LANDMARK Trial: a Randomised Controlled Trial of Myval THV

Study Overview
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Brief Summary
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The primary objective of this study (LANDMARK) is to compare the safety and effectiveness of the Myval THV Series with Contemporary Valves (Sapien THV Series and Evolut THV Series) in patients with severe symptomatic native aortic valve stenosis. This study will be done in total 768 subjects (384:384, Myval THV Series vs. Contemporary Valves) The randomisation will be carried out with an allocation ratio of 1:1 between Myval THV Series vs. Contemporary Valves (Sapien THV Series and Evolut THV Series)

Detailed Description
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LANDMARK Trial is a prospective, randomised, multinational, multicentric, open-label non-inferiority trial of total 768 subjects (384:384, Myval THV Series vs. Contemporary Valves) with severe symptomatic native aortic valve stenosis via transfemoral approach. Device sizes applicable for the Myval THV Series: 20 mm, 21.5 mm, 23 mm, 24.5 mm, 26 mm, 27.5 mm, and 29 mm diameter. Device sizes applicable for the Sapien 3 THV Series: 20 mm, 23 mm, 26 mm, and 29 mm diameter. Device sizes applicable for the Evolut THV Series: 23 mm, 26 mm, 29 mm, and 34 mm diameter. A non-randomised nested registry will be conducted to include patients requiring extra-large size of Myval THV series (XL Nested Registry) - Device sizes applicable for the XL Nested Registry: 30.5 mm and 32 mm.

Official Title
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A Prospective, Multinational, Multicentre, Open-label, Randomised, Non-inferiority Trial to Compare Safety and Effectiveness of Meril's Myval Transcatheter Heart Valve (THV) Series vs. Contemporary Valves (Edwards's Sapien THV Series and Medtronic's Evolut THV Series) in Patients With Severe Symptomatic Native Aortic Valve Stenosis

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Device: Myval THV Series
* Device: Contemporary Valves (Sapien THV Series and Evolut THV Series)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient ≥18 years of age. Patient or their legal representative has provided written informed consent as approved by the Institutional Review Board (IRB)/Institutional Ethics Committee (IEC) of the investigational site to participate in the study. As per local Heart Team assessment, patient is eligible for TAVI and the patient is suitable for implantation with all three study devices. Exclusion Criteria: Patients who are not willing to provide informed consent form, or whose legal heirs object to their participation in the study. Any condition, which in the Investigator's opinion, would preclude safe participation of patient in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The randomisation will be carried out with an allocation ratio of 1:1 between Myval THV Series vs. Contemporary Valves (Sapien THV Series and Evolut THV Series).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Myval THV Series<br>Myval THV Series will include Myval/Myval Inception THVs or any subsequent advanced version commercially available at the study site. This treatment arm will be assigned to 384 / 768 subjects enrolled in a study. | Device: Myval THV Series<br>* The devices in the study are intended to improve aortic valve function for patients with severe symptomatic native aortic valve stenosis who are eligible for TAVR therapy. Every patient must be deemed treatable with an available size of both the test and contemporary heart valves approved for use and commercially available at the investigational centre where the implant procedure is being performed.<br>* Other names: Myval/Myval Inception THVs or any subsequent advanced version commercially available at the study site.;|
| Active Comparator: Contemporary Valves<br>Sapien THV Series will consist of Sapien 3/Sapien 3 Ultra THVs or any subsequent advanced version commercially available at the study site. Evolut THV Series will include Evolut R/Evolut PRO THVs or any subsequent advanced version commercially available at the study site. This treatment arm will be assigned to 384 / 768 subjects enrolled in a study. | Device: Contemporary Valves (Sapien THV Series and Evolut THV Series)<br>* The devices in the study are intended to improve aortic valve function for patients with severe symptomatic native aortic valve stenosis who are eligible for TAVR therapy. Every patient must be deemed treatable with an available size of both the test and contemporary heart valves approved for use and commercially available at the investigational centre where the implant procedure is being performed.<br>* Other names: Sapien THV Series (Sapien 3/Sapien 3 Ultra THVs) and Evolut THV Series (Evolut R/Evolut PRO THVs ) or any subsequent advanced version commercially available at the study site.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Combined Safety and Effectiveness Endpoint as defined by the Valve Academic Research Consortium-3 (VARC-3) | It is the composite of following: All-cause mortality All stroke Bleeding (Type 3 and 4) Acute kidney injury (AKI) (Stage 2, 3 and 4) Major vascular complications Moderate or severe prosthetic valve regurgitation Conduction system disturbances resulting in a new PPI | 30-day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The combined safety and effectiveness endpoint as defined by the Valve Academic Research Consortium-3 (VARC-3) | It is the composite of following: All-cause mortality All stroke Bleeding (Type 3 and 4) AKI (Stage 2, 3 and 4) Major vascular complications Moderate or severe prosthetic valve regurgitation Conduction system disturbances resulting in a new PPI | 1-year | 
| All-cause mortality | As per VARC-3 defined criteria | Pre-discharge, 30-day, 6-month, 1-year, 2-year, 3-year, 4 year, 5-year, 7-year, and 10-year | 
| All stroke | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Acute Kidney Injury (AKI) (Stage 2, 3 and 4) | As per VARC-3 defined criteria | Pre-discharge, 30-day, and 1-year | 
| Bleeding (Type 3 and 4) | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Moderate or severe prosthetic valve regurgitation | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year | 
| New permanent pacemaker implantation (As per VARC-3 defined criteria) | o New PPI rates will be analysed further based on the patient's history of left and/or right bundle branch block. | Pre-discharge, 30-day, 6-month, 1-year, 2-year, 3-year, 4-year, 5-year, 7-year, and 10-year | 
| Conduction disturbances and arrhythmias | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Device success | As per VARC-3 defined criteria | Pre-discharge and 30-day | 
| Early safety at 30 days | As per VARC-3 defined criteria | 30-day | 
| Clinical efficacy at 30 days | As per VARC-3 defined criteria | After 30 days of index procedure | 
| Valve related long-term clinical efficacy | As per VARC-3 defined criteria | 5-years, 7 years and 10 years | 
| Vascular and access related complications | As per VARC-3 defined criteria | Pre-discharge, 30-day, and 1-year | 
| Major vascular complications | As per VARC-3 defined criteria | Pre-discharge, 30-day, and 1-year | 
| Functional improvement from baseline as measured per | New York Heart Association (NYHA) functional classification | Baseline (within 30 days prior to index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year) | 
| Functional improvement from baseline as measured per | New York Heart Association (NYHA) functional classification [Time frame: Baseline (pre-procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year] Six-minute walk test [Time frame: Baseline (pre-procedure), 30-day and 1-year] | [Time frame: Baseline (pre-procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year], [Time frame: Baseline (pre-procedure), 30-day and 1-year] | 
| Echocardiographic endpoints | Effective orifice area (EOA) Index effective orifice area (iEOA) Mean aortic valve gradient Peak aortic valve gradient Peak aortic velocity Total aortic regurgitation, transvalvular regurgitation (except baseline) and paravalvular regurgitation (except baseline) Left ventricular ejection fraction (LVEF) Valve calcification Cardiac output and cardiac index | Baseline, pre-discharge, 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year | 
| Bioprosthetic valve deterioration | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Patient-prosthesis mismatch | Severity patient-prosthesis-mismatch will be based on following For subjects with body mass index (BMI) <30 kg/m2, EOAi: 0.85 - 0.66 cm2 /m2 considered as moderate and ≤0.65 cm2 /m2 considered as severe For subjects with BMI ≥30 kg/m2, EOAi: 0.70 - 0.56 cm2 /m2 considered as moderate and ≤0.55 cm2 /m2 considered as severe BMI = weight(kg)/(height (m))2 | Pre-discharge, 30-day, and 1-year | 
| Length of index hospital stay | o Number of days from hospital admission to discharge. | At discharge | 
| Re-hospitalization | As per VARC-3 defined criteria | 30-day, 1-year, 3-year, and 5-year | 
| Health status as evaluated by Quality of Life questionnaires | o 12-Item Short Form Survey (SF-12) | Baseline (pre-procedure), 30-day, and 1-year | 
| Valve thrombosis | o Valve thrombosis as per VARC-2 is any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Note that valve-associated thrombus identified at autopsy in a patient whose cause of death was not valve-related should not be reported as valve thrombosis. | 30-day, 1-year, 3-year, and 5-year | 
| Coronary obstruction requiring intervention | As per VARC-3 defined criteria | Pre-discharge | 
| Valve malpositioning | As per VARC-3 defined criteria | Pre-discharge | 
| Conversion to open surgery | As per VARC-3 defined criteria | Pre-discharge | 
| Unplanned use of mechanical circulatory support (cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), transcatheter pumps or intra-aortic balloon pump (IABP) | As per VARC-3 defined criteria | Pre-discharge | 
| Implantation of multiple (>1) transcatheter valves during the index hospitalization | As per VARC-3 defined criteria | Index-procedure | 
| Cardiac structural complications | As per VARC-3 defined criteria | 30 days, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Ventricular septal perforation | o Angiographic or echocardiographic evidence of a new septal perforation during or after the TAVI procedure | Pre-discharge | 
| New onset of atrial fibrillation or atrial flutter | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Technical success | As per VARC-3 defined criteria | Post-procedure | 
| Myocardial Infarction | As per VARC-3 defined criteria | Pre-discharge, 30-day, 1-year, 3-year, and 5-year | 
| Endocarditis | As per VARC-3 defined criteria | 30-day, 1-year, 3-year, and 5-year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LANDMARK Trial, Trial to evaluate safety & effectiveness of Myval THV, CE Approved Myval THV Series