Paradise® Ultrasound Renal Denervation System

P220023 · Recor Medical, Inc. · QYI · Nov 7, 2023 · Cardiovascular

Device Facts

Record IDP220023
Device NameParadise® Ultrasound Renal Denervation System
ApplicantRecor Medical, Inc.
Product CodeQYI · Cardiovascular
Decision DateNov 7, 2023
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic

Indications for Use

The Paradise Ultrasound Renal Denervation System (Paradise System) is indicated to reduce blood pressure as an adjunctive treatment in hypertension patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure.

Device Story

The Paradise System is a catheter-based device used by interventional cardiologists in a clinical setting to perform renal denervation. It consists of a 6-French catheter with a piezoelectric ceramic ultrasound transducer inside an inflatable balloon, a generator, a cartridge, and a connection cable. The device is inserted percutaneously via the femoral artery under fluoroscopic guidance. The balloon is inflated in the renal artery, and the generator delivers ultrasound energy circumferentially to thermally ablate and disrupt renal sympathetic nerves. Sterile water is used as a coolant to protect the arterial wall during ablation. The generator uses sensors and control software to manage fluid flow and energy delivery. By reducing sympathetic nerve activity, the device aims to lower systemic arterial blood pressure. The procedure is performed under conscious sedation or anesthesia. The output is a thermal lesion in the peri-arterial tissue. The device is intended to benefit patients by providing an adjunctive treatment for hypertension when medications and lifestyle changes are insufficient.

Clinical Evidence

Evidence based on three prospective, multi-center, randomized, double-blind, sham-controlled clinical studies (RADIANCE-HTN SOLO, TRIO, and RADIANCE II) totaling 506 randomized subjects. Primary effectiveness endpoint was reduction in daytime ambulatory systolic BP at 2 months. SOLO and RADIANCE II met the primary endpoint (p<0.001). TRIO showed a trend (median difference -4.5 mmHg, p=0.0809). Safety was evaluated via a pooled analysis of 367 uRDN-treated patients; the composite Major Adverse Event (MAE) rate was 1.1% (95% CI 0.3%-2.77%). No evidence of clinically significant renal artery stenosis was observed in 238 uRDN subjects at 12 months.

Technological Characteristics

The system uses ultrasound energy for thermal ablation. The catheter features a piezoelectric ceramic transducer within an inflatable balloon (3.5-8 mm sizes). Materials are biocompatible per ISO 10993-1. The generator controls fluid flow (closed-loop coolant) and ultrasound power delivery. Connectivity includes a memory chip in the catheter for parameter storage. Sterilization is via 100% ethylene oxide. Software is used for procedure settings, sensor management, and energy control. Electrical safety and EMC conform to IEC 60601-1 and IEC 60601-1-2.

Indications for Use

Indicated for adult patients (≥18 and ≤75 years) with uncontrolled hypertension despite lifestyle modifications and antihypertensive medications. Contraindicated in patients with renal artery diameter <3 mm or >8 mm, fibromuscular dysplasia, stented renal artery, renal artery aneurysm, >30% 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

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: Paradise® Ultrasound Renal Denervation System Device Procode: QYI Applicant’s Name and Address: ReCor Medical, Inc. 1049 Elwell Court Palo Alto, CA 94303 Date(s) of Panel Recommendation: August 22, 2023 Premarket Approval Application (PMA) Number: P220023 Date of FDA Notice of Approval: November 7, 2023 Breakthrough Device: Granted breakthrough device status on December 4, 2020 for reducing blood pressure in patients with uncontrolled hypertension, who may be inadequately responsive to, or who are intolerant to anti-hypertensive medications. II. INDICATIONS FOR USE The Paradise Ultrasound Renal Denervation System (Paradise System) is indicated to reduce blood pressure as an adjunctive treatment in hypertension patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure. III. CONTRAINDICATIONS The Paradise Catheter is contraindicated in any of the following: - Renal artery diameter &lt; 3 mm and &gt; 8 mm - Renal artery fibromuscular dysplasia (FMD) - Stented renal artery - Renal artery aneurysm - Renal artery diameter stenosis &gt;30% - Pregnancy - Presence of abnormal kidney (or secreting adrenal) tumors - Iliac/femoral artery stenosis precluding insertion of the catheter PMA P220023: FDA Summary of Safety and Effectiveness Data Page 1 of 63 {1} PMA P220023: FDA Summary of Safety and Effectiveness Data Page 2 of 63 ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the labeling for the Paradise Catheter and Paradise Generator/System. ## V. DEVICE DESCRIPTION The Paradise Ultrasound Renal Denervation System (Paradise System) includes the Paradise Catheter with ultrasound transducer, Paradise Generator, Paradise Cartridge, and the Paradise Connection Cable. The Paradise System is a catheter-based system that delivers ultrasound energy circumferentially to thermally ablate and disrupt the renal sympathetic nerves with the goal of achieving a reduction in systemic arterial blood pressure. The Paradise Catheter is delivered percutaneously via femoral artery access, under fluoroscopic guidance using commercially available, compatible introducer sheaths and guiding catheters over a guidewire, into the renal artery. In addition, the Paradise System requires the use of commercially available sterile water (not supplied by ReCor) as a coolant, to protect the arterial wall during thermal ablation. Figure 1 shows the required components of the Paradise System. The Paradise Generator is designed to be used exclusively in conjunction with the Paradise Cartridge and Paradise Connection Cable to circulate cooling fluid and deliver electrical energy to the Paradise Catheter to ensure proper ultrasound energy. The Generator uses a series of sensors and control software for management of fluid flow and ultrasound energy delivery to the Paradise Catheter. Fluid flow through the system allows for the transmission of ultrasound from the Paradise Catheter and removes unwanted heat during treatment. The Paradise Generator contains a touch screen which allows users to operate the Paradise System through the appropriate sequence of steps. The Generator comes with a Paradise Remote that can be used during the procedure. This remote is optional and is for the convenience of the user to operate the generator from within the sterile field. {2} ![img-0.jpeg](img-0.jpeg) Figure 1: Paradise System: Catheter, Generator, Cartridge and Connection Cable The Paradise Catheter with ultrasound transducer is a 6-French renal artery catheter with a cylindrical piezoelectric ceramic ultrasound transducer located inside an inflatable balloon at the distal end of the Catheter. The Catheter has a memory chip that stores power delivery parameters used by the Generator to control the ultrasound energy power delivered by each catheter size and provides for automatic setting of acoustic power for the corresponding artery size to produce the desired target ablation region. The Paradise Catheter is available in 3.5, 4.2, 5, 6, 7, and 8 mm balloon sizes. The Paradise Cartridge is also controlled by the Generator and drives the flow of coolant in and out of the Catheter in a closed-loop fluid circuit. The Paradise Connection Cable provides the electrical connectivity between the Generator and the Catheter and provides an electronic connection for accessing catheter information stored in the Catheter's memory chip. The Paradise Catheter, Cable, and Cartridge are single-use only components. PMA P220023: FDA Summary of Safety and Effectiveness Data {3} VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several approaches for hypertension treatment including lifestyle modifications and pharmacological therapy. Each approach has advantages and disadvantages. A patient should discuss hypertension treatment options with their health care provider to select the method(s) that achieves blood pressure control and meets personal expectations and lifestyle. VII. MARKETING HISTORY The Paradise Ultrasound Renal Denervation System has been marketed in France, Germany, Spain, Switzerland, Italy, UK, Belgium and the Netherlands. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness. VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of potential adverse effects (e.g., complications) associated with device use. The following are possible risks associated with the denervation procedure or response to treatment: - Ablation or thermal injury to vessel, adjacent tissue or other structures from energy application - Acute kidney injury - Angina - Anxiety - Arrhythmia - Atrial tachycardia - Bradycardia - Gastrointestinal complications (diarrhea, nausea, vomiting) - Hypotension/ Dizziness and/or Headaches - Hypertension - Hyperhidrosis - Pain (transient abdominal, lower back) - Renal failure or renal insufficiency - Renal artery aneurysm or pseudoaneurysm - Renal infarction - Renal artery dissection, or perforation - Renal artery stenosis - Vasospasm - Vasovagal response - Stroke or transient ischemic event Additionally, there are renal denervation procedural risks, which are similar to the risks PMA P220023: FDA Summary of Safety and Effectiveness Data Page 4 of 63 {4} of arterial catheterization procedures. The following are potential risks of the catheterization procedure (including renal angiography): - Allergic reaction to contrast - Arterio-enteric fistula - Arterio-venous fistula - Bleeding - Cardiopulmonary arrest - Complications related to pain and anti-anxiety medication protocol - Death - Deep vein thrombosis - Edema - Embolism (pulmonary, renal, peripheral vasculature, plaque) - Hematuria - Infection - Myocardial infarction - Pain - Vascular access site complications (pseudoaneurysm, pain, swelling, hematoma) For the specific adverse events that occurred in the clinical studies, please see Section X below. ## IX. SUMMARY OF NONCLINICAL STUDIES Nonclinical testing of the Paradise System included verification and validation (device, system, and software), biocompatibility of patient-contacting materials, sterilization, packaging, and shelf-life testing, and animal studies. Performance testing was conducted to demonstrate design integrity. Tests identified in standards or guidance documents were performed based on product specification requirements. The following testing was performed on devices representative of proposed commercial devices manufactured by trained operators. "Pass" denotes the devices and system met established product specification and/or performance criteria or were in conformance with the requirements of the relevant standards. Test results confirmed that the Paradise System met product specifications. ## A. Laboratory Studies Design Verification Testing was successfully conducted on the Paradise System and for the individual system components (Paradise Catheter, Paradise Generator, Paradise Cartridge, Paradise Connection Cable) and is summarized in Table 1. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 5 of 63 {5} Table 1: Non-Clinical Bench Testing Results | Test | Test Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Paradise System | | | | | System Compatibility-interfaces-Cartridge and Catheter | To confirm the system interfaces communicates and functions properly. | The Generator shall maintain (inter)connectivity to the Cartridge for a procedure. The Generator shall maintain (inter)connectivity to the Catheter via the connection cable for a procedure. | Pass | | Lesion Extent-computer simulation | To characterize the circumferential energy transfer. | Ablation region within the target range. | Pass | | Coolant: flow rate and pressure measurement accuracy | To confirm appropriate fluid as a catheter balloon coolant, and the pressure measurement and coolant flow rate is within the defined range of accuracy. | Fluid flow rate of the system and pressure measurement will be within tolerances and within acceptable range during sonication. | Pass | | Paradise Catheter | | | | | Balloon size tolerance | To demonstrate the balloon size is within prespecified tolerance limits. | Balloons shall be within tolerance of the nominal diameter at operating pressure | Pass | | Dimensional Analysis | To confirm that the effective length and shaft OD, are within product specifications: | All physical dimensions identified in the product specifications must be met. | Pass | | Acoustic Power output | To confirm the acoustic power output. | The catheter shall be able to output the appropriate amount of acoustic power according to balloon size. | Pass | | Catheter Tensile Strength | To demonstrate the Catheter is able to meet the prespecified tensile strength requirements. | The tensile strength of catheter joints shall be less than the defined maximum values per requirements documentation on each joint or juncture. | Pass | | Catheter Torque Strength | To demonstrate the Catheter is able to meet torsional bond strength requirements. | The catheter shall withstand one complete rotation (360°) of the catheter hub while the tip is in a fixed position. | Pass | | Catheter Durability (Mechanical) | To confirm that the catheter shall be able to perform repeated sonications with no Generator errors while performing multiple insertions and retractions through a test track that simulates normal use. | The generator and catheter should function appropriately with no damage following 12 sonications. | Pass | PMA P220023: FDA Summary of Safety and Effectiveness Data {6} | Test | Test Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Catheter Durability (Acoustic) | To characterize the acoustic durability of the Catheter | The catheter shall be able to output the appropriate amount of acoustic power following the mechanical durability test. | Pass | | Guidewire Compatibility | To characterize the compatibility of the catheter with commercially available 0.014" guidewires. | A 0.014" guidewire shall pass through the shaft lumen, and the guidewire must be able to retract the guidewire after multiple sonications. | Pass | | Kink Resistance | To determine the minimum radius of curvature at which the system fails. | The catheter must be able to achieve target flow rate as specified in product requirement after tracking through a specified bend with a defined radius. | Pass | | Guide Catheter compatibility | To confirm the compatibility of the catheter with commercially available guide catheters. | The device must be compatible with at least one standard guide catheter, have the ability to inject contrast via the guide catheter while the denervation catheter is in place and should complete a simulated procedure. | Pass | | Retraction force | To confirm the retraction force during simulated use. | The values identified in the product specifications must be met | Pass | | Shaft/ Tuohy (hemostasis valve) compatibility | To confirm the compatibility of Catheter with commercially available hemostasis valves and that the shaft meets flow rate specification during use of hemostasis valve. | The device must be compatible with a bleed-back hemostasis valve (Touhy), coolant flow shall not be impeded significantly, such that the flow rate specification cannot be met. | Pass | | Balloon durability | To evaluate performance of balloon and its ability to withstand multiple inflations. | Balloon should function long enough to complete a procedure, after completing catheter durability (mechanical) testing. | Pass | | Burst Pressure | To verify balloon meets burst pressure requirements. | Balloon burst shall exceed pressure requirements. | Pass | | Paradise Generator | | | | | Balloon inflation and deflation control | To confirm that the Generator can control balloon pressure | The Generator shall monitor the balloon pressure. | Pass | | Maximum sonication duration | To confirm that the Generator does not exceed maximum duration of sonication. | The duration of each sonication shall be ≤ 30 seconds. | Pass | PMA P220023: FDA Summary of Safety and Effectiveness Data {7} | Test | Test Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Sonication status-display of sonication time, audible sonication indicator | To confirm that the sonication status is displayed before and during sonication. | The Generator shall display an indication of status preceding Sonication and time remaining during sonication. | Pass | | | To confirm that status of energy delivery is displayed on the Generator screen | The Generator shall display an indication of energy emission status if halted or cancelled prior to completion of sonication. | | | Dimensional: Weight, footprint | To confirm dimensions are within product specifications. | All physical dimensions identified in the product specifications must be met | Pass | | Automatic termination • inflation (high pressure), • energy | To confirm that inflation is terminated automatically in conditions of excess pressure. | During inflation, if the balloon pressure exceeds the pressure at the high end of the operating range, the Generator shall stop inflation and deflate the balloon. The Generator shall monitor delivered power and terminate power if monitored power goes above or below predefined values. | Pass | | Energy delivery • Fixed energy delivery parameters • Lockout | To confirm the Generator delivers energy when prespecified criteria is met. | Sonication time shall be programmed in a database. The Generator shall deliver energy only when the balloon is inflated. | Pass | | Deflated balloon pressure | To confirm the balloon pressure meets requirement when the Generator indicates Catheter balloon is deflated, | The balloon pressure shall be below 0 psi when the Generator indicates the balloon is deflated. | Pass | | Frequency resolution | To confirm the output frequency of the generator meets the resolution specification. | The output frequency of the Generator shall have a resolution of 0.01 MHz. | Pass | | Connection Status | To confirm that Generator detects Catheter, Cartridge. | The Generator shall detect and display the connection status of the Catheter, Cartridge, and when connected, the remote accessory. | Pass | | Manual energy delivery termination | To confirm that Generator can be terminated by means identified. | The user shall be able to terminate Generator energy output upon request through each of the following: - front panel user interface | Pass | PMA P220023: FDA Summary of Safety and Effectiveness Data {8} | Test | Test Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | | | - emergency stop button - remote accessory (if it is utilized) | | | Paradise Connection Cable | | | | | Dimensional: Length | To demonstrate cable length is within prespecified tolerance limits. | All physical dimensions identified in the product specifications must be met | Pass | | Operating life | To verify that the Cable can maintain functional performance after multiple sonication cycles. | The Cable shall be able to operate without having any failures for multiple sonication cycles. | Pass | | Connector cycle life | To verify that the Cable can maintain functional performance after multiple attachment and detachment cycles with the Generator and Catheter. | The Cable shall maintain proper functionality after multiple attachment and detachment cycles with the Generator and Catheter. | Pass | | Paradise Cartridge | | | | | Dimensional: length of fluid lines | To demonstrate the Cartridge fluid line length is within prespecified tolerance limits. | Fluid line length shall be 3.0±0.2 m. | Pass | | Fluid flow capability | To demonstrate the Cartridge can deliver fluid within a prespecified range. | The Cartridge shall be capable of delivering fluid over a specified range. | Pass | | Pressurization capability | To demonstrate the Cartridge is able to withstand prespecified internal pressure limits. | The Cartridge shall be able to withstand internal pressures up to 75psi. | Pass | | Operating life | To verify that the Cartridge can maintain functional performance after multiple inflation, sonication, and deflation cycles. | The Cartridge, when attached to the Generator and connected to a Paradise Catheter, shall be able to operate without having any failures for multiple inflation, sonication, and deflation cycles. | Pass | | Attachment cycle life | To verify the Cartridge can maintain functional performance after specified attachment and detachment cycles with the Generator and Catheter. | The Cartridge shall maintain proper functionality after specified attachment and detachment cycles with the Generator and Catheter. | Pass | | Balloon coolant interface | To demonstrate the functional performance of the Cartridge during simulated use with balloon coolant. | The Cartridge shall have a means to interface with balloon coolant bags and semi-rigid bottles. | Pass | | Pressure sensor capability | To demonstrate Cartridge pressure sensors are within prespecified limits after multiple sonication cycles. | The Cartridge pressure sensors shall remain accurate throughout use. | Pass | PMA P220023: FDA Summary of Safety and Effectiveness Data Page 9 of 63 {9} B. Software Validation The Paradise Generator (Version 1.22) has the primary responsibility for the user interface, procedure settings and control of radiofrequency (RF) power of the Generator. The Paradise Generator is designed to be used exclusively in conjunction with the Paradise Cartridge and Paradise Connection Cable to circulate cooling fluid and deliver electrical energy to the Paradise Catheter to ensure proper therapy. The Generator uses a series of sensors and control software for management of fluid flow and ultrasound energy delivery to the Paradise Catheter. Software testing included a full suite of safety and performance tests in accordance with EN/IEC 60601-1:2006 Clause 14 (Programmable Electrical Medical Systems) and EN/IEC 62304 (Medical Device Software – Software Life-Cycle Processes) and in accordance with the recommendations in the FDA Guidance, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices. The software was evaluated through unit, integration, verification and validation testing to demonstrate that the performance and safety of the Paradise Generator conform to specifications. Cybersecurity testing, including penetration testing was performed on the end-to end system in accordance with the recommendations in FDA guidance, Content of Premarket Submissions for Management of Cybersecurity in Medical Devices and Postmarket Management of Cybersecurity in Medical Devices, to verify that controls have been implemented correctly and are effective during their intended uses. C. Biocompatibility Studies Biocompatibility testing of the Paradise Catheter was performed in accordance with the EN ISO 10993 series of tests as part of an appropriate risk management process in accordance with ISO 14971 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 Paradise Catheter test samples were derived from finished product. The Paradise Catheter is blood contacting and when used as intended, is temporarily placed into the arterial vasculature; the total cumulative exposure is expected to be less than 1 hour. The Paradise Catheter is therefore classified according to ISO 10993-1 as: externally communicating, limited contact (≤24 hours) with circulating blood. Testing of the catheter was done per ISO 10993-1 for devices determined to be externally communicating with limited contact (≤24 hours) with circulating blood. A summary of biocompatibility test results is shown in Table 2 and demonstrates that the Paradise Catheter is biocompatible per ISO-10993-1 for its intended use. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 10 of 63 {10} Table 2: Biocompatibility Testing | Biological Evaluation Test | Test Performed | Results | | --- | --- | --- | | Cytotoxicity | MEM Elution Method (ISO 10993-5) | Pass | | Sensitization | ISO Guinea Pig Maximization Sensitization Test (ISO 10993-10) | Pass | | Irritation | ISO Intracutaneous Irritation Test (ISO 10993-10) | Pass | | Acute Systemic Toxicity | ISO Acute Systemic Injection Test (ISO 10993-11) | Pass | | Material Mediated Pyrogenicity | ISO Materials Mediated Rabbit Pyrogenicity (ISO 10993-11) | Pass | | Hemocompatibility - Hemolysis | ASTM Hemolysis, (Direct and Indirect Contact) (ISO 10993-4) | Pass | | Hemocompatibility - Complement Activation | SC5b-9 Complement Activation Assay (ISO 10993-4) | Pass | | Hemocompatibility-Thrombogenicity | The performance and safety of the Paradise 6F OTW Catheter was evaluated in animal and post-market clinical studies (in the EU) which meets the biological evaluation requirements for the thrombosis and coagulation test categories per ISO 10993-4 | Pass | | Hemocompatibility (Coagulation) | | Pass | # D. Animal Studies A series of non-Good Laboratory Practice (GLP) animal studies were conducted to select, characterize, and optimize the Paradise System ablation settings to achieve a target ablation region for optimal nerve injury while protecting the renal arterial wall and protecting non-target tissues at depth. These studies were followed by GLP studies conducted to evaluate the overall performance and safety of the Paradise System. Two additional "GLP-like" studies were conducted following completion of the GLP studies to 1) select the final ablation settings for use in the RADIANCE clinical studies, and 2) to assess the overall performance of the smaller balloon catheter sizes before implementing for use in the RADIANCE IDE clinical studies. The Paradise System animal studies are summarized in Table 3. PMA P220023: FDA Summary of Safety and Effectiveness Data {11} Table 3: Summary of animal studies | Study type | Study Objective | Duration | Relevant Findings | | --- | --- | --- | --- | | GLP | Design Validation | Acute | The study evaluated the use and performance of the Paradise System against pre-specified user requirements in a porcine model. All requirements were assessed semi-quantitatively by an experienced interventional cardiologist user. The protocol was successfully completed. All validation parameters were met and determined to be clinically acceptable. | | GLP | Evaluate the Safety of the System | 28 days | The vascular safety of the Paradise System was demonstrated in a normotensive porcine model at 28 days following delivery of one, or two, ultrasound emissions delivered bilaterally to the renal arteries. In addition, the ability to ablate the peri-arterial tissue, and injure the renal nerves, in the target region was observed with healing of the peri-adventitial tissue at 28 days. Overall, there was no to minimal injury to the renal artery nor to non-target tissues associated with delivery of ultrasound along the renal artery. All pre-defined acceptance criteria met | | GLP | Evaluate the Safety of the System | 90 days | The vascular safety of the Paradise Ultrasound Renal Denervation System was demonstrated in a normotensive porcine model at 90 days following delivery of one, or two, ultrasound emissions delivered bilaterally to the renal arteries. In addition, the ability to ablate the peri-arterial tissue and injure the renal nerves in the target region was observed with complete healing of the peri-adventitial tissue at 90 days. The safety of non-target tissues was preserved following delivery of ultrasound along the renal artery with the Paradise System. All pre-defined acceptance criteria met. | | GLP | Evaluate the Safety of Overlapping 2 Emissions | 28 days | The vascular safety of overlapping two ultrasound emissions with the Paradise System was demonstrated at 28 days in a normotensive porcine model. Arterial safety, non-target organ safety, tissue ablation area, and nerve injury observed in this study met all pre-defined acceptance criteria. Importantly, the nerve ablation region, and corresponding nerve injury associated with overlapping of two ultrasound emissions, was comparable to that observed with delivery of one or | PMA P220023: FDA Summary of Safety and Effectiveness Data Page 12 of 63 {12} | Study type | Study Objective | Duration | Relevant Findings | | --- | --- | --- | --- | | | | | two ultrasound emission with a minimum gap of a transducer length. All pre-defined acceptance criteria met. | | Validation Study | System Dose Settings | 7 days | The study evaluated three (3) ablation settings in a normotensive porcine model. The vascular response, nerve injury, and ablation region following device use were evaluated. All three ablation settings were deemed acceptable and met the pre-defined acceptance criteria for arterial safety, non-target tissue injury, nerve injury, and target ablation region. The final ablation settings used in the IDE Clinical Studies was determined based on this study and are the same ablation settings for the marketed device. All pre-defined acceptance criteria met. | | Non GLP | Evaluate the performance of the 3.5mm and 4.2mm balloon catheters | 7 days | The study was designed to assess the tissue response to the Paradise System 3.5 mm and 4.2 mm balloon catheters in a normotensive porcine model. The smaller balloon sizes met the pre-determined acceptance criteria for the study in terms of arterial safety, nerve injury, and thermal ablation region. All pre-defined acceptance criteria were met. | E. Sterilization and Packaging The Paradise Catheter, Cartridge, and Connection Cable are supplied sterile, single use and ready to use. These devices are sterilized via 100% ethylene oxide (EO) at a qualified sterilization facility using a validated sterilization cycle. The sterilization process validation was conducted to provide a sterility assurance level (SAL) of at least 10⁻⁶ in accordance with ISO 11135-1, a recognized standard for EO terminally sterilized medical devices. The Paradise Catheter, Paradise Generator, Paradise Cartridge and the Paradise Connection cable were evaluated to demonstrate product and packaging system performance after exposure to applicable conditioning. All components of the Paradise System underwent packaging performance testing in accordance with ASTM D4169. Climatic conditioning and accelerated aging for the components were performed per ASTM D4332. Simulated distribution was conducted as outlined in ASTM D4169 cycle 13. Packaging System performance testing included maintenance of sterile barrier integrity from gross leaks per ASTM F2096, pouch seal strength tested per ASTM F288, and legibility of labeling and Instructions for Use for the subject devices. The units used for packaging validation underwent storage and transit conditioning (including climatic conditioning &amp; simulated distribution challenges), handling without aging or 25 months of accelerated aging, and sterilization (only for sterile components PMA P220023: FDA Summary of Safety and Effectiveness Data {13} i.e., catheter, Cartridge and Cable). ## F. Shelf Life Bench testing was conducted to evaluate the Paradise Catheter for a 1-year shelf life and the Paradise Cartridge and Connection Cable for a 2-year shelf life. ## G. Electrical Safety and Electromagnetic Compatibility Electrical safety and electromagnetic compatibility for the Paradise System was performed per IEC 60601-1 and IEC 60601-1-2 respectively. The Paradise System met the acceptance criteria for electrical safety and electromagnetic compatibility. ## X. SUMMARY OF PRIMARY CLINICAL STUDIES The applicant performed three clinical studies under IDE #G150144 to establish a reasonable assurance of safety and effectiveness of the Paradise Ultrasound Renal Denervation (uRDN) System for the reduction of blood pressure in adult patients with mild to moderate or resistant hypertension in the United States, European Union and the United Kingdom. Data from these clinical studies, RADIANCE-HTN SOLO (SOLO), RADIANCE-HTN TRIO (TRIO) and RADIANCE II were the basis for the PMA approval decision. A summary of each of the clinical studies is presented below. ## A. Study Design All three clinical studies were prospective, multi-center, randomized, double-blind, and Sham-controlled. ### RADIANCE-HTN SOLO Subjects were consented between March 2016 and December 2017. Subjects had their antihypertensive medication discontinued for a period of 4 weeks prior to a reassessment of their hypertension to determine randomization eligibility. One hundred forty-six (146) subjects were randomized to either uRDN treatment (n=74) or Sham control (n=72) at 21 investigational sites in the United States and 18 sites in Europe. The database for this PMA reflected information collected through August 22, 2022. Data are presented through 36 months follow-up. ### RADIANCE-HTN TRIO Subjects were consented between March 2016 and March 2020. Subjects had their current hypertensive regimen replaced with a single triple antihypertensive pill containing a fixed dose of a calcium channel blocker, angiotensin II receptor blocker, and hydrochlorothiazide diuretic, administered once daily during a 4-week stabilization period prior to a hypertension reassessment to determine randomization eligibility. One hundred thirty-six (136) subjects were randomized to either uRDN treatment (n=69) or Sham control (n=67) at 28 investigational sites in the United States and 25 sites in Europe. The database for this PMA reflected information collected through August 22, 2022. Data are presented through 24 months follow-up. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 14 of 63 {14} # RADIANCE II Subjects were consented between January 14, 2019, and May 6, 2022. Subjects had their antihypertensive medication discontinued for a period of 4 weeks prior to a reassessment of their hypertension to determine randomization eligibility. Two hundred twenty-four (224) subjects were randomized to either uRDN treatment (n=150) or Sham control (n=74) at 37 investigational sites in the US and 24 sites in Europe. The database for this PMA reflected information collected through February 23, 2023. Data are presented through 6-months follow-up. Following enrollment, patients were either withdrawn from medications (SOLO and RADIANCE-II) or had their anti-hypertensive medications standardized (TRIO) for four weeks. They were then randomized and underwent either uRDN treatment or a sham procedure (renal angiogram). Subjects were not to make any changes in BP medications prior to 2-months post-uRDN treatment or the sham procedure unless they met elevated blood pressure safety escape criteria. After collection of the primary endpoint data at 2-months, subjects in the three studies underwent guideline-based antihypertensive medication escalation (as needed) between 2- and 6-months post-uRDN or sham procedure to optimize blood pressure control (target home systolic blood pressure ≤135 mmHg and diastolic ≤85 mmHg), with TRIO subjects remaining on the standardized triple pill and having medications added as needed between 2- and 6-months. Beyond 6-months, blood pressure was managed medically per physician discretion. Subjects in SOLO and TRIO remained blinded to treatment assignment for 6 months following uRDN or sham procedure, while RADIANCE-II subjects remained blinded for 12 months. Table 4 provides an overview of the three uRDN trials. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 15 of 63 {15} Table 4: Summary of Clinical Studies | Study Design Parameters | RADIANCE- HTN SOLO (SOLO) | RADIANCE- HTN TRIO (TRIO) | RADIANCE II (R-II) | | --- | --- | --- | --- | | Patient Population | Uncontrolled (OBP ≥140/90 & <180/110 mmHg) on 0-2 anti-hypertensive medications or Controlled (OBP ≤140/90 mmHg) on 1-2 anti-hypertensive medications | Uncontrolled (OBP ≥140/90 mmHg) on 3 or more anti-hypertensive medications | Uncontrolled (OBP ≥140/90 & <180/110 mmHg) on 0-2 anti-hypertensive medications | | Randomized patients | 146 (1:1 uRDN:Sham) | 136 (1:1 uRDN:Sham) | 224 (2:1 uRDN:Sham) | | Medications through primary endpoint at 2m | No anti-hypertensive medications | Single, fixed dose anti-hypertensive medication combination triple pill | No anti-hypertensive medications | | Medications 2-6m | Standardized guideline driven medication escalation to target BP control | | | | Medications beyond 6m | Medications prescribed per physician discretion | | | | Primary Effectiveness Endpoint | The difference in the reduction in average daytime ambulatory systolic BP between uRDN and Sham control, from baseline to 2 months post procedure | | | | Follow up schedule | 2, 6, and 12 months and annually thereafter through 3 years | 2, 6, and 12 months and annually thereafter through 5 years | | | Safety | All adverse events collected and reviewed | | | | Primary Safety Endpoint: | None | None | Patient level composite of the incidence of Major Adverse Events (MAE) at 30 days and the incidence of renal artery stenosis (>70% diameter stenosis) at 6-months | PMA P220023: FDA Summary of Safety and Effectiveness Data {16} | Study Design Parameters | RADIANCE- HTN SOLO (SOLO) | RADIANCE- HTN TRIO (TRIO) | RADIANCE II (R-II) | | --- | --- | --- | --- | | Imaging | • Renal duplex ultrasound performed for all randomized subjects at 2 and 6 months and for uRDN-treated subjects at 24 and 36 months; CTA/MRA was obtained if specific duplex ultrasound parameters (e.g., PSV) were elevated • CTA/MRA at 12 months for subjects treated with uRDN | CTA/MRA at 6 months for all randomized subjects and at 12 months for subjects treated with uRDN | | | Study Duration | 3 years | 3 or 5 years | 5 years | | Status | Complete follow up available through 36 months | Complete follow up available through 24 months | Complete follow up available through 6 months | uRDN: ultrasound renal denervation; BP: blood pressure; OBP: Office BP; CTA: computed tomography angiography; MRA: magnetic resonance angiography; PSV: peak systolic velocity PMA P220023: FDA Summary of Safety and Effectiveness Data {17} PMA P220023: FDA Summary of Safety and Effectiveness Data Page 18 of 63 1. Clinical Inclusion and Exclusion Criteria Enrollment in the RADIANCE studies were limited to subjects who met the following inclusion criteria. Inclusion Criteria common for all RADIANCE studies: - Appropriately signed and dated informed consent - Age ≥18 and ≤75 years at time of consent - Documented history of hypertension - Suitable renal anatomy compatible with the renal denervation procedure and documented by renal CTA or MRA of good quality performed within one year prior to consent - Able and willing to comply with all study procedures Inclusion Criteria specific for SOLO: - Average seated office BP &lt; 180/110 mmHg at screening visit (V0) while on a stable regimen of 1 or 2 antihypertensive medications for at least 4 weeks prior to consent, or average seated office BP ≥140/90 mmHg and &lt;180/110 mmHg despite lifestyle measures on no antihypertensive medications - Documented daytime ABP ≥135/85 mmHg and &lt;170/105 mmHg after 4-week washout/run-in period Inclusion Criteria specific for TRIO: - Average seated office BP ≥140/90 mmHg at screening visit (V0) while on a stable regimen of at least 3 antihypertensive medications of different classes including a diuretic for at least 4 weeks prior to consent - Documented daytime ABP ≥135/85 mmHg after 4-week stabilization period Inclusion Criteria specific for RADIANCE II: - Previously or currently prescribed antihypertensive therapy - Average seated office BP ≥140/90 mmHg &lt;180/120 mmHg at Screening Visit (V0) while stable for at least 4 weeks on 0-2 anti-hypertensive medications of different classes - Documented daytime ABP ≥135/85 mmHg and &lt;170/105 mmHg at Baseline Visit (V1) after 4-week washout/run-in period - Sinus rhythm at the time of procedure Subjects were not permitted to enroll in the RADIANCE studies if they met any of the exclusion criteria. Exclusion Criteria common for all RADIANCE studies: - A single functioning kidney - Presence of abnormal kidney tumors - Renal artery with aneurysm {18} - Pre-existing renal stent or history of renal artery angioplasty - Pre-existing aortic stent or history of aortic aneurysm - Prior renal denervation procedure - Fibromuscular disease of the renal arteries - Presence of renal artery stenosis of any origin ≥30% - Evidence of active infection within 7 days of procedure - Iliac/femoral artery stenosis precluding insertion of the Paradise Catheter - Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma Hb1Ac ≥9.0%) - Documented history of chronic active inflammatory bowel disorders such as Crohn’s disease or ulcerative colitis - eGFR of &lt;40 mL/min/1.73 m2 (by Modification of Diet in Renal Disease formula) - Brachial circumference ≥42 cm - Documented confirmed episode(s) of stable or unstable angina¹ - Documented history of persistent or permanent atrial tachyarrhythmia - Active implantable medical device (e.g., ICD or CRT-D; neuromodulator/spinal stimulator; baroreflex stimulator) - Chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea - History of severe cardiovascular event [myocardial infarction, CABG, acute heart failure requiring hospitalization (NYHA III-IV)]¹ - History of cerebrovascular event (e.g., stroke, transient ischemic event, cerebrovascular accident)¹ - Documented repeat (&gt;1) hospitalization for hypertensive crisis within the prior 12 months¹ - Primary pulmonary hypertension - Documented contraindication or allergy to contrast medium not amenable to treatment - Limited life expectancy of &lt;1 year at the discretion of the Investigator - Any known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, would be unlikely or unable to comply with study protocol requirements or whose participation may result in data analysis confounders (e.g. night shift workers) - Pregnant, nursing or planning to become pregnant (negative pregnancy test required, documented within a maximum of 7 days prior to procedure for all women of childbearing potential. Documentation of effective contraception also required for women of childbearing potential) - Concurrent enrollment in any other investigational drug or device trial (participation in non-interventional Registries is acceptable) ¹ within 3 months prior to consent in TRIO PMA P220023: FDA Summary of Safety and Effectiveness Data Page 19 of 63 {19} Exclusion Criteria specific for SOLO: - Renal artery anatomy on either side, ineligible for treatment including: - Main renal artery diameter &lt;4 mm and &gt;8 mm - Main renal artery length &lt;25 mm - Accessory artery diameter ≥2 mm and &lt;4 mm or ≥8 mm - Prescribed to standard anti-hypertensive cardiovascular medication (e.g. beta blockers) for other chronic conditions (e.g. ischemic heart disease) such that discontinuation might pose serious risk to health Exclusion Criteria specific for TRIO: - Renal artery anatomy on either side, ineligible for treatment including: - Main renal artery diameter &lt;3.5mm or &gt;8mm - Main renal treatable artery length &lt;20 mm (may include proximal branching) - Accessory artery diameter ≥2mm and &lt;3.0mm or ≥8mm - Prescribed for standard anti-hypertensive cardiovascular medication (other than beta blockers) for other chronic conditions (e.g. ischemic heart disease) such that discontinuation might pose serious risk to health - Secondary hypertension not including sleep apnea (documented through clinical work up within 12 months prior to consent) - Documented intolerance or contraindication for any of the anti-hypertensive drugs prescribed as a requirement of the study Exclusion Criteria specific for RADIANCE II: - Renal artery anatomy on either side, ineligible for treatment including: - Main renal artery diameter &lt;3mm or &gt;8mm - Main renal treatable artery length &lt;20 mm (may include proximal branching) - Accessory artery diameter ≥2mm and &lt;3mm or ≥8mm - Known uncorrected causes of secondary hypertension other than sleep apnea 2. Follow-up Schedule The follow-up visit schedule, visit windows and the key assessments conducted at each of the visits for all three studies is provided below in Table 5. All patients were scheduled for in-clinic follow-up (FU) visits at 1, 2, 3, 4, 5, 6, 12, 24, 36, 48² and 60² months post-procedure. Pre-procedure, screening was performed including seated average office blood pressure, a limited medical history review, physical exam, medication review and a QoL questionnaire (EQ-5D; RADIANCE II only). For eligible subjects, additional screenings were performed after medication washout (SOLO, RADIANCE II) or triple pill regimen stabilization (TRIO), including seated office BP measurement, 24- PMA P220023: FDA Summary of Safety and Effectiveness Data Page 20 of 63 {20} hour ambulatory BP (ABP), renal CTA/MRA, urine testing for antihypertensive medications (TRIO and RADIANCE II), and electrocardiography (ECG). A renal angiogram was obtained on all randomized subjects for final confirmation of anatomical eligibility immediately prior to the procedure. Subjects completed a Visual Analog Pain Assessment before and after the procedure. Postoperatively, measured parameters obtained during the study included office BP and changes in medication at every visit. Home BP was measured twice daily during the week prior to all office visits through 12 months. Twenty-four hour ABP was recorded at 2, 6 and 12 months follow up. Follow-up visits occurred monthly through 6 months, followed by a visit at 12 months and annually thereafter through a minimum of 3 years (SOLO/TRIO) or 5 years (RADIANCE II). Adverse events were recorded at all visits. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 21 of 63 {21} Table 5: Visit Schedule | Visit Description | Screening | Baseline Eligibility /Pre-procedure testing | Procedure | Discharge | 1M | 2M | 3M | 4M | 5M | 6M | 12M | 24-36M | 48-60M | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Average Office BP* | X | X | | X+ | X | X | X | X | X | X | X | X | X | | 24-hour Ambulatory BP | | X | | | | X | | | | X | X | | | | Home BP Review € | | X | | | X | X | X | X | X | X | X | | | | Medical history (or review) | X | X | | | X | X | X | X | X | X | X | X | X | | Physical Examination | X | X | | | X | X | X | X | X | X | X | X | X | | Medication Review | X | X | X | X | X | X | X | X | X | X | X | | | | QoL (EQ-5D-5L) (R-II only) | X | X | | | | X | | | | X | X | | | | Renal Duplex Ultrasound (SOLO/TRIO) | | X¥ | | | X$ | X | X X$ | X $ | $ | X | X X$ | T | | | CTA/MRA | | X** | | | | X$ | | | | X X$ | T | | | | Urine Chemistry | | X | | | | X | | | | X | X | | | | Urine for Drug Metabolite (TRIO, R-II) | | X | | | | X | | | | X | | | | | Blood Chemistry | | X | | | | X | | | | X | X | | | | Plasma for Biomarkers (SOLO Only - optional) | | X | | | | X | | | | X | X | | | | Diagnostic renal angiogram | | | X | | | | | | | | | | | PMA P220023: FDA Summary of Safety and Effectiveness Data {22} | Visit Description | Screening | Baseline Eligibility /Pre-procedure testing | Procedure | Discharge | 1M | 2M | 3M | 4M | 5M | 6M | 12M | 24-36M | 48-60M | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Pain Perception Evaluation (Visual Analog Scale) | | | X | X | | | | | | | | | | | Blinding Index | | | | X | | X | | | | X | | | | BP: Blood Pressure; HTN: hypertension; CTA: Computed Tomographic Angiography; MRA; Magnetic Resonance Angiogram. * Average seated Office BP will be from an average of a minimum of 3 seated measurements as well as standing measure unless specified + Measurement of Standing Office BP is optional at Discharge Visit ¥ Recommended. A recent (within 6 months of consent) good quality renal duplex ultrasound is acceptable # within a maximum of 7 days prior to procedure $ if required in the event of clinical suspicion of renal artery stenosis ** A recent (within 12 months of consent) good quality, renal MRA or CTA is acceptable € Home BP readings start 7 days prior to scheduled office visit PMA P220023: FDA Summary of Safety and Effectiveness Data {23} # Assessments Core laboratories or independent experts were used to assess and centralize non-invasive imaging, safety, ABP, and urine (for drug adherence measurements). All primary effectiveness endpoint data were handled directly through the ABP core lab and independent statistician(s). The ABP core lab was used for configuration, distribution, training, and centralization of data collection for ABP measurements taken at Baseline, 2, 6 and 12- month follow up visits (and similarly for any crossover subjects). # Imaging Imaging follow-up in SOLO and TRIO consisted of renal duplex ultrasounds and/or CTA/MRA, as shown in Table 6. Independent experts reviewed all follow-up CTA/MRAs. Imaging follow-up in RADIANCE II consisted of CTA/MRA, as shown in Table 7. Follow-up CTA/MRA imaging studies were reviewed by an imaging core lab. Table 6: SOLO and TRIO Imaging | Imaging Study | Pre-Procedure | Procedure | 2 months | 6 months | 12 months | 324 months | | --- | --- | --- | --- | --- | --- | --- | | Renal Duplex Ultrasound (rDUS) | Recommended | n/a | Required | | n/a | Required – uRDN patients only | | CTA/MRA | Required | n/a | Required only based on rDUS findings | | Required - uRDN patients only | Required only based on rDUS findings | | Angiogram | - | Required | - | | | | Table 7: RADIANCE II Imaging | Imaging Study | Pre-Procedure | Procedure | 2 months | 6 months | 12 months | 324 months | | --- | --- | --- | --- | --- | --- | --- | | CTA/MRA | Required | n/a | - | Required – all randomized | Required – uRDN patients only | Optional | | Angiogram | - | Required | - | - | - | - | PMA P220023: FDA Summary of Safety and Effectiveness Data {24} PMA P220023: FDA Summary of Safety and Effectiveness Data Page 25 of 63 ## 3. Clinical Endpoints All adverse clinical safety events were collected and reported for the duration of all three studies. Severity was determined, as was device and/or procedure relatedness for each event, by the site investigator. Events were assessed by an Independent Data Safety Monitoring Board (DSMB) quarterly. Event rates were calculated for each study treatment group, uRDN and Sham, throughout the duration of the study. In SOLO and TRIO, pre-specified adverse events included: - All-cause mortality - Hypertensive emergency resulting in hospitalization - Hospitalization for heart failure - Stroke, transient ischemic attack, cerebrovascular accident - Acute myocardial infarction (STEMI/non-STEMI) - Any coronary revascularization - End stage renal disease; the need for permanent renal replacement therapy (i.e. the need for dialysis); doubling of plasma creatinine - Any renal artery complication requiring intervention (e.g. dissection; perforation) - Major access site complications requiring intervention - Significant embolic events resulting in end organ damage - Procedure-related pain lasting for &gt; 2 days - Acute renal injury - Significant renal artery stenosis (&gt;50% diameter stenosis) diagnosed by duplex ultrasound and confirmed by renal CTA/MRA or as diagnosed/confirmed by renal CTA/MRA - Severe (&gt;75%) renal artery stenosis as diagnosed by duplex ultrasound and confirmed by renal CTA/MRA or as diagnosed and confirmed by renal CTA/MRA - Need for renal artery angioplasty or stenting ## Primary Safety Endpoint RADIANCE II included a primary safety endpoint consisting of a patient level composite of the incidence of Major Adverse Events (MAE) within 30-days and at 6-months. (There was no pre-specified safety endpoint for SOLO and TRIO.) The 30-day post-randomization safety event rate consisted of the incidence of: - All-cause mortality - New onset (acute) end-stage renal disease (eGFR &lt; 15 mL/min/m2 or need for renal replacement therapy) - Significant embolic event resulting in end-organ damage (e.g., kidney/bowel infarct, lower extremity ulceration or gangrene, or doubling of serum creatinine) - Renal artery perforation requiring an invasive intervention - Renal artery dissection requiring an invasive intervention {25} Major vascular complications (e.g., clinically significant groin hematoma, arteriovenous fistula, pseudoaneurysm) requiring surgical repair, interventional procedure, thrombin injection, or blood transfusion (requiring more than 2 units of packed red blood cells within any 24-hr period during the first 7 days post randomization) Hospitalization for hypertensive or hypotensive crisis Hospitalization for major cardiovascular- or hemodynamic- related events (e.g. heart failure (HF); myocardial infarction (MI); Stroke) New onset Stroke, New onset MI. And The 6-month post randomization safety event rate consisted of the incidence of renal artery stenosis (&gt;70% diameter stenosis) confirmed by CTA or MRA. The MAE rate was compared to a pre-specified performance goal of 9.8%, derived from a review of adverse events in studies of renal artery angioplasty or stenting, estimated to be 14.2% (ranging from 9.5 to 23.2%). To assess the acute and long-term safety of uRDN across the RADIANCE studies, a pooled safety analysis was performed of uRDN treated patients (those treated at initial procedure and those that crossed over). The analysis consisted of an MAE composite endpoint (based on the RADIANCE II study definition) and an assessment of 12-month CTA/MRA imaging studies. The events for the MAE composite endpoint were adjudicated by the RADIANCE II Clinical Events Committee (CEC) run by Cardiovascular Research Foundation (CRF). All 12-month CTA/MRAs were assessed by the CRF Imaging Core Lab to ensure a consistent evaluation of the renal arteries post-procedure. ## Primary Effectiveness Endpoint The primary effectiveness endpoint was the reduction in the average daytime ambulatory systolic BP (SBP) at 2-months post procedure. The study success criterion was a statistically significant difference in the decrease in average daytime ambulatory SBP from baseline to 2-months between uRDN treatment and Sham groups. The mean difference between randomized groups for the change in daytime ambulatory systolic BP at 2 months post-procedure was compared via a linear regression (ANCOVA) model adjusted for subjects' baseline daytime ambulatory systolic BP. Statistical analyses were performed on each study at a two-sided 0.05 alpha level. In SOLO and TRIO, a value of zero was used for the reduction in BP in the intention-to-treat (ITT) analysis for patients missing the 2-month follow-up BP value. In RADIANCE II, multiple imputation was used for BP in the ITT analysis for patients missing the 2-month follow-up BP value. PMA P220023: FDA Summary of Safety and Effectiveness Data Page 26 of 63 {26} In all RADIANCE studies, for patients that met the protocol-defined “High BP Action” changes, their last BP measurement prior to the medication change was used in calculating the reduction in BP in the analysis. The primary effectiveness analyses were performed on the ITT Cohort, which was comprised of all randomized patients regardless of whether they received the assigned study treatment. Additional effectiveness analyses were conducted on the following patient cohorts: - Per-Protocol (PP) population – all randomized patients with successful treatment delivery (defined as a minimum of 2 emissions bilaterally) and who were free from major issues which may have affected the assessment of the treatment. - Complete ABP (CA) population – all randomized patients with ABP values at both baseline and follow-up. ## Secondary Effectiveness Endpoints The following secondary effectiveness endpoints were evaluated: ### RADIANCE-HTN SOLO and TRIO: - Reduction in average 24-hr/night-time ambulatory SBP at 2 months post-procedure (2 assessments) - Reduction in average daytime/24-hr/night-time ambulatory DBP at 2 months post-procedure (3 assessments) ### RADIANCE II: - Reduction in average 24-hr ambulatory SBP at 2 months post-procedure (1 assessment) - Reduction in average 24-hr/daytime ambulatory DBP at 2 months post-procedure (2 assessments) - Reduction in average home SBP and DBP at 2 months post-procedure (2 assessments) - Reduction in average office SBP and DBP at 2 months post-procedure (2 assessments) ## Additional Analyses The following observational assessments of effectiveness were evaluated: ### RADIANCE-HTN SOLO and TRIO: - Reduction in average home SBP &amp; DBP at 2 months post-procedure - Reduction in average office SBP &amp; DBP at 2 months post-procedure PMA P220023: FDA Summary of Safety and Effectiveness Data Page 27 of 63 {27} PMA P220023: FDA Summary of Safety and Effectiveness Data Page 28 of 63 # RADIANCE II: - Reduction in average night-time ambulatory SBP and DBP at 2 months post-procedure # RADIANCE-HTN SOLO, TRIO, and RADIANCE II: - Reduction in average office SBP &amp; DBP at 6- and 12-months post-procedure - Incidence of ambulatory SBP (daytime/24-hr/night-time) reductions of ≥5 mmHg, ≥10 mmHg, and ≥15 mmHg at 2-, 6- and 12-months post-procedure - Percentage of subjects who are controlled in the absence of changes in hypertensive medication at 2-, 6- and 12-months post-procedure (control defined as daytime ABP &lt;135/85 mmHg; nighttime ABP &lt;120/70 mmHg; 24-hr ABP&lt;130/80 mmHg; office BP &lt;140/90 mmHg) - Percentage of subjects who are controlled including any changes in hypertensive medication in each group at 2-, 6- and 12-months post-procedure (control defined as daytime ABP &lt;135/85mmHg; night-time ABP &lt;120/70 mmHg; 24-hr ABP&lt;130/80 mmHg; office BP &lt;140/90 mmHg) # Subgroup Analysis The primary effectiveness endpoint was analyzed for the following pre-specified subgroups: - Age - Race - Sex - Geography: US vs EU/UK - Baseline (Visit 1) daytime ambulatory SBP <median ≥="" vs.="" ≥median=""> - Baseline (Visit 1) office SBP <median ≥="" vs.="" ≥median=""> - Abdominal obesity: Male &gt;102 cm and ≤102 cm; female &gt;88cm and ≤88 cm - Total number of bilateral emissions (4, 5, 6, or &gt;6) # B. Accountability of PMA Cohort ## RADIANCE-HTN SOLO A total of 804 subjects were consented and screened for eligibility into the SOLO Study. One hundred forty-six (146) subjects were randomized (74 uRDN; 72 Sham) from 21 centers in the United States and 18 in Europe. At the time of the database snapshot on August 22, 2022, 146 patients were available for the primary analyses, and 84 subjects had reached the 36-month post-randomization visit. Thirty-seven (37) patients originally randomized to Sham group crossed over to uRDN treatment. Crossover subjects restarted the required post-procedure follow-up schedule, and 34 are continuing to be followed. All other subjects have completed study participation. Subject accountability post-randomization is shown in Figure 2.</median></median> {28} ![img-1.jpeg](img-1.jpeg) Figure 2: SOLO Subject Accountability # RADIANCE-HTN TRIO A total of 990 patients were consented and screened for eligibility into the TRIO Study. One hundred thirty-six (136) subjects were randomized (69 uRDN; 67 Sham) from 28 sites in the US and 25 sites in Europe. At the time of the database lock on August 22, 2022, 78 patients were available for analysis at the 24-month post-randomization visit. Follow-up is on-going. Twenty-one (21) Sham subjects crossed over to treatment to date. Crossover subjects restarted the required post-procedure follow-up schedule. Subject accountability post-randomization is shown in Figure 3. PMA P220023: FDA Summary of Safety and Effectiveness Data {29} ![img-2.jpeg](img-2.jpeg) Figure 3: TRIO Subject Accountability # RADIANCE II A total of 1,038 patients were consented and screened for eligibility. Two hundred twenty-four (224) subjects were randomized (150 uRDN: 74 Sham) at 37 centers in the United States and 24 in Europe. At the time of the database lock on August 13, 2022, all patients had completed their two-month post-procedure visit. An updated database lock was performed on February 23, 2023, at which time all patients had completed their 6-month follow up visit. Twenty-eight patients originally randomized to the Sham group crossed over to treatment. Crossover subjects restarted the required post-procedure assessment schedule, and all are continuing to be followed. Subject accountability post-randomization is shown in Figure 4. PMA P220023: FDA Summary of Safety and Effectiveness Data {30} ![img-3.jpeg](img-3.jpeg) Figure 4: RADIANCE II Subject Accountability # C. Study Population Demographics and Baseline Parameters Table 8 and Table 9 show baseline demographics and medical history for RADIANCE study subjects. The studies enrolled a majority of male patients with an average age in the mid-50s. Fifteen to $20\%$ of patients self-identified as Black or African American. Table 8: Baseline Demographics, ITT, uRDN vs Sham | | SOLO | | TRIO | | RADIANCE II | | | --- | --- | --- | --- | --- | --- | --- | | Measure | Renal Denervation (n=74) | Sham Procedure (n=72) | Renal Denervation (n=69) | Sham Procedure (n=67) | Renal Denervation (n=150) | Sham Procedure (n=74) | | Sex | | | | | | | | Male | 62.1% (46 / 74) | 54.1% (39 / 72) | 81.1% (56 / 69) | 79.1% (53 / 67) | 68.6% (103 / 150) | 77% (57 / 74) | | Female | 37.8% (28 / 74) | 45.8% (33 / 72) | 18.8% (13 / 69) | 20.9% (14 / 67) | 31.3% (47 / 150) | 22.9% (17 / 74) | | Age | 54.4 ± 10.2 | 53.8 ± 10.0 | 52.3 ± 7.5 | 52.8 ± 9.1 | 55.1 ± 9.9 | 54.9 ± 7.9 | | Race | | | | | | | PMA P220023: FDA Summary of Safety and Effectiveness Data {31} | | SOLO | | TRIO | | RADIANCE II | | | --- | --- | --- | --- | --- | --- | --- | | Measure | Renal Denervation (n=74) | Sham Procedure (n=72) | Renal Denervation (n=69) | Sham Procedure (n=67) | Renal Denervation (n=150) | Sham Procedure (n=74) | | American Indian or Alaska Native | 0.0% (0 / 74) | 0.0% (0 / 72) | 0.00% (0 / 68) | 1.52% (1 / 66) | 0% (0 / 150) | 0% (0 / 74) | | Asian | 1.3% (1 / 74) | 0.0% (0 / 72) | 1.47% (1 / 68) | 1.52% (1 / 66) | 0.0% (0 / 150) | 1.3% (1 / 74) | | Black | 16.2% (12 / 74) | 18.0% (13 / 72) | 20.59% (14 / 68) | 19.70% (13 / 66) | 14.0% (21 / 150) | 20.2% (15 / 74) | | Caucasian | 81.0% (60 / 74) | 72.2% (52 / 72) | 66.18% (45 / 68) | 77.27% (51 / 66) | 76.0% (114 / 150) | 75.6% (56 / 74) | | Hispanic or Latino | 1.3% (1 / 74) | 5.5% (4 / 72) | 7.35% (5 / 68) | 0.00% (0 / 66) | 10.0% (15 / 150) | 2.7% (2 / 74) | | Native Hawaiian or other Pacific Islander | 0.0% (0 / 74) | 0.0% (0 / 72) | 0.00% (0 / 68) | 0.00% (0 / 66) | 0.00% (0 / 150) | 0.00% (0 / 74) | | Other/Mixed Race | 0.0% (0 / 74) | 4.17% (3 / 72) | 4.41% (3 / 68) | 0.00% (0 / 66) | 10.00% (15 / 150) | 2.70% (2 / 74) | | BMI | 29.9 ± 5.9 | 29.0 ± 5.0 | 32.8 ± 5.7 | 32.6 ± 5.4 | 30.1 ± 5.2 | 30.6 ± 5.2 | | Abdominal circumference (cm) | 101.5 ± 14.2 | 98.5 ± 15.1 | 109.4 ± 15.5 | 109.2 ± 12.9 | 102.4 ± 12.3 | 104.3 ± 13.1 | | Office Systolic blood pressure (mmHg)* - Screening | 142.6 ± 14.7 | 144.6 ± 15.9 | 161.9 ± 15.5 | 163.6 ± 16.8 | 155.8 ± 11.1 | 154.3 ± 10.6 | | Office Diastolic blood pressure (mmHg)* - Screening | 92.3 ± 10.1 | 93.6 ± 8.3 | 105.1 ± 11.6 | 103.3 ± 12.7 | 101.3 ± 6.7 | 99.1 ± 5.6 | | Pulse* - Screening | 73.2 ± 12.4 | 73.2 ± 12.4 | 74.5 ± 11.0 | 77.6 ± 12.9 | 74.1 ± 12.0 | 73.6 ± 11.9 | | Pulse* - Baseline | 72.0 ± 12.1 | 72.6 ± 12.3 | 76.9 ± 12.2 | 82.0 ± 12.1 | 74.3 ± 11.3 | 72.5 ± 11.5 | PMA P220023: FDA Summary of Safety and Effectiveness Data Page 32 of 63 {32} Table 9: Baseline Medical History, ITT, uRDN vs Sham | | SOLO | | TRIO | | RADIANCE II | | | --- | --- | --- | --- | --- | --- | --- | | Measure | Renal Denervation (n=74) | Sham Procedure (n=72) | Renal Denervation (n=69) | Sham Procedure (n=67) | Renal Denervation (n=150) | Sham Procedure (n=74) | | History of Hypertension | 100% (74 / 74) | 100% (72 / 72) | 100% (69 / 69) | 100% (67 / 67) | 100% (150 / 150) | 100% (74 / 74) | | Hospitalization for hypertensive crisis | 2.7% (2 / 74) | 2.7% (2 / 72) | 21.7% (15 / 69) | 16.4% (11/67) | 6% (9 / 150) | 4% (3 / 74) | | Peripheral vascular disease | 2.7% (2 / 74) | 0% (0 / 72) | 1.4% (1 / 69) | 4.48% (3 / 67) | 0% (0 / 150) | 0% (0 / 74) | | Primary pulmonary hypertension | 0.0% (0 / 74) | 0.0% (0 / 72) | 0.0% (0 / 69) | 0.0% (0/67) | 0.0% (0 / 150) | 0.0% (0 / 74) | | Cerebrovascular event(s) | 0.0% (0 / 74) | 0.0% (0 / 72) | 8.7% (6 / 69) | 5.9% (4 /67) | 0.0% (0 / 150) | 0.0% (0 / 74) | | Type II Diabetes | 2.7% (2 / 74) | 6.9% (5 / 72) | 30.4% (21 / 69) | 25.3% (17 /67) | 6.0% (9 / 150) | 8.1% (6 / 74) | | Sleep Apnea | 8.1% (6 / 74) | 11.1% (8 / 72) | 27.5% (19 / 69) | 16.4% (11/67) | 14.0% (21 / 150) | 17.5% (13/74) | | Chronic kidney disease | 0.00% (0 / 74) | 0.00% (0 / 72) | 4.35% (3 / 69) | 5.97% (4 / 67) | 5.33% (8 / 150) | 4.05% (3 / 74) | | Ischemic heart disease | 0.00% (0 / 74) | 0.00% (0 / 72) | 2.90% (2 / 69) | 1.49% (1 / 67) | 0.00% (0 / 150) | 0.00% (0 / 74) | | Document episodes of Angina | 0.00% (0 / 74) | 0.00% (0 / 72) | 5.80% (4 / 69) | 1.4% (1 / 67) | 0.6% (1 / 150) | 2.70% (2 / 74) | | Prior myocardial infarction | 0.0% (0 / 74) | 0.0% (0 / 72) | 2.9% (2 / 69) | 5.9% (4 / 67) | 0.0% (0 / 150) | 0.0% (0 / 74) | | History of heart failure | 0.0% (0 / 74) | 0.0% (0 / 72) | 1.4% (1 / 69) | 4.4% (3 / 67) | 0.6% (1 / 150) | 0.0% (0 / 74) | | Bradycardia | 1.3% (1 / 74) | 2.7% (2 / 72) | 1.4% (1 / 69) | 0.0% (0 / 67) | 1.3% (2 / 150) | 4.0% (3 / 74) | | Atrial arrhythmias | 0.0% (0 / 74) | 0.0% (0 / 72) | 0.0% (0 / 69) | 4.4% (3 / 67) | 0.0% (0 / 67) | 0.0% (0 / 28) | | Prior atrial ablation | 0.0% (0 / 74) | 0.0% (0 / 72) | 0.0% (0 / 69) | 1.4% (1 / 67) | 0.6% (1 / 150) | 0.0% (0 / 74) | | Ventricular arrhythmias | 0.0% (0 / 74) | 0.0% (0 / 72) | 1.4% (1 / 69) | 2.9% (2 / 67) | 0.0% (0 / 150) | 1.3% (1 / 74) | # D. Treatment and Procedural characteristics The treatment and procedural characteristics of the population treated in the RADIANCE studies are shown in Table 10. The majority of patients were treated under conscious sedation (83% in SOLO, 63% TRIO, and 76% RADIANCE II). The remaining patients were treated under general anesthesia or monitored anesthesia care due to regional hospital practice (OUS). Procedure success in the studies was defined as delivery of a minimum of two emissions bilaterally, which was achieved in $&gt;96\%$ of uRDN subjects across the three studies. In four patients (2 SOLO, 1 TRIO, 1 RADIANCE II), zero or 1 renal artery was treated at time of procedure due to difficulty accessing the renal artery. PMA P220023: FDA Summary of Safety and Effectiveness Data {33} Table 10: Treatment and Procedure Characteristics (ITT) | | SOLO | TRIO | RADIANCE II | | --- | --- | --- | --- | | | Renal Denervation (N=74) | Renal Denervation (N = 69) | Renal Denervation (n=150) | | Procedure time (sheath removal - sheath insertion) (min)1 | 71.9 ± 23.2 | 83.0 | 76.7 ± 25.2 | | Contrast volume (cc) | 138.5 ± 66.6 | 176.9 ± 77.0 | 135.7 ± 67.4 | | Fluoroscopy exposure (minutes) | 13.7 ± 6.8 | 19.0 ± 11.5 | 15.9 ± 8.6 | | Total Number of Emissions2 | 5.3 ± 1.1 | 5.8 ± 1.2 | 5.6 ± 1.0 | | Total Number of Subjects with Accessory and/or Proximal Side Branch Emissions | 12.16% (9/74) | 24.64% (17/69) | 20.00% (30/150) | | Treatment successfully delivered (minimum 2 emissions bilateral) | 71/74 (95.95%) | 67/69 (97.10%) | 148/150 (98.67%) | | Total Emission Time (seconds) | 37.4 ± 8.0 | 40.7 ± 8.1 | 38.9 ± 7.3 | | Data displayed as either n/N (%), Mean±SD, or Median [IQR] (Minimum, Maximum).1Procedure time was defined as the time from arterial sheath placement to sheath removal.2Includes main renal and accessory artery emissions. | | | | # E. Safety and Effectiveness Results # 4. Safety Results The safety analysis was based on all available data on enrolled subjects in each of the three studies at the time of the database lock (August 13, 2022 for SOLO and TRIO and February 23, 2023 for RADIANCE II) and included a pooled cohort of 367 uRDN-treated patients with 30-day and 6-month evaluations. # Primary Safety Results In RADIANCE II, the primary safety endpoint was defined as a patient level composite of the incidence of the Major Adverse Events (MAE) at 30 days and at 6-months post-randomization. No events met the definition of an MAE in either uRDN or Sham patients in RADIANCE II. The composite MAE rate was $0\%$ (95% CI 0.0% - 1.63%). Based on the performance goal of 9.8%, the primary safety endpoint was met (0.0% vs 9.8%, Table 11). The pooled safety analysis was conducted on all uRDN-treated patients enrolled in the RADIANCE studies. As of August 8, 2022, 367 subjects were treated with the Paradise System and received at least one ultrasound emission. These 367 patients were randomized to renal denervation $(n = 290)$ during their index procedure or crossed over to uRDN treatment from the Sham group $(n = 77)$ . The pooled safety PMA P220023: FDA Summary of Safety and Effectiveness Data {34} analysis with individual events is shown in Table 12. Six (6) events in 367 patients met the definition of an MAE per the independent CEC). The MAE composite rate was $1.1\%$ with a $95\%$ confidence interval of $0.3\% - 2.77\%$ . Table 11. Primary Safety Results (ITT) | | MAE Rate | 95% CI | Performance Goal | Result | | --- | --- | --- | --- | --- | | RADIANCE-II | 0.0% | 0 - 1.63% | 9.8% | Met | | Pooled uRDN subjects | 1.1% | 0.3% - 2.77% | -- | -- | The pooled safety analysis with individual events is shown in Table 12. Table 12. Pooled Primary Safety Endpoint for uRDN-treated (Initial Procedure and Crossover) | | SOLO | | TRIO | | RADIANCE-II | | Combined | | --- | --- | --- | --- | --- | --- | --- | --- | | Number of Events (% Subjects with Event) | Initial | Crossover | Initial | Crossover | Initial | Crossover | | | 30-day events | | | | | | | | | All-cause mortality | 0 | 0 | 1 (1.4%) | 1 (4.8%) | 0 | 0 | 2 (0.5%) | | New onset (acute) end-stage renal disease (eGFR< 15 mL/min/m2or need for renal replacement therapy) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Significant embolic event resulting in end-organ damage (e.g., kidney/bowel infarct, lower extremity ulceration or gangrene, or doubling of serum creatinine) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Renal artery perforation requiring an invasive intervention | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Renal artery dissection requiring an invasive intervention | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Major vascular complications (e.g., clinically significant groin hematoma, arteriovenous fistula, pseudoaneurysm) requiring surgical repair, interventional procedure, thrombin injection, or blood transfusion (requiring more than 2 units of packed red blood cells within any 24-hr period during the first 7 days post randomization) | 0 | 0 | 2 (1.4%) | 0 | 0 | 0 | 2 (0.3%) | PMA P220023: FDA Summary of Safety and Effectiveness Data {35} | | SOLO | | TRIO | | RADIANCE-II | | Combined | | --- | --- | --- | --- | --- | --- | --- | --- | | Number of Events (% Subjects with Event) | Initial | Crossover | Initial | Crossover | Initial | Crossover | | | Hospitalization for hypertensive or hypotensive crisis | 0 | 0 | 1 (1.4%) | 0 | 0 | 0 | 1 (0.3%) | | Hospitalization for major cardiovascular- or hemodynamic- related events (e.g., HF; MI; Stroke) | 1 (1.4%) | 0 | 0 | 0 | 0 | 0 | 1 (0.3%) | | New onset Stroke | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | New onset Myocardial Infarction | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | 6-month events | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | New onset renal artery stenosis of more than 70%, confirmed by CT or MR angiography | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Overall Composite* | 1 (1.4%) | 0 | 4 (2.9%) | 1 (4.8%) | 0 | 0 | 6 (1.1%) Exact 95% CI 0.30% - 2.77% | Adverse Device Events (ADEs) and Serious Adverse Device Events (SADEs) are reported in Table 13, Table 14 and Table 15 and for all three studies. ## Adverse effects in the PMA clinical studies Adverse Device Events (ADEs) and Serious Adverse Device Events (SADEs) are reported in Table 13, Table 14 and Table 15 and for all three studies. In the SOLO Study, there were few serious adverse events (SAEs) during the post-procedure period – 1.4% rate of SAE and 3.4% rate of SADE. ADEs within the first 30 days were reported in 42% of the randomized uRDN and Sham patients with the majority associated with vascular access site complications (hematoma, swelling, pain). ADEs were primarily procedure-related, and no events were classified as only device-related based on assessment by the treating physician (Table 13). In the TRIO Study, there were few serious events during the post-procedure period – 3% rate of SAE and 3% rate of SADE. ADEs were reported in 41% of the randomized population (in both the uRDN and Sham groups) with the majority associated with vascular access site complications (hematoma, pain) and self-limited vasospasm. ADEs were primarily procedure-related (e.g., access site complications) and not device-related based on assessment by the treating physician (Table 14). In the RADIANCE II Study, there were few serious events during the post-procedure period – 9% rate of SAE and 5% rate of SADE. ADEs were reported in 56% of the PMA P220023: FDA Summary of Safety and Effectiveness Data {36} randomized population (in both the uRDN and Sham groups) with the majority associated with vascular access site complications (hematoma, pain), back pain, and self-limited vasospasm. ADEs were primarily procedure-related (e.g., access site complications) and not device-related based on assessment by the treating physician (Table 15). Table 13: Adverse Device and Serious Adverse Device Effects by Term and Treatment Group (Randomized Subjects) - SOLO | | Renal Denervation (n=74) | | | | Sham Procedure (n=72) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Adverse Device Event | | Serious Adverse Device Event | | Adverse Device Event | | Serious Adverse Device Event | | | Event type | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | | Abdominal pain | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Angina pectoris | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Asthenia | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Atrial fibrillation | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | | Atrioventricular block - Drug therapy | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | | Back pain | 4 | 5.41 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Bradycardia | 2 | 2.70 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Bradycardia - Drug therapy | 0 | 0.00 % | 2 | 2.70 % | 0 | 0.00 % | 0 | 0.00 % | | Contrast media allergy | 1 | 1.35 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Dizziness postural | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Endotracheal intubation complication | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Haematuria | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Headache | 1 | 1.35 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Hypotension | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Hypotension - Orthostatic Hypotension | 2 | 2.70 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Post procedural complication | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Presyncope - Drug therapy | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | | Pyrexia | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Renal artery stenosis | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Sedation complication | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Sinus tachycardia | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Thrombophlebitis superficial | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Vascular access site dissection | 1 | 1.35 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Vascular access site haematoma | 11 | 14.86 % | 0 | 0.00 % | 13 | 18.06 % | 0 | 0.00 % | | Vascular access site pain | 13 | 17.57 % | 0 | 0.00 % | 10 | 13.89 % | 0 | 0.00 % | | Vascular access site swelling | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.39 % | 0 | 0.00 % | | Vasospasm | 15 | 20.27 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | PMA P220023: FDA Summary of Safety and Effectiveness Data {37} Table 14: Adverse Device and Serious Adverse Device Effects by Term and Treatment Group (Randomized Subjects)- TRIO | | Renal Denervation (n=69) | | | | Sham Procedure (n=67) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Adverse Device Event | | Serious Adverse Device Event | | Adverse Device Event | | Serious Adverse Device Event | | | Event type | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | | Air embolism | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Back pain | 4 | 5.80 % | 0 | 0.00 % | 3 | 4.48 % | 0 | 0.00 % | | Bradycardia | 7 | 10.14 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Bradycardia - Drug therapy | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Dizziness | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.49 % | 0 | 0.00 % | | Drug hypersensitivity - Morphine | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.49 % | 0 | 0.00 % | | Echhymosis | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Headache | 1 | 1.45 % | 0 | 0.00 % | 3 | 4.48 % | 0 | 0.00 % | | Hematoma Infection | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.49 % | | Hyperhidrosis | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.49 % | 0 | 0.00 % | | Hypotension | 4 | 5.80 % | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | | Infection | 0 | 0.00 % | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | | Inflammation | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Investigation normal | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Pain in extremity | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Palpitations | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Post procedural complication | 2 | 2.90 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Renal artery dissection | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Renal artery thrombosis | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Sedation complication - Drug therapy | 0 | 0.00 % | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | | Supraventricular tachycardia | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Vascular access site bruising | 1 | 1.45 % | 0 | 0.00 % | 1 | 1.49 % | 0 | 0.00 % | | Vascular access site dissection | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.49 % | | Vascular access site haematoma | 10 | 14.49 % | 1 | 1.45 % | 5 | 7.46 % | 0 | 0.00 % | | Vascular access site haemorrhage | 1 | 1.45 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Vascular access site pain | 9 | 13.04 % | 0 | 0.00 % | 9 | 13.43 % | 0 | 0.00 % | PMA P220023: FDA Summary of Safety and Effectiveness Data {38} Table 15: Adverse Device and Serious Adverse Device Effects by Term and Treatment Group (Randomized Subjects)- RADIANCE II | | Renal Denervation (n=150) | | | | Sham Procedure (n=74) | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Adverse Device Event | | Serious Adverse Device Event | | Adverse Device Event | | Serious Adverse Device Event | | | Event type | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | # Events | % Subjects | | Abdominal pain | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Allergic reaction | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Anesthesia intubation complication | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Aortic dissection | 0 | 0.00 % | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | | Asystole | 1 | 0.67 % | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | | Back pain | 12 | 8.00 % | 0 | 0.00 % | 3 | 4.05 % | 0 | 0.00 % | | Back pain aggravated | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Blood in stool | 0 | 0.00 % | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | | Bradycardia | 3 | 2.00 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Catheter site pain | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Chest pain | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Contrast media allergy | 1 | 0.67 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Deep vein thrombosis leg | 0 | 0.00 % | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | | Diaphoresis | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Dizziness aggravated | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Fatigue | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Femoral artery pseudoaneurysm | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Flank pain | 0 | 0.00 % | 0 | 0.00 % | 2 | 2.70 % | 0 | 0.00 % | | Groin pain | 8 | 5.33 % | 0 | 0.00 % | 3 | 4.05 % | 0 | 0.00 % | | Headache | 1 | 0.67 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Hypertension aggravated | 2 | 1.33 % | 1 | 0.67 % | 2 | 2.70 % | 0 | 0.00 % | | Hypertensive crisis | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | 1 | 1.35 % | | Hypotension | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Inguinal pain | 4 | 2.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Low back pain | 6 | 4.00 % | 0 | 0.00 % | 1 | 1.35 % | 0 | 0.00 % | | Low blood pressure | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Orthostatic hypotension | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | | Pain in leg | 1 | 0.67 % | 0 | 0.00 % | 0 | 0.00 % | 0 | 0.00 % | PMA P220023: FDA Summary of Safety and Effectiveness Data {39} | | Renal D…
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