended function of the replacement valve, including; No migration, fracture, thrombosis, hemolysis or endocarditis.; No replacement valve stenosis (MV gradient < 10 mmHg).; Replacement valve regurgitation < 2 + (including central and paravalvular leak) and without associated hemolysis.; No increase in AI from baseline (more than 1 grade) and LVOT gradient < 20 mmHg increase from baseline.	30 days.
Other	Additional Efficacy Endpoint - NYHA Class at 30 days.	• Change from baseline in NYHA Class at 30 days.	30 days.
Other	Additional Efficacy Endpoint - Distance walked in 6 MWT at 30 days	• Change from baseline in distance walked measure by the 6 MWT at 30 days.	30 days.
Other	Additional Efficacy Endpoint - KCCQ at 30 days	• Change from baseline in KCCQ at 30 days.	30 days.
Other	Additional Efficacy Endpoint - MR severity at 30 days	• Degree of mitral regurgitation (central and paravalvular) at 30 days.	30 days
Other	Additional Safety Endpoint - Stroke at 30 days and 1 year.	• Stroke at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - Need for ASD Closure	• Iatrogenic ASD causing RV failure or hypoxemia or need for ASD closure at discharge and 30 days.	30 days.
Other	Additional Safety Endpoint - New LVOT Gradient	• New mean LVOT gradient = 20 mmHg, or = 20 mmHg increase from baseline LVOT gradient at 30 days and 1 year.	30 days and 1 year.
Other	Additional Efficacy Endpoint - Mitral Valve Reintervention	• Mitral Valve reintervention at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - Hospitalizations at 1 year	• Number of hospitalizations at 1 year.	1 year.
Other	Additional Efficacy Endpoint - Days Alive Out of the Hospital	• Days alive out of hospital at 1 year from index procedure (ViMAC arm) or from assignment day (Natural History Registry).	1 year.
Other	Additional Safety Endpoint - Hemolysis	• Hemolysis at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - Endocarditis	• Endocarditis at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - Blood Transfusion	• Blood transfusion at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - New Pacemaker Requirement	• New pacemaker requirement at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - New Aortic Valve Insufficiency	• New aortic valve insufficiency at 30 days and 1 year.	30 days and 1 year.
Other	Additional Safety Endpoint - Acute Kidney Injury	• Acute kidney injury (MVARC) at 30 days and 1 year.	30 days and 1 year.
Primary	Primary Safety Endpoint: All Cause Morality and Hospitalization for Heart Failure	A non-hierarchical composite of all-cause mortality and hospitalization for heart failure.	1 year.
Secondary	Secondary Effectiveness Endpoint	• Stroke at 30 days and 1 year.	1 year
Secondary	Secondary Effectiveness Endpoint	• Change from baseline in New York Heart Association Class at 1 year.	1 year.
Secondary	Secondary Effectiveness Endpoint	• Change from baseline in distance walked measure by the 6 Minute Walk Test at 1 year.	1 year.
Secondary	Secondary Effectiveness Endpoint	• Change from baseline in quality-of-life measure by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 1 year.	1 year.
Secondary	Secondary Effectiveness Endpoint	• Echocardiographic assessment of degree of mitral regurgitation (central and paravalvular) at 1 year.	1 year.
Secondary	Secondary Effectiveness Endpoint	• Significant mitral stenosis defined as mean mitral valve gradient by echo > 10 mmHg at 1 year.	1 year.