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Edge-to-edge Mitral Valve Repair in ATTR-CM (MILLENNIAL)

Primary Purpose

Mitral Regurgitation, ATTR-Cardiomyopathy, Edge-to-Edge Mitral Valve Repair

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
TEER
Optimal Medical Therapy
Sponsored by
Medical University of Vienna
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mitral Regurgitation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria (all must be present) Proven ATTR-CM Significant symptomatic MR (3+ or 4+ by independent echocardiographic core laboratory assessment) Subject has been adequately treated per applicable standards, including for coronary artery disease and heart failure (e.g., diuretics) New York Heart Association (NYHA) functional class II, III, or ambulatory IV Local heart team has determined that mitral valve surgery will not be offered as a treatment option, even if the subject is randomized to the control group Left ventricular ejection fraction ≥20% Anatomical feasibility for TEER as per discretion of the implanting investigator Age 18 years or older Subject or guardian agrees to all provisions of the protocol, including the possibility of randomization to the Control group and returning for all required post-procedure follow-up visits, and has provided written informed consent Exclusion criteria (all must be absent) AL-associated cardiomyopathy Aortic or tricuspid valve disease requiring surgery or transcatheter intervention Severe right ventricular dysfunction Hemodynamic instability requiring inotropic support or mechanical heart assistance Leaflet anatomy which may preclude TEER, proper device positioning on the leaflets or sufficient reduction in mitral regurgitation by TEER Life expectancy <12 months due to non-cardiac conditions Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve, or any prior transcatheter mitral valve procedure Echocardiographic evidence of intracardiac mass, thrombus or vegetation Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated) Active infections requiring current antibiotic therapy Transesophageal echocardiography (TEE) is contraindicated or high risk Pregnant or planning pregnancy within next 12 months Currently participating in an investigational drug or another device study that has not reached its primary endpoint

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Interventional

    Control

    Arm Description

    TEER + Optimal Medical Therapy

    Optimal Medical Therapy alone

    Outcomes

    Primary Outcome Measures

    A hierarchical combination of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT through month 24
    Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters). The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the TEER+OMT group will have a greater score than a subject in the placebo group.

    Secondary Outcome Measures

    Evaluate effects of TEER on quality of life (QoL) through Month 24
    Change from Baseline to Month 24 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status.
    Technical, device, and procedural success of TEER (in the TEER group only)
    Technical, device, and procedural success of TEER as defined according to the definitions of the Mitral Valve Academic Research Consortium (MVARC)

    Full Information

    First Posted
    September 27, 2023
    Last Updated
    October 4, 2023
    Sponsor
    Medical University of Vienna
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06075823
    Brief Title
    Edge-to-edge Mitral Valve Repair in ATTR-CM
    Acronym
    MILLENNIAL
    Official Title
    Effectiveness and Safety of Edge-to-edge MItral vaLve Repair in Patients With Severe mitraL rEgurgitatioN aNd cardIac ATTR amyLoidosis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    January 1, 2024 (Anticipated)
    Primary Completion Date
    December 12, 2027 (Anticipated)
    Study Completion Date
    December 12, 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Medical University of Vienna

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    No previous study has evaluated the effectiveness of transcatheter edge-to-edge mitral valve repair (TEER) in patients with ATTR-associated cardiomyopathy (ATTR-CM) and significant mitral regurgitation, as this specific patient population was specifically excluded from previous large TEER trials. From a pathophysiological perspective, effective treatment of significant regurgitant volume and consecutive improvement of forward volume appears highly desirable in a condition with intrinsically low output. However, whether this translates into improved functional capacity, better quality of life, and better clinical outcomes compared to conservative heart failure management alone remains to be investigated.
    Detailed Description
    It is the aim of this trial to investigate the effectiveness of TEER therapy in patients with proven ATTR-CM and concomitant significant MR as compared to medical therapy alone. Effectiveness will be tested via hard clinical outcomes, biomarkers, functional capacity, and quality of life.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Mitral Regurgitation, ATTR-Cardiomyopathy, Edge-to-Edge Mitral Valve Repair

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    100 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Interventional
    Arm Type
    Experimental
    Arm Description
    TEER + Optimal Medical Therapy
    Arm Title
    Control
    Arm Type
    Active Comparator
    Arm Description
    Optimal Medical Therapy alone
    Intervention Type
    Device
    Intervention Name(s)
    TEER
    Intervention Description
    transcatheter edge-to-edge mitral valve repair for significant mitral regurgitation
    Intervention Type
    Other
    Intervention Name(s)
    Optimal Medical Therapy
    Intervention Description
    optimal heart failure management of ATTR-CM
    Primary Outcome Measure Information:
    Title
    A hierarchical combination of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT through month 24
    Description
    Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters). The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the TEER+OMT group will have a greater score than a subject in the placebo group.
    Time Frame
    24 months
    Secondary Outcome Measure Information:
    Title
    Evaluate effects of TEER on quality of life (QoL) through Month 24
    Description
    Change from Baseline to Month 24 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status.
    Time Frame
    24 months
    Title
    Technical, device, and procedural success of TEER (in the TEER group only)
    Description
    Technical, device, and procedural success of TEER as defined according to the definitions of the Mitral Valve Academic Research Consortium (MVARC)
    Time Frame
    12 months
    Other Pre-specified Outcome Measures:
    Title
    Effects of TEER on echocardiographic markers
    Description
    Changes in forward stroke volume, ejection fraction, global longitudinal strain, etc.
    Time Frame
    24 months
    Title
    Effects of TEER on invasive haemodynamics (in the TEER group only)
    Description
    Intraprocedural changes (pre- and post-TEER) in pulmonary pressures in the TEER-group
    Time Frame
    1 day

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion criteria (all must be present) Proven ATTR-CM Significant symptomatic MR (3+ or 4+ by independent echocardiographic core laboratory assessment) Subject has been adequately treated per applicable standards, including for coronary artery disease and heart failure (e.g., diuretics) New York Heart Association (NYHA) functional class II, III, or ambulatory IV Local heart team has determined that mitral valve surgery will not be offered as a treatment option, even if the subject is randomized to the control group Left ventricular ejection fraction ≥20% Anatomical feasibility for TEER as per discretion of the implanting investigator Age 18 years or older Subject or guardian agrees to all provisions of the protocol, including the possibility of randomization to the Control group and returning for all required post-procedure follow-up visits, and has provided written informed consent Exclusion criteria (all must be absent) AL-associated cardiomyopathy Aortic or tricuspid valve disease requiring surgery or transcatheter intervention Severe right ventricular dysfunction Hemodynamic instability requiring inotropic support or mechanical heart assistance Leaflet anatomy which may preclude TEER, proper device positioning on the leaflets or sufficient reduction in mitral regurgitation by TEER Life expectancy <12 months due to non-cardiac conditions Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve, or any prior transcatheter mitral valve procedure Echocardiographic evidence of intracardiac mass, thrombus or vegetation Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated) Active infections requiring current antibiotic therapy Transesophageal echocardiography (TEE) is contraindicated or high risk Pregnant or planning pregnancy within next 12 months Currently participating in an investigational drug or another device study that has not reached its primary endpoint
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Christian Nitsche, MD, PhD
    Phone
    0043 1 40400 46142
    Email
    christian.nitsche@meduniwien.ac.at
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Christian Nitsche, MD, PhD
    Organizational Affiliation
    Medical University of Vienna
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    30280640
    Citation
    Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack MJ; COAPT Investigators. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018 Dec 13;379(24):2307-2318. doi: 10.1056/NEJMoa1806640. Epub 2018 Sep 23.
    Results Reference
    background
    PubMed Identifier
    36008266
    Citation
    Dona C, Nitsche C, Koschutnik M, Heitzinger G, Mascherbauer K, Kammerlander AA, Dannenberg V, Halavina K, Rettl R, Duca F, Traub-Weidinger T, Puchinger J, Gunacker PC, Lamm G, Vock P, Lileg B, Philipp V, Staudenherz A, Calabretta R, Hacker M, Agis H, Bartko P, Hengstenberg C, Fontana M, Goliasch G, Mascherbauer J. Unveiling Cardiac Amyloidosis, its Characteristics, and Outcomes Among Patients With MR Undergoing Transcatheter Edge-to-Edge MV Repair. JACC Cardiovasc Interv. 2022 Sep 12;15(17):1748-1758. doi: 10.1016/j.jcin.2022.06.009. Epub 2022 Aug 22.
    Results Reference
    result
    PubMed Identifier
    35779241
    Citation
    Chacko L, Karia N, Venneri L, Bandera F, Passo BD, Buonamici L, Lazari J, Ioannou A, Porcari A, Patel R, Razvi Y, Brown J, Knight D, Martinez-Naharro A, Whelan C, Quarta CC, Manisty C, Moon J, Rowczenio D, Gilbertson JA, Lachmann H, Wechelakar A, Petrie A, Moody WE, Steeds RP, Potena L, Riefolo M, Leone O, Rapezzi C, Hawkins PN, Gillmore JD, Fontana M. Progression of echocardiographic parameters and prognosis in transthyretin cardiac amyloidosis. Eur J Heart Fail. 2022 Sep;24(9):1700-1712. doi: 10.1002/ejhf.2606. Epub 2022 Jul 27.
    Results Reference
    result
    PubMed Identifier
    35906799
    Citation
    Nitsche C. Echocardiographic tracking of transthyretin cardiomyopathy: which parameters matter the most? Eur J Heart Fail. 2022 Sep;24(9):1713-1715. doi: 10.1002/ejhf.2639. Epub 2022 Aug 12. No abstract available.
    Results Reference
    result

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    Edge-to-edge Mitral Valve Repair in ATTR-CM

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