BAROSTIM NEO® System

P180050 · Cvrx, Inc. · DSR · Aug 16, 2019 · Cardiovascular

Device Facts

• Record ID: P180050
• Device Name: BAROSTIM NEO® System
• Applicant: Cvrx, Inc.
• Product Code: DSR · Cardiovascular
• Decision Date: Aug 16, 2019
• Decision: APPR
• Regulation: 21 CFR 870.3850
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The BAROSTIM NEO® System is indicated for the improvement of symptoms of heart failure – quality of life, six-minute hall walk and functional status, for patients who remain symptomatic despite treatment with guideline-directed medical therapy, are NYHA Class III or Class II (who had a recent history of Class III), have a left ventricular ejection fraction ≤ 35%, a NT-proBNP < 1600 pg/ml and excluding patients indicated for Cardiac Resynchronization Therapy (CRT) according to AHA/ACC/ESC guidelines.

Device Story

The BAROSTIM NEO System is an implantable neurostimulation device designed to improve cardiovascular function in heart failure patients. It consists of an Implantable Pulse Generator (IPG), a Carotid Sinus Lead (CSL), and a programmer system. The system uses BAROSTIM THERAPY to electrically activate carotid baroreceptors, which are natural cardiovascular sensors. By stimulating these receptors, the device mimics the body's natural regulatory response, signaling the brain to reduce sympathetic outflow and increase parasympathetic activity. This results in vasodilation, reduced stress hormones, and decreased cardiac workload, ultimately improving heart failure symptoms. The IPG is implanted subcutaneously, and the lead is placed on the carotid sinus. A physician programs the therapy parameters non-invasively using the external programmer system. The therapy is intended to improve patient quality of life, functional status, and exercise capacity.

Clinical Evidence

Evidence based on the BeAT-HF pivotal trial (IDE G120010), a prospective, multi-center, randomized controlled trial (n=408). The Intended Use Population (n=264) showed statistically significant improvements in 6-minute hall walk (6MHW), quality of life (MLWHF), and NT-proBNP levels at 6 months compared to medical management alone. Safety was demonstrated with a 96.8% MANCE-free rate (lower bound 92.8%) in the device arm.

Technological Characteristics

System includes IPG (hermetic enclosure, battery, circuitry), Carotid Sinus Lead (CSL) with 2mm electrode, and programmer system. Materials include silicone and titanium. Sensing/actuation principle: electrical activation of baroreceptors. Connectivity: 400MHz telemetry for IPG-programmer communication. Software: firmware/software developed under controlled life cycle model. Sterilization: not specified, but components are supplied sterile.

Indications for Use

Indicated for symptomatic heart failure patients (NYHA Class III or II with recent Class III history) despite guideline-directed medical therapy, with LVEF ≤ 35% and NT-proBNP < 1600 pg/ml. Contraindicated in patients with bilateral carotid bifurcations above the mandible, baroreflex failure, autonomic neuropathy, uncontrolled symptomatic bradyarrhythmias, carotid atherosclerosis > 50%, ulcerative carotid plaques, or silicone/titanium allergy.

Regulatory Classification

Identification

A carotid sinus nerve stimulator is an implantable device used to decrease arterial pressure by stimulating Hering's nerve at the carotid sinus.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Stimulator, Carotid Sinus

Device Trade Name: BAROSTIM NEO® System

Device Procode: DSR

Applicant’s Name and Address: CVRx, Inc.
9201 West Broadway Avenue, Suite 650
Minneapolis, Minnesota 55445

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P180050

Date of FDA Notice of Approval: August 16, 2019

Breakthrough Device: Granted breakthrough device status (formerly known as the Expedited Access Pathway, or EAP) on June 25, 2015 because the device met two criteria for addressing an unmet need: (1) no appropriate alternative, and (2) the availability of the device is in the best interest of patients.

II. INDICATIONS FOR USE

The BAROSTIM NEO® System is indicated for the improvement of symptoms of heart failure – quality of life, six-minute hall walk and functional status, for patients who remain symptomatic despite treatment with guideline-directed medical therapy, are NYHA Class III or Class II (who had a recent history of Class III), have a left ventricular ejection fraction ≤ 35%, a NT-proBNP &lt; 1600 pg/ml and excluding patients indicated for Cardiac Resynchronization Therapy (CRT) according to AHA/ACC/ESC guidelines.

III. CONTRAINDICATIONS

Patients are contraindicated if they have:

- Been assessed to have bilateral carotid bifurcations located above the level of the mandible
- Baroreflex failure or autonomic neuropathy
- Uncontrolled, symptomatic cardiac bradyarrhythmias
- Carotid atherosclerosis that is determined by ultrasound or angiographic evaluation greater than 50%
- Ulcerative plaques in the carotid artery as determined by ultrasound or angiographic evaluation
- Known allergy to silicone or titanium

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the BAROSTIM NEO System labeling.

# V. DEVICE DESCRIPTION

The BAROSTIM NEO System includes the following components:

| Device | Model(s) |
| --- | --- |
| Implantable Pulse Generator (IPG):
IPG
Torque Wrench
Port Plug | 2102 |
| Carotid Sinus Lead (CSL) Kit*:
Lead (Model 1036 or 1037)
Implant Adapter (Model 5033)
Implant Tool (Model 5031) | 1036 & 1037 |
| Programmer System (CPS):
Computer/Software
Programmer Interface (PI) | 9010 |
| Carotid Sinus Lead (CSL) Repair Kit
CSL Repair Kit Lead/Tool
Torque Wrench, Tubing | 5010 |

* There are 2 possible kit combinations. A kit is selected based on the CSL length that is needed: long (Model 1037) or short (Model 1036). Each kit contains an Implant Tool (Model 5031) and Implant Adapter (Model 5033).

Figure 1: BAROSTIM NEO System (excluding Implant Adapter and Implant Tool)

The BAROSTIM NEO System is the CVRx next generation system for improving cardiovascular function. The minimally-invasive BAROSTIM NEO System uses CVRx patented BAROSTIM THERAPY® technology to trigger the body's own natural systems by electrically activating the carotid baroreceptors, the body's natural cardiovascular regulation

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sensors. In conditions such as hypertension and heart failure it is believed the baroreceptors, the body's natural sensors, are not functioning properly and are not sending sufficient signals to the brain. This results in the brain sending signals to other parts of the body (heart, blood vessels, kidneys) to constrict the blood vessels, retain water and salt by the kidneys and increase stress-related hormones. When the baroreceptors are activated, signals are sent through neural pathways to the brain. In response, the brain works to counteract this stimulation by sending signals to other parts of the body (heart, blood vessels, and kidneys) that relax the blood vessels and inhibit the production of stress-related hormones. These changes act to reduce after-load and enable the heart to increase blood output, while maintaining or reducing its workload.

## Implantable Pulse Generator (IPG)

The Model 2102 IPG (Figure 2) contains a battery and circuitry in a hermetic enclosure. It provides control and delivery of the activation energy through the Carotid Sinus Lead to the baroreceptors.

The carotid sinus lead is attached to the pulse generator through the connector module. Nominal dimensions for the IPG are listed in Figure 2.

Figure 2: Implantable Pulse Generator

| Parameter | Max Value |
| --- | --- |
| Height | 72 mm |
| Width | 50 mm |
| Thickness | 14 mm |
| Mass | 60 grams |
| Volume | 40cc |

## Carotid Sinus Leads (CSL)

The Carotid Sinus Lead (Figure 3) conducts the activation energy from the IPG to the baroreceptors located on either the left or right carotid sinus. The leads are available in two (2) lengths Model 1036 (40cm), Model 1037 (50cm). Both are supplied with a 2 mm electrode and an Implant Tool interface. These are fully interchangeable to allow for anatomical variations and to be used per the physician's discretion.

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Figure 3: Carotid Sinus Lead

# Implant Adapter

The Model 5033 Implant Adapter is a temporary device used at system implant during the electrode mapping process. The therapy circuit requires two connections; the therapy lead and the IPG case. The implant adapter connects the therapy lead directly to the IPG header port and the case connection is made via a clip placed on the IPG surface.

Figure 4: Implant Adapter

# Implant Tool

The Model 5031 Implant Tool is a temporary device that attaches to the electrode to aid the mapping and implant process. The device integrates into the buckle located on the inactive side of the lead electrode (Figure 5).

Figure 5: Implant Tool

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CVRx Programmer System Model 9010

The Programmer System allows noninvasive communication with the IPG. The Programmer System allows input of therapy parameters and retrieves information regarding the status of the IPG.

The Programmer System consists of the following major components (Figure 6):

- Programmer Software
- Programmer Interface
- Computer

## Programmer Software/Computer

The Programmer Software is installed on the supplied computer. A USB memory device is used to facilitate file transfer to and from the computer. The computer with Programmer Software installed allows programming of parameters in the IPG and provides status indicators from the IPG. The Programmer Software will interrogate, adjust, and monitor the therapies being delivered by the IPG.

## Programmer Interface

The Programmer Interface provides the telemetry interface to the IPG. It is powered via the USB port on the computer.

Figure 6: Programmer System Model 9010

## Optional Accessories for Use with the System

### CSL Repair Kit Model 5010

The CVRx CSL Repair Kit contains tools and material to repair damage to the insulation and/or conductor coils of the therapy lead after chronic implantation.

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Figure 7: Replacement Lead Segment

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

Cardiac Resynchronization Therapy (CRT) is an effective therapy for patients with moderate to severe heart failure that are symptomatic despite guideline directed medical therapy (GDMT) and have a prolonged QRS. Approximately 30% of heart failure patients are indicated to receive CRT. Cardiac Contractility Modulation therapy is available for patients who remain symptomatic despite GDMT and are not indicated for CRT. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The BAROSTIM NEO System is marketed in the European Union and countries recognizing the CE marking for the treatment of heart failure since August 8, 2014. The following is a listing of countries where BAROSTIM NEO System has been marketed for the treatment of heart failure: Austria, Czech Republic, France, Germany, Italy, Lebanon, Monaco, The Netherlands, Slovakia, Spain, Sweden, Turkey, and United Kingdom. As of March 31, 2019, there have been 298 commercial implants for the treatment of heart failure in these countries since distribution began in October of 2014. It has not been withdrawn from marketing for any reason, relating to the safety and effectiveness of the device.

## 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.

- Stroke – a neurological deficit lasting more than 24 hours or less than 24 hours with a brain imaging study showing infarction
- Transient ischemic attack (TIA) – a neurological deficit lasting less than 24 hours without evidence of permanent cerebral infarction
- Systemic embolization – downstream obstruction of a blood vessel by migration of loosened intravascular plaque or clot

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- Surgical or anesthetic complications
- Infection – the need for antibiotics or possible removal of the BAROSTIM NEO System
- Wound complication – including hematoma (i.e. bruising and/or swelling)
- Arterial damage – including carotid artery rupture or hemorrhage (sudden and significant blood loss at a site of blood vessel rupture that may require reoperation or transfusion)
- Pain – an unpleasant sensory experience, including neck and chest pocket pain
- Nerve damage/stimulation – including injury to or stimulation of Cranial, Marginal Mandibular, Glossopharyngeal, Recurrent Laryngeal, Vagus and Hypoglossal Nerves (numbness in head and neck, facial palsy/paralysis, altered speech, altered sense of taste, respiratory constriction, stertorous breathing, excessive salivation, dry cough, vomiting and/or regurgitation, altered sensory and motor function of tongue, altered sensory function of pharynx and oropharynx, altered sensation in external auditory canal), stimulation of extravascular tissue [muscle twitching (fasciculation), pain, tingling, oral sensations]
- Hypotension – a decrease in systolic and diastolic blood pressure below normal levels that may result in dizziness, fainting, and/or falls
- Hypertensive crisis – uncontrolled rise in blood pressure
- Respiratory – including low oxygen saturation, respiratory distress, shortness of breath
- Exacerbation of heart failure
- Cardiac arrhythmias
- Tissue erosion/IPG migration – movement of device resulting in need for reoperation
- Injury to baroreceptors – an injury that results in baroreflex failure
- Fibrosis – replacement of normal tissue by the ingrowth of fibroblasts and the deposition of connective tissue
- Allergic reaction
- General injury to user or subject – may be due to surgical procedure, device use, or interaction with other devices
- Need for reoperation – operation to explant/replace IPG or CSLs due to tissue damage, infection, and/or device failure
- Secondary operative procedure – An increase in the complexity and risk of secondary operative procedures of the neck due to scar tissue and the presence of prosthetic material implanted for this device
- Exacerbation of heart failure
- Cardiac arrhythmias
- Death

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

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# IX. SUMMARY OF NONCLINICAL STUDIES

## A. Laboratory Studies

The results of bench testing follows below, beginning with the IPG, followed by the CSL lead, programmer and accessories.

### 1. BAROSTIM NEO IPG Mechanical Bench Tests

Successful testing of the IPG Hardware was completed and is summarized in the tables below, including acceptance criteria, sample size tested and results.

Table 1: IPG Mechanical Test Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Dimensions, Volume, Mass, Device Sharpness / Roughness, Device Marking, Radiopaque Identifier (X-ray ID), Header Configuration | IPG Dimensional, Mass, Marking Verification and Visual Tests | Dimensional: Device height, width, and thickness shall be less than 72mm, 50mm, and 14mm, respectively.
Volume: Device volume shall be less than 40cc.
Mass: Device mass shall be less than 60g.
Sharpness/Roughness: No external radius shall be less than 1.5mm excluding seal plug boss features, header overlap, adhesive filled recesses, lead bores, or suture holes. Device shall have a matte finish.
Device Marking: The company name, model, and serial number shall be marked on the device verified by inspection and a wet rub test.
Radiopaque Identifier: The devices shall have a unique radiopaque identifier for IPG including company logo and model.
Header Configuration: Connector cavity shall have two ports appropriately connected and marked left/right. | 1 of each model | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Mech Shock, Mechanical Vibration, Temp Changes, Atmospheric Pressure Changes, Shelf Box Drop Test, Shipping Carton ASTM D4169 Test, Internal Moisture Content | IPG Mechanical Verification Tests | Mechanical Shock: After exposure to mechanical shock per EN 60068-2-27, the IPG shall pass all functional tests that it passed prior to exposure.
Mechanical Vibration: After exposure to random vibration per EN 60068-2-64, the IPG shall pass all functional tests that it passed prior to exposure.
Temperature Changes: After exposure to thermal changes as specified in EN 45502-1, section 26.2, the IPG shall pass all functional tests that it passed prior to exposure.
Atmospheric Pressure Changes: After exposure to atmospheric pressure per EN 45502-1, section 25.1, the IPG shall pass visual inspection and all functional tests that it passed prior to exposure.
Shelf Box Drop: After exposure to a shelf box drop test per EN 45502-1, section 10.1, the IPG shall pass all functional tests that it passed prior to exposure.
Shipping Carton: After exposure to a shipping carton test per ASTM D4169, the IPG shall pass all functional tests that it passed prior to exposure.
Internal Moisture Content: The moisture content inside the IPG shall be less than 5000ppmv. | 22 | Pass |
| Connector Module Electrical Seal, Connector Module Interface Compatibility, Connector Module Set Screws | Header to Lead Seal and Integrity tests | Connector Module Electrical Seal: The connector system shall provide an electrical seal of 50KΩ minimum between lead conductor paths after a minimum 10-day soak in 0.9% saline at 37°C.
Connector Module Interface Compatibility: The connector cavity shall be similar to ISO 5841-3 except for the pin cavity diameter. The pin cavity diameter shall be 1.51 +/- 0.04mm.
Connector Module Set Screws: The connector module set screws shall be able to be tightened up to 14 oz-in and then be tightened/loosened 5 times onto a lead using the provided torque wrench and remain functional. | 22 | Pass |
| Connector Module Side Load Strength Test, Connector Module Front Load Strength Test | Header Side Load and Front Load Testing | Connector Module Side Load Strength: The header to IPG case shall withstand a side load of 18 lbs with no damage to the header/IPG case joint as determined by visual inspection at 8x.
Connector Module Front Load Strength: The header to IPG case must withstand a front load of 5 lbs with no damage to the header/IPG case joint as determined by visual inspection at 8x. | 22 | Pass |

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# 2. BAROSTIM NEO IPG Electrical Bench Tests

Successful testing of the IPG Hardware was completed and is summarized in the table below, including test method, sample size, tested and results.

Table 2: IPG Electrical Test Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Current Drain, Therapy, Measurement System, Device Environmental (EN 45502-1 Section 20.2 Defib testing) | IPG Electrical Verification Test | Current Drain: <38μA with therapy off; <148μA with therapy on at nominal settings. Therapy: 1.0mA to 20mA amplitude with resolution of 0.1mA and accuracy of +5/-3%. Measurement System: Lead impedance accuracy of +/-15% within range of 100 to 4500Ω. Defibrillation Robustness: No loss of functionality after exposure to external defibrillation per EN 45502-1, Section 20.2. | 3 | Pass |
| Accelerated Operating Life test | IPG Module Electrical Life Testing | Must meet all device requirements after exposure to accelerated life test equivalent to 10 years. | 22 | Pass |
| Leakage Current, ESD, Time Variable Magnetic Field, Static Magnetic Field, Electronic Article Surveillance, Ultrasound | IPG Safety Testing | Leakage Current: Leakage current in inactive output pathway must be <1μA. ESD: No loss of functionality after exposure to 2000V electro-static discharge. Time Variable Magnetic Field: No loss of functionality after exposure to time variable magnetic field per EN 45502-2-1, Section 27.8. Static Magnetic Field: No loss of functionality after exposure to static magnetic field per EN 45502-2-1, Section 27.7 and ANSI/AAMI PC69. Electronic Article Surveillance: No loss of functionality after exposure to time variable magnetic field per EAS E3 test protocol. | 1 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| | | **Ultrasound:** No loss of functionality after exposure to ultrasonic energy per EN 45502-1, Section 22.1. | | |
| EMI, Diathermy, Cautery | IPG EMI and Diathermy Safety Verification Testing | **EMI:** No loss of functionality after exposure to electromagnetic non-ionizing radiation per EN 45502-1, Section 27.1 and EN 45502-2-1 27.2.

**Diathermy:** No loss of functionality after exposure to electrical fields applied directly to the patient per EN 45502-1, Section 21.1 and EN 45502-2-1, Section 21.2.

**Cautery:** No loss of functionality after exposure to CVRx test method designed to simulate cautery during an implant procedure. | 1 | Pass |
| Maximum temperature rise due to therapy output, Maximum temperature rise due to Single Fault | IPG Temperature Rise Verification Testing | Maximum temperature rise due to therapy output or single fault must be <2°C. | 1 | Pass |
| 400MHz Tx Frequency, Power, Sensitivity, Interference Rejection. Wake Up Receive Sensitivity | IPG RF Verification Tests | **400MHz Tx Frequency:** All channels must be within +/- 100ppm.

**400MHz Tx Power:** All channels must be 1 to 25μW.

**400MHz Rx Sensitivity:** All channels must be at least -87dBm.

**400MHz Interference Rejection:** All channels must reject at least 60dB.

**2.4GHz Wake Up Receive Sensitivity:** All channels must be at least -40dBm. | 3 | Pass |
| ETSI EN 301 839-2, 47 CFR Part 95 Subpart I, RSS-243, ETSI EN 301 489-1 and 489-27, Specific Absorption Rate | IPG RF Standards Testing | **ETSI EN 301 839-2, 47 CFR Part 95 Subpart I, RSS-243, ETSI EN 301 489-1 and ETSI EN 489-27;** All applicable test requirements must pass.

**Specific Absorption Rate:** Partial body SAR must be <=1.5W/kg and whole-body SAR must be <=0.08W/kg per IEEE C95.3. | 1 | Pass |

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# 3. CSL Mechanical and Electrical Bench Tests

Successful testing of the CSL Hardware was completed and is summarized in the table below, including acceptance criteria, sample size tested and results.

Table 3: CSL Testing Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Lead Axial Flexibility | Flexibility test | Lead Body shall elongate a minimum of 5% when an axial load of up to 0.5 lbs is applied Insulation No visual breach Conductor No failure. Confirmed if after testing, each conductor path is functionally intact with electrical continuity maintained from initial test measurement (verified through DC resistance measurement) | 45 | Pass |
| Lead Bending Flexibility | Flexibility test | Lead contacts the entire 180 degree (±5.0 degree) rod surface after a minimum period of 5.0 seconds of load application Insulation No visual breach Terminal Pin to Cathode DC Resistance of 25 to 50 ohms | 45 | Pass |
| Terminal Pin to Lead Body Attachment Strength | Strength test | Joint No visual failure Insulation No visual breach Electrical Continuity maintained; verified through DC resistance measurement | 45 | Pass |
| Terminal Ring to Lead Body Attachment Strength | Strength test | Joint No visual failure Insulation No visual breach Electrical Continuity maintained; verified through DC resistance measurement | 45 | Pass |
| Lead Body to Cathode Electrode Joint Attachment Strength | Strength test | Joint No visual failure Insulation No visual breach Terminal Pin to Cathode DC Resistance of 25 to 50 ohms | 45 | Pass |
| Comprehensive Axial Load | Strength test | Elongation lead must not exhibit permanent elongation in excess of 5% Functional Damage lead must not exhibit permanent functional damage (e.g. visible bond or insulation failures) Joint No visual failure Insulation No visual breach Leakage Current measured between each conductor and the reference electrode and between the conductive path must not exceed 2.0 mA @100V following axial loading Terminal Pin to Cathode DC Resistance of 25 to 50 ohms | 45 | Pass |
| Suture Wing Attachment Strength (Axial) | Strength test | Suture Wing/Molded Transition withstand a minimum of 1.1 lbs axial loading without slipping on the lead body | 22 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Suture Wing Attachment Strength (Perpendicular) | Strength test | **Suture Wing** withstand a minimum of 2 lbs tensile loading without causing molded transition damage | 22 | Pass |
| Suture Tear Out Strength | Strength test | **Suture Wing Substrate** support a minimum load of 1.0 lb and shall not exhibit a complete rupture that allows the suture to separate from the electrode backer or suture wing | 22 | Pass |
| Terminal Durability | Durability test | **Terminal Insertion/Withdrawal** at last cycle, the peak forces required to insert and withdraw the lead terminal must be equal to or less than 3.15 lbs (14 N)

**Terminal Pin and Indifferent Electrode** minimum electrical impedance of at least 50 kΩ

**Terminal Ring and Indifferent Electrode** minimum electrical impedance of at least 50 kΩ

**Terminal Pin and Terminal Ring** minimum electrical impedance of at least 50 kΩ

**Conductor No failure.** Compliance is confirmed if after testing, each conductor path is functionally intact with electrical continuity maintained from initial-test measurement (verified through DC resistance measurement) | 45 | Pass |
| Interface Durability | Durability test | **Implant Tool Tip** restricts movement of the electrode and there is no tearing of the buckles or delamination of the buckles from the backer | 45 | Pass |
| Lead Body Flex Endurance | Flex fatigue test | **Conductor** devices must meet lead body flex testing with no conductor failure. Compliance is confirmed if after 94,000 cycles, each conductor path is functionally intact with electrical continuity maintained (verified through DC resistance measurement method). | 45 | Pass |
| Terminal Flex Endurance | Flex fatigue test | **Conductor Path** confirmed if after 164,000 cycles, each conductor path is functionally intact with electrical continuity maintained (verified through DC resistance measurement method) | 45 | Pass |
| Transition Flex Endurance | Flex fatigue test | **Conductor no failure.** Compliance is confirmed if after 164,000 each conductor path is functionally intact with electrical continuity maintained from pre-flex measurement (verified through DC resistance measurement) | 45 | Pass |
| Connector Dimensions | Dimensional inspection | **Connector Dimensions** samples must meet the connector dimensions identified
**Connector Dimensional Requirements** | 45 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | | | | | | Sample Size | Results |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Description | Equipment | Dimension (mm) | Dimension (inches) | Min (inches) | Max (inches) | | |
| | | Pin Length | Tool scope | 5.08 ± 0.25 | .200 ± .010 | .190 | .210 | | |
| | | Pin Diameter | Micrometer (w/stand) | 1.41 ± 0.03 | .0555 ± .001 | .0545 | .0565 | | |
| | | Ring Length | Tool scope | 4.02 ± 0.2 | .158 ± .008 | .150 | .166 | | |
| | | Ring Diameter | Micrometer (w/stand) | 2.66 ± 0.03 | .105 ± .001 | .104 | .106 | | |
| | | Pin / Ring Offset Length | Tool scope | 9.14 +0.26/- .52 | .360 +.010/- .020 | .340 | .370 | | |
| Terminal Insertion/ Withdrawal | Terminal strength test | Connector Force peak forces required to insert and withdraw the lead terminal into / from the connector gauge must be equal to or less than 3.15 lbs (14 N). Each conductor path must be functionally intact and electrical continuity must be maintained (continuity confirmed through DC resistance measurement). | | | | | | 45 | Pass |
| Set Screw Deformation | Terminal deformation test | Terminal Withdraw (from header) peak force must be equal to or less than 3.15 lbs (14 N)
Connector Force Testing peak forces required to insert and withdraw the lead terminal into / from the connector gauge must be equal to or less than 3.15 lbs (14 N). Each conductor path must be functionally intact and electrical continuity must be maintained (continuity confirmed through DC resistance measurement). | | | | | | 45 | Pass |
| Lead Seal Integrity | Lead/header integrity test | Terminal Pin and Indifferent Electrode minimum electrical impedance of at least 50 kΩ
Terminal Ring and Indifferent Electrode minimum electrical impedance of at least 50 kΩ
Terminal Pin and Terminal Ring minimum electrical impedance of at least 50 kΩ | | | | | | 45 | Pass |

## 4. Programmer System Mechanical Bench Tests

Testing of the Programmer System Hardware was successfully completed and is summarized on the following pages.

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Table 4: Programmer Testing Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Package Shipping (ASTM D4169), Size and Design Features, Environmental Testing (Pressure, Temperature and Humidity), Mechanical Drop, Mechanical Vibration, Transport and Use Size Requirements, Packaging Requirement Assessment | Programmer Interface Mechanical testing | Shipping: Exposure to shipping stresses per ASTM D4169 and thermal stresses at -30C @ ambient RH, 38C @ 85% RH, and 60C @ 30% RH as pre-conditioning.
Size and Design Features: Length x Width x Height must be less than 9X4X9 inches. Weight must be less than 2 pounds. Must include a type B (female) USB connector and a green LED. Housing must be gray in color.
Environmental (Pressure, Temp, Humidity): After exposure to shipping preconditioning per above, the PI shall pass the functional tests that it passed prior to exposure.
Mechanical Drop: After exposure to 50mm drops and tipping, the PI shall pass the functional tests that it passed prior to exposure.
Mechanical Vibration: After exposure to vibration of 0.5G peak, 10 to 500Hz, sinusoidal with 0.5 octave/min sweep rate, 30 minutes in each axis, the PI shall pass the functional tests that it passed prior to exposure.
Transport and Use Size: Accessory case must be capable of holding the PI, PC, PS, cables, and documentation and be transportable. The sum of the case's length, width, and height must not exceed 41 inches. The weight of the case and its contents must not exceed 20lbs.
Packaging Assessment: Analysis must demonstrate that the shipping packaging is compliant to EN13428 and 13430. | 3 | Pass |
| Computer Hardware Configuration, Computer Power Supply Configuration, Computer EMC and Safety | Programmer Computer Verification Tests | Computer Hardware Configuration: The computer must have a color display at least 12” diagonal with minimum 1024x768 resolution. The computer must have a compatible keyboard and pointing device and at least 2 USB 2.0 ports also compatible with USB 1.1. The computer must have a processor with minimum 2 cores and 2Ghz clock speed. The computer must have at least 2GB of RAM and 50GB hard drive capacity.
Computer Power Supply Configuration: The power supply must be specified to operate with 100-240VAC line voltage with either 50 or 60Hz line frequency and the programmer system must have a bill of materials to include a cord set appropriate for the country of operation. The power supply labeling or documentation must state that it complies with either EN60950-1 or EN60601-1.
Computer EMC and Safety: The manufacturer's documentation must state compliance to EMC requirements of EN55022 and EN55024, to the FCC Part 15 Class B conducted and radiated emissions requirements, and to the safety requirements of EN 60950-1. | 1 | Pass |

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Programmer packaging was also tested to representative shipping conditions and according to ASTM D4169. IPG firmware and Programmer software were both developed under a controlled development life cycle model and thoroughly verified and validated for all applicable requirements. Testing was according to risk management process and included code analysis, performance analysis, unit testing, integration testing, and verification testing. System testing was also performed with combined components based on anticipated clinical use scenarios to ensure proper operation as a system.

# 5. Programmer System Electrical Bench Tests

Successful verification testing was performed on the Programmer System; a table summarizing the results is provided below including test method, sample size tested, and results.

Table 5: Programmer Testing Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Supply current, 400MHz Antennas, RSSI, 2.4GHz Antenna | Programmer Interface Electrical Verification Test | Supply current: Must be <500mA 400MHz Antennas: Tx frequency must have +/- 100ppm accuracy; Tx power must be between 10 and 25μW; Rx sensitivity must be at least -85dBm; Interference rejection must be at least 60dB. Received Signal Strength Indicator: Rx sensitivity must be at least -96dBm; Accuracy must be +/- 3dB. 2.4GHz Antenna; Tx frequency must have +/- 100ppm accuracy; Tx power must be 15.75 to 20.0dBm. | 3 | Pass |
| USB, Frequency Hopping Spread Spectrum | Programmer Interface Electrical Verification testing | USB: Must be compatible with USB 2.0 interface Frequency Hopping Spread Spectrum: Must comply with FHSS requirements of ETSI EN 300 328. | 1 | Pass |
| EN 60601-1 (3rd Edition), UL 60601-1, CAN/CSA C22.2 No. 601.1 | Programmer Safety Standards testing | 60601-1: Must comply with all safety requirements of 60601-1 in each geography (i.e. UL 60601-1 for the USA). | 1 | Pass |
| ETSI EN 301 839-2, 47 CFR Part 95 Subpart I, RSS-243, ETSI EN | Programmer RF and EMC Standards testing | Must comply with all applicable RF and EMC requirements | 1 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| 300 328, 47 CFR 15.249, RSS-210, ETSI EN 301 489-1, ETSI EN 301 489-27, ETSI EN 301 489-17, EN 60601-1-2 | | | | |

# 6. Accessories Mechanical and Electrical Bench Tests

Only the Lead Repair Kit (LRK) was deemed to require significant bench testing for the CVRx accessories. Testing of the Lead Repair Kit was successfully completed and is summarized in the table below. The External Interface Magnet (EIM) interface to the IPG was also verified during IPG verification testing.

Successful testing of the Accessories Hardware was completed and is summarized in the tables below, including acceptance criteria, sample size tested and results.

Table 6: Implant Tool and Adapter Testing Summary

| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Implant Tool | | | | |
| Length | Mechanical | Length minimum 6.5 inches long | 22 | Pass |
| Engagement | Mechanical | Movement Compliance shall be confirmed if the implant tool tip restricts movement of the electrode and there is no tearing of the buckles or delamination of the buckles from the backer | 22 | Pass |
| Insertion/Withdrawal | Mechanical | Insertion/Withdrawals allow a minimum of 10 insertion/withdrawals into and out of interface feature without damage to lead electrode assembly | 22 | Pass |
| Axial Load | Mechanical | Joint no visual failure. The device shall withstand a minimum of 0.5 lbs loading and must not exhibit permanent functional damage | 22 | Pass |
| Tip Bend | Mechanical | Tip shall be capable of bending ±45 degrees a minimum of 10 times without breaking or cracking | 22 | Pass |
| Handle Bend | Mechanical | Handle shall be capable of bending 45 degrees without breaking | 22 | Pass |
| Adapter | | | | |
| Connection to IPG | Mechanical | IPG Case each clip is able to slide and retain onto the IPG case
Scratches/Dents negligible cosmetic scratches or dents on the IPG case and by no damage that can be detected with a nitrile gloved finger | 22 | Pass |
| Connection to Mapping Pin | Mechanical | Connector Pin each alligator clip is able to connect and retain on a minimum 0.083 inch diameter pin. | 22 | Pass |
| Axial Load | Mechanical | Joint No visual failure
Insulation No visual breach
DC Resistance between the clip distal ends must be less than or equal to 20 ohms | 22 | Pass |

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Table 7: Lead Repair Kit (LRK) Model 5010 Mechanical and Electrical Test Summary

| Specification Feature | Test Method | Acceptance Criteria | | | | | Sample Size | Results |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Replacement Section | | | | | | | | |
| Terminal Dimensions | Dimensional inspection | Description | Dimension (Inches) | Min (Inches) | Max (Inches) | Measurement Method | 22 | Pass |
| | | Pin Length | .200 ±.010 | .190 | .210 | Tool scope | | |
| | | Pin Diameter (NOT IS-1) | .0555 ±.001 | .0545 | .0565 | Micrometer with stand | | |
| | | Ring Length | .156 ±.008 | .150 | .166 | Tool scope | | |
| | | Ring Diameter | .105 ±.001 | .104 | .106 | Caliper* | | |
| | | Pin / Ring Offset Length | .350 +.010/-.020 | .340 | .370 | Tool scope | | |
| Terminal Insertion/ Withdrawal | Force gage | Connector shall fit completely into the CVRx IPG header. The maximum insertion force and maximum withdrawal force shall not be greater than 3.15 lb (14 N). Each conductor path must be functionally intact and electrical continuity must be maintained (continuity confirmed through DC resistance measurement) | | | | | 22 | Pass |
| Set Screw Deformation | Torque application and force gage | Peak Force required to withdraw the terminal (from header) must be equal to or less than 3.15 lbs (14 N)Insertion and Withdrawal Force the DC resistance of each conductor path in the device shall be 5 ohms max. | | | | | 22 | Pass |
| Lead Seal Integrity | EN 45502-2-1, section 23.3 | Terminal Insertion/Withdrawal at last cycle, the peak forces required to insert and withdraw the lead terminal must be equal to or less than 3.15 lbs (14 N)Terminal Pin and Indifferent Electrode minimum electrical impedance of at least 50 kΩTerminal Ring and Indifferent Electrode minimum electrical impedance of at least 50 kΩTerminal Pin and Terminal Ring minimum electrical impedance of at least 50 kΩConductor No failure. Compliance is confirmed if after testing, each conductor path is functionally intact with electrical continuity maintained from initial-test measurement (verified through DC resistance measurement)Insulation No visual breach (verified using microscope @ 10x magnification) | | | | | 22 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Lead Bending Flexibility | Mechanical test | Lead Body shall be confirmed by visually inspecting each lead body sample at each of the locations/orientations listed above as contacting the entire 180 degree (±5.0 degree) rod surface after a minimum period of 5.0 seconds of load application with no visible insulation failure or conductor failure (verified through DC resistance measurement method) | 22 | Pass |
| Terminal Pin to Lead Body Attachment Strength | Mechanical test | Joint No visual failure
Insulation No visual breach
Electrical Continuity (DC Resistance) between Terminal Pin and Cathode Conductor (clear cable)
Electrical Continuity (DC Resistance) between Terminal Ring and Anode Conductor (blue cable) | 22 | Pass |
| Terminal Ring to Lead Body Attachment Strength | Mechanical test | Joint No visual failure
Insulation No visual breach
Electrical Continuity (DC Resistance) between Terminal Pin and Cathode Conductor (clear cable)
Electrical Continuity (DC Resistance) between Terminal Ring and Anode Conductor (blue cable) | 22 | Pass |
| Comprehensive Axial Load | Mechanical test | Elongation lead must not exhibit permanent elongation in excess of 5%
Function lead must not exhibit permanent functional damage (e.g. visible bond or insulation failures)
Joint No visual failure
Insulation No visual breach
Leakage Current measured between each conductor and the reference electrode and between the two conductive paths must not exceed 2.0 mA @100V following axial loading
Electrical Continuity (DC Resistance) between Terminal Pin and Cathode Conductor (clear cable)
Electrical Continuity (DC Resistance) between Terminal Ring and Anode Conductor (blue cable) | 22 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Terminal Durability | Mechanical test | Terminal Insertion/Withdrawal at last cycle, the peak forces required to insert and withdraw the lead terminal must be equal to or less than 3.15 lbs (14 N)
Terminal Pin and Indifferent Electrode minimum electrical impedance of at least 50 kΩ
Terminal Ring and Indifferent Electrode minimum electrical impedance of at least 50 kΩ
Terminal Pin and Terminal Ring minimum electrical impedance of at least 50 kΩ
Conductor No failure. Compliance is confirmed if after testing, each conductor path is functionally intact with electrical continuity maintained from initial-test measurement (verified through DC resistance measurement)
Insulation No visual breach (verified using microscope @ 10x magnification) | 22 | Pass |
| Lead Body Flex Test | Mechanical test | Conductor All devices must meet the lead body flex testing with no conductor failure. Compliance is confirmed if after 94,000 cycles in each orientation, each conductor path is functionally intact with electrical continuity maintained from pre-flex measurement (verified through DC resistance measurement method of section 5.1). | 22 | Pass |
| Terminal Connection Flex Endurance | Mechanical test | Lead Terminal Connector flex testing with no conductor failures. Compliance is confirmed if after 164,000 cycles in each orientation, each conductor path is functionally intact with electrical continuity maintained (verified through DC resistance measurement) | 22 | Pass |
| DC Resistance | Electromechanical test | Conductor Path DC resistance in the device shall be 5 ohms max | 22 | Pass |
| Insulation Integrity | Electromechanical test | Leakage Current measured between each conductor and the reference electrode, and between any two conductors, may not exceed 2.0 mA during the voltage application | 22 | Pass |
| System Requirements | | | | |
| Lead Body Bending Flexibility | Mechanical test | Lead Body sample must touch the rod at the edges of the rod surface at 90° ± 5° and 270° ± 5° after a period of 5 seconds of load application as demonstrated through visual inspection | 22 | Pass |

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| Specification Feature | Test Method | Acceptance Criteria | Sample Size | Results |
| --- | --- | --- | --- | --- |
| Comprehensive Axial Load | Mechanical test | Elongation lead must not exhibit permanent elongation in excess of 5%
Function lead must not exhibit permanent functional damage (e.g. visible bond or insulation failures)
Joint No visual failure
Insulation No visual breach
Leakage Current measured between each conductor and the reference electrode and between the two conductive paths must not exceed 2.0 mA @100V following axial loading
Electrical Continuity (DC Resistance) between Inner Coil and Cathode Conductor (clear cable)
Electrical Continuity (DC Resistance) between Outer Coil and Anode Conductor (blue cable) | 22 | Pass |
| Flex Endurance | Mechanical test | Conductor Devices must meet the flex testing with no conductor failure.
Compliance is confirmed if after 164,000 cycles in each orientation, each conductor path is functionally intact with electrical continuity maintained (verified through DC resistance measurement) | 22 | Pass |
| Contact Assignment | Electromechanical test | Cathode (clear cable) shall be connected to the Terminal Connector pin (inner coil)
Anode (blue cable) shall be connected to the Terminal Connector ring (outer coil) | 22 | Pass |
| Insulation Integrity | Electromechanical test | Leakage Current measured between each conductor and the reference electrode, and between any two conductors, may not exceed 2.0 mA during the voltage application | 22 | Pass |

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# 7. Software and Firmware Testing

The CVRx Development Life Cycle Model has three phases: Firmware/Software Planning, Firmware/Software Development and Firmware/Software Maintenance. This type of life cycle reflects an iterative process of development in which the firmware/software is planned, assessed, defined, designed, tested, implemented, and controlled. A firmware/software project repeatedly passes through these phases in iterations. The baseline starts in the Firmware/Software Planning Phase. Each subsequent iteration builds on the baseline. All planning and initial risk analysis activities are performed during the Firmware/Software Planning Phase. The software and firmware verification and validation testing was successfully completed.

## a) IPG Firmware

The Firmware for the IPG is verified and validated through testing and documentation of the results. The results of the testing were successful and the analysis found the firmware to be adequate.

## b) Programmer Interface (PI) Firmware

The PI Firmware is verified and validated through code analysis, performance analysis, unit testing, integration testing, and verification testing. The results of the testing were successful and the analysis found the firmware to be adequate.

## c) Programmer Software

The Programmer Software is verified and validated through code analysis, unit testing, integration testing, and verification testing. The results of the testing were successful and the analysis found the software to be adequate.

## d) Cybersecurity

The cybersecurity of the BAROSTIM NEO System has been assessed in a security hazard analysis, including automated and manual testing to assess the system against common vulnerabilities and attacks. Cybersecurity risks and mitigations are documented in the risk management system. The residual cybersecurity risk associated with the BAROSTIM NEO System is currently acceptable.

# 8. Biocompatibility Studies

All testing on the BAROSTIM NEO System was performed in accordance to the ISO 10991 Standard. The IPG was tested for cytotoxicity, maximization sensitization, intracutaneous extract, systemic toxicity extract, and material mediated pyrogens and all tests passed meeting their acceptance criteria.

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Table 8: Summary of BAROSTIM NEO IPG Testing

| Test Method | Summary of Results |
| --- | --- |
| Cytotoxicity Study Using the ISO Elution Method ISO 10993-5: | The test article extract showed no evidence of causing cell lysis or toxicity. The test article extract met the requirements of the test since the grade was less than a grade 2 (mild reactivity). |
| ISO Guinea Pig Maximization Sensitization Test - Extract ISO 10993-10 | The test article extracts showed no evidence of causing delayed dermal contact sensitization in the guinea pig. The test article extracts were not considered sensitizers in the guinea pig maximization test. |
| ISO Intracutaneous Study, Extract ISO 10993-10 | There was no erythema and no edema from the SC test extract injected intracutaneously into rabbits. There was very slight erythema and very slight edema from the SO test extract injected intracutaneously into rabbits. Each test article extract met the requirements of the test since the difference between the test article extracts and corresponding control score was 1.0 or less. |
| ISO Systemic Toxicity - Study - Extract ISO 10993-11 | There was no mortality or evidence of systemic toxicity from the test article extracts. The test article extracts met the requirements of the study. |
| USP Pyrogen Study, Material Mediated ISO 10993-11 | The total rise of rabbit temperatures during the 3 hour observation period was within acceptable USP limits. The test article was judged as nonpyrogenic. |

Table 9: CSL Biocompatibility

| STUDY | RESULT |
| --- | --- |
| Cytotoxicity Study Using the ISO Elution Method 1X MEM Extract Report | Pass |
| ISO Maximization Sensitization Study Extract | Pass |
| ISO Intracutaneous Study Protocol | Pass |
| ISO Systemic Toxicity Study Protocol | Pass |
| USP Pyrogen Study Material Mediated | Pass |
| 2 week Muscle Implant Study | Pass |
| Genotoxicity: Bacterial Reverse Mutation Study | Pass |
| Mouse Peripheral Blood Study | Pass |
| Genotoxicity: Mouse Lymphoma Study | Pass |
| 12 week Muscle Implant Study | Pass |
| 13 Week System Toxicity Study | Pass |
| 26 Week System Toxicity Study | Pass |

# 9. Packaging Tests

# a) IPG, CSL, and CSL Repair Kit

The shelf package consists of a cardboard box with insert tray that supports the sterile package. The shelf package has a label attached to the top and top/side of the box. The sterile package consists of two blister packages (one inside the other). Each blister tray has a lid sealed to the tray, providing a sterilization barrier. The outer package has a label attached to the lid material. The IPG, Carotid Sinus Lead, and CSL Repair Kit Packaging was tested and found to conform to the requirements.

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b) Programmer System

The Programmer System, consisting of the assembled Programmer Interface and PI-PC USB Cable, is placed in the Computer Case Sub-assembly. The computer is placed back in the original manufacturer's box and placed beside the computer case subassembly. Those two are wrapped in disposable cushioning (bubble wrap or equivalent) inside a box for shipping. A shipping label is placed on the shipping box and the box is sealed. The Programmer System Packaging was tested and found to conform to the requirements.

c) Ship Testing

The packaged components of the BAROSTIM NEO System are tested against industry standards to ensure that they remain functional after the shipping process.

10. Shelf Life

a) IPG

The BAROSTIM NEO device and package were subjected to Design Validation Test (DVT) for a one year accelerated shelf life performance. The BAROSTIM NEO IPG and package also completed a real-time shelf life performance DVT. This testing of real-time aged packages for over 2 years at ambient conditions within CVRx and completed preconditioning and performance testing. All test samples passed the testing. The IPG is labeled for two-year shelf life.

b) CSL

The CSL was fully DVT-qualified for a three-year accelerated shelf life performance. CSL real time aging is in progress. The CSL is labeled for two-year shelf life.

c) CSL Repair Kit

The LRK was fully DVT-qualified for a two-year accelerated shelf life performance. The CSL Repair Kit is labeled for two-year shelf life.

B. Animal Studies

CVRx has performed research and Good Laboratory Practice (GLP) safety evaluations of BAROSTIM THERAPY using BAROSTIM NEO System, in an ovine model. The system was tested both acutely and chronically (180 days) in the ovine model consisting of 12 test articles and three ovine animals with therapy ON and OFF. The 180-day study was completed with favorable conclusions for Baroreflex Activation Therapy®

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with the BAROSTIM NEO System regarding gross and histological tissue response and device integrity. No article related gross issues, histological issues, or adverse events were found in the 180-day study. No significant issues were determined when comparing the therapy ON versus therapy OFF groups. The lack of adverse histological findings with and without electrical stimulation supported the safety of the BAROSTIM NEO System for use in clinical testing.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the BAROSTIM NEO System for the reduction of the symptoms of heart failure in the US under IDE G120010. The BAROSTIM NEO® - Baroreflex Activation Therapy® for Heart Failure (BeAT-HF) trial data is the basis for the PMA approval decision. A summary of the BeAT-HF Pivotal Trial is presented below.

## A. Study Design

Subjects were treated between April 5, 2016 and April 22, 2019. The locked database for this PMA, reflected data collected through April 22, 2019 and included 408 randomized subjects. There were 92 investigational sites from both the United States (US, 91) and United Kingdom (UK, 1).

The study was a prospective, multi-center, two-arm, randomized trial in subjects with reduced ejection fraction heart failure. Subjects were randomized in a 1:1 ratio to receive BAROSTIM THERAPY with an implanted BAROSTIM NEO System in addition to medical management (BAT + MM) or to receive medical management (MM) alone (no device implant). A key enrollment criteria includes post-consent screening measurements that was obtained only after the subject completed a medication optimization and 4-week medication stabilization period. For all subjects, the heart failure medication regimen must remain stable during the 4-week medication stabilization period, except for minor adjustments.

The control group (MM arm) subjects were treated identically with regard to all screening and follow-up testing at the same time periods as the device group at screening, baseline and all follow-ups. Prior to randomization, site personnel were required to provide an anticipated implant date. For subjects randomized to the Medical Management Arm, this date was used for the timing of all other trial visits. For subjects randomized to the Device Arm, trial visits were based on the actual date of device implant.

The trial was designed in two phases, Expedited and Extended. The subjects of primary interest for this PMA are the Expedited Phase population. The Expedited Phase population for the analysis of the 6-month endpoints includes all subjects randomized to fulfill the individual sample size requirements for those endpoints (MLWHF QOL, 6MHW, NT-proBNP in both arms of the trial and Major Adverse Neurological &amp; Cardiac Events (MANCE) free rate in the BAT + MM arm only).

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The Extended Phase is designed to collect post-market long-term follow-up data, resulting in assessment of Morbidity and Mortality (M&amp;M) data and a later PMA Supplement application.

The trial oversight used a blinded to arm assignment, core laboratory to analyze and document the NT-proBNP testing. In addition, all heart failure hospitalization and censored events were blindly adjudicated by independent evaluators on the Clinical Events Committee (CEC) and the trial was also overseen by an independent Data Monitoring Committee (DMC) and Adverse Events Committee (AEC). Lastly, an Executive Steering committee (ESC), consisting of independent physicians assisted the sponsor in the development and execution of the trial.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the BeAT-HF study was limited to subjects who met the following inclusion criteria:

1) Age 21 years or above.
2) Currently NYHA Class II or III heart failure. For NYHA Class II, must have been NYHA Class III at any point in time within 3 calendar months prior to enrollment or at time of screening (enrollment is defined as the date the subject provided written consent).
3) Left ventricular ejection fraction ≤ 35% within 45 days prior to randomization.
4) Heart failure accompanied by BNP ≥ 100 or NT-proBNP ≥ 400 within 45 days prior to randomization, or a heart failure hospitalization in the past 12 months.

**Note:** Heart failure hospitalization may include an overnight hospital or hospital-based observation unit stay with a primary diagnosis of heart failure or an emergency room visit with a primary diagnosis of heart failure.

**Note:** Screening BNP/NT-proBNP must be measured in an outpatient setting at a time when the subject is thought to be clinically stable.

**Note:** If subject is taking sacubitril/valsartan (i.e. Entresto®), NT-proBNP must be used for screening eligibility.

5) On optimal, stable, Guideline Directed Medical Therapy (GDMT) per country specific guidelines for the treatment of heart-failure throughout screening/baseline evaluation and for at least 4 weeks prior to obtaining any post-consent screening parameters:

- No more than a 100% increase or a 50% decrease of the dosage of any one medication other than a diuretic.
- Medication changes within a drug class are allowed as long as the equivalent dosage is within the limits specified above.
- Unrestricted changes in diuretics are allowed as long as the subject remains on a diuretic.

6) Six-minute hall walk (6MHW) ≥ 150 m AND ≤ 400 m within 45 days prior to randomization.

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7) The artery planned for the BAROSTIM NEO implant must meet both of the following criteria:

- At least one carotid bifurcation as identification by a bilateral carotid duplex ultrasound within 6 months prior to randomization that is:
a. Below the level of the mandible AND
b. No ulcerative carotid arterial plaques AND
c. No carotid atherosclerosis producing a 50% or greater reduction in linear diameter in the internal carotid AND
d. No carotid atherosclerosis producing a 50% or greater reduction in linear diameter in the distal common carotid

- No prior surgery, radiation, or endovascular stent placement in the carotid artery or the carotid sinus region.

8) If female and of childbearing potential, must use a medically accepted method of birth control (e.g., barrier method with spermicide, oral contraceptive, or abstinence) and agree to continue use of this method for the duration of the trial. Women of childbearing potential must have a negative pregnancy test within 14 days prior to randomization.

9) Received a standard cardiac work up and is an appropriate candidate for the study and the surgical procedure as determined by a trial cardiologist and a trial surgeon.

10) Subjects implanted with a cardiac rhythm management device that does not utilize an intracardiac lead, or implanted with a neurostimulation device, must be approved by the CVRx Clinical department.

11) Signed a CVRx-approved informed consent form for participation in this trial.

Subjects were not permitted to enroll in the BeAT-HF study if they met any of the following exclusion criteria:

1) Received cardiac resynchronization therapy (CRT) within six months of randomization, or is actively receiving CRT.

2) Currently have a Class I indication for a cardiac resynchronization therapy (CRT) device according to AHA/ACC/ESC guidelines for the treatment of congestive heart failure. [1,ii]

3) Known or suspected baroreflex failure or autonomic neuropathy.

4) AHA/ACC Stage D heart failure within 45 days prior to randomization.

5) Body mass index &gt; 40.

6) Serum estimated glomerular filtration rate (eGFR) &lt; 25 ml/min/1.73 m² within 45 days prior to randomization.

7) Recurring resting heart rate of either &lt; 60 bpm or &gt; 100 bpm via clinic measurements within 45 days prior to randomization. (Note: Heart rate &lt; 60 bpm is not applicable to subjects with an implanted device capable of pacing.)

8) Recurring symptomatic hypotension within 45 days prior to randomization.

9) Significant uncontrolled symptomatic bradyarrhythmias or unstable ventricular arrhythmias.

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10) Subjects with any surgery that has occurred, or is planned to occur, within 45 days of the BAROSTIM NEO implant procedure. This includes pacemaker or ICD implants or battery replacements.

11) Episode of NYHA class IV heart failure with acute pulmonary edema within 45 days prior to randomization.

12) Any of the following within 3 months of randomization:
- Myocardial infarction
- Unstable angina
- Percutaneous coronary intervention (e.g. CABG or PTCA)
- Cerebral vascular accident or transient ischemic attack
- Sudden cardiac death

13) Solid organ or hematologic transplant, or currently being actively evaluated for an organ transplant.

14) Has received or is receiving LVAD therapy.

15) Has received or is receiving chronic dialysis.

16) Heart failure secondary to a reversible cause, such as cardiac structural valvular disease, acute myocarditis and pericardial constriction.

17) Primary pulmonary hypertension.

18) Infiltrative cardiomyopathy (e.g. cardiac amyloidosis).

19) Severe COPD or severe restrictive lung disease (e.g. requires chronic steroid use or home oxygen use).

20) Active malignancy.

21) Current or planned treatment with intravenous positive inotrope therapy.

22) Life expectancy less than one year.

23) Clinically significant psychological condition that in the physician's opinion would prohibit the subject's ability to meet the protocol requirements.

24) Unable or unwilling to fulfill the protocol medication compliance, testing, and follow-up requirements (e.g. recent drug abuse).

25) Enrolled and active in another (e.g. device, pharmaceutical, or biological) clinical trial unless approved by the CVRx Clinical department.

26) Subjects with known allergies to silicone and titanium.

2. Follow-up Schedule

All subjects were followed according the table below with both arms being treated using the same schedule.

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Table 10: Time and Events Schedule

| Procedure | Months from Implant |
| --- | --- |
| Screen | BL | Implant | Activate/Pre-discharge | .50 | 1 | 1.5 | 2 | 3 | 6 | 9 | 12 | 15-24* | After 24*** |
| Subject Informed Consent | X | | | | | | | | | | | | |
| Assess Enrollment Criteria | X | | | | | | | | | | | | |
| Demographics/Medical History | X | | | | | | | | | | | | |
| Physical Assessment | X | X | | | X | X | X | X | X | X | X | X | X |
| Subject Medications | X | X | | | X | X | X | X | X | X | X | X | X |
| Adverse Events | X | X | X | X | X | X | X | X | X | X | X | X | X |
| LVEF | X | | | | | | | | | | | | |
| Six Minute Hall Walk | X | X | | | | | | | | X | | X | |
| BNP or NT-proBNP | X | | | | | | | | | | | | |
| Core lab NT-proBNP | | X | | | | | | | | X | | X | |
| eGFR | X | | | | | | | | | | | | |
| Carotid Duplex Ultrasound† | X | | | | | | | | | | | | |
| AHA/ACC Stage | X | | | | | | | | | | | | |
| NYHA Classification | X | X | | | | | | | | X | | X | X** |
| Voice / Eating Tool | | X | | | | | | | | | | | |
| Electrocardiography (ECG) | X | | | | | | | | | | | | |
| MLWHF Questionnaire | | X | | | | | | | | X | | X | X** |
| EQ-5D Questionnaire | | X | | | | | | | | X | | X | X** |
| CRM Arrhythmia Log | | O | | | | | | | | O | | O | O** |
| Ultrasound to Locate Bifurcation | | | X | | | | | | | | | | |
| Implant Procedure Testing | | | X | | | | | | | | | | |
| Device Programming Evaluation | | | | X | X | X | X | X | X | X | X | X | |

X = Required, O = Optional; *Quarterly up to 24 months; **18 and 24 month visit only; *** Semi-annual
†A historical measurement may be used if within 6 months of randomization.
**Bold &amp; Grey = Device Subjects Only**

3. Clinical Endpoints

The primary endpoints for the PMA were assessed at six months for the PMA population as follows:

- Safety - lower bound of the one-sided 95% confidence interval of the MANCE event free rate for the BAT + MM (device arm only) must be greater than 85%.
- Effectiveness - Assessed that for six minute hall walk (6MHW), Minnesota Living With Heart Failure Questionnaire Quality of Life (MLWHFQ QOL or QOL), and NT-pro-BNP that the BAT + MM arm must be statistically better than MM arm.

The initial phase of the trial was evaluated in October 2018. The data showed that the Initial Cohort met the 6MHW and QOL endpoints, but failed to meet the NT-proBNP endpoints. The summary results of the Initial Cohort are shown below.

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Table 11: System or Procedure Related MANCE-Free Rate in Expedited Phase (Initial Cohort) Safety AllBAT + Medical Management Implanted Subjects

| | Total Number of Subjects | Number of Subjects MANCE-Free | MANCE-Free Rate | One-Sided 95% Lower Bound | P-value |
| --- | --- | --- | --- | --- | --- |
| MANCE Event-Free | 125 | 118 | 94.4% | 89.7% | <.001 |

Table 12: Six Minute Walk Distance at 6 Months in Expedited Phase (Initial Cohort) All Randomized Subjects

| | BAT + Medical Management | | Medical Management | | Difference | |
| --- | --- | --- | --- | --- | --- | --- |
| Visit | N | Mean±SD (95% CI) | N | Mean±SD (95% CI) | Δ Means (95% CI) | p-value |
| Baseline | 139 | 294.4 ± 76.4 (281.6, 307.2) | 155 | 289.5 ± 69.1 (278.6, 300.5) | | |
| 6-Month | 106 | 339.0 ± 107.9 (318.3, 359.8) | 127 | 277.5 ± 111.0 (258.0, 297.0) | | |
| 6-Month Change | 106 | 35.5 ± 82.7 (19.6, 51.4) | 127 | -11.2 ± 92.6 (-27.4, 5.1) | 47.8 (25.1, 70.6) | <0.001 |

Table 13: Change in Quality of Life at 6 Months in Expedited Phase (Initial Cohort) All Randomized Subjects

| | BAT + Medical Management | | Medical Management | | Difference | |
| --- | --- | --- | --- | --- | --- | --- |
| Visit | N | Mean±SD (95% CI) | N | Mean±SD (95% CI) | Δ Means (95% CI) | p-value |
| Baseline | 139 | 55.3 ± 24.1 (51.3, 59.4) | 155 | 51.3 ± 24.3 (47.4, 55.2) | | |
| 6-Month | 107 | 32.3 ± 26.3 (27.3, 37.4) | 131 | 42.0 ± 25.7 (37.5, 46.4) | | |
| 6-Month Change | 107 | -22.5 ± 25.0 (-27.3, -17.7) | 131 | -8.3 ± 20.8 (-11.9, -4.7) | -12.6 (-17.9, -7.2) | <0.001 |

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Table 14: Percent Change in NT-proBNP at 6 Months in Expedited Phase (Initial Cohort) All Randomized Subjects

| | BAT + Medical Management | | Medical Management | | Difference | |
| --- | --- | --- | --- | --- | --- | --- |
| Visit | N | Median (IQR) | N | Median (IQR) | Δ Medians (95% CI) | p-value |
| Baseline | 139 | 1096.0 (612.0, 3101.0) | 154 | 1171.0 (622.0, 2485.0) | | |
| 6-Month | 104 | 809.0 (472.0, 2218.5) | 130 | 1093.0 (483.0, 1867.0) | | |
| 6-Month % Change | 104 | -10.5 (-42.6, 30.5) | 129 | -9.3 (-38.7, 36.5) | -1.2 (-19.7, 12.8) | 0.66 |

After evaluating the pre-planned Expedited Phase initial data review in early October 2018, a large, important and clinically relevant population was identified. This subgroup population is characterized by having NYHA Class III or II (recent history of Class III) heart failure, left ventricular ejection fraction $\leq 35\%$ and baseline NT-proBNP $&lt; 1600~\mathrm{pg / ml}$ at the time of baseline. This subgroup, referred to as the Intended Use Population, is the focus of the PMA.

The Intended Use Population for the Expedited Phase analysis of the 6-month efficacy endpoints includes all subjects randomized with a baseline NT-proBNP $&lt; 1600$ that have complete baseline and six-month data for MLWHF QOL, 6MHW and/or NT-proBNP. The evaluation of the MANCE free rate includes all subjects in the BAT + MM arm in the Intended Use Population that have an attempted implant.

# B. Accountability of PMA Cohort

At the time of database lock, of 408 subjects enrolled for the Expedited Phase. A breakdown of the study Intended Use Population subjects that were available for the specified analysis for this PMA as of April 22, 2019 is provided in the Table 15 below.

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Table 15: Analysis Populations for the Expedited Phase - Intended Use

| Description | BAT + Medical Management | Medical Management | Total |
| --- | --- | --- | --- |
| Expedited Phase Population - Intended Use | 130 | 134 | 264 |
| Expedited Phase Six Month Efficacy Analysis Population - Intended Use | 120 | 125 | 245 |
| Not in Expedited Phase Six Month Efficacy Analysis Population - Intended Use | 10 | 9 | 19 |
| No Implant Attempt | 5 | N/A | 5 |
| Died / LVAD / Heart Transplant prior to 6 month visit | 1 | 5 | 6 |
| Withdrew / LTFU prior to 6 month visit | 2 | 0 | 2 |
| Missed 6 month visit | 2 | 4 | 6 |
| Expedited Phase Safety Analysis Population - Intended Use | 125 | N/A | 125 |
| Not in Expedited Phase Safety Analysis Population - Intended Use | 5 | N/A | 5 |
| No Implant Attempt | 5 | N/A | 5 |
| Total Randomized - Intended Use | 130 | 134 | 264 |

Within the population supporting the Expedited Phase, there are two cohorts of data. Data that was previously analyzed in the original PMA dated December 14, 2018, called the Initial Cohort data (summarized above), and data that had not been previously unblinded and analyzed and is also included here, called the Second Cohort data that was collected through April 22, 2019.

## C. Study Population Demographics and Baseline Parameters

The demographics of the study Intended Use Population are typical for a reduced ejection fraction heart failure study performed in the US and UK. Baseline demographics for Expedited Phase Intended Use Population subjects are in Table 16 below. Demographics between the two randomized arms were balanced. Approximately 35% had a history of atrial fibrillation, 24% chronic kidney disease and 47% Type II diabetes. Almost all subjects (93 to 95%) are NYHA Class III at baseline with an average LVEF of 27% for BAT +MM and 28% for MM.

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Table 16: Demographics at Baseline - Intended Use

| Variable | N | Mean ± SD or N (%) | Range | N | Mean ± SD or N (%) | Range | P-value |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Race | | | | | | | |
| Asian | 130 | 3 (2.3%) | N/A | 134 | 2 (1.5%) | N/A | 0.680 |
| Black or African American | 130 | 24 (18.5%) | N/A | 134 | 20 (14.9%) | N/A | 0.510 |
| White | 130 | 97 (74.6%) | N/A | 134 | 96 (71.6%) | N/A | 0.677 |
| Other/Unknown | 130 | 6 (4.6%) | N/A | 134 | 16 (11.9%) | N/A | 0.044 |
| Female | 130 | 24 (18.5%) | N/A | 134 | 29 (21.6%) | N/A | 0.542 |
| Age at Screening (years) | 130 | 62 ± 11 | 27 - 92 | 134 | 63 ± 10 | 35 - 83 | 0.614 |
| BMI (kg/m2) | 130 | 31 ± 5 | 17 - 40 | 134 | 31 ± 5 | 20 - 43 | 0.699 |
| SBP (mmHg) | 130 | 120 ± 17 | 80 - 183 | 134 | 121 ± 16 | 90 - 179 | 0.385 |
| DBP (mmHg) | 130 | 73 ± 10 | 48 - 107 | 134 | 73 ± 10 | 50 - 101 | 0.618 |
| HR (bpm) | 130 | 75 ± 10 | 56 - 99 | 134 | 75 ± 11 | 40 - 100 | 0.864 |
| LVEF (%) | 130 | 27 ± 7 | 10 - 35 | 134 | 28 ± 6 | 12 - 35 | 0.192 |
| Core Lab NT-proBNP (pg/mL)* | 130 | 731 (475, 1021) | 72 - 1582 | 134 | 765 (479, 1052) | 54 - 1587 | 0.786 |
| NYHA: Class III | 130 | 121 (93.1%) | N/A | 134 | 127 (94.8%) | N/A | 0.614 |
| 6 Minute Walk (m) | 130 | 316 ± 68 | 156 - 475 | 134 | 294 ± 73 | 60 - 442 | 0.015 |
| QOL | 130 | 53 ± 24 | 3 - 100 | 134 | 52 ± 24 | 6 - 105 | 0.800 |
| eGFR | 130 | 63.6 ± 16.8 | 32 - 113 | 134 | 61.9 ± 19.5 | 25 - 144 | 0.430 |
| QRS Interval | 130 | 108.9 ± 17.6 | 49 - 168 | 134 | 110.5 ± 25.6 | 23 - 241 | 0.545 |
| LBBB | 130 | 3 (2.3%) | N/A | 134 | 1 (0.7%) | N/A | 0.365 |
| At Least One HF Hospitalization | 130 | 54 (41.5%) | N/A | 134 | 68 (50.7%) | N/A | 0.140 |
| Number of HF Hospitalizations | 130 | 0.6 ± 1.0 | 0 - 6 | 134 | 0.7 ± 0.8 | 0 - 4 | 0.815 |
| Enrolled under Rev. D of Protocol | 130 | 110 (84.6%) | N/A | 134 | 107 (79.9%) | N/A | 0.338 |
| Origin of Subject: Advertising | 130 | 18 (13.8%) | N/A | 134 | 21 (15.7%) | N/A | 0.730 |
| *Results reported as median (IQR). | | | | | | | |

As shown in Table 17, most of the subjects had coronary artery disease (65%) and/or a prior MI (59%). Approximately 35% had a history of atrial fibrillation, 24% chronic kidney disease and 47% Type II diabetes.

Table 17: Medical History Reported Comorbidities - Intended Use

| Variable | N | Mean ± SD or N (%) | Range | N | Mean ± SD or N (%) | Range | P-value |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Coronary Heart Disease | | | | | | | |
| Coronary Artery Disease | 130 | 80 (61.5%) | N/A | 134 | 92 (68.7%) | N/A | 0.246 |
| Myocardial Infarction | 130 | 68 (52.3%) | N/A | 134 | 86 (64.2%) | N/A | 0.061 |
| CABG | 130 | 23 (17.7%) | N/A | 134 | 39 (29.1%) | N/A | 0.030 |
| PCI | 130 | 53 (40.8%) | N/A | 134 | 62 (46.3%) | N/A | 0.387 |
| Cardiac Arrhythmia | | | | | | | |
| Bradycardia | 130 | 13 (10.0%) | N/A | 134 | 14 (10.4%) | N/A | 1.000 |
| Tachycardia | 130 | 43 (33.1%) | N/A | 134 | 46 (34.3%) | N/A | 0.897 |
| Atrial Fibrillation | 130 | 38 (29.2%) | N/A | 134 | 57 (42.5%) | N/A | 0.029 |
| Stroke or TIA | 130 | 24 (18.5%) | N/A | 134 | 30 (22.4%) | N/A | 0.449 |
| Chronic Kidney Disease | 130 | 31 (23.8%) | N/A | 134 | 33 (24.6%) | N/A | 0.887 |
| Diabetes | | | | | | | |
| Type I | 130 | 0 (0.0%) | N/A | 134 | 2 (1.5%) | N/A | 0.498 |
| Type II | 130 | 58 (44.6%) | N/A | 134 | 68 (50.7%) | N/A | 0.327 |

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Baseline heart failure treatments are shown in Table 18 below. Most of the subjects (87%) were on an ACE-I/ARB or ARNI, 95% on a beta blocker and 92% on a diuretic. Approximately 78% had an ICD and &lt;5% had another cardiac device (6 CardioMems, 3 Lifevest and 1 loop recorder).

Table 18: Heart Failure Treatments at Baseline - Intended Use
| | BAT + Medical Management | | | Medical Management | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Treatment | N | Mean ± SD or N (%) | Range | N | Mean ± SD or N (%) | Range | P-value |
| Number of Meds | 130 | 3.9 ± 1.2 | 1 - 8 | 134 | 4.1 ± 1.4 | 1 - 8 | 0.228 |
| ACE-I/ARB | | | | | | | |
| Use | 130 | 75 (57.7%) | N/A | 134 | 79 (59.0%) | N/A | 0.901 |
| % recommended dose | 73 | 29.3 ± 25.5 | 3 - 100 | 79 | 27.6 ± 24.3 | 6 - 100 | 0.672 |
| Beta-Blocker | | | | | | | |
| Use | 130 | 124 (95.4%) | N/A | 134 | 127 (94.8%) | N/A | 1.000 |
| % recommended dose | 124 | 29.8 ± 26.4 | 6 - 125 | 126 | 28.1 ± 27.7 | 3 - 150 | 0.614 |
| Diuretic | | | | | | | |
| Use | 130 | 110 (84.6%) | N/A | 134 | 117 (87.3%) | N/A | 0.596 |
| Ivabradine | | | | | | | |
| Use | 130 | 3 (2.3%) | N/A | 134 | 6 (4.5%) | N/A | 0.501 |
| MRA | | | | | | | |
| Use | 130 | 63 (48.5%) | N/A | 134 | 56 (41.8%) | N/A | 0.322 |
| % recommended dose | 63 | 55.6 ± 36.0 | 25 - 300 | 54 | 59.3 ± 54.1 | 25 - 400 | 0.660 |
| ARNI | | | | | | | |
| Use | 130 | 41 (31.5%) | N/A | 134 | 35 (26.1%) | N/A | 0.344 |
| % recommended dose | 41 | 41.5 ± 20.6 | 25 - 100 | 35 | 42.9 ± 28.6 | 13 - 100 | 0.806 |
| ACE/ARB or ARNI Use | 130 | 115 (88.5%) | N/A | 134 | 113 (84.3%) | N/A | 0.372 |
| ICD | 130 | 101 (77.7%) | N/A | 134 | 106 (79.1%) | N/A | 0.881 |
| Pacemaker (non-ICD) | 130 | 2 (1.5%) | N/A | 134 | 1 (0.7%) | N/A | 0.618 |
| CRT | 130 | 3 (2.3%) | N/A | 134 | 4 (3.0%) | N/A | 1.000 |
| Other cardiac device (e.g., CardioMEMS) | 130 | 6 (4.6%) | N/A | 134 | 4 (3.0%) | N/A | 0.536 |

## D. Safety and Effectiveness Results

### 1. Safety Results

The system or procedure related MANCE endpoint includes all events that occur within 6-months post implant. The analysis includes the BAT + MM in the Intended Use Population who had an implant attempted (n = 125).

As shown in Table 19 below, the MANCE-free rate for the Intended Use Population is 96.8% (121/125) with a lower bound one-sided 95% confidence level of 92.8% (p-value &lt; 0.001). As the lower bound is greater than 85%, the safety endpoint has been met in the Intended Use Population.

Table 19: System or Procedure Related MANCE-Free Rate in BAT + Medical Management - Intended Use
| | Total Number of Subjects | Number of Subjects MANCE-Free | MANCE-Free Rate | One-Sided 95% Lower Bound | P-value |
| --- | --- | --- | --- | --- | --- |
| MANCE Event-Free | 125 | 121 | 96.8% | 92.8% | <.001 |

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The four MANCE components are shown in Table 20 below. There were 2 infections requirement explant, 1 acute decompensated heart failure event and 1 stroke.

Table 20: System or Procedure Related MANCE Events in BAT + Medical Management - Intended Use

| | Implanted Subjects (N=125) | | |
| --- | --- | --- | --- |
| Event | Number of Events | Number of Subjects | Event Rate |
| CV Death | 0 | 0 | 0.0% |
| Stroke | 1 | 1 | 0.8% |
| Cardiac Arrest | 0 | 0 | 0.0% |
| Acute MI | 0 | 0 | 0.0% |
| Acute Decompensated HF | 1 | 1 | 0.8% |
| Hypertensive Crisis | 0 | 0 | 0.0% |
| Severe Complication of HF Treatment | 0 | 0 | 0.0% |
| Systemic and Pulmonary Thromboembolism | 0 | 0 | 0.0% |
| Infection Requiring Explant | 2 | 2 | 1.6% |
| Cranial Nerve Damage | 0 | 0 | 0.0% |
| Non-Elective Major Restorative Procedures | 0 | 0 | 0.0% |
| Total | 4 | 4 | 3.2% |

Out of the 125 subjects implanted in the Intended Use Population, 9 subjects experienced 12 system- or procedure-related complications within six months of implant. The complication-free rate in the Intended Use Population is $92.8\%$ . A listing of complications is shown in Table 21 below.

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Table 21: Six Month System or Procedure Related Complications in BAT + Medical Management - Intended Use

| | Implanted Subjects (N=125) | | |
| --- | --- | --- | --- |
| Event | Number of Events | Number of Subjects | Event Rate |
| Heart Failure, Acute Decompensated Heart Failure | 1 | 1 | 0.8% |
| Muscle and Bone | 1 | 1 | 0.8% |
| Nerve Damage/Stimulation, Cranial Nerve Stimulation | 1 | 1 | 0.8% |
| Other Nerve, Hoarseness | 1 | 1 | 0.8% |
| Respiratory, Other Respiratory, Acute hypercarbic respiratory failure | 1 | 1 | 0.8% |
| Respiratory, Pneumonia | 1 | 1 | 0.8% |
| Severe Complications of Heart Failure Treatment | 1 | 1 | 0.8% |
| Stroke (CVA), Ischemic | 1 | 1 | 0.8% |
| Surgical or Anesthetic Complications, Infection at Implant Site (No Explant) | 1 | 1 | 0.8% |
| Surgical or Anesthetic Complications, Infection at Implant Site Requiring Explanation | 1 | 1 | 0.8% |
| Surgical or Anesthetic Complications, Other Surgical Complication, prolonged intubation | 1 | 1 | 0.8% |
| Thromboembolism, Systemic | 1 | 1 | 0.8% |
| Total | 12 | 9 | 7.2% |

During the study, there were three contralateral ICD implants that had interactions with the NEO IPG. All were noted to have been addressed by reducing the programmed therapy settings for the NEO IPG.

There were no unanticipated adverse events reported in the study.

# 2. Effectiveness Results

Six minute hall walk (6MHW) performed according to a standard protocol, MLWHF QOL Questionnaire data, and blinded core lab evaluated NT-proBNP were collected at the baseline visit and during follow-up at 6-months. Within the population supporting the Expedited Phase, there are two cohorts of data. Data that was previously analyzed in the original PMA Clinical Report, dated December 14, 2018, called the initial data, and data that has not been previously unblinded and analyzed and is included here, called the second cohort that was collected through April 22, 2019. Unless otherwise specified, the data presented is the Initial Cohort and Second Cohort.

Table 22 below shows the six-minute walk differences between the arms in the Second and Initial Cohorts of the Intended Use Population. The results showed a consistent and clinically meaningful and statistically significant improvement between the arms for the Initial, the Second and Combined Cohorts.

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Table 22: Change in Six Minute Walk Distance at 6 Months – Intended Use Second and Initial Cohorts

| | BAT + Medical Management | | Medical Management | | Difference* | |
| --- | --- | --- | --- | --- | --- | --- |
| Cohort | N | Mean±SD (95% CI) | N | Mean±SD (95% CI) | Δ Means (95% CI) | p-value |
| Initial | 69 | 49.0 ± 71.6 (31.8, 66.2) | 80 | -11.9 ± 92.8 (-32.5, 8.8) | 65.4 (38.5, 92.3) | <0.001 |
| Second | 49 | 48.1 ± 58.7 (31.2, 64.9) | 40 | 0.1 ± 79.2 (-25.3, 25.4) | 49.8 (21.8, 77.9) | <0.001 |
| Combined | 118 | 48.6 ± 66.3 (36.5, 60.7) | 120 | -7.9 ± 88.4 (-23.9, 8.1) | 60.1 (40.3, 79.9) | <0.001 |
| *The difference is evaluated based on an ANCOVA model adjusting for the baseline value. | | | | | | |

Table 23 below shows the quality of life differences between the arms in the Second and Initial Cohorts of the Intended Use Population. The results showed a consistent and clinically meaningful and statistically significant improvement between the arms for the Initial, the Second and Combined Cohorts.

Table 23: Change in Quality of Life at 6 Months - Intended Use Second and Initial Cohorts

| | BAT + Medical Management | | Medical Management | | Difference* | |
| --- | --- | --- | --- | --- | --- | --- |
| Cohort |…