← Product Code QZI · P240013 # Sphere-9 Catheter and Affera Ablation System (P240013) _Medtronic, Inc. · QZI · Oct 24, 2024 · Cardiovascular · APPR_ **Canonical URL:** https://fda.innolitics.com/device/P240013 ## Device Facts - **Applicant:** Medtronic, Inc. - **Product Code:** QZI - **Decision Date:** Oct 24, 2024 - **Decision:** APPR - **Device Class:** Class 3 - **Review Panel:** Cardiovascular - **Attributes:** Therapeutic ## Intended Use The Sphere-9 Catheter is indicated for use in cardiac electrophysiological mapping (stimulation and electrogram recording) and for treatment of drug refractory, recurrent, symptomatic persistent atrial fibrillation (episode duration less than 1 year) and radiofrequency ablation of cavotricuspid isthmus dependent atrial flutter when used with the Affera Mapping system. ## Device Story The Sphere-9 Catheter and Affera Ablation System are used by electrophysiologists in a clinical setting for cardiac mapping, pacing, and ablation. The system includes the Sphere-9 Catheter (8F deflectable, expandable 9mm electrode), HexaGen RF Generator, HexaPulse PF Generator, and HexaFlow Irrigation Pump. The catheter provides electromagnetic location data to the Affera Mapping System. The system delivers either RF or PF energy to ablate cardiac tissue. The physician uses the system to isolate pulmonary veins or create linear lesions (e.g., cavotricuspid isthmus). The system provides real-time ablation parameters and feedback. Successful ablation benefits patients by reducing arrhythmia recurrence and improving quality of life. ## Clinical Evidence Prospective, multi-center, randomized global study (SPHERE Per-AF, N=420) compared the investigational device to a control RF catheter. Primary safety endpoint (serious device/procedure-related AEs) was 1.4% (investigational) vs 1.0% (control), demonstrating non-inferiority (p<0.0001). Primary effectiveness (freedom from AF/AFL/AT recurrence) was 73.8% (investigational) vs 65.8% (control), demonstrating non-inferiority (p<0.0001). Superiority was shown for energy application time, treatment time, and total procedure time (p<0.0001). ## Technological Characteristics Sterile, single-use 8F deflectable catheter with an expandable 9mm electrode. Uses passive electromagnetic sensors for mapping. Energy sources: RF (HexaGen) and PF (HexaPulse). Irrigation: HexaFlow pump with custom tubing set. Connectivity: Catheter connects to Affera Mapping System via extension cable. Biocompatibility per ISO 10993-1. Basic safety per IEC 60601-1, IEC 60601-1-2, and IEC 60601-2-2. ## Regulatory Identification For the treatment of atrial fibrillation. ## Reference Devices - THERMOCOOL SMARTTOUCH® SF radiofrequency ablation catheter ## Submission Summary (Full Text) > This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com. > > Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/). {0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) # I. GENERAL INFORMATION Device Generic Names: Ablation Catheter, Generator, Irrigation Pump, Tubing Set, and Catheter Extension cable Device Trade Names: Sphere-9™ Catheter and Affera™ Ablation System Including: Sphere-9™ Catheter (Model AFR-00001); HexaGen™ RF Generator (Model AFR-00004); HexaPulse™ PF Generator (Model AFR-00008); HexaFlow™ Irrigation Pump (Model AFR-00005); Tubing Set (Model AFR-00002); Catheter Extension Cable (Model AFR-00006) Device Procode: Class III / QZI: Percutaneous Cardiac Ablation Catheter For Treatment Of Atrial Fibrillation With Irreversible Electroporation Class III/ OAE: Catheter, Percutaneous, Cardiac Ablation, For Treatment Of Atrial Fibrillation Class III/ OAD: Catheter, Percutaneous, Cardiac Ablation, For Treatment Of Atrial Flutter Applicant's Name and Address: Medtronic, Inc. 8200 Coral Sea Street NE Mounds View, MN 55112 USA Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P240013 Date of FDA Notice of Approval: October 24, 2024 # II. INDICATIONS FOR USE The Sphere-9 Catheter is indicated for use in cardiac electrophysiological mapping (stimulation and electrogram recording) and for treatment of drug refractory, recurrent, symptomatic persistent atrial fibrillation (episode duration less than 1 year) and radiofrequency ablation of cavotricuspid isthmus dependent atrial flutter when used with the Affera Mapping system. PMA P240013: FDA Summary of Safety and Effectiveness Data {1} III. CONTRAINDICATIONS The Sphere-9 Catheter is contraindicated for use under the following circumstances: - In patients with an active systemic infection. - In patients who have had cardiac surgery in the preceding eight weeks, as the risk of perforation may increase. - In patients with intracardiac thrombus or myxoma, as the catheter may precipitate an embolus. - In coronary vessels with diameter smaller than the expandable ablation electrode, as the catheter may damage the coronary vessels. - In patients with prosthetic valves, as the catheter may damage the prosthesis. - Using the transaortic retrograde approach in patients who have had aortic valve replacement. - Using the transseptal approach in patients with an interatrial baffle or patch, as the opening could persist and result in an iatrogenic atrial shunt. IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the labeling (Instructions for Use) for the Sphere-9 Catheter, Tubing Set, Catheter Extension Cable, and Affera Ablation System (HexaGen RF Generator, HexaPulse PF Generator, HexaFlow Irrigation Pump). V. DEVICE DESCRIPTION The Sphere-9 Catheter and Affera Ablation System are used in conjunction with the Affera Mapping System for cardiac mapping, ablation, and pacing. Sphere-9 Catheter The Sphere-9 Catheter is a sterile, single-use 8F deflectable catheter that can be used for cardiac mapping and ablation. The Sphere-9 Catheter (shown in Figure 1) includes a handle to control bidirectional deflection of a steerable shaft. The ablation electrode on the tip of the catheter is compressed to pass through a standard 8Fr introducer sheath or an 8.5Fr steerable guiding sheath and expands to 9mm in diameter when advanced beyond the tip of the sheath. The electrodes in the catheter tip are radiopaque for visualization via standard x-ray fluoroscopy. PMA P240013: FDA Summary of Safety and Effectiveness Data {2} ![img-0.jpeg](img-0.jpeg) Figure 1. Sphere-9 Catheter The Sphere-9 Catheter contains an irrigation nozzle at the center of the expandable electrode. The nozzle is flushed with heparinized saline at a low flow rate during mapping and can be irrigated at a higher flow rate during ablation. The irrigation nozzle is fed by a lumen that connects via a standard Luer connector to a custom tubing set and irrigation pump. The catheter contains passive electromagnetic sensors to allow display of the tip location and orientation by the Affera Mapping System. ## Affera Ablation System The Affera Ablation System is capable of delivering either radiofrequency (RF) energy or pulsed field (PF) energy to ablate cardiac tissue through the Sphere-9 Catheter. The Affera Ablation System is composed of: - HexaGen RF Generator: Acts as the user interface and control unit of the Ablation System and delivers RF energy to the ablation catheter. - HexaPulse PF Generator: Delivers PF energy to the ablation catheter. - HexaFlow Irrigation Pump: Provides controlled irrigation to cool the ablation electrode. Electrical connection is made between the Affera Ablation System and the Sphere-9 Catheter via a disposable Catheter Extension Cable. To complete the electrical circuit for RF or PF energy delivery, the Ablation System requires the use of disposable return electrodes. The system is compatible with return electrodes that are commercially available on the market and used for this purpose. The disposable Tubing Set connects to the Sphere-9 Catheter to provide saline irrigation. ## HexaGen RF Generator The HexaGen RF Generator (Figure 2) delivers radiofrequency current for cardiac ablation. The device includes a touch screen and knobs that allow setting and display of ablation parameters, as well as real-time ablation information. PMA P240013: FDA Summary of Safety and Effectiveness Data {3} ![img-1.jpeg](img-1.jpeg) Figure 2. HexaGen RF Generator The HexaGen RF Generator interfaces with the HexaFlow Irrigation Pump to provide the appropriate irrigation to the catheter. The following components are supplied as part of the device: ![img-2.jpeg](img-2.jpeg) Foot Pedal ![img-3.jpeg](img-3.jpeg) Return Electrode Adapter ![img-4.jpeg](img-4.jpeg) Remote Control - Remote Control Power Supply - Fiber Optic Communication Cable - Generator Link Cable Power Cord Equipotential Cable # HexaPulse PF Generator The HexaPulse PF Generator (Figure 3) is connected to the Sphere-9 Catheter along with the HexaGen RF Generator and HexaMap CIU. The HexaPulse PF Generator delivers low-energy, high-voltage pulses. PMA P240013: FDA Summary of Safety and Effectiveness Data {4} ![img-5.jpeg](img-5.jpeg) Figure 3. HexaPulse PF Generator The following components are supplied as part of the device: - Generator Link Cable - Ablation Return Link Cable - Generator Communication Cable (qty 2) Power Cord - Equipotential Cable ## Catheter Extension Cable The Catheter Extension Cable is a single-use, sterile cable which provides the electrical connection between the Sphere-9 Catheter and the HexaMap catheter interface unit (CIU).¹ The Catheter Extension Cable connectors are keyed, include a retention feature, and contain touch-proof contacts. ![img-6.jpeg](img-6.jpeg) Figure 4. Catheter Extension Cable ## Tubing Set The Tubing Set (Figure 5) is a sterile, single-use disposable peristaltic tubing set used to ¹ Component of the Affera Mapping System, Class II device PMA P240013: FDA Summary of Safety and Effectiveness Data 5 of 46 {5} provide saline irrigation from the HexaFlow Irrigation Pump to the Sphere-9 Catheter. The Tubing Set contains features for mounting into the HexaFlow Irrigation Pump and for interfacing with bubble detector on the Irrigation Pump. The Tubing Set employs a standard IV spike and drip chamber to interface with common irrigation bags, and it connects to the catheter via a standard Luer connector. ![img-7.jpeg](img-7.jpeg) Figure 5. Tubing Set ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of drug refractory, recurrent, symptomatic persistent atrial fibrillation (episode duration less than 1 year) and cavotricuspid isthmus dependent atrial flutter, including the following: - Anti-arrhythmic drugs - Surgical ablation - Catheter Ablation - PF ablation - RF ablation - Laser ablation - Cryoablation 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 Sphere-9 Catheter and Affera Ablation System is currently marketed in the European Economic Area, Switzerland, United Kingdom, Israel, and New Zealand. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness. PMA P240013: FDA Summary of Safety and Effectiveness Data {6} # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Potential adverse events associated with catheter ablation and mapping procedures include, but are not limited to, the following conditions: PMA P240013: FDA Summary of Safety and Effectiveness Data 7 of 46 {7} PMA P240013: FDA Summary of Safety and Effectiveness Data 8 of 46 Access site complications (e.g. hematoma, laceration, arterio-venous fistula) Allergic reaction (including anaphylaxis) Anemia Anesthesia complications Arrhythmia (worsening, or outside of diagnosis, or life-threatening) Atrioesophageal fistula Asymptomatic cerebral ischemia Bleeding Bradycardia Bronchial injury Cardiac perforation / tamponade Cardiac or respiratory arrest Catheter entrapment Cerebrovascular accident (CVA) / stroke Chest pain Conduction system injury Coronary artery spasm/ occlusion/ stenosis Damage/ dislodgement to ICD or implantable pacemaker Death Deep vein thrombosis Embolism Endocarditis Esophageal ulceration / erythema Fluid volume overload Gastric hypomotility Heart failure Hemoptysis Hematoma Hemothorax Hypotension Hypoxia Increased creatinine phosphokinase (CPK) level Infection Myocardial infarction Muscle pain/ soreness Perforation Pericardial effusion Pericarditis Peripheral nerve injury Phrenic nerve palsy / paralysis Pleural effusion Pneumonia Pneumothorax Pseudoaneurysm Pulmonary edema Pulmonary hypertension Pulmonary vein stenosis Radiation injury Renal failure Respiratory insufficiency Skin burn, irritation or rash Stiff left atrial syndrome Transient ischemic attack Vagal nerve injury Valve damage Vasovagal reactions Vessel dissection For the specific adverse events that occurred in the clinical study, please see Section X below. {8} IX. SUMMARY OF NONCLINICAL STUDIES Nonclinical testing was performed to demonstrate the final design meets the defined design inputs. Testing was conducted following recognized standards and demonstrated acceptable results in accordance with the design inputs. Nonclinical testing included design verification (device level, system level, and software), design validation testing, biocompatibility of patient-contacting materials, sterilization, packaging, and shelf-life testing. A. Laboratory Studies Biocompatibility Biocompatibility testing of the Sphere-9 Catheter and Tubing Set was conducted in accordance with ISO 10993-1 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process". The Sphere-9 Catheter is an external communicating device placed in direct contact with circulating blood for a limited duration (less than 24 hours). The Tubing Set is an external communicating device with indirect contact with the blood path for the same duration. Table 1. Summary of Biological Endpoint Testing and Test Articles | Attribute | Test Method | Test Articles | | --- | --- | --- | | Cytotoxicity per ISO-10993-5 | L929 MEM Elution | Sphere-9 Catheter | | | L929 Neutral Red Uptake | Tubing Set | | Hemocompatibility per ISO-10993-4 | Rabbit Blood Hemolysis: Direct Method | Sphere-9 Catheter | | | Rabbit Blood Hemolysis: Indirect Method | Sphere-9 Catheter | | | | Tubing Set | | | SC5B-9 Complement Activation: Direct Contact | Sphere-9 Catheter | | | Thrombogenicity | Sphere-9 Catheter | | Irritation and Sensitization per ISO-10993-10 | Rabbit Intracutaneous Injection Reactivity | Tubing Set | | | Guinea Pig Maximization Sensitization (Kligman) | Tubing Set | | Irritation per ISO 10993-23 | Rabbit Intracutaneous Injection Reactivity | Sphere-9 Catheter | | Sensitization per ISO 10993-10 | Guinea Pig Maximization Sensitization (Kligman) | Sphere-9 Catheter | | Systemic Toxicity per ISO-10993-11 | Acute Systemic Injection | Sphere-9 Catheter | | | | Tubing Set | | Pyrogenicity per ISO-10993-11 | Materials Mediated Pyrogenicity | Sphere-9 Catheter | | | | Tubing Set | PMA P240013: FDA Summary of Safety and Effectiveness Data 9 of 46 {9} PMA P240013: FDA Summary of Safety and Effectiveness Data 10 of 46 # Sphere-9 Catheter Design Verification Non-clinical bench testing was performed and included the following areas: - Exposure to 2X sterilization, environmental conditioning, simulated distribution, and accelerated aging - Dimensional verifications and visual inspections - Tip buckle force - Cooling effectiveness - Irrigation backpressure - Shaft kink resistance - Simulated use - Mini electrode shear strength - Tensile strength - Temperature rise during use - Corrosion resistance - Dielectric strength - Torsional and lateral stiffness - Electrode retraction force - Flex cycling - RF and PF ablation after simulated use - Catheter location verification - Defibrillation resistance testing Testing confirmed acceptable results to all performance requirements. # HexaGen RF Generator and HexaPulse PF Generator Hardware and System Design Verification Non-clinical testing was performed for both the HexaGen RF Generator and HexaPulse PF Generator Module as part of design verification. - Functional performance: electrical performance, operating limits, output characteristics, measurement ranges and accuracy - Physical: generator dimensions, weight, user interface - Safety: basic safety in accordance with IEC 60601-1 Testing confirmed acceptable results to all performance requirements. # HexaGen RF Generator and HexaPulse PF Generator Software Design Verification The software for these devices consists of several modules that work together to control RF and PF energy delivery. Nonclinical testing was performed on all aspects of the software. This included: - Unit/integration/system testing - Firmware verification - Operating system (OS) validation {10} - Cybersecurity feature testing and cybersecurity vulnerability scanning Testing confirmed acceptable results to all software requirements and specifications. ## HexaFlow Irrigation Pump HW Design Verification Nonclinical testing was performed and included the following areas: - Functional performance: bubble detection, audible indicators and volume, maximum pressure, and internal monitoring - Physical: pump dimensions, weight, user interface, ingress protection and tamper resistance, and receptacles Testing confirmed acceptable results to all performance requirements. ## HexaFlow Irrigation Pump Software Design Verification Nonclinical testing was performed on all aspects of the Irrigation Pump software. This included: - Unit/integration/system testing - Firmware verification - Operating system (OS) validation - Cybersecurity feature testing and cybersecurity vulnerability scanning Testing confirmed acceptable results to all software requirements. ## Tubing Set Design Verification Non-clinical bench testing was performed and included the following areas: - Exposure to 2X sterilization, environmental conditioning, simulated distribution, and accelerated aging - Flow rate accuracy - Simulated use - Kink resistance - Static pressure - Tensile strength - Alignment and retention Testing confirmed acceptable results to all performance requirements. ## Catheter Extension Cable Design Verification Non-clinical bench testing was performed and included the following areas: - Exposure to 2X sterilization, environmental conditioning, simulated distribution, and accelerated aging - Mating/unmating cycles PMA P240013: FDA Summary of Safety and Effectiveness Data 11 of 46 {11} - Electrical performance - DC isolation - Mechanical performance Testing confirmed acceptable results to all performance requirements. ## Basic Safety and EMC Design Verification The Sphere-9 Catheter and the Affera Ablation System were tested in accordance with the following standards for basic safety and EMC: - IEC 60601-1 Edition 3.2 2020-08: Medical Electrical Equipment - Part 1: General Requirements for Basic Safety and Essential Performance - IEC 60601-1-2 Edition 4.1 2020-09: Medical Electrical Equipment – Part 1-2: General Requirements for Basic Safety and Essential Performance - Collateral Standard: Electromagnetic disturbances – Requirements and tests - IEC 60601-2-2 Edition 6 2017-03: Medical electrical equipment - Part 2-2: Particular requirements for the basic safety and essential performance of high frequency surgical equipment and high frequency surgical accessories ## System Human Factors/Usability Engineering and Design Validation A risk-based usability engineering process was used to consider human factors as an integral part of the risk management and product development processes. The process was modeled after ANSI/AAMI/IEC 62366-1:2015 Medical devices – Part 1: Application of usability engineering to medical devices. Design validation of the product requirements for each device was completed through a review of objective evidence contained in GLP animal studies, clinical studies, test reports, and other documentation. ## B. Animal Studies During the development of the Sphere-9 Catheter and the Affera Mapping and Ablation System, preclinical acute and chronic animal studies were conducted to support system development and provide an in-depth characterization of the safety profile of the system. Key animal studies conducted with the Sphere-9 Catheter and Affera Ablation System are summarized in Table 2. PMA P240013: FDA Summary of Safety and Effectiveness Data 12 of 46 {12} Table 2. Summary of Animal Studies | Description | Objective | Number of Animals | Follow-up Duration | Results | | --- | --- | --- | --- | --- | | GLP Thigh Preparation Study to Evaluate Lesion Formation and Safety | Characterize lesion formation using the RF-MI and RF-ANT ablation settings at two contact forces (10 g and 30 g) and two orientations (parallel and perpendicular); evaluate safety by assessing for incidence of steam pop, char and/or thrombus formation. | Four swine (eight thighs) | Acute | Lesion dimensions were reported across the range of ablation parameters, contact forces, and orientations. Safe performance was demonstrated as there was no evidence of thrombus, char, and steam pop across all applications of the studied parameters. | | Chronic GLP Study to Evaluate Safety and Performance of Mapping and Ablation | Evaluate the safety and performance of the Sphere-9 Catheter and the Affera Mapping and Ablation System through mimicking clinical use of the device by three different electrophysiologists. | Six canines | Chronic (28 days) | Study demonstrated the safety and performance of the Sphere-9 Catheter and the Affera Mapping and Ablation System. Acceptance criteria for all study endpoints were met: • Overall animal health • Test device safety • Test device performance and effectiveness • Char and thrombus formation | | Chronic Study to Evaluate the Safety of RF and PF Ablation | Evaluate the performance and safety of the Sphere-9 Catheter and the Affera Mapping and Ablation System using provocative measures to evaluate PF ablation adjacent to the phrenic nerve and esophagus and repeated ablations using both RF and PF. | Six swine | Chronic (26-28 days) | Study demonstrated the safety of radiofrequency (RF) and pulse field (PF) ablation with the Sphere-9 Catheter and the Affera Mapping and Ablation System. Acceptance criteria for all study endpoints were met: • Overall animal health • Test device safety | | Acute Study to Evaluate Microbubbles and Embolic Debris | Evaluate and compare solid embolic debris and microbubble formation during ablation in the left atrium with the Sphere-9 Catheter (using both RF and PF ablation) and a commercially available irrigated RF ablation catheter. | Two swine | Acute | The results of the acute study support the safety of RF and PF ablation with the Sphere-9 Catheter and the Affera Mapping and Ablation System with respect to solid embolic debris and microbubble formation. The results of this study suggest that, compared to conventional irrigated RF catheter ablation, the risk of microbubbles, adherent char or thrombus, and embolic debris is similar or lower when ablating with the Sphere-9 Catheter using clinically relevant operating parameters. | PMA P240013: FDA Summary of Safety and Effectiveness Data {13} # C. Additional Studies Sterilization, Packaging, and Shelf Life The Sphere-9 Catheter, Tubing Set, and Catheter Extension Cable are all provided as sterile, single-use devices. These devices are sterilized using ethylene oxide (EO) cycles validated using the overkill approach per ISO 11135. The cycles were validated to achieve a minimum sterility assurance level of $10^{-6}$ . EO and ethylene chlorohydrin (ECH) residuals were under the limits of ISO 10993-7:2008/+A1:2022 after sterilization and aeration processing. The packaged Sphere-9 Catheter, Tubing Set, and Catheter Extension Cable were evaluated to demonstrate product and packaging system performance after exposure to appropriate conditioning. The table below outlines the packaging performance tests. | Test | Test Performed | | --- | --- | | Sterilization | EO sterilization (two cycles) | | Transport Simulation | Thermal conditioning per ISTA 3A | | | Distribution simulation per ASTM D4169-16 DC 13 AL II | | Accelerated Aging | 13-month equivalent per ASTM F1980-16 | | Sterile Barrier Integrity | Pouch Seal Strength per ASTM F88/F88M-15 | | | Gross Leak Detection: Bubble test per ASTM F2096-11 | | Labeling Integrity | Legibility and adhesion | The Sphere-9 Catheter, Tubing Set, and Catheter Extension Cable are labeled for 13-month shelf life. # X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study (SPHERE Per-AF) to establish a reasonable assurance of safety and effectiveness of mapping and ablation with the Sphere-9 Catheter with the Affera Mapping and Ablation System for persistent atrial fibrillation in the US, Czech Republic, and Israel under IDE G210170. 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 study was a prospective, multi-center, randomized, global pre-market clinical study with 360 days of post-ablation follow-up. Subjects were randomly assigned 1:1 to receive treatment with either the Sphere-9 Catheter with the Affera Mapping and Ablation System (investigational device) or the THERMOCOOL SMARTTOUCH® SF radiofrequency ablation catheter (control device). Subjects were blinded to their treatment arm until the completion of their 360-day follow-up visit. Adult subjects with a history of symptomatic persistent atrial fibrillation (PerAF) refractory or intolerant to drugs underwent pulsed field (PF) and radiofrequency (RF) ablation with either the investigational device or RF ablation with the control device. Following the index PMA P240013: FDA Summary of Safety and Effectiveness Data {14} ablation procedure and hospital discharge, study subjects were followed at 10 days, 30 days, 75 days, 90 days, 180 days, and 360 days. Arrhythmia recurrence was monitored with ECG at follow-up visits, 24-hour Holter monitoring at 6 and 12 months, and both scheduled and symptomatic transtelephonic monitor (event monitor) recordings. Patients were enrolled and treated between December 14, 2021, and December 2, 2022. A total of 477 patients were enrolled, and 420 patients were treated. Subjects were enrolled at 22 investigational sites globally, including 18 sites in the United States, 3 sites in Czech Republic, and 1 site in Israel. The study utilized an independent and blinded Clinical Events Committee (CEC) to adjudicate endpoint events, a rhythm monitoring core lab for distribution of equipment for rhythm monitoring and adjudication of arrhythmias, and an imaging core lab for review of chest and brain imaging. The study also utilized an independent Data and Safety Monitoring Board (DSMB) to oversee study progress and review clinical data and safety. 1. Inclusion and Exclusion Criteria Enrollment in the SPHERE Per-AF study was limited to patients who met the following inclusion criteria: 1. Symptomatic PerAF documented by (1) a physician’s note indicating symptoms consistent with AF sustained longer than 7 days but less than 12 months; AND either (2a) a 24-hour Holter documenting continuous AF within the past year OR (2b) two electrocardiograms (from any form of rhythm monitoring, including consumer devices) taken at least 7 days apart within the past year, each showing continuous AF. 2. Failure or intolerance of at least one Class I or III anti-arrhythmic drug (AAD). 3. Suitable candidate for catheter ablation. 4. Adults aged 18 – 80 years. 5. Willing and able to comply with all baseline and follow-up evaluations for the full length of the study. 6. Willing and able to provide informed consent. Patients were not permitted to enroll in the SPHERE Per-AF study if they met any of the following exclusion criteria: 1. Continuous AF lasting for 12 months or longer. 2. AF secondary to electrolyte imbalance, thyroid disease, acute alcohol intoxication, or other reversible or non-cardiac cause. 3. Previous left atrial ablation or surgical procedure (including septal closure or left atrial appendage closure). 4. Valvular cardiac surgical/percutaneous procedure (e.g., ventriculotomy, PMA P240013: FDA Summary of Safety and Effectiveness Data 15 of 46 {15} atriotomy, and valve repair or replacement and presence of a prosthetic valve). 5. Any carotid stenting or endarterectomy. 6. Any cardiac procedure (surgical or percutaneous) or percutaneous coronary intervention within the 90 days prior to the initial procedure. 7. Coronary artery bypass graft (CABG) procedure within the 6 months prior to the initial procedure. 8. Awaiting cardiac transplantation or other cardiac surgery within the 12 months following the initial ablation procedure. 9. Presence of a permanent pacemaker, biventricular pacemaker, or any type of implantable cardiac defibrillator (with or without biventricular pacing function). 10. Documented thromboembolic event (stroke or transient ischemic attack) within 6 months (180 days) prior to the initial ablation procedure. 11. Documented left atrial thrombus on imaging. 12. History of blood clotting or bleeding abnormalities. 13. Any condition contraindicating chronic anticoagulation. 14. Myocardial infarction (MI) within the 3 months (90 days) prior to the initial procedure. 15. Body mass index >40 kg/m² 16. Left atrial diameter >55 mm (anterioposterior). 17. Diagnosed atrial myxoma. 18. Left ventricular ejection fraction (EF) < 35%. 19. Uncontrolled heart failure or NYHA Class III or IV heart failure. 20. Rheumatic heart disease. 21. Hypertrophic cardiomyopathy. 22. Unstable angina. 23. Moderate to severe mitral valve stenosis. 24. Severe mitral regurgitation (regurgitant volume ≥ 60 mL/beat, regurgitant fraction ≥ 50%, and/or effective regurgitant orifice area ≥ 0.40cm²). 25. Primary pulmonary hypertension. 26. Significant restrictive or obstructive pulmonary disease or chronic respiratory condition. 27. Renal failure requiring dialysis. 28. History of severe Gastroesophageal Reflux Disease (GERD) requiring surgical and/or mechanical intervention. 29. Acute illness, active systemic infection, or sepsis. 30. Contraindication to both computed tomography and magnetic resonance angiography. 31. Significant congenital anomaly or medical problem that, in the opinion of the investigator, would preclude enrollment in this study or compliance with follow-up requirements or would impact the scientific soundness of the clinical study results. 32. Any woman known to be pregnant or breastfeeding, or any woman of childbearing potential who is not on a reliable form of birth regulation method or abstinence. 33. Current or anticipated participation in any other clinical study of a drug, device, or biologic during the duration of the study not pre-approved by the Sponsor. 34. Presence of intramural thrombus, tumor, or other abnormality that precludes vascular access, catheter introduction, or manipulation. PMA P240013: FDA Summary of Safety and Effectiveness Data 16 of 46 {16} 35. Known drug or alcohol dependency. 36. Life expectancy less than 12 months. 37. Vulnerable subject (such as a prisoner or handicapped or mentally disabled person). 2. Follow-up Schedule All patients were preoperatively screened at a baseline visit. Postoperatively, all patients were evaluated prior to hospital discharge and were scheduled for follow-up evaluations at 10 days, 30 days, 75 days, 90 days, 180 days, and 360 days post-ablation. Table 3 below provides the schedule of events for the study. Adverse events and complications were recorded at all visits. PMA P240013: FDA Summary of Safety and Effectiveness Data 17 of 46 {17} Table 3. Schedule of evaluations and visits | | Enrollment / Baseline | Ablation | Pre-Discharge | Day 10 Call | Day 30 Visit | Day 75 Call^{1} | Day 90 Visit | Day 180 Visit | Day 360 Visit | Repeat Ablation | Unscheduled | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Window (days) | | 0 | | 7-13 | 14-42 | 60-90 | 76-104 | 150-210 | 330-390 | | | | Informed consent | X | | | | | | | | | | | | Adverse events | X | X | X | X | X | X | X | X | X | X | X | | Eligibility criteria | X | | | | | | | | | | | | Demographics | X | | | | | | | | | | | | Medical history / hospitalization | X | | | X | X | | X | X | X | X | X | | Cardiac medications | X | X | X | X | X | X | X | X | X | X | X | | Physical exam | X | | X | | X | | | | | | X | | 12-Lead ECG | X | | X | | X^{2} | X | X^{3} | X | 3 | | X | | Transthoracic echocardiogram (TTE) / Transesophageal echocardiogram (TEE) | X^{4} | | X^{5} | | | | | | | | | | Thrombus screening^{6} | X^{6} | | | | | | | | | X^{6} | | | Pregnancy test^{7} | 7 | | | | | | | | | X^{7} | | | Randomization | X | | | | | | | | | | | | Ablation | | X | | | | | | | | X | | | Phrenic nerve | | X | X^{8} | | X^{8} | | | | X^{8} | | | | NIH Stroke Scale | X | | X | | | | | | | | | | PV anatomy^{9} | | | | | X^{9} | X | X^{9} | X | 9 | | X^{9} | | Transtelephonic monitoring (TTM) transmission^{10} | | | | | | | X | X | X | | | | Holter Monitor | | | | | | | | X | X | | | | TTM/Holter review | | | | | | | | X | X | | | | Quality of Life | X | | | | | | | X | X | | | 1 Required if the Day 90 visit was not performed within the blanking period (on or before day 90) 2 Allowed to be performed by the referring cardiologist as part of a "hybrid" visit including an office visit with the referring cardiologist and a telephone call with the investigator 3 If the visit was a telehealth visit, transmission of TTM recordings was to be performed in lieu of 12-lead ECG 4 Within 6 months prior to the ablation procedure (including prior to enrollment as part of routine clinical evaluations) 5 TTE was required prior to discharge if the subject had symptoms suggestive of pericardial effusion and/or pericarditis 6 Thrombus screening was required the day before or the day of the ablation procedure 7 Pregnancy test was only required for women of childbearing potential 8 Phrenic nerve evaluation was required if new phrenic nerve injury was observed/suspected in the ablation procedure and unresolved at previous assessment(s) 9 Chest CT or MRI required if the subject experienced symptoms associated with PV stenosis 10 Subjects were instructed to transmit TTM recordings at least monthly and when AF-related symptoms occurred after the 90-day blanking period PMA P240013: FDA Summary of Safety and Effectiveness Data {18} 3. Clinical Endpoints i. Primary Safety Endpoint The primary safety endpoint is the incidence of the following device- or procedure-related serious adverse events (SAEs), as adjudicated by an independent and blinded Clinical Events Committee (CEC), following the index ablation procedure: Within 7 days of ablation procedure: - Death - Myocardial infarction - Phrenic nerve paralysis - Transient ischemic attack (TIA) - Stroke/cerebrovascular accident (CVA) - Thromboembolism - Major vascular access complications / bleeding - Heart block - Gastroparesis - Severe pericarditis - Hospitalization (initial and prolonged) due to cardiovascular or pulmonary AE² Within 30 days of ablation procedure: - Cardiac tamponade/perforation Within 90 days of ablation procedure: - Atrio-esophageal fistula Within 180 days of ablation procedure: - Pulmonary vein stenosis The study aimed to demonstrate noninferiority of the investigational device compared to the control device with respect to the primary safety endpoint. Primary safety noninferiority was tested with a noninferiority margin of 8%. ii. Primary Effectiveness Endpoint The primary effectiveness endpoint is freedom from documented recurrence of atrial fibrillation (AF), atrial flutter (AFL), or atrial tachycardia (AT) based on electrocardiographic data through 12-month follow-up and excluding a 90-day ² Excludes hospitalization due to AF/AFL/AT recurrence. PMA P240013: FDA Summary of Safety and Effectiveness Data 19 of 46 {19} blanking period. The following are considered primary effectiveness endpoint failures: - Inability to isolate all targeted pulmonary veins during the index procedure. - Ablation using devices other than the assigned study device for any left atrial ablation during the index procedure. - Any repeat ablation, surgical ablation, or arrhythmia surgery for treatment of recurrent AF/AFL/AT after the index procedure. - Documented AF/AFL/AT recurrence after the 90-day blanking period. - Class I or III AAD dose increase from the historic maximum ineffective dose (prior to the index procedure) or initiation of a new Class I or III AAD for treatment of AF/AFL/AT after the 90-day blanking period. - DC cardioversion for AF/AFL/AT after the 90-day blanking period. A documented recurrence of AF/AFL/AT based on electrocardiographic data was (a) an episode ≥ 30 seconds in duration documented by ECG, TTM, or Holter monitor or (b) an episode covering an entire 12-lead ECG recording lasting at least 10 seconds. Within the blanking period, recurrent arrhythmias could have been managed with antiarrhythmic drugs or cardioversions. Titration or initiation of Class I and III antiarrhythmic medications was allowed during the blanking period, but use of new or increased Class I or III antiarrhythmic medications after the blanking period was considered a primary effectiveness failure. Repeat ablation at any time after the index ablation procedure was considered a primary effectiveness failure. The study aimed to demonstrate noninferiority of the investigational device compared to the control device with respect to the primary effectiveness endpoint. Primary effectiveness noninferiority was tested with a noninferiority margin of 15%. iii. Secondary Endpoints Secondary endpoints included: - Incidence of early onset (within 7 days of the index ablation procedure), peri-procedural (>7 and ≤30 days), and late onset (>30 days) serious adverse events (SAEs) - Changes in Quality of Life (QOL) - Rate of acute ablation success - Use of antiarrhythmic drugs (AADs) - Ablation lesion sets delivered (ablation strategy) PMA P240013: FDA Summary of Safety and Effectiveness Data 20 of 46 {20} # B. Subject Accountability 477 subjects were enrolled in the study. Of those enrolled in the study, 37 were assigned to the roll-in cohort and had an ablation with the investigational device. Eight (8) subjects exited the study prior to randomization, and 432 were randomized. Of the randomized subjects, 12 exited the study prior to ablation, leaving 420 randomized subjects with an ablation. 444 subjects completed the study (see Figure 6). ![img-8.jpeg](img-8.jpeg) Figure 6: Subject Accountability PMA P240013: FDA Summary of Safety and Effectiveness Data {21} The analysis populations included: - Primary Analysis Cohort (PAC) $^{4}$ (N=420) includes subjects who were randomized and underwent insertion of the assigned study device. - Atrial Flutter Cohort $^{5}$ (N=212) includes subjects who were randomized and received a cavotricuspid isthmus ablation line with the assigned study device. # C. Visit and Rhythm Monitoring Compliance Summaries of the visit, Holter, TTM, and ECG compliance of the PAC subjects based on requirements outlined in the protocol are provided below. Holter, TTM, and ECG compliance represents those that have been received by the core lab and fully adjudicated. Table 4: Compliance Summary - Follow-up Visits | Visit Name | Investigational (N=212) | | | Control (N=208) | | | | --- | --- | --- | --- | --- | --- | --- | | | Visits Expected | Visits Occurred (%) | In-Window Visits (%) | Visits Expected | Visits Occurred (%) | In-Window Visits (%) | | Index Ablation | 212 | 212 (100%) | NA | 208 | 208 (100%) | NA | | Pre-Discharge | 212 | 211 (99.5%) | NA | 208 | 207 (99.5%) | NA | | Day 10 Call | 212 | 212 (100%) | 205 (96.7%) | 208 | 205 (98.6%) | 197 (94.7%) | | Day 30 Visit | 212 | 208 (98.1%) | 200 (94.3%) | 208 | 207 (99.5%) | 185 (88.9%) | | Day 75 Call1 | 153 | 131 (85.6%) | 130 (85.0%) | 145 | 121 (83.4%) | 117 (80.7%) | | Day 90 Visit | 212 | 205 (96.7%) | 190 (89.6%) | 207 | 199 (96.1%) | 181 (87.4%) | | Day 180 Visit | 212 | 205 (96.7%) | 179 (84.4%) | 205 | 202 (98.5%) | 183 (89.3%) | | Day 360 Visit | 210 | 209 (99.5%) | 188 (89.5%) | 201 | 199 (99.0%) | 179 (89.1%) | Day 75 Call was only required if Day 90 Visit was not going to occur within 90 days of the index ablation procedure. TTM compliance is summarized in Table 5. TTM compliance is calculated for each subject in the PAC as the number of effectiveness evaluation months in which a TTM recording was transmitted divided by the total number of effectiveness evaluation months for that subject (typically 9). Expected transmissions are estimated based on a 31-day month. The protocol required TTM recordings at least monthly after the 90-day blanking period. If a subject's actual number of TTM recordings for a month is greater than 1, it is counted as 1 for the purpose of compliance calculation. PMA P240013: FDA Summary of Safety and Effectiveness Data 22 of 46 {22} Table 5: Compliance Summary – TTM | Month | #Occurred / #Expected (%) | | | --- | --- | --- | | | Investigational (N=212) | Control (N=208) | | Overall compliant patient-months | 1592/1875 (84.9%) | 1507/1831 (82.3%) | | Month 4 | 187/212 (88.2%) | 174/207 (84.1%) | | Month 5 | 188/212 (88.7%) | 174/207 (84.1%) | | Month 6 | 181/212 (85.4%) | 169/207 (81.6%) | | Month 7 | 186/212 (87.7%) | 173/206 (84.0%) | | Month 8 | 181/212 (85.4%) | 174/205 (84.9%) | | Month 9 | 178/212 (84.0%) | 175/205 (85.4%) | | Month 10 | 183/211 (86.7%) | 172/205 (83.9%) | | Month 11 | 176/211 (83.4%) | 170/205 (82.9%) | | Month 12 | 132/181 (72.9%) | 126/184 (68.5%) | Holter and 12-lead ECG compliance are summarized in Table 6. The protocol allowed subjects to transmit ECG recordings with the TTM in place of the 12-lead ECG if the visit was telehealth. Among the PAC, 12-lead ECG was collected for 840 of these visits, whereas subjects used the TTM in place of the 12-lead ECG 222 times. Only TTMs collected within the associated visit windows were used in place of ECGs. Table 6: Compliance Summary – Holter and 12-Lead ECG | Visit | #Occurred / #Expected (%) | | | --- | --- | --- | | | Investigational (N=212) | Control (N=208) | | Day 180 Holter^{1} | 178/212 (84.0%) | 170/205 (86.8%) | | Day 360 Holter^{1} | 174/210 (82.9%) | 174/201 (86.6%) | | Day 90 12-Lead ECG + TTM^{2} | (149 + 30)/212 (84.4%) | (141 + 26)/207 (80.7%) | | Day 180 12-Lead ECG + TTM^{2} | (132 + 48)/212 (84.9%) | (130 + 48)/205 (86.8%) | | Day 360 12-Lead ECG + TTM^{2} | (146 + 42)/210 (89.5%) | (142 + 28)/201 (84.6%) | 1 Holters less than 18 hours do not contribute to Holter compliance. Data from all Holters regardless of duration are used for endpoint analysis. 2 If the visit is a telehealth visit, TTM is performed in lieu of 12-lead ECG and included in the count. ## D. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a persistent atrial fibrillation ablation treatment study performed in the US. The subject demographic and baseline health status characteristics of the treated primary analysis cohort subjects are shown in Table 7 below. Table 7. Subject Demographics and Baseline Characteristics | Parameter | Investigational (N = 212) | Control (N = 208) | | --- | --- | --- | | Age (years) | | | | Mean ± SD (N) | 67.8 ± 8.3 (212) | 66.7 ± 8.8 (208) | | Median (Min, Max) | 69.0 (28, 80) | 68.0 (38, 80) | | Sex | | | | Female | 73 (34.4%) | 61 (29.3%) | | Male | 139 (65.6%) | 147 (70.7%) | | Ethnicity | | | | Hispanic or Latino | 2 (0.9%) | 5 (2.4%) | | Not Hispanic or Latino | 206 (97.2%) | 201 (96.6%) | | Not Provided | 4 (1.9%) | 2 (1.0%) | PMA P240013: FDA Summary of Safety and Effectiveness Data {23} Table 7. Subject Demographics and Baseline Characteristics | Parameter | Investigational (N = 212) | Control (N = 208) | | --- | --- | --- | | Race | | | | American Indian or Alaska Native | 1 (0.5%) | 0 (0.0%) | | Asian | 4 (1.9%) | 4 (1.9%) | | Black or African American | 4 (1.9%) | 2 (1.0%) | | Native Hawaiian/Other Pacific Is. | 0 (0.0%) | 1 (0.5%) | | White | 199 (93.9%) | 199 (95.7%) | | Not provided | 4 (1.9%) | 2 (1.0%) | | Medical History | | | | Congestive heart failure | 36 (17.0%) | 26 (12.5%) | | Coronary Artery Disease | 37 (17.5%) | 35 (16.8%) | | Myocardial infarction | 9 (4.2%) | 7 (3.4%) | | Hypertension (systemic) | 160 (75.5%) | 157 (75.5%) | | Cardiomyopathy | 22 (10.4%) | 14 (6.7%) | | Atrial Flutter | 33 (15.6%) | 36 (17.3%) | | Atrial Tachycardia | 5 (2.4%) | 2 (1.0%) | | Stroke/TIA | 16 (7.5%) | 11 (5.3%) | | Chronic obstructive pulmonary disease (COPD) | 16 (7.5%) | 13 (6.3%) | | Diabetes | 38 (17.9%) | 34 (16.3%) | | Obstructive sleep apnea (OSA) | 47 (22.2%) | 57 (27.4%) | | Renal disease | 22 (10.4%) | 15 (7.2%) | | Other structural heart disease | 9 (4.2%) | 11 (5.3%) | | PerAF History | | | | Time from first diagnosis of PerAF (years) | | | | Mean ± SD (N) | 1.3 ± 2.6 (212) | 1.3 ± 2.2 (208) | | Median (Min, Max) | 0.5 (0, 28) | 0.5 (0, 18) | | Duration of longest PerAF episode (weeks) | | | | Mean ± SD (N) | 8.1 ± 9.9 (171) | 7.3 ± 9.0 (172) | | Median (Min, Max) | 4.0 (1, 44) | 3.0 (1, 45) | | Atrial Arrhythmia Cardioversion History | | | | Previous electrical cardioversion for atrial arrhythmias | 146 (68.9%) | 140 (67.3%) | | Previous pharmacological cardioversion for atrial arrhythmias | 13 (6.1%) | 15 (7.2%) | | Height (cm) | | | | Mean ± SD (N) | 175.1 ± 10.0 (211) | 176.7 ± 11.2 (207) | | Median (Min, Max) | 175.0 (140, 200) | 178.0 (137, 208) | | Weight (kg) | | | | Mean ± SD (N) | 92.5 ± 18.4 (211) | 95.3 ± 20.1 (207) | | Median (Min, Max) | 90.0 (53, 149) | 93.0 (53, 144) | | BMI (kg/m²) | | | | Mean ± SD (N) | 30.0 ± 4.8 (211) | 30.3 ± 4.9 (207) | | Median (Min, Max) | 29.7 (17, 40) | 30.3 (19, 40) | | LA Diameter (mm) | | | | Mean ± SD (N) | 43.0 ± 6.1 (210) | 44.0 ± 5.4 (208) | | Median (Min, Max) | 43.0 (22, 55) | 44.0 (24, 55) | | LVEF (%) | | | | Mean ± SD (N) | 57.7 ± 7.2 (212) | 55.5 ± 8.0 (208) | | Median (Min, Max) | 60.0 (35, 75) | 55.0 (35, 75) | | CHA2DS2-VASC Score | | | | Mean ± SD (N) | 2.4 ± 1.4 (212) | 2.3 ± 1.4 (207) | | Median (Min, Max) | 2.0 (0, 6) | 2.0 (0, 5) | | CHA2DS2-VASC Score | | | | 0 | 17 (8.0%) | 22 (10.6%) | | 1 | 36 (17.0%) | 39 (18.8%) | PMA P240013: FDA Summary of Safety and Effectiveness Data 24 of 46 {24} Table 7. Subject Demographics and Baseline Characteristics | Parameter | Investigational (N = 212) | Control (N = 208) | | --- | --- | --- | | ≥ 2 | 159 (75.0%) | 146 (70.2%) | | Heart Failure | | | | NYHA Class I | 27 (12.7%) | 28 (13.5%) | | NYHA Class II | 47 (22.2%) | 36 (17.3%) | | Not Available | 1 (0.5%) | 0 (0.0%) | | No signs of heart failure | 137 (64.6%) | 144 (69.2%) | | Failed AAD Type^{1} | | | | Class I | 65 (30.7%) | 66 (31.7%) | | Class II | 98 (46.2%) | 91 (43.8%) | | Class III | 147 (69.3%) | 133 (63.9%) | | Class IV | 18 (8.5%) | 17 (8.2%) | 1 Percent of total subjects having one or more failed medications within each AAD Class ## E. Safety and Effectiveness Results ### 1. Primary Analyses #### i. Primary Safety Endpoint Among the 420 primary analysis cohort subjects, the primary safety endpoint occurred in 3 (1.4%) subjects in the investigational arm and 2 (1.0%) subjects in the control arm. The three primary safety events in the investigational arm were hospitalizations due to cardiovascular or pulmonary adverse events including chronic obstructive pulmonary disease exacerbation, pulmonary edema, and hemoptysis. In the control arm, the two primary safety endpoints were hospitalizations due to cardiovascular or pulmonary adverse events including one for hypervolemia and one for hypoxia. The difference in the incidence of primary safety events between the investigational and control arms was 0.5% (90% CI: [-2.8%, 3.7%]). Based on the prespecified safety non-inferiority margin of 8%, the investigational device was non-inferior to the control device, p<0.0001. A summary of the primary safety endpoint events and non-inferiority testing are summarized in Table 8 and Table 9, respectively. Table 8. Primary Safety Endpoint Components | Primary Safety Endpoint Event | # Events (# Subjects, % Subjects) | | | --- | --- | --- | | | Investigational (N=212) | Control (N=208) | | Primary Safety Endpoint Failure | 3 (3, 1.4%) | 2 (2, 1.0%) | | Within 7 days of procedure | | | | Death | 0 (0, 0.0%) | 0 (0, 0.0%) | | Myocardial infarction | 0 (0, 0.0%) | 0 (0, 0.0%) | | Phenic nerve paralysis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Transient ischemic attack (TIA) | 0 (0, 0.0%) | 0 (0, 0.0%) | | Stroke/cerebrovascular accident (CVA) | 0 (0, 0.0%) | 0 (0, 0.0%) | | Thromboembolism | 0 (0, 0.0%) | 0 (0, 0.0%) | | Major vascular access complications / bleeding | 0 (0, 0.0%) | 0 (0, 0.0%) | | Heart block | 0 (0, 0.0%) | 0 (0, 0.0%) | | Gastroparesis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Severe pericarditis | 0 (0, 0.0%) | 0 (0, 0.0%) | PMA P240013: FDA Summary of Safety and Effectiveness Data {25} Table 8. Primary Safety Endpoint Components | Primary Safety Endpoint Event | # Events (# Subjects, % Subjects) | | | --- | --- | --- | | | Investigational (N=212) | Control (N=208) | | Hospitalization (initial or prolonged) due to cardiovascular or pulmonary AE | 3 (3, 1.4%) | 2 (2, 1.0%) | | Within 30 days of procedure | | | | Cardiac tamponade/perforation | 0 (0, 0.0%) | 0 (0, 0.0%) | | Within 90 days of procedure | | | | Atrio-esophageal fistula | 0 (0, 0.0%) | 0 (0, 0.0%) | | Within 180 days of procedure | | | | Pulmonary vein stenosis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Table 9. Primary Safety Endpoint – Farrington Manning Non-Inferiority Test | | | | | | --- | --- | --- | --- | --- | | Parameter | Number, Percent of Failures (90% CI) | | Difference (90% CI) | One-sided p-value (Non-Inferiority Margin = 8%) | | | Investigational (N=212) | Control (N=208) | Investigational – Control | | | Primary Safety Endpoint Failure | 3, 1.4% (0.4%, 3.6%) | 2, 1.0% (0.2%, 3.0%) | 0.5% (-2.8%, 3.7%) | <0.0001 | ii. Primary Effectiveness Endpoint Of the 420 subjects in the primary analysis cohort, 412 completed the study or had a primary effectiveness failure and were included in the final analysis of the primary endpoint (210 subjects in the investigational arm, 202 subjects in the control arm). Freedom from primary effectiveness endpoint failure for the investigational arm was 73.8% compared to 65.5% in the control arm. The difference in primary effectiveness endpoint success for the investigational device and the control device was 8.0% (95% CI: [-0.9%, 16.8%]). Based on the prespecified effectiveness non-inferiority margin of 15%, the investigational device was non-inferior to the control device, p<0.0001. A summary of the primary effectiveness endpoint and non-inferiority testing are summarized in Table 10 and Table 11, respectively. PMA P240013: FDA Summary of Safety and Effectiveness Data {26} Table 10. Primary Effectiveness Endpoint and Failure Modes | Parameter | Investigational (N=210) | Control (N=202) | | --- | --- | --- | | Primary Effectiveness Endpoint Success | 155 (73.8%) | 133 (65.8%) | | Primary Effectiveness Endpoint Failure¹ | 55 (26.2%) | 69 (34.2%) | | Inability to isolate all targeted pulmonary veins during the index procedure | 0 (0.0%) | 0 (0.0%) | | Any left atrial ablation done with non-assigned study device during the index procedure | 0 (0.0%) | 2 (1.0%) | | Any repeat ablation or surgery for AF/AFL/AT recurrence after the index procedure | 10 (4.8%) | 17 (8.4%) | | DC cardioversion for AF/AFL/AT recurrence during the effectiveness evaluation period | 13 (6.2%) | 13 (6.4%) | | Documented AF/AFL/AT recurrence during the effectiveness evaluation period | 49 (23.3%) | 55 (27.2%) | | Class I/III AAD dose increase from the historic maximum ineffective dose or initiation of new class I/III AAD during the effectiveness evaluation period | 8 (3.8%) | 15 (7.4%) | ¹ Failure modes are not mutually exclusive since the same subject can experience multiple failure modes. Table 11. Primary Effectiveness Endpoint Result | Parameter | Number, Percent of Successes (95% CI) | | Difference (95% CI) | One-sided p-value (Non-Inferiority Margin = 15%) | | --- | --- | --- | --- | --- | | | Investigational (N=210) | Control (N=202) | Investigational – Control | | | Primary Effectiveness Endpoint Success | 155, 73.8% (67.5%, 79.3%) | 133, 65.8% (59.1%, 72.0%) | 8.0% (-0.9%, 16.8%) | <0.0001 | Kaplan-Meier estimates of freedom from primary effectiveness endpoint failure are presented in Figure 7 for the investigational arm (blue) and the control arm (red). The log-rank test $p$-value was 0.064. Note that the window for the Day 360 visit extended from study day 330 to study day 390, so data censoring during the last 30 days is expected, accounting for the low number at risk at day 360. In case of failure at the Day 360 visit, within the visit window but beyond study day 360, the date of failure was set to study day 360 so that the failure was included in the Kaplan-Meier analysis. PMA P240013: FDA Summary of Safety and Effectiveness Data 27 of 46 {27} ![img-9.jpeg](img-9.jpeg) Figure 7: Primary Effectiveness Endpoint: Kaplan-Meier Plot Population: PAC # 2. Secondary Analyses (Sequential Superiority Testing) Prespecified superiority testing was performed for four endpoints including three procedural times and the primary effectiveness endpoint. Energy application time was 29.2 minutes less (95% CI: [-31.7, -26.8]), treatment time was 26.8 minutes less (95% CI: [-32.2, -21.4]), and total procedure time was 25.1 minutes less (95% CI: [-33.0, -17.3]) in the investigational arm compared to the control arm. The investigational device was superior for each of these three endpoints compared to the control device, with one-sided $p < 0.0001$ for each of the three hypothesis tests. The null hypothesis of no difference between the underlying rate of the primary effectiveness endpoint in the two arms was not rejected, with one-sided $p = 0.039$ $\alpha = 0.025$ . While the observed rate of primary effectiveness endpoint success was numerically higher with the investigational device, primary effectiveness with the investigational device was not shown to be superior to the control device. PMA P240013: FDA Summary of Safety and Effectiveness Data {28} Table 12. Sequential Superiority Testing | Parameter | Mean ± SD (N) or Proportion of subjects (95% CI) (N) | | Difference (95% CI) | One-sided p-value | α-level | Success (Yes/No) | | --- | --- | --- | --- | --- | --- | --- | | | Investigational | Control | Investigational - Control | | | | | Energy application time (min) | 7.1 ± 2.0 (212) | 36.4 ± 17.7 (206) | -29.2 (-31.7, -26.8) | <0.0001 | 0.005 | Yes | | Treatment time (min)1 | 46.7 ± 20.0 (212) | 73.5 ± 34.4 (208) | -26.8 (-32.2, -21.4) | <0.0001 | 0.005 | Yes | | Procedure time (min)2 | 100.9 ± 30.8 (212) | 126.1 ± 49.2 (208) | -25.1 (-33.0, -17.3) | <0.0001 | 0.005 | Yes | | Primary Effectiveness Endpoint Success | 73.8% (67.5%, 79.3%) (210) | 65.8% (59.1%, 72.0%) (202) | 8.0% (-0.9%, 16.8%) | 0.039 | 0.025 | No | 1 Treatment time is defined as the time from first ablation to last ablation. 2 Procedure time is defined as the time from venous access to sheath removal. # 3. Additional Analyses # i. Secondary Safety Endpoint A total of 123 serious adverse events (57 in the investigational arm, 66 in the control arm) occurred during or post index ablation procedure in subjects in the PAC. Table 13 summarizes the incidence of early onset (within 7 days of the index ablation procedure) SAEs, incidence of peri-procedural ( $>7$ and $\leq 30$ days) SAEs, and incidence of late onset ( $>30$ days) SAEs stratified by treatment group. Table 13. Secondary Safety Endpoint: SAEs by Timepoint | Parameter | # Events (#, % of Subjects) | | | --- | --- | --- | | | Investigational (N=212) | Control (N=208) | | SAEs during procedure or ≤ 7 days after procedure | 9 (7, 3.3%) | 8 (8, 3.8%) | | SAEs 8 – 30 days after procedure | 5 (4, 1.9%) | 4 (4, 1.9%) | | SAEs > 30 days after procedure | 43 (28, 13.2%) | 54 (33, 15.9%) | # ii. Adverse events Adverse events were collected starting at the time of signing the informed consent form through the duration of the subject's participation in the study. There were no unanticipated adverse device effects reported in the study. All adverse events related to the primary safety endpoint were reviewed and adjudicated by an independent and blinded Clinical Events Committee (CEC). A total of 271 adverse events were reported in the study. 126 were serious adverse events, and 87 were classified as being related or possibly related to the study device and/or procedure. Table 14 summarizes the 16 serious adverse events related or possibly related to the study device and/or procedure. Adverse events are reported per the Medical Dictionary for Regulatory Activities (MedDRA) preferred term. PMA P240013: FDA Summary of Safety and Effectiveness Data {29} Table 14. Primary Analysis Cohort: Procedure or Device Related Serious Adverse Events During or After the Index Ablation Procedure Summary by MedDRA Category | | | # Events (# Subjects, % Subjects) | | | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Investigational (N=212) | Control (N=208) | | Total | Total | 9 (8, 3.8%) | 7 (7, 3.4%) | | Cardiac disorders | Bradycardia | 2 (2, 0.9%) | 0 (0, 0.0%) | | | Myocardial infarction | 0 (0, 0.0%) | 1 (1, 0.5%) | | | Pericardial effusion | 1 (1, 0.5%)1 | 0 (0, 0.0%) | | | Pericarditis | 0 (0, 0.0%) | 1 (1, 0.5%) | | Gastrointestinal disorders | Oesophageal mucosa erythema | 0 (0, 0.0%) | 1 (1, 0.5%) | | Infections and infestations | Sepsis | 1 (1, 0.5%) | 1 (1, 0.5%) | | Injury, poisoning and procedural complications | Vascular access site haemorrhage | 1 (1, 0.5%) | 0 (0, 0.0%) | | Investigations | Troponin increased | 1 (1, 0.5%) | 0 (0, 0.0%) | | Metabolism and nutrition disorders | Hypervolaemia | 0 (0, 0.0%) | 1 (1, 0.5%) | | Respiratory, thoracic and mediastinal disorders | Chronic obstructive pulmonary disease | 1 (1, 0.5%) | 0 (0, 0.0%) | | | Haemoptysis | 1 (1, 0.5%) | 0 (0, 0.0%) | | | Hypoxia | 0 (0, 0.0%) | 1 (1, 0.5%) | | | Pleuritic pain | 0 (0, 0.0%) | 1 (1, 0.5%) | | | Pulmonary oedema | 1 (1, 0.5%) | 0 (0, 0.0%) | 1 Subject had a history of pericardial effusion (diagnosed in 2021). In May 2023, 284 days post index ablation procedure, pericardial effusion was noted after subject underwent a TEE after presenting with dyspnea and lower extremity edema. Seven (7) deaths occurred in the study, of which one was prior to the index ablation procedure, one was in a Roll-In subject, and five were in the primary analysis cohort. None of the deaths were reported to be device- or procedure-related. iii. Secondary Effectiveness Endpoint – Quality of Life (QOL) The Atrial Fibrillation Effect on Quality-of-Life (AFEQT) score is a QOL measure specific to atrial fibrillation, with a range of 0 (complete disability) to 100 (no disability). The SF-12v2 Health Survey is a validated general QOL survey that can be summarized using two overall scores, the Mental Component Summary and the Physical Component Summary. Each score ranges from 0 to 100, with higher scores indicating improved QOL. The AFEQT Questionnaire and the SF-12v2 Health Survey were performed at baseline, Day 180 and Day 360 follow-up timepoints. In both the investigational and control arms, there was a trend of increased scores (improved quality of life) on both the AFEQT and SF-12v2 Health Survey at Day 180 and Day 360 follow-up when compared to baseline assessments. PMA P240013: FDA Summary of Safety and Effectiveness Data 30 of 46 {30} ![img-10.jpeg](img-10.jpeg) Figure 8: AFEQT Total Score Trend ![img-11.jpeg](img-11.jpeg) | N | 212 | 196 | 207 | | --- | --- | --- | --- | | Mean | 66.4 | 90.0 | 89.0 | | Std Dev | 21.5 | 13.2 | 13.7 | | N | 208 | 198 | 194 | | --- | --- | --- | --- | | Mean | 68.5 | 88.7 | 90.9 | | Std Dev | 20.3 | 14.7 | 13.3 | ![img-12.jpeg](img-12.jpeg) Figure 9: SF-12v2 Mental Component Score Trend ![img-13.jpeg](img-13.jpeg) PMA P240013: FDA Summary of Safety and Effectiveness Data {31} ![img-14.jpeg](img-14.jpeg) Baseline Day 180 Day 360 Figure 10: SF-12v2 Physical Component Score Trend | Baseline | Day 180 | Day 360 | | --- | --- | --- | | N | 198 | 193 | 193 | | --- | --- | --- | --- | | Mean | 44.8 | 49.6 | 49.8 | | Std Dev | 9.0 | 9.0 | 8.8 | ![img-15.jpeg](img-15.jpeg) Baseline Day 180 Day 360 | N | 198 | 193 | 193 | | --- | --- | --- | --- | | Mean | 44.8 | 49.6 | 49.8 | | Std Dev | 9.0 | 9.0 | 8.8 | iv. Secondary Effectiveness Endpoint - Acute Procedural Success Table 15 shows the rate of acute procedural success with the assigned study device, defined as confirmation of entrance block in all targeted pulmonary veins, rate of pulmonary vein isolation on a per-vein basis, and rate of acute block across linear ablations. Rate of acute procedural success, defined as isolation of all targeted pulmonary veins using only the assigned study catheter, was $100\%$ in the investigational arm and $99.5\%$ in the control arm, with one control subject requiring use of a non-study catheter to achieve isolation of the left superior pulmonary vein. On a per-vein basis, pulmonary vein isolation was achieved with the assigned study catheter in $100\%$ and $99.9\%$ of the investigational and control arm subjects, respectively. Additional linear ablation was only required for treatment of documented macroreentrant tachycardias, and empiric linear lesions were discouraged. Acute procedural success for linear ablations is defined as confirmed block across the lesion using ablation with only the assigned study catheter. There were 115 cavotricuspid isthmus (CTI) lines treated in the investigational arm and 97 in the control arm. Rate of acute block across CTI lines was $100\%$ in the investigational and control arms. Rate of acute block across mitral isthmus lines was $100\%$ in the investigational arm and $95\%$ in the control arm, with one control subject requiring the additional use of alcohol ablation to achieve block in the Vein of Marshall. There were 198 subjects with treated LA roof, posterior or inferior lines in the PMA P240013: FDA Summary of Safety and Effectiveness Data {32} investigational arm and 137 in the control arm. Rate of acute block across these lines were 100% in both arms. Table 15. Secondary Effectiveness: Acute Ablation Result (Isolation/Block with Assigned Study Device) | Parameter | Numerator / Denominator (%) | | Difference | | --- | --- | --- | --- | | | Investigational | Control | Investigational - Control | | Acute pulmonary vein isolation with the assigned study device (per subject)^{1} | 212/212 (100%) | 207/208 (99.5%) | 0.5% | | Pulmonary veins isolated with the assigned study device (per vein)^{2} | 844/844 (100%) | 828/829 (99.9%) | 0.1% | | Cavotricuspid isthmus line with the assigned study device (per subject)^{3} | 115/115 (100%) | 97/97 (100%)^{4} | 0.0% | | Mitral isthmus line with the assigned study device (per subject)^{5} | 72/72 (100%) | 21/22 (95.5%) | 4.5% | | LA roof, posterior, or inferior line with the assigned study device (per subject)^{6} | 198/198 (100%) | 137/137 (100%) | 0.0% | 1 Percent of subjects with confirmed entrance block in all targeted PVs out of all subjects with PVI attempted. 2 Percent of pulmonary veins isolated (i.e. with confirmed entrance block) out of all pulmonary veins targeted. 3 Percent of subjects with confirmed bidirectional block out of all subjects with cavotricuspid isthmus line targeted. 4 In one control patient the cavotricuspid isthmus line was blocked with an RF catheter that was not the assigned study device. No attempt was made to use the control device for this lesion. Lesion excluded from this table. 5 Percent of subjects with confirmed block (bidirectional, or unidirectional if bidirectional block was not tested) out of all subjects with mitral isthmus line targeted. 6 Percent of subjects in whom LA roof, posterior or inferior line was targeted with confirmed block across all such lines (bidirectional, or unidirectional if bidirectional block was not tested). Program Name: SEE-AcuteAbl Res.sas v. Secondary Effectiveness Endpoint – Use of Antiarrhythmic Drugs Table 16 summarizes the use of Class I or III antiarrhythmic drugs at baseline and at the Day 360 visit or study exit. A trend of decreased antiarrhythmic drug use was observed in both study arms. Table 16. Secondary Effectiveness: Class I or III Antiarrhythmic Drug Usage Summary during Effectiveness Evaluation Period | Parameter | At Baseline | | At Day 360 or Study Exit | | | --- | --- | --- | --- | --- | | | # Subjects (%) | | # Subjects (%) | | | | Investigational (N=212) | Control (N=208) | Investigational (N=212) | Control (N=208) | | Any Class I or III | 143 (67.5%) | 135 (64.9%) | 37 (17.5%) | 33 (15.9%) | | Any Class I | 41 (19.3%) | 39 (18.8%) | 12 (5.7%) | 9 (4.3%) | | Any Class III | 103 (48.6%) | 96 (46.2%) | 25 (11.8%) | 24 (11.5%) | 4. Subgroup Analyses The subgroup analysis results (as shown in Table 17 and Table 18) do not suggest heterogeneity of treatment effect by sex, age, or left atrial diameter. PMA P240013: FDA Summary of Safety and Effectiveness Data 33 of 46 {33} Table 17. Primary Safety Endpoint Subgroup Analysis | Parameter | Category | #Failures / #Subjects (%) | | Difference (95% CI) | Heterogeneity Test p-value | | --- | --- | --- | --- | --- | --- | | | | Investigational | Control | Investigational - Control | | | Sex | Female | 2/73 (2.7%) | 0/61 (0.0%) | 2.7% (-3.3%, 9.5%) | 0.31 | | | Male | 1/139 (0.7%) | 2/147 (1.4%) | -0.6% (-4.2%, 2.7%) | | | Age | <65 | 1/61 (1.6%) | 2/73 (2.7%) | -1.1% (-8.1%, 6.3%) | 0.32 | | | ≥65 | 2/151 (1.3%) | 0/135 (0.0%) | 1.3% (-1.5%, 4.7%) | | | LA Diameter (mm) | <45 | 2/125 (1.6%) | 0/106 (0.0%) | 1.6% (-1.9%, 5.7%) | 0.34 | | | ≥45 | 1/85 (1.2%) | 2/102 (2.0%) | -0.8% (-5.9%, 4.6%) | | Table 18. Primary Effectiveness Endpoint Subgroup Analysis | Parameter | Category | #Successes / #Subjects (%) | | Difference (95% CI) | Heterogeneity Test p-value | | --- | --- | --- | --- | --- | --- | | | | Investigational | Control | Investigational - Control | | | Sex | Female | 50/72 (69.4%) | 31/59 (52.5%) | 16.9% (0.1%, 33.0%) | 0.30 | | | Male | 105/138 (76.1%) | 102/143 (71.3%) | 4.8% (-5.6%, 15.0%) | | | Age | <65 | 50/61 (82.0%) | 53/71 (74.6%) | 7.3% (-7.1%, 21.2%) | 0.98 | | | ≥65 | 105/149 (70.5%) | 80/131 (61.1%) | 9.4% (-1.7%, 20.4%) | | | LA Diameter (mm) | <45 | 100/124 (80.6%) | 72/105 (68.6%) | 12.1% (0.8%, 23.4%) | 0.22 | | | ≥45 | 55/84 (65.5%) | 61/97 (62.9%) | 2.6% (-11.5%, 16.4%) | | # 5. Atrial Flutter Post Hoc Analyses The study protocol required CTI linear ablation in cases with documented typical right AFL either prior to or during the index ablation procedure. The protocol also required confirmation of bidirectional conduction block across each line created during the index procedure. Post-hoc analyses of treatment of CTI-dependent AFL were conducted using the atrial flutter cohort. The atrial flutter cohort consists of a total of 212 randomized subjects (115 investigational arm, 97 control arm) who received a CTI ablation line with the assigned study device, of whom 8 subjects exited the study early. Table 20 summarizes the arrhythmia history and site reported justification for CTI line. # i. Demographics and Baseline Parameters The subject demographic, baseline health status characteristics, and rationale for CTI line for of the treated atrial flutter cohort subjects are shown in Table 19 and Table 20. Table 19. Subject Demographics and Baseline Characteristics Population: Atrial Flutter Cohort | Parameter | Investigational (N = 115) | Control (N = 97) | | --- | --- | --- | | Age (years) | | | | Mean ± SD (N) | 67.9 ± 8.0 (115) | 66.9 ± 8.5 (97) | | Median (Min, Max) | 69.0 (28, 80) | 68.0 (44, 80) | | Sex | | | | Female | 42 (36.5%) | 29 (29.9%) | PMA P240013: FDA Summary of Safety and Effectiveness Data {34} Table 19. Subject Demographics and Baseline Characteristics Population: Atrial Flutter Cohort | Parameter | Investigational (N = 115) | Control (N = 97) | | --- | --- | --- | | Male | 73 (63.5%) | 68 (70.1%) | | Ethnicity | | | | Hispanic or Latino | 0 (0.0%) | 2 (2.1%) | | Not Hispanic or Latino | 111 (96.5%) | 94 (96.9%) | | Not Provided | 4 (3.5%) | 1 (1.0%) | | Race | | | | American Indian or Alaska Native | 1 (0.9%) | 0 (0.0%) | | Asian | 3 (2.6%) | 1 (1.0%) | | Black or African American | 2 (1.7%) | 2 (2.1%) | | Native Hawaiian/Other Pacific Is. | 0 (0.0%) | 0 (0.0%) | | White | 109 (94.8%) | 93 (95.9%) | | Not provided | 0 (0.0%) | 1 (1.0%) | | Medical History | | | | Congestive heart failure | 13 (11.3%) | 14 (14.4%) | | Coronary Artery Disease | 18 (15.7%) | 15 (15.5%) | | Myocardial infarction | 5 (4.3%) | 3 (3.1%) | | Hypertension (systemic) | 84 (73.0%) | 73 (75.3%) | | Cardiomyopathy | 6 (5.2%) | 5 (5.2%) | | Atrial Flutter | 23 (20.0%) | 26 (26.8%) | | Atrial Tachycardia | 3 (2.6%) | 0 (0.0%) | | Stroke/TIA | 9 (7.8%) | 9 (9.3%) | | Chronic obstructive pulmonary disease (COPD) | 8 (7.0%) | 8 (8.2%) | | Diabetes | 17 (14.8%) | 17 (17.5%) | | Obstructive sleep apnea (OSA) | 18 (15.7%) | 26 (26.8%) | | Renal disease | 8 (7.0%) | 6 (6.2%) | | Other structural heart disease | 2 (1.7%) | 0 (0.0%) | | PerAF History | | | | Time from first diagnosis of PerAF (years) | | | | Mean ± SD (N) | 1.1 ± 1.9 (115) | 1.2 ± 2.1 (97) | | Median (Min, Max) | 0.4 (0, 12) | 0.5 (0, 11) | | Typical AFL History | | | | Time from first diagnosis of typical AFL (years) | | | | Mean ± SD (N) | 1.3 ± 2.1 (23) | 1.9 ± 3.4 (26) | | Median (Min, Max) | 0.5 (0, 8) | 0.2 (0, 11) | | BMI (kg/m²) | | | | Mean ± SD (N) | 29.5 ± 4.9 (114) | 30.4 ± 5.1 (96) | | Median (Min, Max) | 29.0 (17, 40) | 30.4 (19, 40) | | LA Diameter (mm) | | | | Mean ± SD (N) | 42.8 ± 6.3 (115) | 43.4 ± 5.6 (97) | | Median (Min, Max) | 43.0 (22, 55) | 43.5 (24, 54) | | LVEF (%) | | | | Mean ± SD (N) | 58.2 ± 6.8 (115) | 55.0 ± 8.6 (97) | | Median (Min, Max) | 60.0 (35, 74) | 55.0 (35, 75) | | CHA2DS2-VASC Score | | | | Mean ± SD (N) | 2.5 ± 1.4 (115) | 2.4 ± 1.3 (96) | | Median (Min, Max) | 3.0 (0, 6) | 3.0 (0, 5) | | CHA2DS2-VASC Score | | | | 0 | 9 (7.8%) | 8 (8.2%) | | 1 | 19 (16.5%) | 17 (17.5%) | | ≥ 2 | 87 (75.7%) | 71 (73.2%) | | Heart Failure | | | | NYHA Class I | 17 (14.8%) | 14 (14.4%) | PMA P240013: FDA Summary of Safety and Effectiveness Data {35} Table 19. Subject Demographics and Baseline Characteristics Population: Atrial Flutter Cohort | Parameter | Investigational (N = 115) | Control (N = 97) | | --- | --- | --- | | NYHA Class II | 25 (21.7%) | 22 (22.7%) | | Not Available | 0 (0.0%) | 0 (0.0%) | | No signs of heart failure | 6 (5.2%) | 4 (4.1%) | | No history of heart failure | 67 (58.3%) | 57 (58.8%) | | Failed AAD Type^{1} for treatment of PerAF | | | | Class I | 29 (25.2%) | 21 (21.6%) | | Class II | 42 (36.5%) | 34 (35.1%) | | Class III | 89 (77.4%) | 70 (72.2%) | | Class IV | 12 (10.4%) | 6 (6.2%) | 1 Percent of total subjects having one or more failed medications within each AAD Class Table 20: Subject Rationale for CTI Line: Arrhythmia History, Procedural AFL, Site Reported Justification Population: Atrial Flutter Cohort | Parameter | Investigational (N=115) | Control (N=97) | | --- | --- | --- | | History of typical atrial flutter - or - Atrial flutter observed prior to index ablation procedure - or - Site reported atrial flutter as justification for CTI line | 84 (73.0%) | 72 (74.2%) | | History of Typical Atrial Flutter | 23 (20.0%) | 26 (26.8%) | | Atrial Flutter observed during index ablation procedure prior to first ablation | 7 (6.1%) | 10 (10.3%) | | Typical Atrial Flutter | 5 (4.3%) | 10 (10.3%) | | Atypical Atrial Flutter | 1 (0.9%) | 0 (0.0%) | | Atrial Flutter - Unspecified | 1 (0.9%) | 0 (0.0%) | | Justification for CTI Line during index ablation procedure | | | | Typical Atrial Flutter | 7 (6.1%) | 11 (11.3%) | | Atypical Atrial Flutter | 1 (0.9%) | 1 (1.0%) | | Atrial Flutter - Unspecified | 71 (61.7%) | 59 (60.8%) | | Empirical justification for CTI Line | 36 (31.3%) | 26 (26.8%) | | N/A justification for CTI Line | 0 (0.0%) | 0 (0.0%) | ii. Atrial Flutter Ablation Safety Endpoint The post hoc atrial flutter ablation safety endpoint was a composite endpoint based on the incidence of the device- or procedure-related serious adverse events listed in Table 21 following the index ablation procedure. Of the subjects in the atrial flutter cohort, one subject from each treatment arm met the atrial flutter ablation safety endpoint. One subject from the investigational arm was hospitalized for chronic obstructive pulmonary disease exacerbation, and one subject from the control arm was hospitalized for hypoxia. The incidence of these atrial flutter safety events was similar between the study arms, occurring in 0.9% vs. 1.0% of subjects in the investigational and control arm, respectively. PMA P240013: FDA Summary of Safety and Effectiveness Data 36 of 46 {36} Population: Atrial Flutter Cohort Table 21. Atrial Flutter Safety Events | | # Events (# Subjects, % Subjects) | | | --- | --- | --- | | Primary Safety Endpoint Event | Investigational (N=115) | Control (N=97) | | Primary Safety Endpoint Failure | 1 (1, 0.9%) | 1 (1, 1.0%) | | Within 7 days of procedure | | | | Death | 0 (0, 0.0%) | 0 (0, 0.0%) | | Myocardial infarction | 0 (0, 0.0%) | 0 (0, 0.0%) | | Phrenic nerve paralysis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Transient ischemic attack | 0 (0, 0.0%) | 0 (0, 0.0%) | | Stroke / cerebrovascular accident | 0 (0, 0.0%) | 0 (0, 0.0%) | | Thromboembolism | 0 (0, 0.0%) | 0 (0, 0.0%) | | Major vascular access complications / bleeding | 0 (0, 0.0%) | 0 (0, 0.0%) | | Heart block | 0 (0, 0.0%) | 0 (0, 0.0%) | | Gastroparesis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Severe pericarditis | 0 (0, 0.0%) | 0 (0, 0.0%) | | Hospitalization (initial or prolonged) due to cardiovascular or pulmonary AE¹ | 1 (1, 0.9%) | 1 (1, 1.0%) | | Within 30 days of procedure | | | | Cardiac tamponade/perforation | 0 (0, 0.0%) | 0 (0, 0.0%) | ¹ Excludes hospitalization due to AF/AFL/AT recurrence Population: Atrial Flutter Cohort Table 22. Atrial Flutter Safety Event Rate | Parameter | Number, Percent of Failures | | Difference | | --- | --- | --- | --- | | | Investigational (N=115) | Control (N=97) | Investigational - Control | | CTI Safety Endpoint Failure | 1, 0.9% | 1, 1.0% | -0.2% | ### iii. Acute Effectiveness of Atrial Flutter Ablation The post hoc analysis of atrial flutter acute ablation effectiveness was based on acute procedural success, defined as completion of the cavotricuspid isthmus ablation line with only the assigned study device followed by confirmation of bidirectional conduction block. Acute procedural success was demonstrated in all subjects in the atrial flutter cohort. In investigational cohort subjects whom a cavotricuspid isthmus line was delivered, RF alone was used in 67.0% of these lines, while a combination of RF and PF energy was used in 30.4%, and PF alone was used for the remaining 2.6%. Population: Atrial Flutter Cohort Table 23. Atrial Flutter Acute Ablation Outcomes Effectiveness | | # Subjects/# Subjects Ablated (% Subjects) | | | --- | --- | --- | | Parameter | Investigational (N=115) | Control (N=97) | | Atrial flutter acute ablation effectiveness success | 115/115 (100%) | 97/97 (100%) | PMA P240013: FDA Summary of Safety and Effectiveness Data {37} Population: Atrial Flutter Cohort Table 24. Atrial Flutter Acute Ablation Effectiveness Success Rate | Parameter | Number, Percent of Successes | | Difference | | --- | --- | --- | --- | | | Investigational (N=115) | Control (N=97) | Investigational - Control | | CTI Acute Effectiveness Success | 115, 100% | 97, 100% | 0.0% | iv. Chronic Effectiveness of Atrial Flutter Ablation The atrial flutter cohort post hoc chronic effectiveness analysis presented in Table 25 evaluates freedom from documented recurrence of AFL based on electrocardiographic data. The following are considered atrial flutter ablation chronic effectiveness failures: - Documented AFL recurrence after the index procedure. - Any repeat ablation for AF/AFL/AT recurrence with documented CTI reconnection after the index procedure - DC cardioversion for AFL recurrence after the index procedure There was one subject in the investigational arm, and six subjects in the control arm who did not complete the Day 360 follow-up and did not experience a chronic effectiveness failure event. These subjects were considered to be missing the chronic effectiveness outcome and therefore were not included in the analysis presented in Table 26. The observed rate of chronic effectiveness was higher in the investigational arm than in the control arm. Freedom from chronic effectiveness endpoint failure for the investigational arm was $86.8\%$ compared to $76.9\%$ in the control arm. The difference in chronic effectiveness endpoint success for the investigational and control device was $9.9\%$ . Population: Atrial Flutter Cohort Table 25. Chronic Effectiveness Outcomes and Failure Modes | Parameter | Investigational (N=114) | Control (N=91) | | --- | --- | --- | | Chronic Effectiveness Success | 99 (86.8%) | 70 (76.9%) | | Chronic Effectiveness Failure1 | 15 (13.2%) | 21 (23.1%) | | Documented AFL after the index procedure | 13 (11.4%) | 16 (17.6%) | | Within 90 days | 0 (0.0%) | 4 (4.4%) | | Within 180 days | 5 (4.4%) | 5 (5.5%) | | Within 360 days | 8 (7.0%) | 7 (7.7%) | | Any repeat ablation for AF/AFL/AT recurrence with documented CTI reconnection after the index procedure | 1 (0.9%) | 3 (3.3%) | | Within 90 days | 0 (0.0%) | 0 (0.0%) | | Within 180 days | 1 (0.9%) | 0 (0.0%) | | Within 360 days | 0 (0.0%) | 3 (3.3%) | | DC cardioversion for AFL recurrence after the index procedure | 2 (1.8%) | 5 (5.5%) | | Within 90 days | 1 (0.9%) | 4 (4.4%) | | Within 180 days | 1 (0.9%) | 0 (0.0%) | | Within 360 days | 0 (0.0%) | 1 (1.1%) | 1 Failure modes are not mutually exclusive since the same subject can experience multiple failure modes. PMA P240013: FDA Summary of Safety and Effectiveness Data {38} Table 26. Chronic Effectiveness Success Rate Population: Atrial Flutter Cohort | | Number, Percent of Successes | | Difference | | --- | --- | --- | --- | | Parameter | Investigational (N=114) | Control (N=91) | Investigational - Control | | CTI Chronic Effectiveness Success | 99, 86.8% | 70, 76.9% | 9.9% | Kaplan-Meier estimates of freedom from atrial flutter ablation chronic effectiveness failure are presented in Figure 11 for the investigational arm (blue) and the control arm (red). The log-rank test $p$-value was 0.077. Note that the window for the Day 360 visit extended from study day 330 to study day 390, so data censoring during the last 30 days is expected, accounting for the low number at risk at day 360. In case of failure at the Day 360 visit, within the visit window but beyond study day 360, the date of failure was set to study day 360 so that the failure was included in the Kaplan-Meier analysis. ![img-16.jpeg](img-16.jpeg) Figure 11: Atrial Flutter: Chronic Effectiveness Kaplan-Meier Plot Population: Atrial Flutter Cohort PMA P240013: FDA Summary of Safety and Effectiveness Data {39} v. Serious Adverse Events A total of 62 serious adverse events (27 in investigational arm, 35 in control arm) occurred during or post index ablation procedure in the atrial flutter cohort. Table 27 summarizes the incidence of early onset (within 7 days of the index ablation procedure) SAEs, incidence of peri-procedural (>7 and ≤30 days) SAEs, and incidence of late onset (>30 days) SAEs. Table 27. SAEs by Timepoint Population: Atrial Flutter Cohort | | # Events (# Subjects, % Subjects) | | | --- | --- | --- | | SAE by Timepoint | Investigational (N=115) | Control (N=97) | | SAEs during procedure or ≤ 7 days after procedure | 4 (3, 2.6%) | 5 (5, 5.2%) | | SAEs 8-30 days after procedure | 3 (2, 1.7%) | 2 (2, 2.1%) | | SAEs > 30 days after procedure | 20 (13, 11.3%) | 28 (21, 21.6%) | 6. Pediatric Extrapolation In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population. F. 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 SPHERE Per-AF clinical study included 79 investigators of whom six had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below: - Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0 - Significant… --- **Source:** [https://fda.innolitics.com/device/P240013](https://fda.innolitics.com/device/P240013) **Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. 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