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Trial of Replacement Heart Valves in Patients With Narrowing of the Heart Valves (LANDMARK)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04275726
Recruitment Status : Not yet recruiting
First Posted : February 19, 2020
Last Update Posted : February 24, 2020
Sponsor:
Information provided by (Responsible Party):
Meril Life Sciences Pvt. Ltd.

Brief Summary:

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 approximately 768 subjects (384:384, Myval THV Series vs. Contemporary Valves)

The randomization 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)


Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Device: Myval THV Series Device: Contemporary Valves (Sapien THV Series and Evolut THV Series) Not Applicable

Detailed Description:

LANDMARK Trial is a prospective, randomized, multinational, multicentric, open-label non-inferiority trial of approximately 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.

The randomization 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) (Stratification and equal allocation will be done for each valve within contemporary valves, i.e., 50% Sapien THV Series and 50% Evolut THV Series)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 768 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The randomization 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) (Stratification and equal allocation will be done for each valve within contemporary valves, i.e., 50% Sapien THV Series and 50% Evolut THV Series)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Multinational, Multicentre, Open-label, Randomized, Non-inferiority Trial to Compare Safety and Effectiveness of Myval THV Series vs. Contemporary Valves in Patients With Severe Symptomatic Native Aortic Valve Stenosis
Estimated Study Start Date : June 1, 2020
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : August 31, 2032

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Myval THV Series

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
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.
Other Name: Myval/Myval Inception THVs or any subsequent advanced version commercially available at the study site.

Active Comparator: Contemporary Valves

Stratification and equal allocation will be done for each valve within contemporary valves, i.e., 50% Sapien THV Series and 50% Evolut THV Series.

  • 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)
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.
Other Name: 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.




Primary Outcome Measures :
  1. Primary Combined Safety and Effectiveness Endpoint as defined by the Valve Academic Research Consortium-2 (VARC-2) [ Time Frame: 30-day ]

    It is the composite of following:

    • All-cause mortality
    • All stroke
    • Life-threatening or disabling bleeding
    • Acute kidney injury (stage 2 or 3)
    • Major vascular complications
    • Moderate or severe prosthetic valve regurgitation
    • Conduction system disturbances resulting in a new permanent pacemaker implantation.


Secondary Outcome Measures :
  1. The combined safety and effectiveness endpoint as defined by the Valve Academic Research Consortium-2 (VARC-2) [ Time Frame: 1-year ]

    It is the composite of following:

    • All-cause mortality
    • All stroke
    • Life-threatening or disabling bleeding
    • Acute kidney injury (stage 2 or 3)
    • Major vascular complications
    • Moderate or severe prosthetic valve regurgitation
    • Conduction system disturbances resulting in a new permanent pacemaker implantation.

  2. All-cause mortality [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 6-month, 1-year, 2-year, 3-year, 4 year, 5-year, 7-year, and 10-year ]
    As per VARC-2 criteria

  3. All stroke (disabling and non-disabling) [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, and 5-year ]
    Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least one mRS category from an individual's pre-stroke baseline Non-disabling stroke: an mRS score of 2 at 90 days or one that does not result in an increase in at least one mRS category from an individual's pre-stroke baseline

  4. Acute Kidney Injury (AKI) [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, and 1-year ]
    Based on the Acute Kidney Injury Network (AKIN) System-Stage 2 or Stage 3 (including renal replacement therapy)

  5. Life-threatening or disabling bleeding [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, and 5-year ]
    As per VARC-2 criteria

  6. Moderate or severe prosthetic valve regurgitation [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    As per VARC-2 criteria

  7. New permanent pacemaker implantation [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 6-month, 1-year, 2-year, 3-year, 4-year, 5-year, 7-year, and 10-year ]
    New permanent pacemaker implantation rates will be analyzed further based on the patient's history of left and/or right bundle branch block.

  8. Conduction disturbances and arrhythmias [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, and 5-year ]
    As per VARC-2 criteria

  9. Device success [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) and 30-day ]
    As per VARC-2 criteria

  10. Early safety at 30 days [ Time Frame: 30-day ]
    As per VARC-2 criteria

  11. Clinical efficacy at 30 days [ Time Frame: After 30 days of index procedure ]
    As per VARC-2 criteria

  12. Time-related valve safety [ Time Frame: 30-day, 1-year, 3-year and 5-year ]
    As per VARC-2 criteria

  13. Vascular and access related complications [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, and 1-year ]
    As per VARC-2 criteria

  14. Major vascular complications [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, and 1-year ]
    As per VARC-2 criteria

  15. Functional improvement from baseline as measured per [ Time Frame: Baseline (within 30 days prior to index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year) ]
    New York Heart Association (NYHA) functional classification

  16. Functional improvement from baseline as measured per [ Time Frame: Baseline (within 30 days prior to index procedure), 30-day and 1-year ]
    Six-minute walk test

  17. Echocardiographic endpoints (1) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Effective orifice area (EOA)

  18. Echocardiographic endpoints (2) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Index effective orifice area (iEOA)

  19. Echocardiographic endpoints (3) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Mean aortic valve gradient

  20. Echocardiographic endpoints (4) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Peak aortic valve gradient

  21. Echocardiographic endpoints (5) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Peak aortic velocity

  22. Echocardiographic endpoints (6) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Total aortic regurgitation, transvalvular regurgitation (except baseline) and paravalvular regurgitation (except baseline)

  23. Echocardiographic endpoints (7) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Left ventricular ejection fraction (LVEF)

  24. Echocardiographic endpoints (8) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Valve calcification

  25. Echocardiographic endpoints (9) [ Time Frame: Baseline (within 30 days prior to index procedure), pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, 5-year, 7-year, and 10-year ]
    - Cardiac output and cardiac index

  26. Prosthetic valve dysfunction [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, and 5-year ]
    VARC-2 criteria

  27. Patient-prosthesis mismatch [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, and 1-year ]
    Severity patient-prosthesis mismatch will be based on following For subjects with BMI <30 kg/m2, index effective orifice area (iEOA) 0.85 - 0.65 cm2 /m2 considered as moderate and <0.65 cm2 /m2 considered as severe For subjects with BMI ≥30 kg/m2, index effective orifice area (iEOA) 0.90 - 0.60 cm2 /m2 considered as moderate and <0.60 cm2 /m2 considered as severe BMI = weight(kg)/(height (m)) 2

  28. Length of index hospital stay [ Time Frame: Number of days from admission to discharge (expected average of 7 days) ]
    • Number of days from index procedure to discharge

  29. Hospitalization for valve-related symptoms or worsening congestive heart failure [ Time Frame: 30-day, 1-year, 3-year, and 5-year ]
    NYHA class III or IV

  30. Health status as evaluated by Quality of Life questionnaires [ Time Frame: Baseline (Within 30 days prior to index procedure), 30-day, and 1-year ]
    • SF-12

  31. Valve thrombosis [ Time Frame: 30-day, 1-year, 3-year, and 5-year ]
    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

  32. Coronary obstruction [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) ]
    Coronary obstruction requiring intervention

  33. Valve malpositioning [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) ]
    As per VARC-2 criteria

  34. Conversion to open surgery [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) ]
    Conversion to open surgery

  35. Unplanned use of cardiopulmonary bypass (CPB) [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) ]
    Unplanned use of CPB for haemodynamic support at any time during the TAVI procedure

  36. Ventricular septal perforation [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure) ]
    Angiographic or echocardiographic evidence of a new septal perforation during or after the TAVI procedure

  37. New onset of atrial fibrillation or atrial flutte [ Time Frame: Pre-discharge (within 24 hours prior to discharge or maximum of 7 days after index procedure), 30-day, 1-year, 3-year, and 5-year ]
    atrial fibrillation or atrial flutter

  38. Endocarditis [ Time Frame: 30-day, 1-year, 3-year, and 5-year ]
    Endocarditis

  39. Major bleeding event [ Time Frame: 30-day, 1-year, 3-year, and 5-year ]
    As per VARC-2 criteria



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient must be ≥65 years of age and he/she or their legal representative has provided written informed consent as approved by the Institutional Review Board (IRB)/Ethics Committee of the investigational site to participate in the study and agreed to its provisions.
  2. Patient is eligible for treatment with all three devices in the study considering individual's vascular anatomy and morphology - especially the aortic root complex and the vascular access site.
  3. A patient who has senile degenerative severe aortic valve stenosis with

    1. echocardiographically derived criteria according to ACC/AHA guidelines for TAVI:

      • Stage D1 (severe high-gradient AS) - Mean gradient ≥40 mmHg or jet velocity ≥4.0 m/s AND aortic valve area (AVA) of <1.0 cm2 or indexed aortic valve area of ≤0.6 cm2 /m2

      OR

      • Stage D2 (severe symptomatic low-flow low-gradient severe AS) - Low left ventricular (LV) ejection fraction (<50%) with an aortic valve area ≤1.0 cm2. Aortic velocity is <4.0 m/s at rest but increases to at least 4.0 m/s on low-dose dobutamine

      OR

      • Stage D3 (severe symptomatic low-flow low-gradient severe AS) - Normal LVEF (>50%), aortic valve area ≤1.0 cm2 (or indexed aortic valve area of ≤0.6 cm2/m2) with an aortic velocity <4.0 m/s and mean gradient <40 mmHg and a stroke volume index <35 ml/m2.

    2. suitable for TAVR procedure as per the Heart Team assessment.
  4. The patient with New York Heart Association (NYHA) functional class ≥II. -

Exclusion Criteria:

  1. Patients who are not willing to provide an informed consent form, or whose legal heirs object to their participation in the study.
  2. Evidence of an acute myocardial infarction ≤30 days before the trial procedure (WHO definition).
  3. Mixed aortic valve disease (aortic stenosis with predominant aortic regurgitation >3+).
  4. Pre-existing prosthetic heart valve in any position, or prosthetic ring, or any type of mitral repair device.
  5. Patients undergoing concomitant procedures on the pulmonic valve, mitral valve, tricuspid valve or the ascending aorta.
  6. Severe mitral annular calcification (MAC), or severe (greater than 3+) mitral insufficiency.
  7. Blood dyscrasias as defined: leukopenia (WBC<3000 cell/mL), acute anemia (Hb <9 g/dL), thrombocytopenia (platelet count <50,000 cell/mL), history of bleeding diathesis or coagulopathy, or hypercoagulable states.
  8. Significant coronary artery disease requiring revascularization as per Heart Team assessment.
  9. Need for emergency surgery for any reason within 30 days of index procedure.
  10. Any planned surgical or peripheral procedure to be performed in next 30 days after the index procedure.
  11. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 1-month of randomization.
  12. Active peptic ulcer or upper GI bleeding within 90 days before index procedure.
  13. Hemodynamic instability requiring inotropic support or mechanical heart assistance before index procedure.
  14. Hypertrophic cardiomyopathy (HCM) with or without obstruction.
  15. Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) <30%.
  16. Intracardiac mass, thrombus or vegetation as evident from echocardiography, CT or MRI.
  17. Known hypersensitivity or contraindication to cobalt, chromium, nickel, heparin, aspirin, ticlopidine (Ticlid), or P2Y12 inhibitors or coumadin derivatives (warfarin) or Factor X or A inhibitors, contrast media, which cannot be adequately premedicated.
  18. Native aortic annulus size <18 mm or >28 mm (as per measured perimeter-derived diameter for self-expanding or area-derived diameter for balloon expanding valves by CT scan).
  19. Unicuspid or bicuspid aortic valve as evident from echocardiography or CT or MRI.
  20. Cardiogenic shock (low cardiac output, vasopressor dependence, or mechanical hemodynamic support).
  21. Cerebrovascular accident (CVA) or a Transient Ischemic Attack (TIA) within 6 months prior to the index procedure.
  22. Origin of coronary ostia <10 mm from annular plane as measured on CT Scan and cannot be protected by standard techniques.
  23. Renal insufficiency [serum creatinine >3.0 mg/dl (265.2 mmol/litre)] and/or end-stage renal disease necessitating chronic dialysis.
  24. Life expectancy <24 months due to non-cardiac co-morbid conditions including carcinomas, chronic liver disease, chronic renal disease or chronic end-stage pulmonary disease.
  25. Significant aortic disease or peripheral artery disease (including disease of the upper and lower extremity arteries, renal arteries, and abdominal or thoracic aortic systems which as per Heart Team assessment is significant and unsuitable to perform TAVR procedure) including aneurysm defined as maximal luminal diameter ≥5 cm; marked tortuosity (hyperacute bend), thrombus, prior aortic graft, aortic arch atheroma [particularly if thick (>5 mm), protruding or ulcerated] or narrowing (especially with calcification and surface irregularities) of the abdominal or thoracic aorta, severe "unfolding" and tortuosity of the thoracic aorta.
  26. Ilio-femoral vessel characteristics such as severe tortuosity, calcification or stenosis, aneurysm of iliofemoral origin to the entire aorta (including common femoral, external iliac, common iliac and the origin of common iliac), which in investigator's opinion would be improper for safe vascular access or implantation of the device.
  27. Currently participating in an investigational drug or another device study.
  28. Active bacterial endocarditis within 6 months of procedure.
  29. Active infection requiring antibiotic treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04275726


Contacts
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Contact: Ashok S Thakkar, Dr +91-260-3052242 ext 242 ashok.thakkar@merillife.com

Sponsors and Collaborators
Meril Life Sciences Pvt. Ltd.
Investigators
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Study Chair: Ashok S Thakkar, Dr Meril Life Sciences Pvt. Ltd.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Meril Life Sciences Pvt. Ltd.
ClinicalTrials.gov Identifier: NCT04275726    
Other Study ID Numbers: MLS/MYV-2/LANDMARK
2020-000137-40 ( EudraCT Number )
First Posted: February 19, 2020    Key Record Dates
Last Update Posted: February 24, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Meril Life Sciences Pvt. Ltd.:
LANDMARK Trial
Trial to evaluate safety & effectiveness of Myval THV
CE Approved Myval THV Series
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Aortic Valve Disease
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction