Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure (TAVR UNLOAD)

• ClinicalTrials.gov Identifier: NCT02661451
• Recruitment Status: Recruiting
• First Posted: January 22, 2016
• Last Update Posted: November 4, 2019
• Sponsor: Cardiovascular Research Foundation, New York
• Collaborators: Cardialysis BV; Boston Biomedical Associates LLC
• Information provided by (Responsible Party): Cardiovascular Research Foundation, New York

Tracking Information

• First Submitted Date: January 15, 2016
• First Posted Date: January 22, 2016
• Last Update Posted Date: November 4, 2019
• Actual Study Start Date: September 2016
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 31, 2019)

• All-Cause Death [ Time Frame: 12 months ]
  Hierarchical occurrence within efficacy assessment time interval (EATI) of:
• Disabling Stroke [ Time Frame: 12 months ]
  Hierarchical occurrence within efficacy assessment time interval (EATI) of:
• Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke -or - Clinically significant worsening of heart failure (heart failure hospitalization equivalent). [ Time Frame: 12 months ]
  Hierarchical occurrence within efficacy assessment time interval (EATI) of:
• Change in KCCQ relative to baseline [ Time Frame: 12 months ]
  Hierarchical occurrence within efficacy assessment time interval (EATI) of:

Original Primary Outcome Measures (submitted: January 21, 2016)

• All-Cause Death within 12 months [ Time Frame: 12 months ]
  Hierarchical occurrence within one year of:

  1. All-cause death
  2. Disabling Stroke
  3. Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke
  4. Change in KCCQ relative to baseline
• Disabling Stroke within 12 months [ Time Frame: 12 months ]
  Hierarchical occurrence within one year of:

  1. All-cause death
  2. Disabling Stroke
  3. Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke
  4. Change in KCCQ relative to baseline
• Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke within 12 months [ Time Frame: 12 months ]
  Hierarchical occurrence within one year of:

  1. All-cause death
  2. Disabling Stroke
  3. Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke
  4. Change in KCCQ relative to baseline
• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) relative to baseline within 12 months [ Time Frame: 12 months ]
  Hierarchical occurrence within one year of:

  1. All-cause death
  2. Disabling Stroke
  3. Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke
  4. Change in KCCQ relative to baseline

• Change History: Complete list of historical versions of study NCT02661451 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 31, 2019)

• MACCE defined as the composite of all-cause death, all stroke, and hospitalizations for heart failure or symptomatic aortic valve disease or clinically significant worsening of heart failure within EATI. Hierarchical occurrence within EATI of: [ Time Frame: 12 month ]
  1. All-cause death
  2. Disabling stroke
  3. Hospitalizations related to heart failure, symptomatic aortic valve disease or non-disabling stroke or clinically significant worsening of heart failure (heart failure event)
• -All-cause death within EATI [ Time Frame: 12 month ]
  -All-cause death within EATI

Original Secondary Outcome Measures (submitted: January 21, 2016)

Composite of all-cause death, disabling stroke and renal replacement therapy at 30 days, 6 months and 12 months [ Time Frame: 30 days, 6 months and 1 year ]

Composite of all-cause death, disabling stroke and renal replacement therapy

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure (TAVR UNLOAD)
• Official Title: Transcatheter Aortic Valve Replacement to UNload the Left Ventricle in Patients With ADvanced Heart Failure: A Randomized Trial (TAVR UNLOAD)
• Brief Summary: The objective of this study is to determine the safety and efficacy of transcatheter aortic valve replacement (TAVR) via a transfemoral approach in HF patients with moderate AS as compared with OHFT.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Aortic Valve Stenosis

Intervention

• Device: SAPIEN 3 THV
• Biological: Optimal Heart Failure Therapy

Study Arms

• Experimental: TAVR (with SAPIEN 3 THV) and OHFT
  Transcatheter heart valve and Optimal Heart Failure Therapy
  Interventions:

  • Device: SAPIEN 3 THV
  • Biological: Optimal Heart Failure Therapy
• Active Comparator: OHFT
  Optimal Heart Failure Therapy
  Intervention: Biological: Optimal Heart Failure Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 31, 2019): 300
• Original Estimated Enrollment (submitted: January 21, 2016): 600
• Estimated Study Completion Date: March 2022
• Estimated Primary Completion Date: December 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

All candidates for this study must meet all of the following inclusion criteria:

1. Age ≥18 years
2. NYHA class ≥ 2

3. NT-proBNP > 900pg/mL (or BNP > 200 pg/mL) or hospitalization for HF within the 2 years;

   Note: To account for the decrease in natriuretic peptide levels with overweight/obesity, NT-proBNP and BNP levels cutoff will be reduced by 4% for every increase of 1 kg/m2 in BMI above a reference BMI of 20 kg/m2).

4. Under appropriate and stable guideline-directed HF therapy for a minimum of 1 month. o Patients are expected to be on appropriate pharmacologic therapy and if indicated CRT for heart failure. (12, 13) Patients with aortic stenosis may not be able to tolerate maximal doses of heart failure medications and no specific guidelines exist for the medical treatment of heart failure in the setting of aortic stenosis. It is expected that the heart failure PI will review the medical therapy and confirm that it is appropriate for the patient's condition.

5. Moderate AS confirmed by the echo core lab. Moderate AS is defined as an aortic valve area (AVA) >1.0 cm2 and ≤1.5 cm2 on rest echo or if ≤1.0 cm2 at rest and low-flow AS is suspected when the an AVA > 1.0 cm2 with low dose dobutamine stress echo (DSE). Patients with AVA<1.0 cm2 but with an indexed AVA of >0.6 cm2/m2 on either rest or DSE are also eligible. Similarly, patients with AVA >1.5 cm2 but with indexed AVA<0.9 cm2/m2 on either rest of DSE are also eligible.

   Note: Typically such cases will demonstrate,

   • • Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg at rest and aortic valve area (AVA) > 1.0 cm2 and ≤1.5 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) at rest

   OR

   • Mean trans-aortic gradient (MG) ≥ 20 mmHg and < 40 mmHg and aortic valve area (AVA) ≤1.0 cm2 at rest AND MG < 40 mmHg and aortic valve area (AVA)
   • >1.0 cm2 (or AVA < 1.0 cm2 but indexed AVA > 0.6 cm2) with low dose dobutamine stress echo (DSE).

   In atypical cases (for example mean gradient is below 20 mmHg but valve area is consistent with moderate AS, the final eligibility determination in regards to diagnosis of moderate AS will be made by the echocardiographic core lab.

6. Left ventricular (LV) ejection fraction (EF) < 50% at rest
7. Anatomically suitable for transfemoral TAVR with the SAPIEN 3 or SAPIEN 3 Ultra THV
8. Able to provide independent informed consent (i.e., not requiring a legally authorized representative)

Exclusion Criteria

Candidates are excluded from the study if any of the following conditions are present:

1. LVEF < 20% or persistent need for intravenous inotropic support
2. Hospitalization for acute decompensated HF within 2 weeks prior to randomization
3. Cardiac resynchronization therapy (CRT) device implantation within 1 month prior to randomization
4. Coronary artery revascularization (PCI or CABG) within 1 month prior to randomization
5. In need and suitable for revascularization per heart team consensus
6. Severe aortic and/or mitral regurgitation
7. Congenital unicuspid or congenital bicuspid aortic valve
8. Concomitant non-aortic valvular disease with a formal indication for valve surgery per established guidelines (ESC/ACC/AHA)
9. Previous aortic valve replacement (mechanical or bioprosthetic)
10. Severe RV dysfunction
11. Previous stroke with permanent disability (modified Rankin score ≥ 2)
12. Severe lung disease as indicated by FEV1 <30% predicted or need for chronic daytime supplemental oxygen therapy
13. Severe chronic kidney disease: glomerular filtration rate (GFR) < 30 mL/min by MDRD or need for renal replacement therapy
14. Gastrointestinal (GI) bleeding within the past 3 months
15. Liver cirrhosis Child-Pugh C
16. Active systemic infection, including active endocarditis
17. Unwilling to accept blood transfusion
18. Evidence of intracardiac mass, thrombus or vegetation
19. Absence of minimum amount of aortic valve calcification necessary for TAVR with the SAPIEN 3 or SAPIEN 3 Ultra THV
20. Hypersensitivity or contraindication to clopidogrel, aspirin, or to oral anticoagulation if indicated (e.g. subject in atrial fibrillation)
21. Sensitivity to contrast media which cannot be adequately pre-medicated
22. Women of child-bearing potential
23. Clinical signs of dementia
24. Other medical, social, or psychological conditions that precludes appropriate consent and follow-up
25. Life expectancy < 2 years due to cancer or other non-cardiac chronic diseases
26. Unwillingness to undergo follow-up investigations
27. Currently participating in an investigational drug or another device trial that has not reached its primary endpoint (excluding registries)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ori Ben Yehuda, MD; obenyehuda@crf.org

Contact: Barbara Santiago; bsantiago@crf.org

• Listed Location Countries: Canada, Netherlands, United States

Administrative Information

• NCT Number: NCT02661451
• Other Study ID Numbers: TAVR Unload
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Cardiovascular Research Foundation, New York
• Study Sponsor: Cardiovascular Research Foundation, New York

Collaborators

• Cardialysis BV
• Boston Biomedical Associates LLC

• Investigators: Not Provided
• PRS Account: Cardiovascular Research Foundation, New York
• Verification Date: October 2019