Symplicity Spyral™ Renal Denervation System

P220026 · Medtronic, Inc. · QYI · Nov 17, 2023 · Cardiovascular

Device Facts

Record IDP220026
Device NameSymplicity Spyral™ Renal Denervation System
ApplicantMedtronic, Inc.
Product CodeQYI · Cardiovascular
Decision DateNov 17, 2023
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic

Indications for Use

The Symplicity Spyral Multi-Electrode Renal Denervation Catheter and the Symplicity G3 RF Generator are indicated to reduce blood pressure as an adjunctive treatment in patients with hypertension in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure.

Device Story

The Symplicity Spyral Renal Denervation System is a catheter-based device used by physicians in a clinical setting to treat hypertension. The system consists of a single-use, multi-electrode catheter and a reusable RF generator. The catheter is inserted via the femoral artery and guided to the renal arteries using fluoroscopic guidance. Once positioned, the catheter's four gold electrodes are deployed in a spiral configuration against the renal artery wall. The generator delivers radiofrequency energy to the renal nerves, which are ablated to reduce sympathetic nerve activity. The generator uses an automated algorithm to control treatment based on real-time impedance and temperature feedback. The procedure is performed under sedation/anxiolysis. By reducing sympathetic nerve activity, the device aims to lower blood pressure, providing a treatment option for patients who do not achieve adequate control with lifestyle changes and medications alone.

Clinical Evidence

Evidence based on two prospective, randomized, sham-controlled clinical trials (HTN-OFF MED and HTN-ON MED) and a global registry (GSR). HTN-OFF MED (N=366) showed a 3.9 mmHg greater reduction in 24-hour ambulatory SBP (p<0.001) for rfRDN vs. sham at 3 months. HTN-ON MED (N=337) primary endpoint (24-hour SBP at 6 months) was not met, though office SBP reduction favored rfRDN. Safety profile demonstrated a 0.4% MAE rate (1/253) in the pooled primary safety population, meeting the 7.1% performance goal.

Technological Characteristics

System includes a 6 Fr compatible, 117 cm length catheter with 4 gold radiopaque electrodes in a helical array and a reusable RF generator. Energy source: 460 ±5 kHz RF energy. Materials: Biocompatible per ISO 10993-1. Connectivity: Standalone, no network/ethernet support. Sterilization: E-beam irradiation (catheter). Software: Automated algorithm for temperature/impedance-controlled ablation.

Indications for Use

Indicated for adult patients (≥20 and ≤80 years old) with uncontrolled hypertension despite lifestyle modifications and antihypertensive medications. Contraindicated in patients with renal artery diameter <3mm or >8mm, fibromuscular dysplasia, stented renal artery (<3 months), renal artery aneurysm, >50% renal artery stenosis, pregnancy, abnormal kidney/adrenal tumors, or iliac/femoral artery stenosis precluding catheter insertion.

Regulatory Classification

Identification

For denervating the renal nerves to lower blood pressure

Reference Devices

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Ablation catheter, renal denervation Device Trade Name: Symplicity Spyral™ Renal Denervation System Device Procode: QYI Applicant’s Name and Address: Medtronic Vascular 3576 Unocal Place Santa Rosa, CA 95403 USA Date of Panel Recommendation: August 23, 2023 Application: (PMA) Number: P220026 Date of Notice of Approval: 11/17/2023 Breakthrough Device: Granted breakthrough device status on March 27, 2020 for the reduction of blood pressure in patients with uncontrolled hypertension despite the use of anti-hypertensive medications or in patients who may have documented intolerance to anti-hypertensive medications. II. INDICATIONS FOR USE The Symplicity Spyral Multi-Electrode Renal Denervation Catheter and the Symplicity G3 RF Generator are indicated to reduce blood pressure as an adjunctive treatment in patients with hypertension in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure. III. CONTRAINDICATIONS The Symplicity Spyral Multi-Electrode Renal Denervation Catheter and the Symplicity G3 RF Generator are contraindicated in any of the following: - Renal artery diameter &lt;3mm or &gt;8mm - Renal artery fibromuscular dysplasia (FMD) - Stented renal artery (&lt;3 months prior to RDN procedure) - Renal artery aneurysm - Renal artery diameter stenosis &gt;50% - Pregnancy - Presence of abnormal kidney (or secreting adrenal) tumors - Iliac/femoral artery stenosis precluding insertion of the catheter PMA P220026: FDA Summary of Safety and Effectiveness Data {1} PMA P220026: FDA Summary of Safety and Effectiveness Data ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Symplicity Spyral multi-electrode renal denervation catheter and Symplicity G3 RF generator labeling. ## V. DEVICE DESCRIPTION The Symplicity Spyral Renal Denervation (rfRDN) System is comprised of two main components: a single-use, disposable catheter (Symplicity Spyral multi-electrode renal denervation catheter, also referred to Symplicity Spyral catheter) and a reusable radiofrequency (RF) generator (Symplicity G3 Renal Denervation RF generator, also referred to as Symplicity G3 RF generator). An optional remote control and power cord are included with the generator. ### Symplicity Spyral Multi-Electrode Renal Denervation Catheter The Symplicity Spyral multi-electrode rfRDN catheter is designed to be used with the Symplicity G3 RF generator. The catheter connects to the generator using the integrated cable attached to the catheter handle. The catheter requires the use of a 0.36 mm (0.014 in) guidewire for delivery, preferably without hydrophilic coating. For a straighter electrode array during delivery, Medtronic recommends using an extra support guidewire such as the Medtronic Thunder guidewire. In addition, an adult-sized dispersive electrode (also known as a neutral electrode, return electrode pad, or grounding pad) must be placed on the patient and connected to the generator for the therapy to be delivered. The catheter has an effective length of 117 cm and is compatible with a 6 Fr guide catheter. It is designed for treating vessels with diameters ranging from 3 mm to 8 mm. As shown in Figure 1 the catheter features 4 gold radiopaque electrodes at the spiral (helical) distal end. The electrodes are deployed into a spiral (helical) shape by partially retracting the guidewire proximal to the spiral section of the catheter. The catheter treatment length (the distance between the most distal and proximal electrodes) of a function of the vessel diameter (Table 1). A radiopaque tip marker is located 1 mm proximal to the catheter tip and assists in catheter positioning using fluoroscopic guidance. The catheter also features a straightening tool that facilitates safe insertion of the guidewire into the catheter (Figure 2). This tool is located near the handle and slides along the catheter shaft to straighten the distal end. Refer to the Symplicity Spyral catheter Instructions for Use for additional details. {2} ![img-0.jpeg](img-0.jpeg) Figure 1. Representative Image of Self-Expanding Electrode Array Assembly (Spiral Configuration) Table 1: Symplicity Spiral Catheter Treatment Length | Vessel Diameter (mm) | Treatment Length (mm) | | --- | --- | | 3 | 21 | | 4 | 20 | | 5 | 20 | | 6 | 19 | | 7 | 18 | | 8 | 17 | ![img-1.jpeg](img-1.jpeg) Figure 2. Overview of Symplicity Spiral Catheter # Symplicity G3 RF Generator and Touch Screen The generator uses an automated algorithm to control the treatment based on real-time temperature and impedance feedback. Refer to the Symplicity G3 RF generator user manual for further information. The front panel of the Symplicity G3 RF generator touch screen shows information such as impedance, temperature, ablation time, and messages. The front panel also features an RF activation button. Channels on the generator screen correspond to each electrode on the catheter. The generator touch screen and remote control allow the user to navigate different options, such as the selection or deselection of channels, viewing previous ablation data sets, or selecting the left or right kidney. PMA P220026: FDA Summary of Safety and Effectiveness Data {3} VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of hypertension including lifestyle modifications and pharmacological therapy. Each approach has its advantages and disadvantages. A patient should fully discuss hypertension treatment options with their health care provider to select the method(s) that achieve blood pressure control and meets expectations and lifestyle. VII. MARKETING HISTORY The Symplicity Spyral Renal Denervation System was first CE Marked in the European Union on 15 October 2013. The Symplicity G3 RF generator data in this section is for the predicate Symplicity G3 RF generator, which is currently commercially available in the countries listed in Table 2. Table 2. Commercialized Geographies for the Symplicity Spyral Renal Denervation System | Countries | | | | | --- | --- | --- | --- | | Australia | Dominican Republic | Kazakhstan | Romania | | Argentina | Ecuador | Kuwait | Russia | | Austria | Egypt | Latvia | Saudi Arabia | | Bangladesh | El Salvador | Liechtenstein | Singapore | | Bahamas | Estonia | Lithuania | Slovakia | | Belgium | Finland | Luxembourg | Slovenia | | Brazil | France | Malaysia | South Africa | | Brunei | Germany | Malta | South Korea | | Bulgaria | Greece | Mexico | Spain | | Cayman Islands | Guatemala | Netherlands | Sweden | | Chile | Hong Kong | New Zealand | Switzerland | | Colombia | Hungary | Nicaragua | Taiwan | | Costa Rica | Iceland | Norway | Thailand | | Croatia | India | Panama | Turkey | | Curacao | Indonesia | Peru | United Kingdom | | Cyprus | Ireland | Philippines | Venezuela | | Czech Republic | Israel | Poland | | | Denmark | Italy | Portugal | | The Symplicity Spyral Renal Denervation System has not been withdrawn from commercial distribution for any reason related to 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 (listed in alphabetical order). - Allergic reaction to contrast - Arterial damage, including injury from energy application - Hypotension - Hypotension causing end organ hypoperfusion PMA P220026: FDA Summary of Safety and Effectiveness Data {4} - Arterial dissection or perforation - Arterial spasm - Arterial stenosis - Arterio-enteric fistula - Arteriovenous fistula - Bleeding - Blood clots or embolism - Bruising - Cardiopulmonary arrest - Complications associated with medications commonly utilized during the procedure, such as narcotics, anxiolytics, or other pain or anti-vasospasm medications - Death - Deep vein thrombosis - Edema - Electrolyte imbalance - Heart rhythm disturbances, including bradycardia - Hematoma - Hematoma - retroperitoneal - Hematuria - Hypertension - Hypotension – orthostatic - Infection - Kidney damage including renal failure - Kidney perforation - Myocardial infarction - Nausea or vomiting - Pain or discomfort - Peripheral ischemia - Pulmonary embolism - Proteinuria - Pseudoaneurysm - Radiocontrast neuropathy - Renal artery aneurysm - Skin burns from a failure of the dispersive electrode pad - Stroke There may be other potential adverse events that are unforeseen at this time. For the specific adverse events that occurred in the clinical studies, please see Section X, Summary of Primary Clinical Studies, below. ## IX. SUMMARY OF NONCLINICAL STUDIES Nonclinical testing of the Symplicity Spyral Renal Denervation System included verification and validation (device, system, and software), biocompatibility of patient-contacting materials, sterilization, packaging, shelf life testing, and animal studies. Performance testing was conducted to demonstrate design integrity. Tests that were identified in standards or guidance documents were performed based on design inputs. ## A. Biocompatibility Biocompatibility testing of the Symplicity Spyral Renal Denervation System was evaluated based on device contact and duration in accordance with ISO 10993-1: 2009 and (R)2013 and FDA Guidance, Use of International Standard ISO 10993-1, “Biological Evaluation of Medical Devices Part 1: Evaluation and testing within a risk management process”. The Symplicity Spyral catheter test samples were derived from the finished product. The catheter is classified according to ISO 10993-1 as an externally communicating medical device with limited contact (≤24 hours) with circulating blood. The Symplicity G3 RF generator, remote control, DVI-D cable, power cord and cart do not have any direct or PMA P220026: FDA Summary of Safety and Effectiveness Data {5} indirect tissue contact and are provided non-sterile; therefore, biocompatibility testing was not required for these components. A summary of the results is provided in Table 3 and demonstrates that the Symplicity Spyral catheter is biocompatible per ISO 10993-1. Biocompatibility testing was completed according to Good Laboratory Practice (GLP) requirements 21 CFR 58, and the results provide objective evidence that the catheter is biocompatible per its intended use. Table 3. Summary of Biocompatibility Testing - Symplicity Spyral Catheter | Test Performed | Test Method (applicable ISO Part Number) | Acceptance Criteria | Results | | --- | --- | --- | --- | | Cytotoxicity | MEM Elution Using L 929 Fibroblast Cells (ISO 10993-5; ISO 10993-12) | The test article must result in a grade of 2 or less | Pass Non-cytotoxic | | Sensitization | ISO Guinea Pig Maximization Sensitization Test (ISO 10993-10; ISO 10993-12) | A grade of ≥1 in the test group indicates sensitization provided the corresponding control group is grade <1 | Pass Non-sensitizing | | Irritation or Intracutaneous Reactivity | ISO Intracutaneous Irritation Reactivity Test (ISO 10993-10; ISO 10993-12) | The difference between the test extract mean score and corresponding control mean score must be ≤1.0 | Pass Non-irritant | | Acute Systemic Toxicity | ISO Acute Systemic Injection Test (2 Extracts) (ISO 10993-11; ISO 10993-12) | If during the observation period, none of the test animals shows a significantly greater reaction than the corresponding control animals, the test article meets the test requirements | Pass Non-toxic | | Material-Mediated Pyrogenicity | ISO Materials Mediated Rabbit Pyrogenicity (ISO 10993-11; ISO 10993-12) | If no animal shows an individual rise in temperature of 0.5°C or more above its baseline temperature, the test article meets the requirements for the absence of pyrogens | Pass Non-pyrogenic | | Hemocompatibility | Complement Activation SC5b-9 with supplied comparison (ISO 10993-4; ISO 10993-12) | If the SC5b-9 concentration in the test article is statistically similar to at least the negative control, inactivated NHS control, or the sponsor-provided control, the test article is not considered an activator of the complement system. | Pass Not a complement activator | PMA P220026: FDA Summary of Safety and Effectiveness Data {6} PMA P220026: FDA Summary of Safety and Effectiveness Data # B. In vitro Engineering and Bench Testing ## Symplicity Spyral Renal Denervation (rfRDN) System Testing was conducted on the Symplicity Spyral Renal Denervation System (generator, catheter, and optional accessories) according to harmonized test standards for active medical devices and to software verification/validation requirements, following uniquely designed test protocols for the device. The Symplicity Spyral Renal Denervation system met international certification requirements for safety in compliance such as: ANSI/AAMI ES60601-1:2005/A1:2012-08, IEC 60601-1:2005, COR1:2006, COR2:2007, AMD1:2012, IEC 60601-6:2010/AMD1:2013 IEC 60601-1-2:2014. The Symplicity Spyral Renal Denervation System passed design verification (functional) bench testing including dimensional, strength, reliability, mechanical, and electrical integrity. Testing included performance of the Symplicity G3 RF generator used in conjunction with the Symplicity Spyral multi-electrode renal denervation catheter and all other system components. Table 4 shows the tests performed on the Symplicity Spyral Renal Denervation (rfRDN) system, the purpose of the tests, the acceptance criteria, and the test results (pass/fail). Pass denotes the device and systems met the established product specification and/or performance criteria. Table 4. Summary of Functional Testing - Symplicity Renal Denervation (rfRDN) System | Test | Test Summary/Purpose | Acceptance Criteria | Results (Pass/Fail) | | --- | --- | --- | --- | | Tip Length | The purpose of this test is to measure the distance from the distal end of the catheter to the distal end of the tip bond. | Lower Spec: 4 mm Upper Spec: 8 mm | Pass | | Tip to Marker Band Distance | The purpose of this test is to measure the distance from the distal end of the catheter to the distal end of the marker band. | Upper Spec: 1.5 mm | Pass | | Catheter Working Length (Straight) | The purpose of this test is to measure the distance from the distal end of the catheter to the distal end of the straightening tool in the straight configuration. | Lower Spec: 114 cm Upper Spec: 120 cm | Pass | | Exchange Joint Distance from Tip (Straight) | The purpose of this test is to measure the distance from the catheter tip to the exchange joint in the straight configuration. | Lower Spec: 25 cm Upper Spec: 35 cm | Pass | | Tip to Femoral Marker Distance (Straight) | The purpose of this test is to measure the distance from the distal end of the catheter to the distal end of the femoral marker in the straight configuration | Lower Spec: 45 cm Upper Spec: 65 cm | Pass | | Catheter Max Profile (Intermediate Bond OD) | The purpose of this test is to measure the outside diameter of the intermediate bond which represents the maximum catheter profile. | Upper Spec: 1.55 mm (0.061") | Pass | {7} PMA P220026: FDA Summary of Safety and Effectiveness Data | Test | Test Summary/Purpose | Acceptance Criteria | Results (Pass/Fail) | | --- | --- | --- | --- | | Cable to Handle Tensile | The purpose of this test is to measure the tensile strength of the catheter cable and handle connection. | Lower Spec: 15N (3.37lbs) | Pass | | Deployed Array Length/Compliance | The purpose of this test is to measure the array length in the deployed configuration. | Lower Spec: 5 mm Upper Spec: 26.5 mm | Pass | | Compatibility with accessories | The purpose of this test is to ensure that the device does not lock-up in or on standard procedural accessories during simulated use in a transfemoral bench top model. | Catheter interfaces with accessories without damaging catheter. | Pass | | Loading Tool Compatibility | The purpose of this test is to ensure that the loading tool allows for a guidewire to be loaded during simulated use. | Able to insert wire into device without damaging catheter. | Pass | | Catheter Integrity | The purpose of this test is to perform a visual assessment of the catheter to identify damage to the device after simulated use in a transradial bench top model. | Catheter does not exhibit visual damage post simulated use. | Pass | | Tip Bond Tensile | The purpose of this test is to measure tensile strength of the bond between the distal tip and the catheter per ISO 10555-1. | Lower Spec: 5N (1.12 lbs) | Pass | | Electrode Tensile | The purpose of this test is to measure tensile strength of the bond between the electrode and the catheter. | Lower Spec: 5N (1.12 lbs) | Pass | | Intermediate Bond Tensile | The purpose of this test is to measure tensile strength of the intermediate bond of the catheter per ISO 10555-1. | Lower Spec: 5N (1.12 lbs) | Pass | | Exchange Joint Tensile | The purpose of this test is to measure tensile strength of the exchange joint bond of the catheter per ISO 10555-1. | Lower Spec: 5N (1.12 lbs) | Pass | | Proximal Shaft to Handle Tensile | The purpose of this test is to measure tensile strength of the bond between the catheter shaft and the handle per ISO 10555-1. | Lower Spec: 5N (1.12 lbs) | Pass | | Kink Resistance | The purpose of this test is to perform a visual assessment of the catheter to ensure that no kinks are observed on the device after simulated use in a transradial bench top model. | No kinking Post Simulated Use | Pass | | Impedance Measurement | The purpose of this test is to ensure that the generator and system are able to measure the simultaneous impedance accurately between each RF channel and return electrode from 175 to 1200 ohms before and during RF energy delivery. | 175 Ω to 250 Ω, ±20% 251 Ω to 700 Ω, ±10% 701 Ω to 1200 Ω, ±15% | Pass | {8} | Test | Test Summary/Purpose | Acceptance Criteria | Results (Pass/Fail) | | --- | --- | --- | --- | | RF output power | The purpose of this test is to ensure that the generator and system are able to deliver power with the specified accuracy to all four channels | 6.5W maximum per electrode ±20% accuracy with impedance of 175 Ω to 200 Ω ±10% accuracy with impedance of 201 Ω to 1200 Ω | Pass | | Temperature range | The purpose of this test is to ensure that the system is able to measure temperature of each electrode accurately before and during RF delivery. | Measurement 37°C to 65°C ±3°C | Pass | | RF output frequency | The purpose of this test is to ensure that the generator and system are able to deliver RF power of 6.5 W at a frequency of 460 ±5 kHz | 455-465 kHz | Pass | | RF Treatment duration | The purpose of this test is to ensure that the system is able to deliver RF power for the specified treatment time. | 60 seconds (+/-1 second) | Pass | ## C. Software Testing The software for Symplicity G3 RF generator and remote control was verified/validated and documented according to the FDA guidance document “Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices.” The software testing included a full suite of safety and performance tests. The software was evaluated through unit, integration, verification and validation testing to demonstrate that the performance and safety of the Symplicity G3 RF generator and remote control passed specifications. Cybersecurity risk analysis and testing was conducted per FDA guidance document “Guidance of Premarketing Submissions for Management of Cybersecurity in Medical Devices.” Risk analysis and verification testing of risk controls performed ensures that the Symplicity Spyral Renal Denervation system is secure and trustworthy throughout its full life cycle. As described in the Symplicity G3 RF generator user manual, the following security information is included to help manage cybersecurity risks and/or to ensure the safe and effective use of the device. ## Data security The Symplicity G3 generator uses and stores treatment data. The system does not protect exported data. Exported data should be handled in accordance with your facility’s security policy for data handling and storage. Medtronic recommends that you always export data to an encrypted mass storage device. ## Cybersecurity events If you suspect a cybersecurity event has occurred (such as strange or unexpected behavior, even if a fault or check status condition is not generated), stop using the PMA P220026: FDA Summary of Safety and Effectiveness Data {9} generator (if possible). Contact your IT department or Medtronic support for information on how to confirm and respond to the suspected incident. If you have further questions related to cybersecurity, contact your IT department or Medtronic support. ## Security Risk Considerations In addition to following the intended use and instructions necessary for the safe and effective use of the Symplicity G3 Generator, the following compensating controls for product implementation in the user's environment are recommended by Medtronic: - The Symplicity G3 Generator does not support hospital network or other ethernet connectivity. - Only personnel authorized by the hospital should access, use, or move the Symplicity G3 Generator, to avoid exposing the system to security risks. Medtronic recommends maintaining good physical access controls over the Symplicity G3 Generator. - Software updates are to be installed by authorized Medtronic service personnel only. DO NOT install any software on the system, to avoid unintended system behavior. ## D. Sterilization and Shelf Life The Symplicity Spyral catheter is provided as a sterile, single use medical device and is not intended for reuse or re-sterilization. The Symplicity Spyral catheter is sterilized using a validated electron beam irradiation (E-beam) sterilization process that provides a sterility assurance level (SAL) of $10^{-6}$. Sterilization validation was completed in accordance with the requirements of EN556, ISO11137/TIR13004. The Symplicity G3 RF generator, remote control, DVI-D cable, power cord and cart are provided as non-sterile. A shelf life of 3 years has been established for the Symplicity Spyral catheter based on product and package shelf life testing. The Symplicity Spyral catheter was tested following accelerated aging to an equivalent of 3 years per an approved shelf life protocol. Testing demonstrated the Symplicity Spyral catheter met the established acceptance criteria. The Symplicity G3 generator is re-usable durable medical equipment and was designed and validated to provide a useful life of 5 years or more based on actual usage. The Symplicity Spyral catheter is a single use, disposable, sterile device. Catheter packaging was designed and validated to ensure the sterility and integrity of individually packaged and sealed devices. The packaging validation was performed in accordance with ISO 11607-1:(2022) and applicable packaging standards (ISO 2233, ASTM F88, ASTM 2096, ASTM D4169, ASTM D4332, and F1929). The packaging validation supports the 3 year shelf life for the Symplicity Spyral catheter. PMA P220026: FDA Summary of Safety and Effectiveness Data {10} The Symplicity G3 RF generator, remote control, DVI-D cable, and power cord are provided non-sterile and protected by a Pelican case. The packaging validation demonstrates the selected packaging provides basic protection of the unit during expected transit cycles. Packaging validation was completed in accordance with applicable packaging standards (ISO 2233, ASTM D4169, and ASTM D4332). ## E. Animal Studies Medtronic conducted several in-vivo animal studies in a porcine model to develop the RF treatment parameters and characterize the performance and safety of the Symplicity Spyral Multi-Electrode Renal Denervation Catheter, utilized in conjunction with the Symplicity G3 RF Generator: 1. A long-term GLP (180-day timepoint) study was designed to characterize the safety of the treatment parameters and device performance of the Symplicity Spyral Renal Denervation System and to evaluate the physiological effects of RF renal denervation on the renal sympathetic functionality, as compared to untreated animals. 2. A series of non-GLP design studies (7 and 28 days timepoints) were completed to confirm the device design concepts and system specifications. For each preclinical study, the following were evaluated to assess device and procedure safety: clinical observations, clinical pathology, angiography, gross pathology, and histopathology/histomorphometry. Renal cortical axonal density and renal cortical norepinephrine concentrations were also evaluated. A summary and description of animal studies are provided in Table 5. PMA P220026: FDA Summary of Safety and Effectiveness Data 11 {11} Table 5. Summary of In Vivo Animal Studies | Study Type | No. and Type of Animals | Study Follow-up Duration | Study Purpose | Study Arms Evaluated | Results | | --- | --- | --- | --- | --- | --- | | GLP Chronic Study in Domestic Swine (FS235) | 17 Domestic Farm Swine | 180 days | A design validation study to demonstrate the long term safety of the Spyral Multi-Electrode Denervation Catheter as well as the physiological effects of renal denervation | Arm 1: Symplicity Spyral Renal Denervation Catheter with the Symplicity RF Generator Arm 2: Untreated control | No clinically significant complications in the treated vessels, adjacent structures, and kidneys based on arteriography, histopathology and blood biochemistry. Successful assessment and treatment of post-operative clinical concerns (e.g., pain, postoperative abnormalities). Successful determination of bilateral renal cortical norepinephrine concentration for each study arm. | | Non-GLP Chronic Swine Study (PS629) | 20 Domestic Swine | 28 days | Comparison of the Symplicity Spyral Catheter and Generator System performance to the multi-electrode RF and Symplicity Flex RF Catheters / Generators Systems. | Arm 1: Symplicity Spyral Renal Denervation Catheter with the Symplicity RF Generator Arm 2: Multi-electrode RF catheter with Symplicity G2X4 Generator Arm 3: Symplicity Flex Catheter with Symplicity G2 Generator Arm 4: Untreated control | Successful Delivery of treatment modalities in 90% of animal. No clinically significant complications in the treated renal vessels, adjacent structures, and kidneys based on arteriography, histology, and blood chemistries. Renal cortical NE concentration for Arm1 equivalent or lower than Arm 2 and Arm 3. | | Non-GLP Sub-Acute Swine Study (PS701) | 59 Domestic Swine | 7 days | Evaluation of treatment locations and various renal denervation parameters and duration combinations using the Symplicity Spyral RF Catheter System. | Arm 1-4: Symplicity Spyral Renal Denervation Catheter with the Symplicity RF Generator (multiple treatment parameters and locations) | No clinically significant complications in the treated renal vessels, adjacent structures, and kidneys based on arteriography, histology, and blood chemistries. Successful determination of renal cortical NE concentration and histology assessment (renal cortical axon quantification). | PMA P220026: FDA Summary of Safety and Effectiveness Data {12} | Study Type | No. and Type of Animals | Study Follow-up Duration | Study Purpose | Study Arms Evaluated | Results | | --- | --- | --- | --- | --- | --- | | | | | | Arm 5: Symplicity Flex Catheter with Symplicity G2 GeneratorArm 6: Contralateral untreated vessels | | | Non-GLP Sub-Acute Swine Study PS716) | 48 Domestic Swine | 7 days | Confirm location of renal denervation and compare ablation parameters and application combinations using the Symplicity Spyral RF Catheter System. | Arm 1-4: Symplicity Spyral Renal Denervation Catheter with the Symplicity RF Generator (multiple treatment parameters and locations)Arm 5: Contralateral untreated vessels (left renal) | Successful delivery of treatment modalities in 90% of animals.No clinically significant complications in the treated renal vessels, adjacent structures, and kidneys based on arteriography, histology, and blood chemistries.Reduced norepinephrine concentration and renal nerve viability and cortical axon density following RF treated group compared to the untreated group. | | Non-GLP Chronic Swine Study (PS717) | 16 Domestic Swine | 28 days | Subacute evaluation of RF parameters and methodology selected for renal ablation delivery using the Symplicity Spyral Catheter System. | Arm 1: Symplicity Spyral Renal Denervation Catheter with the Symplicity RF Generator.Arm 2: Untreated Control | No clinically significant complications in the treated renal vessels, adjacent structures, and kidneys based on arteriography, histology, and blood biochemistries.Reduced norepinephrine concentration and renal nerve viability and cortical axon density following RF treated group as compared to the untreated group | PMA P220026: FDA Summary of Safety and Effectiveness Data {13} Collectively, the preclinical studies demonstrate the safety of RF delivery to the target renal vessels and the physiological impact of RF ablations on renal cortical norepinephrine concentration and cortical axon density. Safety evaluation of RF ablations demonstrated the following: - Clinical pathology results at pre-screen and terminal time points were within normal limits. No significant pain was exhibited by the animals. - Post-treatment and terminal angiography indicated normal vessel perfusion for all treated animals. No clinically significant abnormal findings were attributed to RF changes. - Histopathology and histomorphometry evaluation of treated renal arteries showed complete healing following RF ablations. No clinically significant complications attributed to the RF treatment were observed in the kidneys and surrounding tissues. Bioanalytical and immunohistochemistry analyses consistently showed a significant and sustained reduction in sympathetic function at each study timepoint evaluated (7 days, 28 days, and 180 days). Renal norepinephrine concentrations and cortical axon density were significantly reduced in the group treated with Symplicity Spyral Renal Denervation Catheter and the Symplicity RF Generator compared to non-treated vessels. ## X. SUMMARY OF PRIMARY CLINICAL STUDIES The applicant performed two clinical studies—SPYRAL HTN-OFF MED and SPYRAL HTN ON-MED—to evaluate the safety and effectiveness of rfRDN with the Symplicity Spyral Renal Denervation System for reduction of blood pressure in patients with uncontrolled hypertension compared to a sham-controlled population, in the absence and presence of anti-hypertensive medications, respectively. The studies were conducted in the US, Canada, Japan, Europe, and Australia under IDE # G150036. Data from these clinical studies were the basis for the PMA approval decision. Summaries of the clinical studies are presented below. ## A. Study Design The HTN-OFF MED and HTN-ON MED studies were conducted in two cohorts: an initial Pilot Cohort to determine the feasibility of the study design and a second prospectively powered Expansion Cohort that expanded the study via an adaptive Bayesian design. Pilot and Expansion Cohorts were designed as a multi-center, international, prospective, single blinded, randomized, interventional, sham-controlled cohorts. The sham control procedure consisted of an aortogram and selective renal angiography performed with subjects blinded to treatment allocation to confirm eligible renal artery anatomy. Eligible subjects randomized to sham control remained blinded and on the catheterization lab table for at least 20 minutes prior to the inducer sheath removal. Patients, follow-up physicians, and research staff remained blinded through 6 months in the Expansion Cohorts or 12 months in the Pilot Cohorts. PMA P220026: FDA Summary of Safety and Effectiveness Data {14} PMA P220026: FDA Summary of Safety and Effectiveness Data # HTN-OFF MED Study Design In both Pilot and Expansion Cohorts, patients were randomized 1:1 to rfRDN or Sham. Antihypertensive medications were withdrawn from 3-4 weeks prior to the rfRDN or sham procedure through 3 months post-treatment (unless pre-specified elevated BP escape criteria (defined as office SBP ≥180 mmHg or &lt;115 mmHg associated with symptoms of hypotension or safety concern requiring medication changes) were met). The HTN-OFF MED study utilized a Bayesian adaptive design, and the Expansion cohort interim analyses could be performed at 210 and 240 evaluable subjects to determine if the enrollment could be stopped prior to a maximum study size of 300 subjects. HTN-OFF enrollment was stopped after the first interim analysis. Patients were treated between June 2015 and January 2020. The database for this PMA reflected data collected through May 2022 and included 366 patients. There were 41 investigational sites. # HTN-ON MED Study Design In the HTN-ON MED study, Pilot Cohort patients and the first 26 patients in the prospectively powered Expansion Cohort (patients 81–106) were randomized 1:1 to rfRDN or Sham, and patients 107 onward were randomized 2:1 to rfRDN or Sham rfRDN. The randomization scheme was changed to allow for more rfRDN safety data for primary safety endpoint. Antihypertensive medication was to remain unchanged between baseline and the 6-month primary endpoint assessment unless pre-specified elevated BP escape criteria (defined as Office SBP ≥180 mmHg or &lt;115 mmHg associated with symptoms of hypotension or safety concern requiring medication changes) were met. A Bayesian adaptive design was used for the primary analysis, and expansion cohort interim analyses could be performed at 110 and 149 evaluable subjects to determine if the enrollment could be stopped. HTN-ON enrollment continued to full enrollment (257 subjects). Patients were treated between October 2015 and March 2022. The database for this PMA reflected data collected through November 2022 and included 337 patients. There were 42 investigational sites. In both HTN-OFF MED and HTN-ON MED, Pilot Cohorts remained blinded through 12 months, and Expansion Cohort subjects remained blinded through 6 months. For both studies, the cohorts and definition used in this clinical summary are described in Table 6. {15} Table 6. Study Cohorts and Number of Subjects for HTN-OFF MED and HTN-ON MED | | HTN-OFF MED | HTN-ON MED | | --- | --- | --- | | Pilot Cohort: Subjects enrolled in the pilot study | 80 | 80 | | Expansion Cohort: Subjects enrolled following pilot study | 251 | 257 | | Additional subjects enrolled following positive interim analysis | 35 | -- | | Primary (Bayesian) Cohort: Expansion + discounted Pilot | Up to 331 Based on Bayesian analysis | Up to 337 Based on Bayesian analysis | | Full Cohort: All enrolled subjects | 366 | 337 | 1. Clinical Inclusion and Exclusion Criteria Enrollment in the studies was limited to subjects who met the following inclusion criteria: Table 7. Key Inclusion Criteria for the HTN-OFF MED and HTN-ON MED Studies | | HTN-OFF MED | HTN-ON MED | | --- | --- | --- | | Age | Individual is ≥20 and ≤80 years old at time of enrollment (consent) | | | OBP¹ | OSBP ≥150 mmHg and <180 mmHg ODBP ≥90 mmHg | | | ABP² | 24-hour SBP ≥140 mmHg and <170 mmHg | | | Medication | Willing to discontinue antihypertensive medications at Screening Visit 1 through the three-month post-procedure visit | • On 1-3 antihypertensive medications at ≥50% maximal dose • Stable medication regimen for ≥6 weeks | ¹ Baseline OBP and ABPM (ambulatory blood pressure monitoring) are determined at Screening Visit 2 ² ABP considered valid if the number of successful daytime readings captured is ≥21 and the number of successful nighttime readings captured ≥12 OBP: Office BP; ABP: Ambulatory BP; SBP: systolic BP; DBP: diastolic BP, OSBP: office systolic BP, ODBP: office diastolic BP Subjects were not permitted to enroll in the studies if they met any of the following exclusion criteria: - Individual has undergone prior renal denervation (RDN) - Ineligible renal artery anatomy, including: - Main renal artery for each kidney less than 3 mm or greater than 8 mm - Lacking a main renal artery that does not allow 4 simultaneous quadratic RF ablations in the main renal artery or equivalent - Presence of fibromuscular dysplasia (defined as visible beading of the artery on angiography) PMA P220026: FDA Summary of Safety and Effectiveness Data {16} &gt;50% stenosis in any treatable vessel - Renal artery stent placed &lt;3 months prior to procedure. - Renal artery aneurysm (defined as any localized increase in diameter of vessel) - Treatment within 5 mm of a segment in the renal artery which contains any of the following: atheroma, calcification, or renal artery stent - eGFR &lt;45 mL/min/1.73m² using 4 variable MDRD calculation - Type 1 diabetes mellitus or Type 2 diabetes mellitus with HbA1C &gt; 8.0% - Individual with ≥1 episode(s) of orthostatic hypotension not related to medication changes within the past year or reduction of SBP of ≥20 mmHg or DBP of ≥10 mmHg within 3 minutes of standing coupled with symptoms during the screening process (at screening visit 2) - Individual requires chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea (e.g. CPAP, BiPAP). - History of narcotic drug abuse, is currently on Methadone, or who has used narcotic drugs more than once in the month prior to screening visit 1 - Individual is taking SGLT2 inhibitors or GLP-1 agonists that have been prescribed &lt;90 days prior to screening visit 1 or who does not plan to remain on these drugs for the duration of the trial - Individual with primary pulmonary hypertension - Individual with untreated secondary cause of hypertension (either known or suspected) or is taking drugs that increase sympathetic tone that could contribute to hypertension - Individual with frequent intermittent or chronic pain that results in treatment with non-steroidal anti-inflammatory drugs for two or more days per week over the month prior to screening visit 2. (Patients are permitted to take aspirin or clopidogrel for cardiovascular risk reduction.) - Individual with HIV on anti-retroviral drug therapy without documentation that hypertension preceded initiation of anti-retroviral drug treatment - Individual has one or more of the following conditions: stable or unstable angina within 3 months of enrollment, myocardial infarction within 3 months of enrollment; heart failure, cerebrovascular accident or transient ischemic attack, or atrial fibrillation at any time. Patients are permitted to take aspirin or clopidogrel for cardiovascular risk reduction. Patients who received catheter or surgical treatment for atrial fibrillation and are in sinus rhythm are not excluded. - Individual has a scheduled or planned surgery that, in the opinion of the Investigator, may affect study endpoints - Individual has a documented condition that would prohibit or interfere with ability to obtain an accurate blood pressure measurement using the protocol-specified automatic/office blood pressure monitor (e.g., upper arm circumference outside cuff size ranges available by geography or arrhythmia such as atrial fibrillation that interferes with automatic monitor’s pulse sensing and prohibits an accurate measurement) - Individual works night shifts PMA P220026: FDA Summary of Safety and Effectiveness Data 17 {17} - Individual has severe cardiac valve stenosis for which, in the opinion of the investigator, a significant reduction of blood pressure is contraindicated - Individual has a documented confounding medical condition, which in the opinion of the investigator, may adversely affect the safety of the participant (e.g., patients with clinically significant peripheral vascular disease, aortic aneurysm, bleeding disorders such as thrombocytopenia, hemophilia, or significant anemia) - Individual is pregnant, nursing or planning to become pregnant during the course of the study follow-up. (Pre-menopausal female participants must have a negative serum or urine human chorionic gonadotropin pregnancy test prior to angiography.) - Individual has a known unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or would be unlikely or unable, in the opinion of the investigator, to comply with study follow-up requirements - Individual is currently enrolled in a concurrent investigational drug or device study, unless approved by the study sponsor. (For the purpose of this protocol, participants involved in extended follow-up studies for products that were investigational but are currently commercially available are not considered enrolled in an investigational study.) - Individual is currently taking mineralocorticoid receptor antagonists. (Subjects may be enrolled as long as mineralocorticoid receptor antagonists are weaned off at least 8 weeks prior to screening visit 1.) - Individual has an active peptic ulcer or gastrointestinal (GI) bleeding within the prior six months from consent - Individual has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions - Individual has polycystic kidney disease, unilateral kidney, atrophic kidney, or history of renal transplant 2. Follow-up Schedule The follow-up schedule for selected endpoints from the HTN-OFF MED and HTN-ON MED studies is shown in Table 8 and Table 9, respectively. Subjects initially randomized to Sham control who underwent crossover to rfRDN were followed according to the same schedule as subjects initially randomized to rfRDN. PMA P220026: FDA Summary of Safety and Effectiveness Data 18 {18} Table 8: HTN-OFF MED Follow-up Schedule | Required Assessments | Screening visit 1 | 2 Wk visit (Screening) ± 3 days | Screening visit 2 (within 3-4 weeks of SV2) | rfRDN or Sham Procedure | Prior to Discharge | 2 Wk, 4Wk, 6 Wk, 8 Wk | 3M | 4M visit (for SBP ≥140 mmHg at 3M ±7days | 6M | 12M-36M | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Medical History | X | | | | | | | | | | | Clinical Assessment | | X | X | | | X | X | X | X | X | | Prescribe BP Medications | | | | | | | X | X | | | | Witnessed pill intake (if subject is taking antihypertensive medications), Complete after OBP measurements. | | | | | | | | | X | X | | Renal Denervation or Sham Procedure | | | | X | | | | | | | | Office Blood Pressure | X | X | X | | X | X | X | X | X | X | | 24-Hour ABPM | | | X | | | | X | | X | X | | Blood Tests (uric acid, lipid panel and high-sensitivity CRP² (hs-CRP)) | | | X | | | | | | | | | Blood Tests (Chem-7)⁴ | | | X | | X | X (4 wk only) | X | | X | X | | Blood Tests (renin and aldosterone) | | | X | | | | X | | | | | Serum or Urine Pregnancy Test | | | X | | | | | | | | | Drug testing | | | X | | | | X | X | X | X | | Renal Artery Imaging -Angiogram | | | | X | | | | | | | | Renal Artery Imaging | | | X⁵ | | | | | X | X¹ | ⁵ | | Blinding Assessment | | | | | X | | X | | X | | | EQ-5D and SF-36 | | | X | | | | X | | X | X | | Mortality Assessment² | | | | | | X (4 weeks and 8 weeks) | X | | X | X | | Medication Review, Event Review | All adverse events (AE) and medication review. After 12 months, previously reported AEs will need to be reviewed and updated as needed | | | | | | | | SAE and all Medication Review | | | 3 Months (90 days): 76-104 days, 4 Months (120 days): 113 -127 days, 6 Months (180 days): 166-194 days, 12 Months (360 days): 330-390 days, 24 Months (720 days): 690-750 days, 36 Months (1080 days): 1050-1110 days | | | | | Post-Procedure Assessment Windows: Wk= ± 3 days; M months ± 14 days for 3M and 6M visits; ±30 days for 12M-36M visits | | | | | | PMA P220026: FDA Summary of Safety and Effectiveness Data {19} Table 9. HTN-ON MED Study Follow-Up Schedule | Required Assessments | Screening visit 1 | Screening visit 2 | rfRDN or Sham Procedure | Prior to Discharge | 1M | 3M | 6M | 12M-36M | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Medical History | X | | | | | | | | | Clinical assessment | | X | | | X | X | X | X | | Renal Denervation or Sham Procedure | | | X | | | | | | | Office Blood Pressure | X | X | | X | X | X | X | X | | 24-Hour ABPM | | X | | | | X | X | X | | Witnessed pill taking | | X | | | | X | X | X | | Blood tests (uric acid, lipid panel and high sensitivity CRP^{b}) | | X | | | | | | | | Blood Tests (Chem-7)^{1} | | X | | X | X | X | X | X | | Serum or Urine Pregnancy Test | | X | | | | | | | | Drug testing | | X | | | | X | X | X | | Renal Artery Imaging - Angiogram | | | X | | | | | | | Renal Artery Imaging - Duplex Ultrasound | | X^{4} | | | | X | X^{1} | 5 | | Blinding Assessment for Subjects and Assessors | | | | X | | X | X | | | EQ-5D | | X | | | | X | X | X | | Mortality Assessment^{2} | | | | | X | X | X | X | | Medication Review and Event Review | All adverse events (AE) and all medication review After 12 months, previously reported AEs need to be reviewed and updated as needed. Serious AEs and all medication review continue at 24M and 36M. | | | | | | | | | 1 month (30 days): 16-44 days, 3 months (90 days): 76-104 days, 6 months (180 days): 166-194 days, 12 months (360 days): 330-390 days, 24 months (720 days): 690-750 days, 36 months (1080 days): 1050-1110 days. | Post-Procedure (M=months ± 14 days for 1M, 3M and 6M visits, months ± 30 days for 12M-36M visits) | | | | | | | | | 1 DUS required as first line imaging modality at 6M. Repeat DUS, MRA, CTA or angiogram to be used if DUS is nondiagnostic. Renal angiography used if repeat DUS/CTA/MRA nondiagnostic or >60-70% diameter stenosis suspected. The 6M DUS not required for subjects crossing over at 6M if crossover is completed within 30 days of 6M visit. 2 Conduct if follow-up missed. 3 Bicarbonate not measured for subjects enrolled in Japan and Europe. 4 Baseline duplex ultrasound, CTA, or MRA submitted if obtained per standard of care prior to procedure within one year from the date of screening visit 1. 5 CTA/MRA required as first line imaging modality at 12M (and 24M and 36M as applicable). For treatment and crossover subjects only: Repeat DUS, MRA, or CTA used if prior imaging modality nondiagnostic. If repeat DUS/CTA/MRA nondiagnostic or evidence of a clinically significant stenosis (>60-70%) seen, an angiogram must be obtained and submitted to the Angiographic Core Laboratory. Subjects who have already completed their 12-month follow-up without renal imaging required to undergo renal imaging at next scheduled follow-up unless they have a renal angiogram due to crossover. For the participating sites in Germany and the UK, only renal MRA imaging at the 12-month follow-up visit (or 24 or 36M follow-up as applicable) performed. For these countries, if the initial MRA is non-diagnostic, a repeat MRA should be performed. If the initial MRA or repeat renal MRAs are non-diagnostic and an additional repeat MRA is not expected to yield the required information for a diagnostic study, a DUS can be completed. 6 High-sensitivity CRP not required for subjects enrolled at sites where high-sensitivity CRP test cannot be locally performed. | | | | | | | | | PMA P220026: FDA Summary of Safety and Effectiveness Data {20} PMA P220026: FDA Summary of Safety and Effectiveness Data # 3. Clinical Endpoints ## Primary Safety Endpoint The pre-specified primary safety analysis was a pooled analysis of first 253 evaluable rfRDN-treated subjects (initial procedure or crossover) from the HTN-OFF MED and HTN-ON MED trials, defined as a patient-level composite of the incidence of the following major adverse events (MAEs): - 1-month post-randomization adjudicated by the clinical events committee - All-cause mortality - End stage renal disease - Significant embolic events resulting in end-organ damage - Renal artery perforation requiring intervention - Renal artery dissection requiring intervention - Vascular complications (e.g., complications that require surgical repair, interventional procedures, thrombin injection or blood transfusion) - Hospitalization for hypertensive crisis not related to non-adherence with BP medications or the study protocol And - Renal artery stenosis (RAS) at 6 months, as defined as &gt;70% diameter stenosis by angiography confirmed by the angiographic core lab Events for the composite MAE were adjudicated by the Clinical Events Committee (CEC). A performance goal of 7.1% for the primary safety endpoint was derived from a literature review of event rates for renal interventions, such as renal stenting. Under the assumption that the true rate is 3.5%, and using a one-sided 0.05 level of significance, an evaluable sample size of 253 renal denervation patients yields 80% power to reject the null hypothesis in favor of the alternative. The exact binomial test was used for the sample size calculation for the primary safety endpoint hypothesis. ## Primary Effectiveness Endpoint The primary effectiveness endpoints for HTN-OFF MED and HTN-ON MED were evaluated on the intent-to-treat (ITT) population, which included all randomized patients analyzed according to their randomized treatment, using a Bayesian power prior approach adjusting for baseline BP (primary analysis), frequentist analysis of covariance (ANCOVA) adjusting for baseline BP, and other alternative approaches. The primary effectiveness endpoint was defined as: - HTN-OFF MED: Change in SBP from baseline to 3-months post-procedure (prior to restarting BP medications) measured by 24-hour ABPM between the rfRDN and Sham groups - HTN-ON MED: Change in SBP from baseline to 6-months post-procedure measured by 24-hour ABPM between the rfRDN and Sham groups {21} PMA P220026: FDA Summary of Safety and Effectiveness Data # Powered Secondary Effectiveness Endpoint for HTN-OFF MED - Change in office SBP from baseline to 3 months post-procedure compared between treatment groups using a Bayesian power prior approach adjusting for baseline SBP # Secondary Effectiveness Endpoint for HTN-OFF MED and HTN-ON MED - Change in SBP from baseline (screening visit 2) to 3, 6, 12, 24, and 36 months post-procedure measured by 24-hour ABPM - Change in office SBP from baseline (screening visit 2) to 1, 3, 6, 12, 24, and 36 months post-procedure - Proportion of subjects achieving target OBP (SBP &lt; 140 mmHg) at 1, 3, 6, 12, 24, and 36 months post-procedure - Change in office DBP from baseline (screening visit 2) to 1, 3, 6, 12, 24, and 36 months post-procedure - Change in DBP from baseline (screening visit 2) to 3, 6, 12, 24 and 36 months post-procedure measured by 24-hour ABPM - Quality of life (QOL) assessed by EQ5D and SF36 (HTN-OFF MED only) - Antihypertensive medication usage throughout the study, including elevated BP escape patients and subjects with medication changes within 3-months (HTN-OFF MED) and 6-months (HTN-ON MED) follow-up. Medication burden is reported using two indices: MedIndex 1: The ratio of prescribed daily doses to maximum recommended daily dose, summed for all prescribed antihypertensive drugs $$ \text{MedIndex 1} = \sum_{\text{no.meds}} \left( \text{class weight} \left[ \frac{\text{prescribed dose}}{\text{maximum dose}} \right] \right) $$ MedIndex 2: MedIndex1 multiplied by number of medications $$ \text{MedIndex 2} = \sum_{\text{no.meds}} \text{no.meds} \left( \text{class weight} \left[ \frac{\text{prescribed dose}}{\text{maximum dose}} \right] \right) $$ # Secondary Safety Endpoints for HTN-OFF MED and HTN-ON MED - Acute procedural events at 1-month post-procedure (rfRDN vs. Sham subjects) at 1 month post-procedure: - Significant embolic event resulting in end-organ damage - Renal artery perforation or dissection requiring intervention - Vascular complications - End-stage renal disease - ≥40% decline in eGFR {22} PMA P220026: FDA Summary of Safety and Effectiveness Data - New MI or stroke - Renal artery re-intervention - Major bleeding per the TIMI definition (intracranial hemorrhage, ≥5 g/dl decrease in hemoglobin concentration, ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure) - Increase in serum creatinine &gt;50% from Screening Visit 2 - Renal artery stenosis (&gt;70% diameter stenosis) confirmed by angiography and determined by the angiographic core laboratory - Hospitalization for hypertensive crisis not related to non-adherence with BP medications or study protocol - Chronic safety endpoints at 3, 6, 12, 24, and 36 months post-procedure (rfRDN vs. Sham subjects) - All-cause mortality - End-stage renal disease - Significant embolic event resulting in end-organ damage - ≥40% decline in eGFR - New MI or stroke - Renal artery re-intervention - Major bleeding per the TIMI definition - Increase in serum creatinine &gt;50% vs. screening visit 2 - Renal artery stenosis (&gt;70% diameter stenosis confirmed by angiography and determined by the angiographic core laboratory (at 6 and 12 months), or if renal artery imaging was performed outside of the protocol-specified windows - Hospitalization for hypertensive crisis not related to non-adherence with BP medications or the study protocol - RAS through 12-month based on CTA/MRA imaging. A sub-study was performed on at least 150 HTN-OFF MED or HTN-ON MED rfRDN patients to assess renal artery damage and diameter stenosis &lt;70%. ## B. Accountability of PMA Cohort ### HTN-OFF MED At the time of database lock, of 366 patients randomized in the HTN-OFF MED study, 99.7% (365) patients are available for analysis at the 3 month/ follow-up visit (final visit evaluated for safety and effectiveness as the basis for the PMA submission). Figure 3 shows subject accountability through 12 months for the HTN-OFF MED Full Cohort, including the crossover group which received rfRDN &gt;6-months the post-sham procedure. Of the first 80 Pilot Cohort patients, 38 were randomized to the rfRDN group and 42 to the Sham group. In the Expansion Cohort, 251 patients were randomized for a total of 331 patients (166 patients to rfRDN and 165 patients to Sham). An additional 35 patients were randomized {23} prior to stopping enrollment for success (182 rfRDN and 184 Sham = 366 total), which comprise the Full cohort (Figure 3). At the 3-month timepoint, 155 patients in the rfRDN group and 147 patients in the Sham group completed an evaluable 24-hour BP assessment (Figure 4). After 6 months, patients were unblinded and Sham patients were given the option to receive rfRDN procedure (cross over) if they met the anatomical and kidney function criteria. Over 75% of Sham patients opted to crossover to receive rfRDN. ![img-2.jpeg](img-2.jpeg) Figure 3. HTN-OFF MED Full Cohort Subject Accountability through 12 Months PMA P220026: FDA Summary of Safety and Effectiveness Data {24} Figure 4: HTN-OFF MED Full Cohort Blood Pressure Endpoint Data Capture Through 12 Months ![img-3.jpeg](img-3.jpeg) Escape defined as Office SBP $\geq 180\mathrm{mmHg}$ OR $&lt; 115\mathrm{mmHg}$ associated with symptoms of hypotension or safety concern requiring medication changes. # HTN-ON MED At the time of database lock, of 337 patients enrolled in the HTN-ON MED study, $97.9\%$ (330) of patients were available for analysis at the 6 month follow-up visit (final visit evaluated for safety and effectiveness as the basis for the PMA submission). Figure 5 shows subject accountability through 12 months for the HTN-ON MED Full Cohort. Of the first 80 Pilot Cohort patients, 38 were randomized to the rfRDN group and 42 to the Sham group. An additional 257 patients were randomized in the Expansion Cohort for a total of 337 patients forming the Full Cohort (206 patients in the rfRDN group and 131 in the Sham group, Figure 5). A total of 181 $(54\%)$ patients were enrolled outside the US. PMA P220026: FDA Summary of Safety and Effectiveness Data {25} At the 6-month timepoint, 192 patients in the rfRDN group and 116 patients in the Sham group completed an evaluable 24-hour BP assessment (Figure 6). Notably, $80\%$ of patients in the Expansion Cohort had primary endpoint visits during the COVID-19 pandemic. ![img-4.jpeg](img-4.jpeg) Figure 5: HTN-ON MED Full Cohort Subject Accountability Through 12 Months PMA P220026: FDA Summary of Safety and Effectiveness Data {26} ![img-5.jpeg](img-5.jpeg) Escape defined as Office SBP $\geq 180\mathrm{mmHg}$ OR $&lt; 115\mathrm{mmHg}$ associated with symptoms of hypotension or safety concern requiring medication changes. Figure 6: HTN-ON MED Full Cohort Blood Pressure Endpoint Data Capture Through 12 Months # C. Study Population Demographics and Baseline Parameters # 1. HTN-OFF MED Baseline Demographics / Characteristics Baseline characteristics were well-balanced between the rfRDN and Sham groups and between Pilot and Expansion Cohorts. The majority of patients were male and white, and the median age was 53 years (Table 10). Most patients had hypertension for $&gt;5$ years, and there was a low incidence of comorbidities such as diabetes and sleep apnea. Coronary artery disease was the only characteristic that was significantly different in the Full Cohort $(p = 0.007)$ between the two treatment groups (0% in the rfRDN group; 4.3% (8/184) in the Sham group). PMA P220026: FDA Summary of Safety and Effectiveness Data {27} Table 10. HTN-OFF MED Select Baseline Characteristics | | Pilot Cohort | | Expansion Cohort | | Full Cohort (Pilot + Expansion + Add'l Subjects) | | | --- | --- | --- | --- | --- | --- | --- | | Subject Baseline Characteristic | rfRDN (N=38 Subjects) | Sham (N=42 Subjects) | rfRDN (N=128 Subjects) | Sham (N=123 Subjects) | rfRDN (N=182 Subjects) | Sham (N=184 Subjects) | | Age (yrs) | 55.8 ± 10.1 | 52.8 ± 11.5 | 51.4 ± 10.9 | 52.5 ± 10.0 | 52.5 ± 10.8 | 52.7 ± 10.1 | | Male | 68.4% (26/38) | 73.8% (31/42) | 63.3% (81/128) | 66.7% (82/123) | 64.3% (117/182) | 69.6% (128/184) | | Length of hypertension diagnosis >5 yrs | 60.5% | 42.9% | 53.9% | 58.5% | 56.1% (102/182) | 56.0% (103/184) | | Geography | | | | | | | | US | 34.2% (13/38) | 34.2% (13/38) | 55.5% (71/128) | 52.8% (65/123) | 50% (91/182) | 46.2% (85/184) | | OUS | 64.8% (25/38) | 64.8% (25/38) | 44.5% (57/128) | 47.2% (58/123) | 50% (91/182) | 53.8% (99/184) | | Race | | | | | | | | White | 26.3% (10/38) | 23.8% (10/42) | 28.9% (37/128) | 32.5% (40/123) | 30.8% (56/182) | 32.6% (60/184) | | Black or African American | 13.2% (5/38) | 11.9% (5/42) | 24.2% (31/128) | 21.1% (26/123) | 20.3% (37/182) | 17.4% (32/184) | | Asian | 2.6% (1/38) | 2.4% (1/42) | 3.9% (5/128) | 0.8% (1/123) | 3.8% (7/182) | 1.1% (2/184) | | Japanese from Japan | 5.3% (2/38) | 4.8% (2/42) | 0.8% (1/128) | 0.0% (0/123) | 1.6% (3/182) | 1.1% (2/184) | | Not reportable per local laws or regulations | 52.6% (20/38) | 57.1% (24/42) | 41.4% (53/128) | 44.7% (55/123) | 42.9% (78/182) | 47.3% (87/184) | | Other | 0.0% (0/38) | 0.0% (0/42) | 0.8% (1/128) | 0.8% (1/123) | 0.5% (1/182) | 0.5% (1/184) | | Hispanic/Latino/Spanish origin | | | | | | | | Yes | 2.6% (1/38) | 2.4% (1/42) | 3.1% (4/128) | 1.6% (2/123) | 2.7% (5/182) | 2.2% (4/184) | | No | 44.7% (17/38) | 40.5 (17/42) | 54.7% (70/128) | 53.7% (66/123) | 53.8% (98/182) | 50.5% (93/184) | | Not reportable per local law or reg | 52.6% (20/38) | 57.1% (24/42) | 41.4% (53/128) | 44.7% (55/123) | 42.9% (78/182) | 47.3% (87/184) | | Unknown | 0.0% (0/38) | 0.0% (0/42) | 0.8% (1/128) | 0.0% (0/123) | 0.5% (1/182) | 0.0% (0/184) | | BMI | 29.8 ± 5.1 | 30.2 ± 5.1 | 31.5 ± 6.1 | 31.1 ± 5.6 | 31.2 ± 6.0 | 31.0 ± 5.5 | | Diabetes Mellitus Type 2 | 2.6% (1/38) | 7.1% (3/42) | 3.9% (5/128) | 4.9% (6/123) | 4.4% (8/182) | 6.0% (11/184) | | Current Smoker | 10.5% (4/38) | 23.8% (10/42) | 18.8% (24/128) | 13.8% (17/123) | 17.0% (31/182) | 15.8% (29/184) | | Obstructive sleep apnea | 7.9% (3/38) | 7.1% (3/42) | 8.6% (11/128) | 7.3% (9/123) | 8.2% (15/182) | 7.1% (13/184) | PMA P220026: FDA Summary of Safety and Effectiveness Data {28} | | Pilot Cohort | | Expansion Cohort | | Full Cohort (Pilot + Expansion + Add'l Subjects) | | | --- | --- | --- | --- | --- | --- | --- | | Subject Baseline Characteristic | rfRDN (N=38 Subjects) | Sham (N=42 Subjects) | rfRDN (N=128 Subjects) | Sham (N=123 Subjects) | rfRDN (N=182 Subjects) | Sham (N=184 Subjects) | | History of coronary artery disease* | 0.0% (0/38) | 4.8% (2/42) | 0.0% (0/128) | 4.9% (6/123) | 0.0% (0/182) | 4.3% (8/184) | | History of stroke / transient ischemic attack* | 5.3% (2/38) | 0.0% (0/42) | 0.0% (0/128) | 0.0% (0/123) | 1.1% (2/182) | 0.0% (0/184) | | Peripheral Artery Disease | 2.6% (1/38) | 0.0% (0/42) | 0.0% (0/128) | 0.0% (0/123) | 0.5% (1/182) | 0.0% (0/184) | *Occurring &gt; 3 months before randomization Data displayed as % (n/N) Table 11: HTN-OFF MED Patient Baseline Blood Pressure | | Pilot Cohort | | Expansion Cohort | | Full Cohort (Pilot + Expansion + Add'l Subjects) | | | --- | --- | --- | --- | --- | --- | --- | | Subject Baseline Blood Pressure (mmHg) | rfRDN (N=38 subjects) | Sham (N=42 subjects) | rfRDN (N=128 Subjects) | Sham (N=123 Subjects) | rfRDN (N=182) | Sham (N=184) | | Office measurements | | | | | | | | Systolic blood pressure | 162.0 ± 7.6 | 161.4 ± 6.4 | 162.9 ± 7.9 | 163.4 ± 7.8 | 162.8 ± 7.8 | 163.2 ± 7.7 | | Diastolic blood pressure | 99.9 ± 6.8 | 101.5 ± 7.5 | 101.6 ± 7.0 | 102.2 ± 7.0 | 101.1 ± 7.1 | 102.2 ± 7.3 | | 24-hour measurements (ABPM) | | | | | | | | Systolic blood pressure | 153.4 ± 9.0 | 151.6 ± 7.4 | 150.8 ± 7.7 | 150.8 ± 7.5 | 151.2 ± 7.9 | 151.3 ± 7.6 | | Diastolic blood pressure | 99.1 ± 7.7 | 98.7 ± 8.2 | 97.6 ± 7.7 | 99.2 ± 7.2 | 97.6 ± 7.9 | 99.3 ± 7.5 | Data displayed as mean ± SD PMA P220026: FDA Summary of Safety and Effectiveness Data {29} # Procedure Characteristics The mean procedure time, defined as the time from when arterial access was obtained until arterial closure, was 99 minutes in the rfRDN group. The denervation time was approximately 1 hour (Table 12). Pain medication requirements were significantly greater in the rfRDN group. Table 12: HTN-OFF MED Procedure Characteristics (Full Cohort) | Treatment | rfRDN (N=182) | Sham (N=184) | Crossover (N=125) | | --- | --- | --- | --- | | Procedure Time1 (minutes) | | | | | Mean ± SD | 99.3 ± 36.2 | 52.9 ± 16.6 | 80.2 ± 26.1 | | Median (min, max) | 93.0 (40, 239) | 51.5 (25, 128) | 77.0 (32, 196) | | Amount of Contrast used (cc) | 207.8 ± 96.1 | 74.1 ± 37.4 | 171.2 ± 75.5 | | Intra-procedural medication | | | | | Pain Meds | 29.7% (54/182) | 17.4% (32/184) | 24.8% (31/125) | | Sedatives/Anxiolytics | 100.0% (182/182) | 98.4% (181/184) | 96.8% (121/125) | | Atropine | 2.2% (4/182) | 0.0% (0/184) | 3.2% (4/125) | | Hospital Stay (days) | 1.0 ± 0.1 | 1.0 ± 0.2 | 1.0 ± 0.2 | | Device Success3 | 100.0% (181/181) | -- | 100.0% (125/125) | | Procedural Success4 | 100.0% (181/181) | -- | 100.0% (125/125) | | Denervation Time4 (minutes) | | | | | Mean ± SD | 59.7 ± 24.3 | NA | 53.1 ± 19.1 | | Median (min, max) | 55.0 (10, 207) | | 49.0 (20, 135) | | Number of Ablation Attempts | | | | | n5 | 181 | NA | 125 | | Mean ± SD | 46.6 ± 15.3 | | 47.2 ± 16.1 | | Median (min, max) | 45.0 (18, 109) | | 45.0 (22, 117) | | Number of Main Arteries Treated | | | | | n5 | 181 | NA | 125 | | Mean ± SD | 2.2 ± 0.6 | | 2.3 ± 0.6 | | Median (min, max) | 2.0 (1, 5) | | 2.0 (2, 4) | | Number of Main Arteries Ablations | | | | | n5 | 181 | NA | 125 | | Mean ± SD | 18.2 ± 9.7 | | 17.8 ± 8.8 | | Median (min, max) | 16.0 (1, 62) | | 16.0 (5, 60) | | Number of Branches Treated | | | | | n5 | 181 | NA | 125 | | Mean ± SD | 5.8 ± 2.6 | | 6.0 ± 2.5 | | Median (min, max) | 6.0 (0, 17) | | 6.0 (0, 14) | PMA P220026: FDA Summary of Safety and Effectiveness Data {30} PMA P220026: FDA Summary of Safety and Effectiveness Data # 2. HTN-ON MED Baseline Demographics / Characteristics Baseline characteristics were well-balanced between the rfRDN and Sham groups and between Pilot and Expansion Cohorts (Table 13), except there was a slightly higher proportion of US subjects in the Expansion Cohort compared with Pilot Cohort (data not shown). In the Full Cohort, both the rfRDN and Sham groups were predominantly male (81.1% vs 78.6%) with median ages of 56 and 55 years, respectively. Subjects were mostly white or race not reported. The rate of patients reported as Black or African American was 17.0% and 19.1% in the rfRDN and Sham groups, respectively. Table 13: HTN-ON MED Select Baseline Characteristics | | Pilot Cohort | | Expansion Cohort | | Full Cohort (Pilot + Expansion) | | | --- | --- | --- | --- | --- | --- | --- | | Subject Baseline Characteristic | rfRDN (N=38 Subjects) | Control (N=42 Subjects) | rfRDN (N=168 Subjects) | Control (N=89 Subjects) | rfRDN (N=206 Subjects) | Control (N=131 Subjects) | | Age (yrs) | 53.9 ± 8.7 | 53.0 ± 10.7 | 55.5 ± 9.0 | 55.4 ± 8.7 | 55.2 ± 9.0 | 54.6 ± 9.4 | | Male | 86.8% (33/38) | 81.0% (34/42) | 79.8% (134/168) | 77.5% (69/89) | 81.1% (167/206) | 78.6% (103/131) | | Length of hypertension diagnosis >5 yrs | 60.5% (23/38) | 81.0% (34/42) | 72.1% (121/168) | 82.0% (73/89) | 69.9% (144/206) | 81.7% (107/131) | | Geography | | | | | | | | US | 39.5% (15/38) | 42.9% (18/42) | 45.2% (76/168) | 52.8% (47/89) | 44.2% (91/206) | 49.6% (65/131) | | OUS | 60.5% (23/38) | 57.1% (24/42) | 54.8% (92/168) | 47.2% (42/89) | 55.8% (115/206) | 50.4% (66/131) | 31 {31} | | Pilot Cohort | | Expansion Cohort | | Full Cohort (Pilot + Expansion) | | | --- | --- | --- | --- | --- | --- | --- | | Subject Baseline Characteristic | rfRDN (N=38 Subjects) | Control (N=42 Subjects) | rfRDN (N=168 Subjects) | Control (N=89 Subjects) | rfRDN (N=206 Subjects) | Control (N=131 Subjects) | | Race | | | | | | | | White | 34.2% (13/38) | 35.7% (15/42) | 34.5% (58/168) | 37.1% (33/89) | 34.5% (71/206) | 36.6% (48/131) | | Black or African American | 10.5% (4/38) | 11.9% (5/42) | 18.5% (31/168) | 22.5% (20/89) | 17.0% (35/206) | 19.1% (25/131) | | Asian | 0.0% (0/38) | 2.4% (1/42) | 1.2% (2/168) | 3.4% (3/89) | 1.0% (2/206) | 3.1% (4/131) | | Japanese from Japan | 7.9% (3/38) | 2.4% (1/42) | 7.1% (12/168) | 5.6% (5/89) | 7.3% (15/206) | 4.6% (6/131) | | Not reportable per local laws or regulations | 47.4% (18/38) | 47.6% (20/42) | 36.9% (62/168) | 29.2% (26/89) | 38.8% (80/206) | 35.1% (46/131) | | Other | 0.0% (0/38) | 0.0% (0/42) | 0.0% (0/168) | 1.1% (1/89) | 0.0% (0/206) | 0.8% (1/131) | | Hispanic/Latino/Spanish origin | | | | | | | | Yes | 0% (0/38) | 0% (0/42) | 1.8% (3/168) | 4.5% (4/89) | 1.5% (3/206) | 3.1% (4/131) | | No | 52.6% (20/38) | 52.4% (22/42) | 60.7% (102/168) | 65.2% (58/89) | 59.2% (122/206) | 61.1% (80/131) | | Not reportable per local law or reg | 47.4% (18/38) | 47.6% (20/42) | 36.9% (62/168) | 30.3% (27/89) | 38.8% (80/206) | 35.9% (47.131) | | Unknown | 0.0% (0/38) | 0.0% (0/42) | 0.6% (1/168) | 0.0% (0/89) | 0.5% (1/206) | 0.0% (0/131) | | BMI | 31.4 ± 6.4 | 32.5 ± 4.6 | 31.4 ± 6.0 | 32.0 ± 5.4 | 31.4 ± 6.0 | 32.1 ± 5.2 | | Diabetes Mellitus Type 2 | 13.2% (5/38) | 19.0% (8/42) | 10.1% (17/168) | 16.9% (15/89) | 10.7% (22/206) | 17.6% (23/131) | | Current Smoker | 21.1% (8/38) | 26.2% (11/42) | 14.3% (24/168) | 11.2% (10/89) | 15.5% (32/206) | 16.0% (21/131) | | Obstructive sleep apnea | 5.3% (2/38) | 23.8% (10/42) | 12.5% (21/168) | 14.6% (13/89) | 11.2% (23/206) | 17.6% (23/131) | | History of coronary artery disease | 2.6% (1/38) | 2.4% (1/42) | 6.0% (10/168) | 9.0% (8/89) | 5.3% (11/206) | 6.9% (9/131) | | History of stroke / transient ischemic attack* | 0.0% (0/38) | 2.4% (1/42) | 0.6% (1/168) | 1.1% (1/89) | 0.5% (1/206) | 1.5% (2/131) | | Peripheral Arterial Disease | 0.0% (0/38) | 0.0% (0/42) | 0.0% (0/168) | 0.0% (0/89) | 0.0% (0/206) | 0.0% (0/131) | *Occurring &gt; 3 months before randomization Data displayed as % (n/N) PMA P220026: FDA Summary of Safety and Effectiveness Data {32} Baseline systolic and diastolic BPs and rates of comorbidities were similar between groups (Table 14). The majority of patients in the rfRDN and Sham groups had hypertension for $&gt;5$ years (69.9% vs 79.4%, respectively, Table 13). Table 14: HTN-ON MED Patient Baseline Blood Pressure | Subject Baseline Blood Pressure(mmHg) | Pilot Cohort | | Expansion Cohort | | Full Cohort | | | --- | --- | --- | --- | --- | --- | --- | | | rfRDN N = 38 | Sham N = 42 | rfRDN N = 168 | Sham N = 89 | rfRDN N = 206 | Sham N = 131 | | Office measurements | | | | | | | | Systolic blood pressure | 164.4 ± 7.0 | 163.5 ± 7.5 | 162.6 ± 7.8 | 162.9 ± 8.2 | 163.0 ± 7.7 | 163.1 ± 7.9 | | Diastolic blood pressure | 99.5 ± 6.9 | 102.7 ± 8.0 | 101.5 ± 6.9 | 100.9 ± 6.9 | 101.2 ± 7.0 | 101.5 ± 7.3 | | 24-hour measurements (ABPM) | | | | | | | | Systolic blood pressure | 152.1 ± 7.0 | 151.3 ± 6.8 | 149.0 ± 6.8 | 148.3 ± 6.9 | 149.6 ± 7.0 | 149.3 ± 7.0 | | Diastolic blood pressure | 97.2 ± 6.9 | 97.9 ± 8.4 | 96.5 ± 7.7 | 94.6 ± 7.2 | 96.6 ± 7.6 | 95.7 ± 7.7 | Both the rfRDN and Sham groups were prescribed an average of 1.9 anti-hypertensive medication classes at baseline, and drug testing for medication adherence showed that rfRDN patients were taking an average of 1.7 anti-hypertensive medication classes vs. 1.6 in the Sham group (Table 15). Table 15: HTN-ON MED Full Cohort Baseline Anti-Hypertensive Medications Detected by Drug Testing | Category | Baseline Prescribed Regimen | | Medications Detected by Drug Testing at Baseline | | | --- | --- | --- | --- | --- | | | rfRDN (N=206) | Sham (N=131) | rfRDN (N=206) | Sham (N=131) | | Number of anti-hypertensive medication classes | | | | | | Mean ± SD | 1.9 ± 0.8 | 1.9 ± 0.8 | 1.7 ± 0.9 | 1.6 ± 0.9 | | Median | 2.0 | 2.0 | 2.0 | 1.0 | | Min, Max | 1, 4 | 1, 4 | 0, 5 | 0, 5 | | Number of medication classes, n (%) | | | | | | 1 | 80 (38.8%) | 47 (35.9%) | 80 (38.8%) | 57 (43.5%) | | 2 | 67 (32.5%) | 47 (35.9%) | 78 (37.9%) | 41 (31.3%) | | 3 | 58 (28.2%) | 36 (27.5%) | 29 (14.1%) | 20 (15.3%) | | 4** | 1 (0.5%) | 1 (0.8%) | 6 (2.9%) | 2 (1.5%) | PMA P220026: FDA Summary of Safety and Effectiveness Data {33} | Category | Baseline Prescribed Regimen | | Medications Detected by Drug Testing at Baseline | | | --- | --- | --- | --- | --- | | | rfRDN (N=206) | Sham (N=131) | rfRDN (N=206) | Sham (N=131) | | Medication class, n (%) | | | | | | Diuretic | 84 (40.8%) | 57 (43.5%) | 49 (23.8%) | 34 (26.0%) | | Calcium Channel Blocker | 110 (53.4%) | 73 (55.7%) | 106 (51.5%) | 59 (45.0%) | | ACE-I/ARB | 158 (76.7%) | 99 (75.6%) | 145 (70.4%) | 87 (66.4%) | | Beta Blocker | 37 (18.0%) | 24 (18.3%) | 38 (18.4%) | 26 (19.8%) | | Other | 1* (0.5%) | 0 | 9 (4.4%) | 2 (1.5%) | ACE-I: angiotensin-converting enzyme inhibitor; ARB; angiotensin receptor blocker; SD: standard deviation *Vasodilator **One patient was prescribed Metoprolol at baseline for a "Heart Disease" indication in addition to 3 other anti-hypertensive medication classes. ## Procedure Characteristics The mean procedure time, defined as the time from when arterial access was obtained until arterial closure, was 91 minutes in the rfRDN group. The denervation time was 54 minutes (Table 16). At the time of the PMA submission, crossover data were only available from 24 subjects in the Pilot Cohort. Table 16: HTN-ON MED Full Cohort Procedure Characteristics | Treatment | rfRDN (N=206) | Sham (N=131) | Pilot Crossover (N=24) | | --- | --- | --- | --- | | Procedure Time¹ (minutes) | | | | | Mean ± SD | 91.3 ± 31.2 | 51.2 ± 19.5 | 82.9 ± 26.9 | | Median (min, max) | 88.5 (33, 210) | 48.0 (23, 162) | 80.0 (40, 160) | | Amount of Contrast used (cc) | 204.2 ± 81.4 | 69.9 ± 35.8 | 196.0 ± 93.7 | | Intra-procedural medication | | | | | Pain meds | 21.8% (45/206) | 17.6% (23/131) | 33.3% (8/24) | | Sedatives/Anxiolytics | 98.5% (203/206) | 98.5% (129/131) | 95.8% (23/24) | | Atropine | 2.9% (6/206) | 0.0% (0/131) | 12.5% (3/24) | | Hospital Stay (days) | 1.0 ± 0.2 | 1.0 ± 0.2 | 1.0 ± 0.0 | | Device success² | 100.0% (205/205) | -- | 100.0% (24/24) | | Procedure success³ | 99.5% (204/205) | -- | 100.0% (24/24) | | Denervation Time⁴ (minutes) | | | | | Mean ± SD | 54.4 ± 19.2 | NA | 53.1 ± 27.0 | | Median (min, max) | 52.0 (17, 133) | | 52.0 (0, 141) | | Number of Ablation Attempts | | | | | n⁵ | 205 | NA | 24 | | Mean ± SD | 47.4 ± 16.5 | | 50.8 ± 21.6 | ¹ PMA: Patient Association of Medical Officers; SD: Standard Deviation ² PMA: Patient Association of Medical Officers; SD: Standard Deviation PMA P220026: FDA Summary of Safety and Effectiveness Data {34} | Treatment | rfRDN (N=206) | Sham (N=131) | Pilot Crossover (N=24) | | --- | --- | --- | --- | | Median (min, max) | 44 (16, 107) | | 45 (17, 115) | | Number of Main Arteries Treated | | | | | n^{5} | 205 | NA | 24 | | Mean ± SD | 2.3 ± 0.6 | | 2.2 ± 0.4 | | Median (min, max) | 2.0 (1, 5) | | 2.0 (2, 3) | | Number of Main Arteries Ablations | | | | | n^{5} | 205 | NA | 24 | | Mean ± SD | 19.4 ± 9.5 | | 18.5 ± 7.8 | | Median (min, max) | 18.0 (5, 82) | | 18.5 (0, 33) | | Number of Branches Treated | | | | | n^{5} | 205 | NA | 24 | | Mean ± SD | 5.8 ± 2.7 | | 7.4 ± 4.3 | | Median (min, max) | 6.0 (0, 14) | | 6.0 (2, 19) | | Number of Branch Ablations | | | | | n^{5} | 205 | NA | 24 | | Mean ± SD | 28.0 ± 14.6 | | 32.3 ± 18.2 | | Median (min, max) | 25.0 (0, 82) | | 28.5 (7, 86) | NA: not applicable; SD: standard deviation; 1 Arterial closure - arterial access obtained 2 Final Guide Catheter Removal - Initial Symplicity Spyral Catheter Insertion 3 Successful delivery of any RF 4 Successful delivery of any RF in the absence of in hospital MAE 5 Number of main arteries treated, not number of patients ## D. Safety Results Safety was evaluated in the pre-specified pooled safety population, which included the first 253 consecutive patients treated with rfRDN in the OFF and ON-MED studies. Safety evaluations were also performed for the individual studies comparing rfRDN to Sham and independently adjudicated by the CEC. ### 1. Primary Safety Endpoint Analysis The primary safety endpoint was the incidence of major adverse events (MAE) at 1-month post-procedure and renal artery stenosis evaluated at 6 months for the first 253 consecutive patients treated with rfRDN (initial procedure or crossover) in the HTN-OFF MED and HTN-ON MED studies. The primary safety endpoint results are shown in Table 17. The primary safety endpoint rate was 0.4% with one-sided upper 95% confidence interval of 1.9%. The 7.1% performance goal was met (p-value &lt; 0.001). PMA P220026: FDA Summary of Safety and Effectiveness Data {35} PMA P220026: FDA Summary of Safety and Effectiveness Data # Additional Analyses FDA also requested a post-hoc safety analysis on rfRDN-treated subjects from the four studies and all studies pooled using the same endpoint definitions. The results were similar across the studies, as shown in Table 17. There were 2 pseudoaneurysms 1 required surgical repair and 1 required thrombin injection. Table 17: Primary Safety Endpoint for the Pooled and Individual Studies (rfRDN Subjects) | | MAE Rate | One-sided upper 95% CI | p-value | | --- | --- | --- | --- | | Pre-specified Analysis of first 253 evaluable | 0.4% (1/253) | 1.9% | <0.001 | | All Subjects Pooled | 0.4% (2/537) | 1.2% | <0.001 | | HTN-OFF Full Cohort | 0.0% (0/182) | -- | -- | | HTN-OFF Crossover | 0.0% (0/125) | -- | -- | | HTN-ON Full Cohort | 1.0% (2/206) | -- | -- | | HTN-ON Crossover | 0.0% (0/24) | -- | -- | Data displayed as % (n/N) p-value for all pooled subjects not adjusted for multiplicity # 2. Secondary Safety Endpoint Results The rates of pre-specified MAE through 6 months for the HTN-OFF MED and HTN-ON MED (Full Cohorts) studies are shown in Table 18 for the rfRDN and Sham groups. The rates of MAEs were low and similar between the cohorts and studies. Table 18: HTN-OFF MED and HTN-ON MED MAEs through 6 months for rfRDN and Sham Subjects | | HTN-OFF % Subjects with Events (n/N) | | HTN-ON % Subjects with Events (n/N) | | | --- | --- | --- | --- | --- | | | rfRDN (n=182) n (%) | Sham (n=184) n (%) | rfRDN (n=206) n (%) | Sham (n=131) n (%) | | All-cause mortality | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | | New myocardial infarction | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | | Major Bleeding | 0 (0%) | 2 (1.1%) | 0 (0%) | 0 (0%) | | Significant embolic events resulting in end organ damage | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | | Any renal artery reintervention | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | | Vascular complications requiring surgical repair, interventional procedure, thrombin injection, or blood transfusion | 0 (0%) | 1 (0.5%) | 2(1.0%) | 1 (0.8%) | | Hypertensive emergency resulting in hospitalization | 1 (0.6%) | 0 (0%) | 0 (0%) | 0 (0%) | {36} | | HTN-OFF % Subjects with Events (n/N) | | HTN-ON % Subjects with Events (n/N) | | | --- | --- | --- | --- | --- | | | rfRDN (n=182) n (%) | Sham (n=184) n (%) | rfRDN (n=206) n (%) | Sham (n=131) n (%) | | New Stroke | 0 (0%) | 1 (0.5%) | 0 (0%) | 1 (0.8%) | | New renal artery stenosis (>70% diameter stenosis) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | Data displayed as % (n/N) In HTN-OFF MED, the incidence of serious AEs (SAEs) was similar between treatment groups and the majority of events were only experienced by one patient. The only SAEs that occurred in more than one patient were sepsis, vascular site hematoma, and arthralgia. SAEs were reported in 8.7% and 11.5% of patients randomized to rfRDN and Sham groups, respectively, in the HTN-ON MED study. The only event that was experienced by more than one patient was vascular access site pseudoaneurysm (Table 19). Table 19: HTN-OFF MED (24 Months) &amp; HTN-ON MED (6 Months) Serious Adverse Events in &gt;1 Patient | | HTN-OFF (24 Months) % Subjects with Events (n/N) | | HTN-ON (6 Months) % Subjects with Events (n/N) | | | --- | --- | --- | --- | --- | | | rfRDN (N=182) n (%) | Sham (N=184) n (%) | rfRDN (N=206) n (%) | Sham (N=131) n (%) | | Any Serious Adverse Event | 31 (17%) | 27 (14.7%) | 18 (8.7%) | 15 (11.5%) | | Sepsis | 2 (1.1%) | 2 (1.1%) | 0 (0%) | 0 (0%) | | Vascular Access Site Hematoma | 1 (0.5%) | 2 (1.1%) | 2 (1.0%) | 1 (0.8%) | | Arthralgia | 1 (0.5%) | 5 (2.7%) | 0 (0%) | 0 (0%) | | Vascular Access Site Pseudoaneurysm | 0 (0%) | 0 (0%) | 2 (1.0%) | 1 (0.8%) | Data displayed as % (n/N) 3. Adverse effects that occurred in the PMA clinical studies In the HTN-OFF MED study, 82% of patients in the rfRDN group and 84% of patients in the Sham group experienced an AE. The most common AEs reported were headache and vascular access site hematoma (Table 20). The incidence and severity of hematomas was similar between groups and is expected for arterial interventional procedures. Overall, AEs were balanced across study groups. PMA P220026: FDA Summary…
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