Trilogy Transcatheter Heart Valve System

P250024 · JenaValve Technology, Inc. · NPT · Mar 17, 2026 · Cardiovascular

Device Facts

• Record ID: P250024
• Device Name: Trilogy Transcatheter Heart Valve System
• Applicant: JenaValve Technology, Inc.
• Product Code: NPT · Cardiovascular
• Decision Date: Mar 17, 2026
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Trilogy Transcatheter Heart Valve System is indicated for the treatment of symptomatic, severe native tricuspid aortic valve regurgitation (not due to acute endocarditis, rheumatic heart disease, or acute aortic dissection) in patients who are judged by a Heart Team, including a cardiac surgeon, to be at high or greater risk for surgical aortic valve replacement (i.e., predicted risk of surgical mortality ≥ 8% at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical co-morbidities unmeasured by the STS risk calculator).

Device Story

Trilogy Transcatheter Heart Valve (THV) System treats severe native tricuspid aortic regurgitation; self-expanding nitinol frame with three porcine pericardial leaflets; features flared Sealing Ring and three Locators with radiopaque tantalum markers to capture native leaflets. Delivery system includes 20 Fr catheter, 22 Fr pre-shaped introducer sheath, and loading tools. Used in hybrid room/OR by cardiac surgeons; delivered transfemorally. Device functions by replacing native valve function to reduce regurgitation; improves hemodynamics and patient functional status (NYHA class, KCCQ score). Benefits include treatment for high-risk patients with limited options; risks include stroke, conduction disturbances (pacemaker requirement), bleeding, and vascular complications. Engineering testing indicates limited durability (3.5 years); long-term clinical durability not established.

Clinical Evidence

PMA based on ALIGN-AR prospective, multicenter, single-arm study (N=180) and CAP cohort (N=320). Primary safety endpoint (30-day composite) met (26.7% event rate vs 40.5% PG). Primary effectiveness endpoint (1-year all-cause mortality) met (6.2% vs 25% PG). Secondary endpoint (KCCQ improvement) met (20.6-point increase). Hemodynamic success: 88.7% of patients had none-to-trace AR at 1 year. Permanent pacemaker implantation rate was 24.0% at 30 days. CT sub-study evaluated leaflet thrombosis.

Technological Characteristics

Self-expanding nitinol frame; porcine pericardial leaflets; polyester sutures. Sizes: 23, 25, 27 mm. Delivery system: 20 Fr catheter, 22 Fr PTFE-lined stainless-steel braid-reinforced Pebax sheath with hydrophilic coating. Sterilization: THV via terminal liquid sterilization (0.5% glutaraldehyde); delivery system via ethylene oxide. MR Conditional. Complies with ISO 5840-1:2021 and ISO 5840-3:2021.

Indications for Use

Indicated for symptomatic, severe native tricuspid aortic valve regurgitation (excluding acute endocarditis, rheumatic heart disease, or acute aortic dissection) in adult patients at high or greater risk for surgical aortic valve replacement. Contraindicated in patients unable to tolerate anticoagulation/antiplatelet therapy, with known hypersensitivity to nitinol (nickel/titanium) or contrast agents, or with active infection/endocarditis.

Regulatory Classification

Identification

To replace a patient's aortic heart valve. They are different from the classified device (heart valves) in that they are placed percutaneously and do not require open chest surgery or a cardiotomy for placement.

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Aortic valve, prosthesis, percutaneously delivered

Device Trade Name: Trilogy Transcatheter Heart Valve System

Device Procode: NPT

Applicant's Name and Address: JenaValve Technology, Inc.
4 Cromwell
Irvine, CA 92618

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P250024

Date of FDA Notice of Approval: March 17, 2026

Breakthrough Device: Granted breakthrough device status on December 20, 2019, because the device can provide for more effective treatment of an irreversibly debilitating disease; as well as represents a breakthrough technology and is in the best interest of patients.

## II. INDICATIONS FOR USE

The Trilogy Transcatheter Heart Valve System is indicated for the treatment of symptomatic, severe native tricuspid aortic valve regurgitation (not due to acute endocarditis, rheumatic heart disease, or acute aortic dissection) in patients who are judged by a Heart Team, including a cardiac surgeon, to be at high or greater risk for surgical aortic valve replacement (i.e., predicted risk of surgical mortality $\geq 8\%$ at 30 days, based on the Society of Thoracic Surgeons (STS) risk score and other clinical co-morbidities unmeasured by the STS risk calculator).

## III. CONTRAINDICATIONS

The Trilogy Transcatheter Heart Valve System is contraindicated in patients who cannot tolerate an anticoagulation/antiplatelet regimen, have known hypersensitivity to nitinol alloy (nickel and titanium) or contrast agents that cannot be managed with premedication, or who have active bacterial endocarditis or other active infection.

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Trilogy Transcatheter Heart Valve System labeling.

# V. DEVICE DESCRIPTION

The Trilogy Transcatheter Heart Valve System consists of the Transcatheter Heart Valve (THV), Introducer Sheath, Delivery Catheter, and Loading Tools.

The Trilogy THV, as shown in Figure 1, is made of a self-expanding nitinol frame with three porcine pericardial leaflets sewn on using polyester sutures. The THV design includes a flared Sealing Ring that extends from the inflow in the left ventricular outflow track (LVOT) to the annular basal plane. The frame has three (3) Locators that contain radiopaque tantalum markers covered by pericardial tissue. The Locators clip onto the native leaflets such that when the THV is deployed, the native leaflets are captured between the Locators and the stent frame body. The frame features large open Intermediate Strut cells. THV commissural alignment centers the Intermediate Strut cells within the coronary cusps, which is intended to preserve future access to coronary ostia. The THV is available in three sizes: 23 mm, 25 mm, and 27 mm.

Figure 1: Trilogy THV

The Trilogy Delivery System is comprised of the Trilogy Delivery Catheter, an introducer sheath and dilator, and loading tools. The Trilogy Delivery Catheter, as shown in Figure 2, is used to position and deploy the Trilogy THV into the native aortic valve and comprises three main shafts: the Guidewire Shaft, the Torque Tube and the Deflecting Catheter. The Delivery Catheter has an outer diameter of 20 Fr, a working length of approximately 126 cm, and is designed to be used over a 0.035" guidewire and to pass through the Introducer Sheath.

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Figure 2: Trilogy Delivery Catheter

The Trilogy Introducer Sheath is a 22 Fr outer diameter (OD) Sheath, as shown in Figure 3. It is made of a PTFE-lined, stainless-steel braid-reinforced, multi-durometer Pebax jacket with a distal platinum-iridium marker band. The Sheath has a working length of $85~\mathrm{cm}$ and is pre-shaped. The pre-shaped Sheath is intended to conform to the shape of the aortic arch when the Dilator is removed and before the Delivery Catheter is transferred. The OD of the distal end has a hydrophilic coating. The Sheath protects the THV and patient anatomy during Delivery Catheter advancement into the ascending aorta.

Figure 3: Trilogy Introducer Sheath with Dilator

The Trilogy Loading Tools, as shown in Figure 4, are used to load the Trilogy THV onto the Delivery Catheter.

Figure 4: Trilogy Loading Tools

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are limited treatment options for patients with symptomatic, severe native tricuspid aortic valve regurgitation (AR) who are deemed to be at high or greater risk for surgical aortic valve replacement (SAVR). When surgery is not offered, patients are often treated conservatively with medical therapy. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

VII. MARKETING HISTORY

The Trilogy Transcatheter Heart Valve System is commercially available in Austria, Denmark, France, Germany, Hong Kong, Ireland, Italy, Netherlands, Switzerland, and the United Kingdom. It has not been withdrawn from marketing for any reason related to its safety or effectiveness.

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

- Death
- Allergic reaction to anesthesia, contrast media, antithrombotic therapy, device materials
- Anemia
- Angina
- Aortic root distortion
- Atelectasis
- Arrhythmia
- Arteriovenous (AV) fistula
- Blood loss requiring transfusion
- Cardiovascular or vascular injury, such as perforation or damage (dissection) of vessels, myocardium or valvular structures that may require intervention
- Cardiac arrest
- Cardiac failure
- Cardiogenic shock
- Chest pain/discomfort
- Conduction system injury
- Coronary flow obstruction/transvalvular flow disturbance
- Deep vein thrombosis
- Device acute migration or malposition
- Device dysfunction (regurgitation and/or stenosis)
- Device embolization
- Device thrombosis
- Dislodgement of previously implanted devices (i.e., pacing lead)

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- Dyspnea
- Electrolyte imbalance
- Embolic event: air, calcific material, thrombus, device fragments
- Endocarditis
- Exercise intolerance or weakness
- Fever
- Hematoma or ecchymosis
- Hemolysis/hemolytic anemia
- Hypertension or hypotension
- Infection including incisional site infection, septicemia and endocarditis
- Inflammation
- Mechanical failure of delivery system, and/or accessories
- Myocardial infarction
- Pain
- Pericardial effusion/cardiac tamponade
- Pleural effusion
- Pneumothorax
- Pulmonary edema
- Radiation injury
- Renal insufficiency or renal failure
- Reoperation
- Respiratory insufficiency or respiratory failure
- Stroke/transient ischemic attack
- Syncope
- Systemic or peripheral ischemia
- Systemic or peripheral nerve injury

For the specific adverse events that occurred in the clinical study, please see Section X below.

## IX. SUMMARY OF NON-CLINICAL STUDIES

### A. Laboratory Studies

Nonclinical laboratory studies on the Trilogy Transcatheter Heart Valve System were performed in accordance with but not limited to: ISO 5840-1:2021, Cardiovascular implants – Cardiac valve prostheses – Part 1: General Requirements, and ISO 5840-3:2021, Cardiovascular implants – Cardiac valve prostheses – Part 3: Heart valve substitutes implanted by transcatheter techniques, along with relevant FDA guidance documents.

### 1. Biocompatibility

Biocompatibility assessments were completed on the Trilogy Transcatheter Heart Valve System in accordance with ISO 10993-1, Biological Evaluation of Medical Devices - Part 1: Evaluation and testing within a risk management process, and the FDA Guidance for

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Industry and Food and Drug Administration Staff, Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. The required testing for each component was determined based on the nature and duration of body contact per ISO 10993-1. The test articles consisted of patient-contacting device components after exposure to all manufacturing processes, including sterilization. The biocompatibility test results for the Trilogy THV, Trilogy Delivery Catheter, Introducer Sheath and Dilator, and Loading Tools are summarized in the tables below.

| Table 1: Summary of Biocompatibility Testing – Trilogy THV | | |
| --- | --- | --- |
| Biological Effect Per ISO 10993-1 | Test Method | Results |
| Cytotoxicity | MEM Elution Cytotoxicity | Non-cytotoxic |
| Sensitization | Guinea Pig Maximization | Non-sensitizing |
| Irritation | Intracutaneous Reactivity (Rabbit) | Non-irritant |
| Acute Systemic Toxicity | Acute Systemic Toxicity Test in Mice | Non-toxic |
| Hemocompatibility | In vitro hemolysis (indirect contact) | Non-hemolytic |
| | In vitro hemolysis (direct contact) | Non-hemolytic |
| | Complement activation test | No risk to activate complement |
| | Partial Thromboplastin Time (PTT) | Non-coagulant |
| | In vivo thrombogenicity with domestic sheep | No evidence of clinically significant thrombus or thromboembolism after implantation for up to 20-weeks |
| Material Mediated Pyrogenicity | USP Material Rabbit Mediated Pyrogen Study | Non-pyrogenic |
| Genotoxicity | Ames Assay – plate incorporation | Non-mutagenic |
| | Chromosomal aberration assay | Non-mutagenic |

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| Biological Effect Per ISO 10993-1 | Test Method | Results |
| --- | --- | --- |
| Physiochemical* | Chemical characterization of volatile organic compounds, semivolatile organic compounds, nonvolatile organic compounds, and elements followed by toxicological risk assessment | Exposure estimates, safety margins, and the likelihood of extractable chemicals from the implant producing unacceptable carcinogenic or non-carcinogenic health risks in the adult patient population under the proposed conditions and duration of clinical use (long term; >30 days) were acceptable. |
| *The Trilogy loading tools were also considered in the physiochemical assessment via simulated use with the device prior to extraction. | | |
| Table 2: Summary of Biocompatibility Testing – Trilogy Delivery Catheter, Introducer Sheath and Dilator | | |
| --- | --- | --- |
| Biological Effect Per ISO 10993-1 | Test Method | Results |
| Cytotoxicity | MEM Elution Cytotoxicity | Non-cytotoxic |
| Sensitization | Guinea Pig Maximization | Non-sensitizing |
| Irritation | Intracutaneous Reactivity (Rabbit) | Non-irritant |
| Acute Systemic Toxicity | Acute Systemic Toxicity Test in Mice | Non-toxic |
| Hemocompatibility | In vitro hemolysis (indirect contact) | Non-hemolytic |
| | In vitro hemolysis (direct contact) | Non-hemolytic |
| | Complement activation test | No risk to activate complement |
| | Partial Thromboplastin Time (PTT) | Non-coagulant |
| | In vivo thrombogenicity in domestic sheep | No evidence of clinically significant thrombus or thromboembolism after procedure |
| Material Mediated Pyrogenicity | USP Material Rabbit Mediated Pyrogen Study | Non-pyrogenic |

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| Table 3: Summary of Biocompatibility Testing – Loading Tools | | |
| --- | --- | --- |
| Biological Effect Per ISO 10993-1 | Test Method | Results |
| Cytotoxicity | MEM Elution Cytotoxicity | Non-cytotoxic |
| Sensitization | Guinea Pig Maximization | Non-sensitizing |
| Irritation | Intracutaneous Reactivity (Rabbit) | Non-irritant |
| Acute Systemic Toxicity | Acute Systemic Toxicity Test in Mice | Non-toxic |
| Hemolysis | ASTM Extract Method | Non-hemolytic |

2. Bench Testing

A summary of the bench testing results is summarized in Table 4 and Table 5.

| Table 4: Summary of Design Performance Testing – Trilogy THV | | |
| --- | --- | --- |
| Test | Purpose | Results |
| THV Foreshortening | To evaluate the relationship of the THV length and diameter between catheter-loaded and deployed conditions. | Met design requirements and acceptance criteria |
| THV Corrosion and Nickel Ion release | To verify the corrosion resistance of the THV and determine the nickel ion release rate. | Met design requirements and acceptance criteria |
| Galvanic Corrosion | To determine the susceptibility of the metallic components of the THV stent to corrosion in a simulated physiological environment. | Met design requirements and acceptance criteria |
| Chronic Outward Force (CoF), Radial Resistive Force (RRF), and Migration Resistance | To determine the valve has acceptable CoF and RRF to ensure migration resistance and delivery system compatibility. | Met design requirements and acceptance criteria |
| Accelerated Wear Testing | To assess long-term valve performance through accelerated wear testing. | Met minimum prespecified hydrodynamic performance specifications through 150M cycles, which did not meet the 200M-cycle requirement in ISO 5840-1:2023 |
| Dynamic Failure Mode Analysis | Characterize potential failure modes affecting valve durability. | Demonstrated a gradual degradation failure mode |

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| Test | Purpose | Results |
| --- | --- | --- |
| Finite Element Analysis | To determine mechanical strain during valve loading, deployment and cyclic loading. Results used to assess the fatigue life of the device. | No fracture of valve structural components predicted within a minimum of 600 million cycles under clinically representative challenging conditions. |
| Fatigue Resistance | To demonstrate the fatigue resistance of the THV stent to 600 million cycles. | No fractures observed following 600 million cycles of fatigue testing. |
| Magnetic Resonance Imaging (MRI) Compatibility | To evaluate MRI safety and compatibility of the Trilogy THV and ensure that the Trilogy THV is not affected by scanning at 1.5 Tesla and 3.0 Tesla field strengths. | Trilogy THV can be labeled “MR Conditional.” |
| Hydrodynamic Assessment | To determine the hydrodynamic performance of the valve in terms of effective orifice area and regurgitation under aortic cardiac conditions. | Met prespecified minimum hydrodynamic performance for each condition. |
| Tissue Characterization | Characterize shrinkage temperature to confirm the effectiveness of glutaraldehyde crosslinking. | Met design requirements and acceptance criteria |
| | Characterize tissue properties via uniaxial tensile testing, ball burst testing, and histological staining. | Characterization Only |
| Table 5: Summary of Design Performance Testing – Trilogy Delivery System | | |
| --- | --- | --- |
| Test | Purpose | Results |
| Visual inspection | To verify the Trilogy Delivery System is free of visible defects or damage. | Met design requirements and acceptance criteria. |
| Dimensional inspection | To ensure the prespecified dimensions of the Trilogy Delivery System are met. | Met design requirements and acceptance criteria. |
| Flushing | To ensure inner lumens of the Trilogy Delivery System can be flushed with standard syringes. | Met design requirements and acceptance criteria. |
| Hydrophilic Coating Integrity and Particulate Characterization | To evaluate and characterize particulate counts via light obscuration and hydrophilic coating integrity of the Introducer Sheath after a simulated use procedure. | Met design requirements and acceptance criteria. |
| Leakage | To ensure the Trilogy Delivery System maintains hemostasis. | Met design requirements and acceptance criteria. |

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| Test | Purpose | Results |
| --- | --- | --- |
| Bond Strength | Verification that the bonds and tubing of the Trilogy Delivery System remain intact when subjected to prespecified tensile testing and/or simulated use. | Met design requirements and acceptance criteria. |
| Simulated Use | To verify the functionality of the Trilogy THV System, including loading, tracking, deployment, and retrieval in a simulated clinical setting. | Met design requirements and acceptance criteria. |
| Corrosion Testing | To verify the corrosion resistance of the Delivery Catheter. | Met design requirements and acceptance criteria. |

# B. Animal Studies

The Trilogy Transcatheter Heart Valve System underwent Good Laboratory Practice-compliant preclinical in vivo evaluations in an ovine model as summarized in Table 6.

| Table 6: Summary of Animal Studies | |
| --- | --- |
| Acute GLP Animal Study | |
| Test Purpose / Requirement | An acute animal study was performed to evaluate the in vivo safety and performance of the Delivery System |
| Device Tested | Size 25- & 27-mm THV, Trilogy Delivery System |
| Animal Model & Sample Size | Sheep, N = 5 |
| Test Method | Implants performed by study physician under beating heart conditions. Physician evaluation of access, introduction, visualization, delivery, deployment, and system removal. |
| Study Duration | Acute |
| Results | All five animals survived transfemoral implantation. |
| Conclusions | All devices were delivered and implanted as intended. All devices were well seated. No adverse events or test device-related complications occurred during any procedure and all animals remained hemodynamically stable throughout the procedure.The results of the acute animal study demonstrated the safety and performance of the subject Trilogy Heart Valve System in an in vivo (ovine) model. |
| 90-Day GLP Aortic Implant Study | |
| Test Purpose / Requirement | A 90-day chronic animal study was performed to evaluate the safety and performance of the Trilogy THV in an in vivo model |
| Device Tested | Size 25-mm THV, Trilogy Delivery System* |
| Animal Model & Sample Size | Sheep, N = 7 |
| Test Method | Implants performed by study physician under beating heart conditions, under brachiocephalic delivery. Device implant |

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| | characteristics and ease of use were evaluated at the time of the procedure by the implanting physician. |
| --- | --- |
| Study Duration | 90 days |
| Results | Six animals survived to a minimum of 90 days. One death occurred prior to the planned implant duration due to complications related to the sheep anatomy. |
| Conclusions | All devices were delivered and implanted as intended. All devices were well seated, stable, and stents were intact with no strut fracture. For the six surviving animals, there were no clinically significant injuries to adjacent anatomic structures or other clinically significant device-related events under histological assessment.
The results of the 90-Day study demonstrated the safety and performance of the subject Trilogy Heart Valve in an in vivo (ovine) model. |
| Long-term GLP Aortic Implant Study | |
| Test Purpose/ Requirement | Evaluation of the safety and performance of the THV under long term in vivo conditions. |
| Device Tested & Sample Size | Size 25-mm THV#
Control and Test: Trilogy Delivery System* |
| Animal Model & Sample Size | Sheep, N=12 |
| Test Method | Implants performed by study physician under beating heart conditions using left subclavian delivery. Device implant characteristics and ease of use were evaluated at the time of the procedure by the implanting physician. |
| Study Duration | 20 weeks |
| Results | Seven animals survived as planned (137-138 days). Five deaths occurred prior to the planned implant duration due to complications unrelated to the device. |
| Conclusions | All devices were delivered and implanted as intended. All devices were well seated, stable, and stents were intact with no strut fracture. No clinically significant injuries to adjacent anatomic structures or other clinically significant device-related events under gross and histological assessment.
Host/tissue interface results were characteristic of implanted transcatheter aortic valves. Echocardiographic evaluations demonstrated low gradients to study completion. |
| *The 90-day and long-term implant studies used earlier delivery system iterations. These studies were considered representative of the final device as the delivery system modifications were minor and the primary purpose of the 90-day and long-term implant studies was to understand the longer-term function of the implant.
#n=9 devices used proprietary tissue processing (representative of final device) and n=3 devices used contractor tissue processing. Host/tissue interface results were comparable among groups. | |

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# C. Sterilization

The Trilogy THV is sterilized by terminal liquid sterilization (TLS) in buffered 0.5% glutaraldehyde solution. The validated TLS process has demonstrated a Sterility Assurance Level (SAL) of 10⁻⁶, following ISO 14160:2020, Sterilization of health care products -- Liquid chemical sterilizing agents for single-use medical devices utilizing animal tissues and their derivatives.

The Trilogy Delivery Catheter, Introducer Sheath, and Loading Tools are sterilized by ethylene oxide (EO). The EO sterilization processes have demonstrated Sterility Assurance Levels (SAL) of 10⁻⁶ in accordance with ISO 11135-1:2014+A1:2018, Sterilization of health care products – Ethylene oxide – Requirements for development, validation and routine control of a sterilization process for medical devices.

# D. Packaging and Shelf-life

The Trilogy THV is stored in a jar filled with buffered glutaraldehyde solution tightly sealed with a lid and silicone disc/seal to form the primary sterile barrier. The jar is contained within a shelf carton with foam pieces (secondary packaging).

The Trilogy Delivery System components (Trilogy Delivery Catheter, Trilogy Introducer Sheath, and Loading Tools) are packaged separately. Each component is packaged in a sealed Tyvek/Nylon pouch and shelf carton.

The packaging validation for the sterile components of the Trilogy THV System was conducted per ASTM D4332 Standard Practice for Conditioning Containers, Packages, or Packaging Components for Testing, ASTM D4169 Standard Practice for Performance Testing of Shipping Containers and Systems, ASTM F1980 Standard Guide for Accelerated Aging of Sterile Barrier Systems and Medical Devices, ASTM F2203 Standard Test Method for Linear Measurement Using Precision Steel Rule, ASTM F2096 Standard Test Method for Detecting Gross Leaks in Packaging by Internal Pressurization (Bubble Test), and ASTM F88/F88M Standard Test Method for Seal Strength of Flexible Barrier Materials. The packaging validation demonstrated that the packaging system was able to maintain a sterile barrier after exposure to environmental conditioning, distribution simulation, and aging.

The shelf life of the Trilogy THV is 16 months based on real-time aging of the THV and accelerated aging of the packaging. The shelf-life of all components of the Trilogy Delivery System is 1 year based on accelerated aging. Packaging integrity and product functional testing were conducted on aged samples to ensure that the components meet specifications throughout the stated shelf life.

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# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study under IDE #G150035 (entitled the “ALIGN-AR” study) to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve replacement with the Trilogy Transcatheter Heart Valve System in patients with symptomatic, severe aortic regurgitation (not due to acute endocarditis, rheumatic heart disease, or acute aortic dissection) who are at a high or greater risk for surgical aortic valve replacement (SAVR). Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

The ALIGN-AR study was a prospective, multicenter, single-arm study. Patients were treated between July 10, 2018, and August 29, 2022. The database for this PMA reflected data collected through October 5, 2023, and included 180 patients. There were 20 investigational sites in the United States.

The ALIGN-AR study was a prospective, multicenter, single-arm study. The ALIGN-AR study utilized: a Case Review Board (CRB) to confirm subject suitability prior to enrollment; an independent Clinical Events Committee (CEC) to adjudicate safety events and protocol deviations; and an independent core laboratory to assess echocardiography data and computed tomography (CT) data.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the ALIGN-AR study was limited to patients who met the following inclusion criteria:

- Adult subjects with severe AR (Grade ≥ 3) as assessed by echocardiography based on American Society of Echocardiography (ASE) guidelines using a multiparametric approach with:
- Jet width ≥65% of LVOT
- Vena contracta width of >6 mm
- Holodiastolic flow reversal in proximal abdominal/descending aorta
- Jet deceleration rate/pressure half time < 200 ms

AND

For Grade 3
- Regurgitant volume 45-59 ml/beat
- Regurgitant fraction 40-49%
- Effective regurgitant orifice area (EROA) 0.2-0.29 cm²

OR

For Grade 4
- Regurgitant volume ≥ 60 ml/beat
- Regurgitant fraction 50%
- EROA ≥ 0.3 cm²

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- Patient symptomatic according to New York Heart Association (NYHA) functional class II or higher
- Patient with high risk for SAVR as documented by heart team and Heart Team agrees that patient can undergo SAVR for “bail out”/to address unfavorable circumstances if necessary
- Patient has suitable anatomy to accommodate the insertion and delivery of the Trilogy Transcatheter Heart Valve System
- Patient or the patient’s legal representative has provided written informed consent
- Patient or the patient’s legal representative agrees to comply with all required post-procedure follow-up visits

Patients were not permitted to enroll in the ALIGN-AR study if they met any of the following exclusion criteria:

- Congenital uni- or bicuspid aortic valve morphology
- Previous prosthetic aortic valve (bioprosthesis or mechanical) implant
- Mitral regurgitation > moderate
- Clinically significant coronary artery disease (CAD) requiring revascularization within 30 days prior to index procedure, or planned CAD revascularization procedure within 12 months after index procedure
- Echocardiographic evidence of left ventricular thrombus
- Endocarditis within 180 days prior to the index procedure
- Hypertrophic cardiomyopathy with or without obstruction
- Severe pulmonary hypertension (systolic pulmonary artery pressure > 80 mmHg)
- Severe right ventricle (RV) dysfunction as assessed clinically and by echo
- Severely reduced left ventricular ejection fraction (LVEF < 25%)
- Aortic annular perimeter-derived diameter of < 21.0 mm or >28.6 mm or perimeter < 66 mm or >90 mm (assessed by Multi-Detector CT (MDCT) measurement)
- Aortic annulus angulation >70° (assessed by MDCT measurement)
- Straight length of ascending aorta of < 55 mm
- Significant disease of ascending aorta, including ascending aortic aneurysm (defined as maximal luminal diameter of 50 mm or greater) or atheroma (including if thick [>5 mm], protruding or ulcerated)
- Need for urgent or emergent TAVR procedure for any reason
- Cardiogenic shock or hemodynamic instability requiring inotropic support or ventricular assist device within 30 days prior to index procedure
- Myocardial infarction < 30 days prior to index procedure
- Cerebrovascular event (transient ischemic attack (TIA), stroke) < 180 days prior to index procedure
- Severe renal insufficiency (GFR < 30 ml/min) at Screening, OR renal disease requiring renal replacement therapy within 180 days prior to index procedure
- Blood dyscrasias as defined: leukopenia (WBC < 3000/mm³), or thrombocytopenia (platelets < 90,000/μl) or anemia (Men: Hgb < 8.1 g/dl; Women: Hgb < 7.4 g/dl)
- Active peptic ulcer or upper gastrointestinal bleeding < 90 days prior to index procedure

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- Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine or clopidogrel, nitinol, tantalum or allergy to contrast agents that cannot be premedicated
- Contraindication to intraoperative transesophageal echocardiography and/or MDCT scan
- Estimated life-expectancy of < 24 months
- Patient is enrolled in another investigational medical device or drug study which has not completed the required primary endpoint follow-up. (Note: Patients involved in a long-term surveillance phase of another study are eligible for enrollment in this study)
- Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the patient from providing appropriate informed consent
- Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up assessments)
- Unable to comply with follow-up requirements

In addition to the exclusion criteria above, subjects were excluded from the CT sub-study if the following condition was present:

- Inability to have high-quality MDCT study for any reason performed (e.g., atrial fibrillation with rapid ventricular response)

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 30 days, 6 months, 12 months, and then annually through 5 years.

Preoperative and post-operative assessments included physical assessment, laboratory measurements, imaging tests, as well as health status questionnaires. Adverse events and complications were recorded at all visits.

3. Clinical Endpoints

Primary Safety Endpoint

With regards to safety, the primary safety endpoint was a composite of major adverse events at 30 days consisting of the following components:

- All-cause mortality
- All stroke
- Life threatening or major bleeding
- Acute kidney injury (AKI) Stage 2, 3 or dialysis
- Surgery/intervention related to the device (including coronary intervention)
- Major vascular complications

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- Permanent pacemaker implantation
- Moderate or severe total aortic regurgitation

With regard to success/failure criteria, the hypothesis for the primary safety endpoint was defined as follows:

H₀: Pt ≥ 40.5%
H₁: Pt < 40.5%

where Pt is the proportion of patients with a composite safety endpoint event at 30 days and 40.5% was the pre-specified performance goal (PG), which was derived from past TAVR trials in aortic stenosis patients with high or greater surgical risk. The primary safety endpoint assessment was performed at a one-sided significance level of 0.025.

## Primary Effectiveness Endpoint

With regards to effectiveness, the primary effectiveness endpoint was the incidence of all-cause mortality at 1 year. With regard to success/failure criteria, the primary effectiveness hypothesis was defined as follows:

H₀: π ≥ 25%
H₁: π < 25%

where π was the proportion of patients with all-cause mortality at 1 year and 25% was the PG derived from reported mortality rates for patients with severe, symptomatic AR treated via conservative medical management, weighted by NYHA Classification (70% NYHA Class III/IV and 30% NYHA class I/II). The primary effectiveness endpoint assessment was performed at a one-sided significance level of 0.025.

## Secondary Endpoint

The secondary effectiveness endpoint was the change in health status from baseline to 1-year, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. Only subjects who had KCCQ score measured at both baseline and 1-year were included in this analysis.

The secondary endpoint was to be tested only if both the primary safety and effectiveness hypotheses were successful. With regard to success/failure criteria, the hypothesis for the secondary endpoint was defined as:

H₀: μₜ ≤ 10 points
H₁: μₜ > 10 points

where: μₜ was the mean change in KCCQ score from baseline to 1 year and 10 points was the pre-specified performance goal. The secondary endpoint was evaluated using a paired t-test with one-sided significance level of 0.025.

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# Descriptive Endpoints

Key descriptive endpoints included the following:

- KCCQ overall summary score
- NYHA functional class
- 6-minute walk test distance (6MWT) distance
- Proportion of patients with none-to-trace AR
- Echocardiographic parameters

# B. Accountability of PMA Cohort

At the time of database lock, a total of 180 patients out of 346 patients enrolled for screening had the procedure started (Enrolled/Eligible Patient [EP] population) and 177 patients had the study valve implanted (Valve Implant [VI] Population). The primary analysis populations and patient disposition are summarized in Table 7 and Table 8, respectively.

| Table 7: Subject Accounting Summary (Primary Analysis Population) | | |
| --- | --- | --- |
| Analysis Population | Definition | Number of Patients |
| Eligible Patient (EP) | All patients who had the procedure started. | 180 |
| Valve Implant (VI) | All patients who had a study valve implanted upon leaving the procedure room. | 177* |
| *Two patients did not have a study valve successfully implanted because of valve embolization followed by surgical aortic valve replacement (n=1) and embolization followed by commercial THV implantation (n=1). A third patient did not receive a study valve implanted due to an aortic dissection that developed during the procedure but before the Trilogy THV was inserted into the body. This patient was treated with a commercial THV device. | | |

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| Table 8: ALIGN-AR Patient Disposition Summary | | |
| --- | --- | --- |
| | 30-Day | 1-Year |
| Total Patients | 180 | 180 |
| Non-eligible† | 4 | 15 |
| Death | 4 | 14 |
| Withdrawal | 0 | 0 |
| Lost to follow-up | 0 | 0 |
| Exit for other reason | 0 | 1 |
| Eligible | 176 | 165 |
| Visit Completed | 175 | 160 |
| Missed visit‡ | 1 | 5 |
| Follow-up Compliance* | 99.4% | 96.7% |
| † Includes all patients who exited the study prior to the end of the follow-up visit window and who have not had the visit.‡ Data extract date has exceeded the end of the visit window, and the patients have not completed the visit.* Follow-up Compliance is calculated as follows: (Number with visit completed) / (Number eligible). | | |

# C. Study Population Demographics and Baseline Characteristics

The demographics and baseline characteristics of the subjects, as shown in Table 9, present an elderly cohort of patients, with comorbidities consistent with the high operative risk of the population. The STS score $(4.04 \pm 3.37)$ is lower than anticipated for a high surgical risk population, but all patients were determined to be high risk by a cardiac surgeon, often based on factors not measured by the STS risk calculator. Factors considered by the heart team included hostile chest, frailty, right ventricular dysfunction, pulmonary hypertension, and need for concomitant procedures that elevated surgical risk as denoted by the heart team surgeon (e.g., coronary artery bypass grafting (CABG) or mitral valve intervention). Study enrollment ensured that the proportion of patients with NYHA III/IV was between 0.6 and 0.8 to align with the PG derivation assumption for the primary effectiveness endpoint.

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| Table 9: Patient Demographics and Baseline Characteristics – EP Population | |
| --- | --- |
| Description | Summary Statistics*
N=180 |
| Age (years) | 75.5 ± 10.77 (180) |
| Sex | |
| Male | 52.8% (95/180) |
| Female | 47.2% (85/180) |
| Race | |
| American Indian or Alaska Native | 0.6% (1/180) |
| Asian | 7.2% (13/180) |
| Black or African American | 10.6% (19/180) |
| White | 72.8% (131/180) |
| Not available | 8.9% (16/180) |
| BMI (kg/m²) | 25.10 ± 5.64 (179/180) |
| KCCQ Overall Summary Score | 55.34 ± 27.06 (177/180) |
| NYHA Functional Class | |
| I | 0 |
| II | 32.2% (58/180) |
| III | 62.8% (113/180) |
| IV | 5.0% (9/180) |
| STS Score (%) | |
| Mean ± SD | 4.04 ± 3.37 |
| Median | 3.08 |
| Q1, Q3 | 1.91, 4.92 |
| Min, Max | 0.59, 21.03 |
| Comorbidities | |
| Atrial Fibrillation/Flutter | 40.0% (72/180) |
| COPD | 17.8% (32/180) |
| Diabetes: Any | 14.4% (26/180) |
| Endocarditis | 11.7% (21/180) |
| Peripheral vascular disease | 11.7% (21/180) |
| Renal insufficiency | 32.8% (59/180) |
| Stroke | 10.6% (19/180) |
| Systemic hypertension | 82.8% (149/180) |
| Left bundle branch block | 8.3% (15/180) |
| Right bundle branch block | 13.3% (24/180) |
| Procedure History | |
| Permanent pacemaker | 16.7% (30/180) |
| Prosthetic Valve Implant | 8.3% (15/180) |
| Previous CABG | 11.1% (20/180) |

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| Description | Summary Statistics*
N=180 |
| --- | --- |
| Previous PCI | 20.6% (37/180) |
| Echocardiographic core lab assessment | |
| AR Severity** | |
| Severe | 65.2% (116/178) |
| Moderate-Severe | 32.0% (57/178) |
| Moderate | 2.8% (5/178) |
| Vena Contracta of Central AR jet | 0.67 ± 0.13 (177/180) |
| Aortic Valve Mean Gradient (mmHg) | 8.66 ± 6.58 (176/180) |
| AR regurgitant fraction (by PISA) | 55.3 ± 12.9 (124/180) |
| AR regurgitant volume (by PISA) | 55.5 ± 17.2 (130/180) |
| LV End Diastolic Diameter (cm) | 5.59 ± 0.84 (165/180) |
| LV End Systolic Diameter (cm) | 3.96 ± 1.02 (165/180) |
| LV End Systolic Diameter Index (cm/m²) | 2.26 ± 0.66 (164/180) |
| LV End Diastolic Volume by Simpson (ml) | 144.6 ± 56.7 (157/180) |
| LV End Systolic Volume by Simpson (ml) | 70.6 ± 38.9 (157/180) |
| LV Ejection Fraction by Simpson (%) | 53.8 ± 11.4 (157/180) |
| LV mass index (g/m²) | 180.1 ± 63.0 (164/180) |
| N = total number of patients; BMI = body mass index; KCCQ; Kansas City
Cardiomyopathy Questionnaire; NYHA= New York Heart Association; STS = Society
of Thoracic Surgeons (score); SD= Standard Deviation; Min = minimum; Max =
maximum; COPD = Chronic Obstructive Pulmonary Disease; CABG = Coronary
Artery Bypass Grafting; PCI = Percutaneous Coronary Intervention; AR= Aortic
Regurgitation; PISA = Proximal Isovelocity Surface Area; LV = Left Ventricle
*Categorical variables: % (n/N.); continuous variables: mean ± standard deviation (n)
**AR severity was missing/not evaluable by echocardiogram in 2 subjects. | |

## D. Safety and Effectiveness Results

### 1. Primary Safety Endpoint

The primary safety endpoint results are presented in Table 10. An event within the composite 30-day primary safety endpoint occurred in 48 (26.7%) subjects treated with the Trilogy THV. The 97.5% upper confidence interval (CI) was 34.1%, which was less than the pre-specified performance goal of 40.5%. Thus, the primary safety endpoint was met.

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| Table 10: Primary Safety Endpoint Results (EP Population) | | | | |
| --- | --- | --- | --- | --- |
| Event | Summary Statistics* (N=180) | One-sided 97.5% Upper Confidence Interval ** | Performance Goal | p-value |
| Composite Endpoint Failures*** | 48 (26.7%) | 34.1% | 40.5% | <0.0001 |
| * no. of patients with an event (%)
** One-sample binomial proportion test with normally approximated variance and a one-sided statistical significance level of alpha=0.025
*** The primary safety endpoint was a composite of major adverse events at 30 days consisting of: all-cause mortality, all stroke, life threatening or major bleeding, acute kidney injury (AKI) Stage 2, 3 or dialysis, surgery/intervention related to the device (including coronary intervention), major vascular complications, permanent pacemaker implantation, and moderate or severe total aortic regurgitation | | | | |

Each component of the composite safety endpoint is further described in Table 11. The most common event within 30-days was new permanent pacemaker implantation in 36/150 (24.0%) of subjects without prior pacemakers. A post-hoc multivariable analysis suggested the following factors were potentially associated with permanent pacemaker implantation: pre-existing right bundle branch block, prior history of congestive heart failure, annular perimeter ≥85mm, and severe baseline AR (as compared to moderate-severe AR). There were 4 deaths (2.2%) within 30 days. There was 1 subject with moderate or severe total aortic regurgitation within 30 days. This subject was described as having moderate AR by the core laboratory, and at 1 year, the AR was deemed mild in this subject.

| Table 11: Primary Safety Composite Endpoint Components (EP Population) | |
| --- | --- |
| Primary Safety Composite Endpoint | Summary Statistics* (N=180) |
| Composite endpoint at 30 days post-procedure | 26.7% (48) |
| All-cause mortality | 2.2% (4) |
| All stroke | 2.2% (4) |
| Life-threatening or major bleeding | 4.4% (8) |
| Acute kidney injury (AKI) stage 2, 3 or dialysis | 1.1% (2) |
| Major vascular complications | 3.9% (7) |
| Surgery/intervention related to the device (including coronary intervention) | 2.8% (5) |
| Permanent pacemaker implantation** | 24.0% (36) |
| Moderate or severe total aortic regurgitation | 0.6% (1) |
| *% (no. of patients with the event)
**Subjects with prior pacemakers (n=30) were excluded | |

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# 2. Primary Effectiveness Endpoint

The primary effectiveness endpoint was 1-year mortality assessed in the VI population. In the 177 VI subjects, there were 11 subjects $(6.2\%)$ who expired at 1-year follow-up. The one-sided $97.5\%$ upper CI was $11.5\%$ , which is below the pre-specified PG of $25\%$ , $(P &lt; 0.0001)$ based on expected mortality rates for severe AR patients treated by medical management (Table 12). The Kaplan-Meier curve for overall all-cause mortality through 1 year is presented in Figure 5.

| Table 12: Primary Effectiveness Endpoint Results (VI Population) | | | | |
| --- | --- | --- | --- | --- |
| Primary Efficacy Variable | Summary Statistics* (N=177) | One-sided 97.5% Upper Confidence Interval** | Performance Goal | p-value |
| All-Cause Mortality | 11 (6.2%) | 11.5% | 25% | <0.0001 |
| * no. of patients with an event (%) ** Weighted PG analysis using z-test, with z derived as specified by Lu and Xu1 | | | | |

Figure 5: Kaplan-Meier Analysis of All-Cause Mortality through 1 Year (VI Population)

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# 3. Secondary Endpoint

The analysis of the pre-defined secondary endpoint in the trial was based on the VI subjects who completed a KCCQ assessment at baseline and at 1 year. As shown in Table 13, the mean improvement seen in the 141 patients that completed the KCCQ assessment both at baseline and 1-year follow-up was 20.6 ± 24.3 points, with a 97.5% lower CI of 15.9 points. These results show that the mean improvement of KCCQ per patient treated with the Trilogy THV is significantly greater than 10 points (P&lt;0.0001), confirming that the pre-specified PG was met. The mean KCCQ overall summary score (KCCQ-OS) was 55.7 ± 26.9 at baseline and 77.6 ± 22.7 at 1-year for the entire VI population. Twenty-four (24) patients (15.8%) had a moderate improvement in KCCQ-OS (increase between 10 and &lt; 20 points), and 41.4% had a large improvement (≥ 20-point increase). 10.5% of patients had a worse (&gt; 5-point decrease from baseline) KCCQ-OS at 1-year.

| Table 13: Secondary Effectiveness Endpoint, KCCQ Improvement at 1-Year (VI Population) | | | | |
| --- | --- | --- | --- | --- |
| Secondary Efficacy Variable | Summary Statistics* (N=177) | 97.5% Confidence Interval** | Performance Goal | p-value |
| Change in KCCQ | 20.6 ± 24.3 (141/177) | 15.9 – 25.2 | 10-point KCCQ improvement | <0.0001 |
| * mean ± standard deviation (no./total no.) **Paired t-test with a one-sided nominal significance level of 0.025 | | | | |

# 4. Valve Hemodynamics

The AR severity for the VI population through 1 year is shown in Figure 6. At 1 month after implantation with the Trilogy THV, 0 subjects presented moderate-severe or severe AR and 136 subjects (79.1%) had none to trace AR. The AR reduction was maintained through 1 year, with 88.7% (125/141) of subjects having none to trace AR. One subject (0.7%; 1/141) had moderate AR with no subjects having greater than moderate AR.

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Note: The number of subjects available at follow-up visits is lower than the total VI population $(n = 177)$ due to follow-up visits without echocardiographic evaluation, patients that missed visits and deaths.

# Figure 6: Total Aortic Regurgitation through 1-Year (VI population)

Paravalvular leak (PVL) was measured post-implantation and is displayed in Figure 7. At 1 month, the majority of subjects had none or trace PVL $(80.8\%)$ . PVL improved through 1-year, with $92.2\%$ of subjects having none or trace PVL and no subjects having greater than mild PVL at the 1-year evaluation.

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Note: The number of subjects available at follow-up visits is lower than the total VI population (n=177) due to follow-up visits without echocardiographic evaluation, patients that missed visits and deaths.
Figure 7: Paravalvular Regurgitation/Leak through 1-Year (VI population)

Effective orifice area (EOA) and aortic mean gradient through 1 year are presented below in Figure 8. EOA was $2.87 \pm 0.56 \, \text{cm}^2$ at 30 days and $2.78 \pm 0.61 \, \text{cm}^2$ at 1 year. Mean aortic valve pressure gradient was $8.59 \pm 6.56 \, \text{mmHg}$ at baseline, which decreased to $3.88 \pm 1.62 \, \text{mmHg}$ at 30 days and $4.25 \pm 1.83 \, \text{mmHg}$ at 1 year.

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Figure 8: Mean EOA and Aortic Valve (AoV) Mean Gradient Through 1-Year (VI Population)

# 5. Left Ventricle (LV) Remodeling

Decreases in left ventricular LV end systolic volume (LVESV) and LV mass index were observed from screening through 1-year (Figure 9 and Figure 10, respectively). Additional echocardiographic measurements are shown in Table 14.

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Figure 9: Mean LVESV and Standard Error Through 1 Year (VI Population)

Figure 10: Mean LV Mass Index and Standard Error Through 1 Year (VI Population)

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| Table 14: Left Ventricular Remodeling (VI Population) | | | | |
| --- | --- | --- | --- | --- |
| Description | Screening | 1-Month | 6-Month | 1-Year |
| LV End Systolic Volume** (mL) | 70.8 ± 39.1
(154) | 67.3 ± 41.0
(171) | 59.0 ± 39.2
(146) | 52.1 ± 40.1
(137) |
| LV End Diastolic Volume** (mL) | 144.8 ± 56.7
(154) | 132.6 ± 83.1
(171) | 115.9 ± 50.3
(146) | 109.9 ± 50.1
(137) |
| LV End Systolic Diameter (cm) | 4.0 ± 1.0
(162) | 3.7 ± 1.0
(170) | 3.5 ± 0.9
(149) | 3.4 ± 0.9
(138) |
| LV End Diastolic Diameter (cm) | 5.6 ± 0.8
(162) | 5.0 ± 0.9
(172) | 4.8 ± 0.8
(149) | 4.8 ± 0.8
(138) |
| LV Mass (g) | 323.9 ± 123.6
(162) | 254.3 ± 109.0
(139) | 235.1 ± 95.4
(108) | 219.5 ± 101.4
(99) |
| LV Mass Index (g/m²) | 180.4 ± 63.2
(161) | 139.2 ± 54.7
(138) | 131.3 ± 48.2
(108) | 120.6 ± 50.5
(99) |
| LV: left ventricular continuous variables: mean ± standard deviation (no.)
** calculated by Simpson’s method | | | | |

## 6. Additional Functional Assessments

Using the 6-minute walk test (6MWT), the mean distance walked was $807.5 \pm 434.1$ feet at baseline and $901.3 \pm 546.9$ feet at 1-year for the VI population. The mean change from baseline in total distance walked per subject was $78.4 \pm 471.3$ feet. The NYHA functional class of patients at baseline through 1-year is presented in Figure 11. At 1-year post-procedure, $8.6\%$ of patients were NYHA class III or IV compared to $67.2\%$ at baseline.

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Figure 7: NYHA Classification through 1-Year (VI Population)

# 7. Procedural Information and Technical Success

The procedural information for the EP population is presented in Table 15. Overall, the mean procedure time was $71.4 \pm 24.3$ min, the mean fluoroscopy time was $25.5 \pm 10.2$ min, and the mean hospital stay duration was $2.2 \pm 2.4$ days. General anesthesia was used for the majority of procedures with $8.9\%$ of patients receiving conscious sedation. The most commonly implanted valve size was $27$ mm (57.2% of subjects). Three subjects did not receive a Trilogy THV. Two patients had ectopic Trilogy implantation and were successfully implanted with a second Trilogy THV in the correct position.

| Table 15: Procedural Characteristics (EP Population) | |
| --- | --- |
| Characteristics | Summary Statistics* N=180 |
| Sedation Method | |
| General Anesthesia | 164 (91.1%) |
| Conscious Sedation | 16 (8.9%) |
| Femoral Access Site | |
| Right | 138 (76.7%) |
| Left | 42 (23.3%) |
| Access Technique Used | |
| Cut-down | 3 (1.7%) |
| Puncture | 177 (98.3%) |

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| Characteristics | Summary Statistics*
N=180 |
| --- | --- |
| Pre-implant BAV performed prior to insertion of study sheath | |
| Yes | 5 (2.8%) |
| No | 175 (97.2%) |
| All 3 locators engaged within the cusps | 177 (98.3%) |
| Post-implant BAV performed after Trilogy implantation | |
| Yes | 7 (3.9%) |
| No | 167 (92.8%) |
| Missing | 6 (3.8%) |
| Average Procedure Time (min) | 71.4 ± 24.3 |
| Average Fluoroscopy Time | 25.5 ± 10.2 |
| Valve Size Used | |
| 23 mm | 41 (22.8%) |
| 25 mm | 36 (20.0%) |
| 27 mm | 103 (57.2%) |
| Number of Trilogy THVs Implanted | 177 (98.3%) |
| 0 | 3 (1.7%) |
| 1 | 175 (97.2%) |
| 2 | 2 (1.1%) |
| Average Hospital Duration (days) | 2.2 ± 2.4 |
| *continuous variables: mean ± standard deviation; categorical variables: no. (%) | |

Technical success at time of exit from the operating room (OR), hybrid room, or catheterization laboratory was defined as absence of procedural mortality; successful access, delivery and retrieval of transcatheter delivery system; deployment and correct positioning of a single intended THV; and freedom from re-intervention related to the device or access procedure. Technical success was achieved in 171 of the 180 subjects (95.0%) for whom implantation of the THV was attempted as shown in Table 16. Two patients did not have a Trilogy THV successfully implanted because of valve embolization followed by surgical aortic valve replacement (n=1) and embolization followed by commercial THV implantation (n=1). A third patient did not receive a Trilogy THV due to an aortic dissection that developed during the procedure but before the Trilogy THV was inserted into the body. This patient was treated with a commercial THV device.

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| Table 16: Technical Success at Time of Exit from OR, Hybrid Room or Catheterization laboratory (EP Population) | |
| --- | --- |
| Technical Success | Summary Statistics* (N=180) |
| Technical Success at time of exit from OR, hybrid room or catheterization laboratory | 171 (95.0%) |
| Successful access, delivery, and retrieval of Trilogy Introducer Sheath | 179 (99.4%) |
| Successful access, delivery, and retrieval of Trilogy Delivery System | 179 (99.4%) |
| Successful deployment and positioning of first intended Trilogy THV | 175 (97.2%) |
| Freedom from emergency surgery/re-intervention on Trilogy THV | 176 (97.8%) |
| Patient exited hybrid/Operating Room alive | 180 (100.0%) |
| Access intervention | 4 (2.2%) |
| OR: operating room; THV: transcatheter heart valve *categorical variables: no. (%) | |

# 8. Subgroup Analyses

A pre-specified subgroup analysis was performed on the primary safety and effectiveness endpoints of the ALIGN-AR trial based on sex (male vs. female). The study population was evenly balanced by sex (52.5% male, 47.5% female). All-cause mortality at 1-year stratified by sex is shown in Table 17 below and was comparable between male and females.

| Table 17: All-Cause Mortality at 1-year by Sex (VI Population) | | | |
| --- | --- | --- | --- |
| Enrollment Subgroup | N | Event Rate (n) | Event Rate (%) |
| Male | 93/177 (52.5%) | 6 | 6.5% |
| Female | 84/177 (47.5%) | 5 | 6.0% |

The 30-day composite safety endpoint event rates (overall and individual events) stratified by sex are provided in Table 18. The rate of composite endpoint failure was numerically higher in males (30.5%; 29/95) than females (22.4%; 19/85).

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| Table 18: Primary Safety Composite Endpoint at 30 Days by Sex (EP Population) | | |
| --- | --- | --- |
| Event | Summary Statistics* (N=180) | |
| | Male (N=95) | Female (N=85) |
| Composite endpoint at 30 days post-procedure | 29 (30.5%) | 19 (22.4%) |
| All-cause mortality | 2 (2.1%) | 2 (2.4%) |
| All stroke | 3 (3.2%) | 1 (1.2%) |
| Life-threatening or major bleeding | 5 (5.3%) | 3 (3.5%) |
| AKI stage 2, 3, or dialysis | 1 (1.1%) | 1 (1.2%) |
| Major vascular complications | 4 (4.2%) | 3 (3.5%) |
| Surgery/intervention related to the device (including coronary intervention) | 4 (4.2%) | 1 (1.2%) |
| Permanent pacemaker implantation | 21 (22.1%) | 15 (17.6%) |
| Moderate or severe total aortic regurgitation | 1 (1.1%) | 0 (0.0%) |
| AKI: acute kidney injury
*categorical variables: no. (%) | | |

All-cause mortality at 1-year and the 30-day composite safety endpoint event rates (overall and individual events) stratified by race are provided in Table 19 and Table 20 respectively.

| Table 19: All-Cause Mortality at 1-year by Race (VI Population) | | |
| --- | --- | --- |
| Race | No. Events | No./Total No. Patients |
| American Indian or Alaska Native | 0 | 0/1 |
| Asian | 0 | 0/13 |
| Black or African American | 3 | 3/19 |
| White | 8 | 8/129 |
| Not available | 0 | 0/15 |

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| Table 20: Primary Safety Composite Endpoint at 30 Days by Race (EP Population) | | | | | |
| --- | --- | --- | --- | --- | --- |
| Event | Summary Statistics* | | | | |
| | American Indian or Alaska Native (N=1) | Asian (N=13) | Black or African American (N=19) | White (N=131) | Not available (N=16) |
| Composite endpoint at 30 days post-procedure | 0 | 5 (38.5%) | 8 (42.1%) | 33 (25.2%) | 2 (12.5%) |
| All-cause mortality | 0 | 0 | 1 (5.3%) | 3 (2.3%) | 0 |
| All stroke | 0 | 0 | 1 (5.3%) | 2 (1.5%) | 1 (6.3%) |
| Life-threatening or major bleeding | 0 | 2 (15.4%) | 1 (5.3%) | 4 (3.1%) | 1 (6.3%) |
| AKI stage 2, 3, or dialysis | 0 | 0 | 0 | 1 (0.8%) | 1 (6.3%) |
| Major vascular complications | 0 | 1 (7.7%) | 1 (5.3%) | 4 (3.1%) | 1 (6.3%) |
| Surgery/intervention related to the device (including coronary intervention) | 0 | 0 | 0 | 4 (3.1%) | 1 (6.3%) |
| Permanent pacemaker implantation | 0 | 3 (27.3%) | 6 (42.9%) | 26 (23.2%) | 1 (8.3%) |
| Moderate or severe total aortic regurgitation | 0 | 0 | 0 | 1 (0.8%) | 0 |
| AKI: acute kidney injury
*categorical variables: no. (%) | | | | | |

## 9. Adverse Events

An overview of the VARC-2 clinical events through 1-year are presented in Table 21.

| Table 21: VARC-2 Clinical Events (VI Population) | | |
| --- | --- | --- |
| Event | Summary Statistics* (N=177) | |
| | 30-Days | 1 Year |
| All Cause death | 2 (1.1%) | 11 (6.2%) |
| Cardiac Death | 1 (0.6%) | 8 (4.5%) |
| Non-cardiac Death | 1 (0.6%) | 3 (1.7%) |
| Permanent Pacemaker Implantation** | 34 (23.1%) | 40 (27.2%) |
| AKI stage 2, 3 or dialysis | 0 | |
| Myocardial infarction | 0 | 2 (1.1%) |
| Stroke | 2 (1.1%) | 8 (4.5%) |
| Disabling stroke | 0 | 1 (0.6%) |
| Non disabling stroke | 2 (1.1%) | 7 (4.0%) |

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| Event | Summary Statistics* (N=177) | |
| --- | --- | --- |
| | 30-Days | 1 Year |
| All Bleeding | 14 (7.9%) | 18 (10.2%) |
| Major/Life threatening bleeding | 7 (4.0%) | 9 (5.1%) |
| Minor bleeding | 8 (4.5%) | 10 (5.6%) |
| Vascular complications | 11 (6.2%) | 11 (6.2%) |
| Major | 5 (2.8%) | 5 (2.8%) |
| Minor | 6 (3.4%) | 6 (3.4%) |
| Rehospitalization | 2 (1.1%) | 9 (5.1%) |
| Heart failure related | 2 (1.1%) | 8 (4.5%) |
| Index procedure related | 0 | 0 |
| TAVR valve related | 0 | 1 (0.6%) |
| Valve intervention due to prosthetic valve thrombosis | 0 | 0 |
| Valve intervention due to endocarditis | 0 | 1 (0.6%) |
| *categorical variables: no. (%)**Subjects with prior pacemakers (n=30) were excluded | | |

## 10. CT Sub-Study

A subset of patients was enrolled in a computed tomography (CT) sub-study to evaluate Hypoattenuation Leaflet Thrombosis (HALT) and reduced leaflet motion (RLM). The primary assessment of the CT sub-study was completed post-implant at baseline (approximately 30-90 days) and at approximately 1 year. A total of 29 patients were enrolled in the CT Sub-Study. Of these, 16 patients underwent the 1-month CT, and 8 patients underwent the 1-year CT. All patients with the 1-year CT also had the 1-month CT. Six (6/16) patients had HALT identified at 30-days (3 patients had &lt;25% normal motion, 2 patients had 25 to 50% normal motion, and 1 patient had &gt;75% normal motion). Five (5) of the 6 incidences of HALT involved the posterior leaflet and 1 involved the anterolateral leaflet. HALT was observed in 3/8 patients at 1-year: 1 patient did not have HALT at 30 days but had &lt;25% normal motion at 1-year; 1 patient had HALT with &gt;75% normal motion at 30 days that changed to 25-50% normal motion at 1 year; and 1 patient had unchanged findings comparing 30-day results to 1 year (HALT with &lt;25% normal motion). No patient with HALT had a clinical event including stroke or death.

## Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

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# XI. FINANCIAL DISCLOSURE

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The ALIGN-AR Study involved 30 investigators of which none were full-time or part-time employees of the sponsor and 3 investigators had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f), as described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 3
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 0

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data.

# XII. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

As part of the review of the PMA application, FDA also considered the supplemental clinical information summarized below.

## A. Study Design

The ALIGN-AR continued access program (CAP) study was a single-arm, prospective, multicenter study carried out under IDE G150035 after completing enrollment of the ALIGN-AR pivotal study cohort.

1. Clinical Inclusion and Exclusion Criteria
The inclusion and exclusion criteria for the ALIGN-AR CAP cohort were the same as the ALIGN-AR main cohort.

2. Follow-up Schedule
The follow-up schedule and pre- and post-procedure assessments were the same as the ALIGN-AR main cohort.

3. Clinical Endpoints
The ALIGN-AR CAP cohort used the same primary safety and effectiveness endpoints as the ALIGN-AR study. No hypothesis testing was pre-specified for the CAP cohort; endpoints were analyzed with descriptive statistics only.

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# B. Accountability of CAP Cohort

The data presented represents the first 320 patients enrolled in the ALIGN-AR CAP cohort. Subjects were enrolled between December 13, 2022 and October 16, 2024. Five of the 320 patients did not receive the Trilogy valve; to be conservative all 320 patients regardless of procedure success have been included in all analyses. Patient accountability through 1 year is summarized in Table 22 and Table 23.

| Table 22: Subject Accounting Summary in the CAP Cohort | |
| --- | --- |
| Description | ALIGN-AR CAP (N=320) |
| Screened | 710 |
| Eligible | 320 |
| Table 23: CAP Cohort Patient Disposition Summary | | |
| --- | --- | --- |
| | 30-Day | 1-Year |
| Total Patients | 320 | 320 |
| Non-eligible† | 3 | 31 |
| Death | 3 | 24 |
| Withdrawal | 0 | 4 |
| Lost to follow-up | 0 | 1 |
| Exit for other reason | 0 | 2 |
| Eligible | 317 | 289 |
| Visit Completed | 312 | 282 |
| Missed visit‡ | 5 | 7 |
| Follow-up Compliance* | 98.4% | 97.6% |
| † Includes all patients who exited the study prior to the end of the follow-up visit window and who have not had the visit. ‡ Data extract date has exceeded the end of the visit window, and the patients have not completed the visit. * Follow-up Compliance is calculated as follows: (Number with visit completed) / (Number eligible). | | |

# C. Study Population Demographics and Baseline Characteristics

The demographics and baseline characteristics of the ALIGN-AR CAP study are summarized in Table 24. The CAP cohort demographic and baseline characteristics were consistent with the population enrolled in the main cohort.

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| Table 24 Study Population Demographics Baseline Measures in the CAP Cohort | |
| --- | --- |
| Description | Summary Statistics*
N=320 |
| Age (years) | 77.3 ± 10.0 (320) |
| Sex | |
| Male | 54.4% (174/320) |
| Female | 45.6% (146/320) |
| Race | |
| American Indian or Alaska Native | 0.0% (0/319) |
| Asian | 4.4% (14/319) |
| Black or African American | 6.3% (20/319) |
| White | 80.3% (256/319) |
| Native Hawaiian or Pacific Islander | 0.0% (0/319) |
| Not available | 8.5% (27/319) |
| BMI (kg/m²) | 26.0 ± 5.4 (320) |
| KCCQ Overall Summary Score | 22.5 ± 22.6 (274/320) |
| NYHA functional class | |
| I | 0.0% (0/320) |
| II | 42.2% (135/320) |
| III | 54.4% (174/320) |
| IV | 3.4% (11/320) |
| STS Score (%) | |
| Mean ± SD | 3.71 ± 3.25 |
| Median | 2.87 |
| Q1, Q3 | 1.78, 4.42 |
| Min, Max | 0.58, 28.10 |
| Comorbidities | |
| Atrial Fibrillation/Flutter | 38.4% (123/320) |
| COPD | 15.9% (51/320) |
| Diabetes: Any | 16.9% (54/320) |
| Endocarditis | 2.5% (8/320) |
| Peripheral vascular disease | 9.1% (29/320) |
| Renal insufficiency | 28.1% (90/320) |
| Stroke | 9.4% (30/320) |
| Systemic hypertension | 79.1% (253/320) |
| Left bundle branch block | 4.7% (15/318) |
| Right bundle branch block | 10.1% (32/318) |
| Procedure History | |
| Permanent pacemaker | 14.4% (46/320) |
| Prosthetic Valve Implant | 3.4% (11/320) |
| Previous CABG | 8.1% (26/320) |
| Previous PCI | 18.4% (59/320) |
| Echocardiographic core lab assessment | |
| AR Severity | |

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| Description | Summary Statistics*
N=320 |
| --- | --- |
| Severe | 53.1% (169/318) |
| Moderate-Severe | 46.2% (147/318) |
| Moderate | 0.6% (2/318) |
| Vena Contracta of Central AR jet | 0.69 ± 0.38 (222/320) |
| Aortic Valve Mean Gradient (mmHg) | 6.93 ± 4.33 (314/320) |
| Aortic Regurgitation regurgitant fraction (by PISA) | 51.7 ± 13.4 (164/320) |
| Aortic Regurgitation regurgitant volume (by PISA) | 51.4 ± 17.3 (186/320) |
| LV End Diastolic Diameter (cm) | 55.7 ± 8.0 (298/320) |
| LV End Systolic Diameter (cm) | 39.5 ± 8.5 (298/320) |
| LV End Systolic Diameter Index (cm/m²) | 21.6 ± 5.0 (298/320) |
| LV End Diastolic Volume by Simpson (ml) | 153.9 ± 54.6 (290/320) |
| LV End Systolic Volume by Simpson (ml) | 70.4 ± 33.3(290/320) |
| LV Ejection Fraction by Simpson (%) | 55.2 ± 9.3 (291/320) |
| LV mass index (g/m2) | 137.4 ± 47.0 (257/320) |
| N = total number of patients; BMI = body mass index; KCCQ; Kansas City Cardiomyopathy Questionnaire; NYHA= New York Heart Association; STS = Society of Thoracic Surgeons (score); SD= Standard Deviation; Min = minimum; Max = maximum; COPD = Chronic Obstructive Pulmonary Disease; CABG = Coronary Artery Bypass Grafting; PCI = Percutaneous Coronary Intervention; AR= Aortic Regurgitation; PISA = Proximal Isovelocity Surface Area; LV = Left Ventricle
*Categorical variables: % (n/N.); continuous variables: mean ± standard deviation (n) | |

## D. Safety and Effectiveness Results

### 1. Primary Safety Endpoint

The primary safety endpoint results are presented in Table 25. An event within the composite 30-day primary safety endpoint occurred in 85 (26.6%) subjects treated with the Trilogy THV. Similar to the main cohort outcomes, the most common event was new permanent pacemaker implantation in 64/274 (23.4%) in subjects without prior pacemaker. There were 3 deaths (0.9%) within 30 days. There were 2 subjects with moderate or severe total aortic regurgitation within 30 days.

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| Table 25 Primary Safety Composite Endpoint Breakdown in the CAP Cohort | |
| --- | --- |
| Primary Safety Composite Endpoint | Summary Statistics*
N=320 |
| Composite endpoint at 30 days post-procedure | 26.6% (85) |
| All-cause mortality | 0.9% (3) |
| All stroke | 2.2% (7) |
| Life-threatening or major bleeding | 2.5% (8) |
| Acute kidney injury (AKI) stage 2, 3 or dialysis | 0.3% (1) |
| Major vascular complications | 2.5% (8) |
| Surgery/intervention related to the device (including coronary intervention) | 3.8% (12) |
| Permanent pacemaker implantation** | 23.4% (64) |
| Moderate or severe total aortic regurgitation | 0.7% (2) |
| *categorical variables: % (no.)
**Subjects with prior pacemakers (n=46) were excluded | |

2. Primary Effectiveness Endpoint

The primary effectiveness endpoint was all-cause mortality at 1-year. In the ALIGN-AR CAP cohort, there were 24 subjects (7.6%) who expired at 1-year follow-up as shown in Table 26. The Kaplan-Meier curve for overall all-cause mortality through 1 year is presented in Figure 12.

| Table 26: Primary Efficacy Endpoint Results in the CAP Cohort | | |
| --- | --- | --- |
| Primary Efficacy Variable | Summary Statistics (N=314) | |
| | n | % |
| All-Cause Mortality | 24 | 7.6 |

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Figure 12: Kaplan-Meier Analysis of All-Cause Mortality through 1 Year CAP Cohort

3. Kansas City Cardiomyopathy Questionnaire (KCCQ)

The KCCQ overall summary score increased from $60.3 \pm 23.5$ at baseline to $83.9 \pm 17.0$ at 1 year. The mean improvement seen in the 274 patients that completed the KCCQ assessment both at baseline and 1-year follow-up was $22.5 \pm 22.6$ points.

4. Valve Hemodynamics

The AR severity for the CAP cohort through 1 year is shown in Figure 13. At 1 month after implantation with the Trilogy THV, 0 subjects presented moderate-severe or severe AR, and 247 subjects $(80.9\%)$ had none to trace AR. The AR reduction was maintained through 1 year, with $85.6\%$ (215/251) of subjects having none to trace AR. One subject $(0.4\%; 1/251)$ had moderate AR with no subjects having greater than moderate AR.

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Figure 13: Total Aortic Regurgitation through 1-Year in the CAP Cohort

Paravalvular leak (PVL) was measured post-implantation and is displayed in Figure 14. The majority of subjects $(83.4\%)$ had none or trace PVL at 1-month. PVL improved through 1-year, with $94.8\%$ of subjects having none or trace PVL.

Figure 14: Paravalvular Regurgitation/Leak through 1-Year in the CAP Cohort

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EOA and aortic mean gradient through 1 year are presented below in Figure 15. EOA was $3.05 \pm 0.69 \, \text{cm}^2$ at 30 days and $2.80 \pm 0.61 \, \text{cm}^2$ at 1 year. Aortic valve mean gradient was $6.93 \pm 4.33 \, \text{mmHg}$ at baseline, which decreased to $3.64 \pm 1.85 \, \text{mmHg}$ at 30 days and $4.35 \pm 1.83 \, \text{mmHg}$ at 1 year.

Figure 15: Mean EOA and Aortic Valve (AoV) Mean Gradient Through 1 Year in the CAP Cohort.

# 5. Left Ventricular Remodeling

Decreases in LV end systolic volume (LVESV) and LV mass index were observed from screening through 1-year (Figure 16 and Figure 17, respectively). Additional echocardiographic measurements are shown in Table 27.

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Figure 16: LVESV Through 1 Year in the CAP Cohort

Figure 17: LV Mass Index Through 1 Year in the CAP Cohort

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| Table 27 Left Ventricular Remodeling in the CAP Cohort | | | | |
| --- | --- | --- | --- | --- |
| Description | Screening | 1-Month | 6-Month | 1-Year |
| LV End Systolic Volume** (mL) | 70.4 ± 33.3 (290) | 66.4 ± 34.9 (307) | 60.0 ± 31.8 (270) | 60.7 ± 32.9 (249) |
| LV End Diastolic Volume** (mL) | 153.9 ± 54.6 (290) | 129.1 ± 46.8 (307) | 119.8 ± 44.5 (270) | 123.2 ± 47.7 (249) |
| LV End Systolic Diameter (cm) | 3.95 ± 0.85 (298) | 3.77 ± 0.81 (301) | 3.57 ± 0.84 (272) | 3.44 ± 0.80 (244) |
| LV End Diastolic Diameter (cm) | 5.57 ± 0.80 (298) | 5.00 ± 0.78 (301) | 4.87 ± 0.80 (273) | 4.78 ± 0.75 (244) |
| LV Mass (g) | 253.2 ± 92.5 (257) | 195.8 ± 74.7 (273) | 189.8 ± 71.9 (260) | 174.6 ± 63.0 (242) |
| LV Mass Index (g/m2) | 137.4 ± 47.0 (257) | 105.6 ± 36.8 (273) | 102.3 ± 35.7 (260) | 93.9 ± 30.8 (242) |
| LV: left ventricular continuous variables: mean ± standard deviation (no.) ** calculated by Simpson's method | | | | |

# 6. Additional Functional Metrics

Using the 6-minute walk test (6MWT), the mean distance walked was $896.3 \pm 397.9$ feet at baseline and $976.3 \pm 495.0$ feet at 1-year for the CAP cohort. The mean change from baseline in total distance walked per subject was $42.2 \pm 496.4$ feet. The NYHA functional class of patients at baseline through 1-year is presented in Figure 18. At 1-year postprocedure, $6.2\%$ of patients were NYHA class III or IV compared to $57.8\%$ at baseline.

Figure 18: NYHA Classification through 1-Year in the CAP Cohort

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7. Adverse Events

An overview of the VARC-2 clinical events through 1-year for the CAP cohort are presented in Table 28.

| Table 28: VARC-2 Clinical Events in the CAP Cohort | | |
| --- | --- | --- |
| Event | Summary Statistics* | |
| | 30-Days (N=320) | 1 Year¹ (N=314) |
| All Cause death | 3 (0.9%) | 24 (7.6%) |
| Cardiac Death | 3 (0.9%) | 16 (5.1%) |
| Non-cardiac Death | 0 (0.0%) | 8 (2.5%) |
| Permanent Pacemaker Implantation** | 64 (23.4%) | 72 (26.8%) |
| AKI Stage 2, 3 or dialysis | 1 (0.3%) | |
| Myocardial infarction | 1 (0.3%) | 2 (0.6%) |
| Stroke | 7 (2.2%) | 15 (4.8%) |
| Disabling stroke | 2 (0.6%) | 4 (1.3%) |
| Non disabling stroke | 5 (1.6%) | 11 (3.5%) |
| All Bleeding | 12 (3.8%) | 14 (4.5%) |
| Major/Life threatening bleeding | 8 (2.5%) | 10 (3.2%) |
| Minor bleeding | 4 (1.3%) | 4 (1.3%) |
| Vascular complications | 19 (5.9%) | 19 (6.1%) |
| Major | 8 (2.5%) | 8 (2.5%) |
| Minor | 11 (3.4%) | 11 (3.5%) |
| Rehospitalization | 6 (1.9%) | 21 (6.7%) |
| Heart failure related | 2 (0.6%) | 15 (4.8%) |
| Index procedure related | 4 (1.3%) | 4 (1.3%) |
| TAVR valve related | 0 | 3 (1.0%) |
| Valve intervention due to prosthetic valve thrombosis | 0 | 1 (0.3%) |
| Valve intervention due to endocarditis | 0 | 0 |
| *Categorical variables: no. (%)
**Subjects with prior pacemakers (n=46) were excluded
¹ A subject is included in the 1-year denominator if they either experienced any adverse event within 365 days of the procedure or had at least 305 days of follow-up; otherwise the denominator is set to missing and they are excluded. 6 out of 320 subjects had no adverse events and <305 days of follow-up due to either withdrawal or lost-to-follow-up, giving a denominator of 314 at 1-year. The percentage calculation is based on the total number of patients per category of event. | | |

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# XIII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory System Devices panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

# XIV. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

## A. Effectiveness Conclusions

The primary effectiveness endpoint of all-cause mortality at 1-year was 6.2% in the ALIGN-AR subjects treated with the Trilogy THV (VI population). The upper bound of the one-sided 97.5% confidence interval was 11.5%, which was significantly lower than the pre-specified performance goal (PG) of 25%, indicating the study met its primary effectiveness endpoint. The mean change from baseline in KCCQ-OS at 1-year post-procedure was 20.6 points with a 2-sided 95% CI lower bound of 15.9, which was higher than the pre-specified performance goal (mean improvement of 10 points); therefore, the key secondary endpoint was met. The patients overall demonstrated improvements in valve hemodynamics including aortic regurgitation (AR). At baseline, 64.6% of subjects had severe AR, 31.6% had moderate-severe AR, and 2.8% had moderate AR while at 1-year 88.7% (125/141) of subjects had none to trace AR. Only one subject (0.7%; 1/141) had moderate AR and no subjects having greater than moderate AR at 1-year. The percentage of patients with a ≥1 NYHA class improvement from baseline to 1-year was 82.8%, indicating an improvement in functional status. These results were confirmed in the ALIGN-AR CAP cohort.

## B. Safety Conclusions

The risks of the device are based on nonclinical laboratory studies and clinical data collected in the ALIGN-AR study to support PMA approval as described above. The results from the nonclinical studies performed on the Trilogy THV System (e.g., biocompatibility, hydrodynamic performance, and structural integrity) demonstrated that this device is suitable for implant. Engineering testing demonstrated a limited valve durability equivalent to 3.5 years, which did not meet the 5 years recommended by the relevant international standard.

The composite event rate of all-cause mortality, all stroke, life threatening or major bleeding, AKI Stage 2, 3 or dialysis, surgery/intervention related to the device (including coronary intervention), major vascular complications, permanent pacemaker implantation and moderate or severe total aortic regurgitation at 30 days was 26.7% (i.e., the primary safety endpoint). The upper bound of the one-sided 97.5% confidence interval was 34.1%, which was significantly lower than the pre-determined performance goal (PG) of 40.5%. As such, the pivotal study met the pre-specified primary endpoint. Notably, the rate of new

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permanent pacemaker implantation was 24.0% within 30 days. The safety results from the primary analysis cohort were confirmed by the ALIGN-AR CAP cohort.

## C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. They include improved hemodynamics and improved health and functional statuses as measured by KCCQ and NYHA functional class, respectively.

The probable risks of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. They include death, stroke, conduction disturbances requiring a new pacemaker, life-threatening bleeding, myocardial infarction, and major vascular complications.

The probable risks and benefits for the Trilogy Transcatheter Heart Valve system also considered that engineering testing demonstrated a limited valve durability equivalent to 3.5 years. However, the intended patient population for the Trilogy Transcatheter Heart Valve system is patients who are high or greater risk for surgical aortic valve replacement and thus have limited treatment options. Additionally, patients who experience structural valve deterioration may have the option of future valve-in-valve therapy with a transcatheter heart valve. The probable benefits of providing treatment to a patient population with limited treatment options outweigh the probable risks of limited valve durability in engineering testing. Long-term durability has not been established in a clinical setting for the Trilogy transcatheter heart valve.

### 1. Patient Perspective

Patient perspectives considered during the review included patient reported outcomes as measured by KCCQ.

In conclusion, given the available information above, the data support that for patients with symptomatic, severe native tricuspid aortic valve regurgitation (not due to acute endocarditis, rheumatic heart disease, or acute aortic dissection) who are judged by a Heart Team, including a cardiac surgeon…