STRATOS LV CRT-P AND STRATOS LV-T CRT-P, COROX OTW BP LEAD AND COROX OTW-S BP LEAD

P070008 · Biotronik, Inc. · NKE · May 12, 2008 · Cardiovascular

Device Facts

• Record ID: P070008
• Device Name: STRATOS LV CRT-P AND STRATOS LV-T CRT-P, COROX OTW BP LEAD AND COROX OTW-S BP LEAD
• Applicant: Biotronik, Inc.
• Product Code: NKE · Cardiovascular
• Decision Date: May 12, 2008
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Stratos LV/LV-T pulse generators are indicated for patients who have moderate to severe heart failure (NYHA Class III/IV), including left ventricular dysfunction (EF ≤35%) and QRS ≥120 ms and remain symptomatic despite stable, optimal heart failure drug therapy. The Corox OTW BP and Corox OTW-S BP left ventricular pacing leads are bipolar steroid-eluting leads, intended for permanent implantation in the left ventricle via the coronary veins to provide pacing and/or sensing when used in conjunction with a compatible IS-1 pulse generator.

Device Story

Stratos LV/LV-T are rate-adaptive CRT-P pulse generators providing biventricular pacing for heart failure management. Inputs include cardiac signals (right ventricular sensing) and physical activity (internal accelerometer). The device transforms these inputs via programmable pacing modes and rate-adaptation algorithms to deliver electrical stimulation to the right atrium, right ventricle, and left ventricle via IS-1 leads. The Stratos LV-T includes Home Monitoring for remote data transmission. Physicians use the programmer to set pulse amplitude/width and review diagnostic data. The Corox OTW(-S) BP leads are transvenous, steroid-eluting leads (dexamethasone acetate) for left ventricular pacing, featuring helical or wedge-based fixation. The system aims to improve cardiac resynchronization, functional capacity, and quality of life in symptomatic heart failure patients.

Clinical Evidence

Evidence includes four clinical studies: AVAIL (n=118, prospective, randomized), OVID (n=89, OUS registry), OPTION (n=200, randomized, CRT-D comparator), and everesT (n=148, OUS registry). Primary endpoints included complication-free rates (target 85%) and composite improvement in 6-minute walk test and QOL. Combined safety data (n=164) showed 87.2% complication-free rate at 6 months. Effectiveness was supported by non-inferiority to CRT-D/CRT-P comparators in functional capacity and QOL improvements.

Technological Characteristics

Triple-chamber, rate-adaptive CRT-P. Materials: silicone, polyurethane, MP35N/DFT conductors, platinum/iridium electrodes. Sensing: right ventricular. Energy: internal battery. Connectivity: wireless Home Monitoring (Stratos LV-T). Sterilization: ethylene oxide. Leads: steroid-eluting (dexamethasone acetate). Standards: EN 45502-1, EN 45502-2-1, ISO 5841-3 (IS-1), ISO 10993.

Indications for Use

Indicated for patients with moderate to severe heart failure (NYHA Class III/IV), left ventricular dysfunction (EF ≤35%), and QRS ≥120 ms, remaining symptomatic despite optimal drug therapy. Contraindicated for patients with unipolar pacing requirements (if ICD implanted), impaired AV nodal conduction (for single chamber atrial pacing), or chronic refractory atrial tachyarrhythmias (for atrial pacing). Leads contraindicated for coronary sinus anomalies, damaged coronary sinus tissue, venous anomalies precluding transvenous implantation, or dexamethasone acetate intolerance.

Regulatory Classification

Identification

These devices are indicated for patients who have moderate to severe heart failure. These new devices use an additional lead to provide synchronized pacing of the heart, in addition to the regular features of a pacemaker. These products are sought for the treatment of patients who have moderate to severe heart failure.

Predicate Devices

• Philos DR (P950037/S12)
• Protos (P950037/S28)
• Tupos LVT/ATx (P050023)

Reference Devices

• Lumax HF-T 300 (P050023/S1)
• Lumax HF-T 340 (P050023/S1)
• Elox P 60 BP

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA

## I. GENERAL INFORMATION

Device Generic Name: Implantable Pacemaker Pulse Generator with Cardiac Resynchronization Therapy (CRT) and Left Ventricular (LV) Pacing Leads

Device Trade Name: Stratos LV CRT-P
Stratos LV-T CRT-P
702.U Programmer Software for the ICS 3000
Corox OTW BP Lead
Corox OTW-S BP Lead

Applicant's Name and Address: BIOTRONIK, Inc.
6024 Jean Road
Lake Oswego, OR 97035

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P070008

Date of FDA Notice of Approval: May 12, 2008

Expedited: Not Applicable

## II. INDICATIONS

### Stratos LV and Stratos LV-T CRT-Ps

The Stratos LV/LV-T pulse generators are indicated for patients who have moderate to severe heart failure (NYHA Class III/IV), including left ventricular dysfunction (EF ≤35%) and QRS ≥120 ms and remain symptomatic despite stable, optimal heart failure drug therapy.

### Corox OTW(-S) BP Lead

The Corox OTW BP and Corox OTW-S BP left ventricular pacing leads are bipolar steroid-eluting leads, intended for permanent implantation in the left ventricle via the coronary veins to provide pacing and/or sensing when used in conjunction with a compatible IS-1 pulse generator.

## III. CONTRAINDICATIONS

### Stratos LV and Stratos LV-T CRT-Ps

Use of Stratos LV/LV-T pulse generators is contraindicated for the following patients:

- Unipolar pacing is contraindicated for patients with an implanted cardioverter-defibrillator (ICD) because it may cause unwanted delivery or inhibition of ICD therapy.
- Single chamber atrial pacing is contraindicated for patients with impaired AV nodal conduction.
- Dual chamber and single chamber atrial pacing is contraindicated for patients with chronic refractory atrial tachyarrhythmias.

### Corox OTW(-S) BP Lead

The use of the Corox OTW BP and Corox OTW-S BP leads are contraindicated under the following circumstances:

- Coronary sinus anomalies
- Tissue in the coronary sinus area that has been damaged by an infarction
- Any anomalies of the venous system that preclude transvenous implantation of the lead
- Patient cannot tolerate a single systemic dose of up to 1.0 mg of dexamethasone acetate (DXA)

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Stratos LV/LV-T CRT-P and Corox OTW lead technical manuals.

# V. SYSTEM DESCRIPTION

## Stratos LV(-T) CRT-Ps

The Stratos LV and Stratos LV-T CRT-Ps are rate adaptive pacemakers designed to provide Cardiac Resynchronization Therapy (CRT). The Stratos CRT-Ps provide all standard bradycardia pacemaker therapy with the additional capabilities of biventricular pacing for CRT. Biventricular pacing in the Stratos CRT-Ps can be programmed to initially pace in either the right or left ventricular chambers with separately programmable outputs for both left and right channels. Sensing of cardiac signals only occurs in the right ventricular chamber.

The Stratos CRT-Ps can also provide single and dual chamber pacing in a variety of rate-adaptive and non-rate adaptive pacing modes. Pacing capability is supported by an extensive diagnostic set. For motion-based rate-adaptation, the Stratos CRT-Ps are equipped with an internal accelerometer. This sensor produces an electric signal during physical activity of the patient. If a rate-adaptive (R) mode is programmed, then the accelerometer sensor signal controls the stimulation rate.

The Stratos LV-T additionally also employs BIOTRONIK's Home Monitoring™ technology, which is an automatic, wireless, remote monitoring system for management of patients with implantable devices. With Home Monitoring, physicians can review data about the patient's cardiac status and CRT-P's functionality between regular follow-up visits, allowing the physician to optimize the therapy process. Stratos CRT-Ps are also designed to collect diagnostic data to aid the physician's assessment of a patient's condition and the performance of the implanted device.

The bipolar IS-1 connections are used for pacing and sensing (right atrial and ventricle) and the additional IS-1 connection is used for pacing in the left ventricle in either a bipolar or unipolar configuration depending on the left ventricular lead. The pulse amplitude and pulse width of each of the three channels is separately programmable.

Stratos CRT-Ps are designed to meet all indications for Cardiac Resynchronization Therapy in CHF patients as well as those for bradycardia therapy as exhibited in a wide variety of patients. The Stratos family is comprised of two CRT-Ps that are designed to handle a multitude of situations.

| Stratos LV | Triple chamber, rate-adaptive, unipolar/bipolar pacing CRT-P |
| --- | --- |
| Stratos LV-T | Triple chamber, rate-adaptive, unipolar/bipolar pacing CRT-P with Home Monitoring |

## Corox OTW(-S) BP Leads

BIOTRONIK's Corox OTW (-S) BP leads are transvenous, steroid-eluting left ventricular pacing leads designed for use with a compatible cardiac resynchronization therapy (CRT) device that accepts leads with a bipolar (BP) IS-1 connector configurations. The leads can be positioned in the target vein using either the over-the-wire techniques or stylet driven methods.

The leads are constructed with multifilar conductors insulated with medical grade silicone and coated with polyurethane. There are two separate distal ends available with the Corox OTW leads, as described below. In addition to the bipolar leads that are helix shaped at the lead tip (Corox OTW BP), the Corox OTW-S BP has a bend in the distal tip that fixates by "wedging" across a vessel.

- Corox OTW BP left ventricular leads have distal ends that are helix shaped at the lead tip, which is designed to adhere to the coronary vein when the stylet or guide wire is removed. This system provides for flexible control and positioning of the lead during implantation while the stylet or guidewire is in place. Additionally, the helical shape of the distal end of the lead fixates the electrode within the vessel after the stylet or guide wire is removed. This fixation design is a clinically proven fixation mechanism for larger vessels.

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- Corox OTW-S BP has a silicone thread attached to the lead body between the tip and ring electrodes, which fixates by "wedging" across a vessel. The distal end between the electrodes also exhibits a slight two dimensional bend, which facilitates the steering of the lead in the coronary venous system. This fixation option is designed for implantation in smaller coronary vessels.

The lead conductor of the Corox OTW(-S) BP consists of quadrafillar MP35N/DFT (25% Silver) arranged in a 2 x 2 coradial helix and insulated against each other by a layer of (blue or white) ethylene tetrafluoroethylene (ETFE) with a thickness of 50μm.

The Corox OTW Steroid lead features a tip and ring electrode, each with a fractal surface structure of iridium that provides a larger effective tissue interface. The electrode is comprised of a platinum/iridium alloy base.

The Corox OTW(-S) BP leads include a steroid-eluting collar at the ring electrode and at the distal tip of the lead to aid in decreasing the inflammation that often occurs after implantation of a pacing lead. Each steroid collar nominally contains 0.5 mg of dexamethasone acetate (DXA). Upon exposure to body fluids, the steroid elutes from the collar into the body tissue by diffusion.

The Corox OTW(-S)-BP leads are available in lengths of 77 or 87 cm, which are designated as Corox OTW(-S) 75-BP Steroid and Corox OTW(-S) 85-BP Steroid, respectively. The Corox OTW(-S)-BP lead fits through a 7 F lead introducer.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for patients who require a pacemaker and also have heart failure. 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. Patients who require a pacemaker and also have heart failure are routinely treated with legally marketed pulse generators and medications. Medications include both those to treat arrhythmias and medications to treat heart failure. Additional treatments for heart failure include, but are not limited to, exercise and nutrition programs, heart transplantation, and other legally marketed CRT-Ps.

## VII. MARKETING HISTORY

### Stratos LV(-T) CRT-Ps

The Stratos LV received CE certification on August 14, 2002 and re-certification on August 14, 2007.

The Stratos LV/LV-T have been distributed in the following countries: European Union and Switzerland, Argentina, Australia, Brazil, Canada, Chile, China, Columbia, Cuba, Egypt, Guatemala, Hong Kong, India, Indonesia, Iran, Iraq, Israel, Jordan, Lebanon, Macedonia, Mexico, Panama, Russian Federation, Saudi Arabia, Singapore, South Africa, Turkey, Ukraine, Uruguay, and Venezuela.

All reportable complaints for Stratos are associated with an OUS recall of the Stratos pulse generator: On July 24, 2006, 84 Stratos LV-T devices were recalled due to a lot of potentially defective low-voltage capacitors. All physicians were informed accordingly, and devices not yet implanted were returned to BIOTRONIK. Associated to this, eleven devices were returned for analysis. All devices proved to be fully functional. It is important to note the following key points regarding this recall:

- No patient injuries or deaths associated with this recall have been reported.
- The recall was initiated as a precautionary method and was not triggered by any field complaints.
- BIOTRONIK has initiated long-term testing for the capacitors under question. None of these low-voltage capacitors have failed during the testing.
- The recall has been terminated by the German competent authority.
- FDA has reviewed the details associated with this recall during a GMP inspection. No deviations were noted.

The Stratos LV/LV-T CRT-Ps have not been withdrawn from marketing in any country for any reason relating to the safety and effectiveness of the device.

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# Corox OTW(-S) BP Leads

BIOTRONIK received approval of the Corox OTW BP and Corox OTW-S BP left ventricular leads in Europe on July 17, 2006.

There have been three clinical events associated with these leads reported to date:

1. A lead was explanted due to high pacing impedances. Analysis of the lead demonstrated a lead fracture due to excessive mechanical stress as the result of the Subclavian Crush Syndrome (i.e., clavicular - first rib entrapment). The analysis did not show any sign of a material or manufacturing problem.

2. A lead was explanted due to an insulation defect. Analysis of the lead demonstrated a lead fracture due to excessive mechanical stress as the result of the Subclavian Crush Syndrome (i.e., clavicular - first rib entrapment). The analysis did not show any sign of a material or manufacturing problem.

3. A lead was explanted due to loss of capture. The analysis was based on the inspection of the quality documents accompanying this particular device, as the lead was not returned for analysis. There was no sign of any inconsistency during the manufacturing process which might be related to the clinical observation.

The Corox OTW(-S) BP has been distributed in the following countries: European Union and Switzerland, Argentina, Australia, Brazil, Canada, Chile, China, Colombia, Croatia, Egypt, India, Iran, Israel, Lebanon, New Zealand, Panama, Russia, South Africa, Turkey, Uruguay, and Venezuela.

The Corox OTW(-S) BP lead has not been withdrawn from marketing in any country for any reason relating to the safety and effectiveness of the device.

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

## Stratos LV(-T) CRT-Ps

The following are possible adverse events that may occur relative to the implant procedure and chronic implant of the Stratos LV/LV-T CRT-Ps:

- Air embolism
- Allergic reactions to contrast media
- Arrhythmias
- Bleeding
- Body rejection phenomena
- Cardiac tamponade
- Chronic nerve damage
- Damage to heart valves
- Elevated pacing thresholds
- Extrusion
- Fluid accumulation
- Infection
- Keloid formation
- Lead dislodgment
- Lead fracture / insulation damage

- Lead-related thrombosis
- Local tissue reaction / fibrotic tissue formation
- Muscle or nerve stimulation
- Myocardial damage
- Myopotential sensing
- Pacemaker mediated tachycardia
- Pneumothorax
- Pocket erosion
- Hematoma
- Device migration
- Thromboembolism
- Undersensing of intrinsic signals
- Venous occlusion
- Venous or cardiac perforation

## Corox OTW(-S) BP LV Leads

Potential complications resulting from the use of left ventricular leads include, but are not limited to: thrombosis, embolism, body rejection phenomena, cardiac tamponade, pneumothorax, muscle/nerve stimulation, valve damage, fibrillation, infection, skin erosion and ventricular ectopy. Lead perforation through the myocardium has been rarely observed. The table below summarizes some of the potential symptoms indicating a complication and possible corrective actions:

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Table 1: Potential Complications and Corrective Actions

| Symptom | Potential Complication | Potential Corrective Action |
| --- | --- | --- |
| Loss of pacing or sensing | Lead dislodgement | Reposition lead |
| | Lead fracture | Replace lead |
| | Setscrew penetration of lead insulation | Replace lead |
| | Improper lead / pulse generator connection | Reconnect lead to pulse generator |
| Increase/ decrease in threshold | Fibrotic tissue formation | Adjust pulse generator output; Replace/reposition lead |

# IX. SUMMARY OF PRE-CLINICAL STUDIES

## A. NON-CLINICAL LABORATORY STUDIES - STRATOS LV/LV-T CRT-Ps

The service times for the Stratos LV/LV-T devices from beginning of service (BOS) to elective replacement indication (ERI) is expected to be 51 months with a lead impedance of 500 ohms and 60 months with a lead impedance of 1000 ohms. All estimates assume a pacing rate of 60 ppm, pulse amplitude of 3.6 V at 0.4 ms. The Use Before Dating is 18 months after the battery is connected during the manufacturing process.

The Stratos LV/LV-T CRT-Ps are a derivation of BIOTRONIK's legally marketed Philos DR (P950037/S12) and Protos (P950037/S28) pulse generators with biventricular pacing capabilities added to provide cardiac resynchronization therapy (CRT). Nearly all of the components used for the Stratos LV/LV-T are identical to those used for the Philos DR and Protos devices, including all blood / tissue contact materials; therefore, these components were validated with previously approved devices.

## i. Finished Device Testing

The Stratos LV/LV-T CRT-Ps finished devices have been subjected to validation testing according to the BIOTRONIK's validation plans. The Stratos LV/LV-T CRT-Ps have passed all in vitro laboratory validation tests with acceptance based on Stratos LV/LV-T CRT-Ps product specifications.

| Table 2: Summary of Finished Device Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Drop Test in Packaging | Testing was performed according to European Standards EN 45502-1^{1}, Section 10.1 | Pass |
| Transportation Test | Testing was performed according to European Standard EN 45502-2-1^{2}, Sec. 10.1. | Pass |
| Humidity and Vacuum Storage | Protection from Temperature and Humidity Changes according to European Standard EN 45502-2-1^{2}, Sect. 10.1. | Pass |
| Ultrasound Resistance | Exposure to Ultrasound according to European Standard EN 45502-1^{1}, Sect. 22.1 | Pass |
| Changes in Air Pressure | Exposure to Air Pressure Changes according to European Standard EN 45502-1^{1}, Sect. 25.1 | Pass |
| Temperature Cycle | Exposure to Temperature Changes according to European Standard EN 45502-2-1^{2}, Sect.26.2. | Pass |

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| Table 2: Summary of Finished Device Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Temperature Shock | The validation standard refers to the requirements from the norm DIN IEC 68-2-14: 6'87³, Section 1 (Temperature Change) and MIL-STD 883D⁴, Method 1011.9 (Thermal Shock). | Pass |
| In Vitro 500 Hours | The pulse generator is required to function within specifications and with identical programming values before and after the 500 hour In Vitro Test. | Pass |
| Dimensional and Visual Inspection of the Header | Visual and dimensional inspection is performed according ISO 5841-3:12'92⁵ (IS-1) for the header ports and internal BIOTRONIK specification for the other header characteristics (i.e., position of the antenna, wiring, lead drill holes, anchors, x-ray markers, and suture holes). | Pass |
| In Vitro 2000 Hours | The pulse generator is required to function within specifications and with identical programming values before and after the 2000 hour In Vitro Test. | Pass |
| Visual Inspection of the inner structure | The units were inspected to ensure proper arrangement of the subassembly and parts in terms of function and further processing. | Pass |
| Mechanical shock test | Exposure to Mechanical Shock according to European Standard EN45502-1¹, Sect.23.7. | Pass |
| Vibration test | Exposure to Vibration according to European Standard EN45502-2-1², Sect. 23.2 | Pass |
| Header Shearing Test | The housing is mounted firmly and the header is stressed on its upper edge till it detaches from the housing. The test is passed if the mean shear value of five units ≥1.5 N/mm². | Pass |
| Pulse Generator Casting | The Stratos casting was inspected per EN 45502-1:1996¹, Section 15.2. | Pass |
| Fixation Force of the Connector Block | The shear force of the connector block was determined by pulling the leads. Devices must withstand a force of >25 N when the torque is tightened to 6N / cm. | Pass |
| Corrosion Test In-Vitro | A housing with 4 anchors was stored for 2000h at 50°C in a 0.9% NaCl solution. The welding was visually inspected before and after the test. | Pass |
| T-Option: Home Monitoring Statistics Test (Functional Test with Implant) | For the Stratos LV-T device, selection, transmission and interrogation of Home Monitoring parameters from the programmer was confirmed. Using a patient simulator and a patient device, transmission and accuracy of patient-activated and periodic messages were confirmed. | Pass |
| Input Impedance | Testing performed according to European Standard EN 45502-2-1:1998², Sect. 6.1.3 | Pass |
| Noise Suppression | The sensing signal of the atrial and ventricular channels and the pacing signals of the triggered channels must appear sequentially in the IEGM (intracardiac electrogram) printout. The atrial and ventricular sensing signals must still be able to be differentiated from the noise signal. | Pass |
| Electric Neutrality of Pacemakers | Testing was performed according to European Standards EN 45502-2-1:1998², Sect. 16.2. | Pass |

³ DIN IEC 68-2-14: Environmental testing - Part 2: Tests. Test N: Change of temperature
⁴ MIL-STD 883D: Test Method Standard, Microcircuits
⁵ ISO 5841-3: Implants for surgery – Cardiac pacemaker. Part 3: Low-profile connectors (IS-1) for implantable pacemakers

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| Table 2: Summary of Finished Device Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Longevity / Use Before Date | Calculation must be prepared for mean value data and -3-sigma data of battery discharge characteristics to achieve the total service life and use before date. | Pass |
| Defibrillation Protection | Testing according to European Standard, EN 45502-1:1997³, Sect. 20.2. | Pass |

## ii. Firmware

Embedded Software validation testing was designed to confirm the overall safety and functionality of the Stratos LV/LV-T CRT-Ps. The Stratos LV/LV-T embedded software successfully passed all test requirements. Validation testing was performed to verify that the Stratos LV/LV-T embedded software functioned as specified during and after exposure to a variety of external conditions and origins. The acceptance criteria for testing of the Stratos LV/LV-T firmware were based on internal BIOTRONIK specifications and all test data was acceptable.

| Table 3: Firmware Validation Testing (Stratos LV / LV-T) | |
| --- | --- |
| Firmware Tests | Successfully Performed |
| Exposure to External / Internal Influences | • Demodulation of Product
• High Rate Protection (Rate Limiting by Maximum Activity Rate (MAR) and Upper Tracking Rate (UTR))
• Influences on Device during RF Telemetry
• Temperature Changes
• Effect of Light |
| Elective Replacement Indication (ERI) and End of Service (EOS) | • Measurement of Current Consumption
• ERI Onset
• Service Life Calculations / Use Before Date
• Enabling ERI Detection Independent of Implant Detection |
| Electrical Characteristics | • Electric Neutrality
• Measurement of Input / Output Impedance
• Input Filter Response
• Sensing Input Amplifiers
• Far-Field Sensing
• Response to Reset
• Crosstalk Sensitivity of Biventricular Sensing/Pacing
• Pacing Impedance Measurements (Automatic Lead Check)
• Repeatability of Output Current Analog Telemetry
• Rate and AV Delay Limitation
• Synchronization Behavior
• AES Detection & Post AES Stimulation
• Rate Management
• VES Lock-In Protection
• ICD Compatibility
• CRC Check before Every Program Activation
• Cyclic RAM Check
• Secure ROM Behavior
• Sensitivity within a Pacing Interval / Input Sensitivity as a Function of Time after Pace
• Stress Tests: Rate Adaptive and Non-Rate Adaptive
• Electric Neutrality / Electrostatic Discharge Susceptability
• Impulse Parameters
• Programming Responses |

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| Table 3: Firmware Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Firmware Tests | Successfully Performed | |
| Sensor Response Threshold | • Only Affected by Frequencies Between 2 and 10 Hz
• Response During Patient Activity without exceeding Maximum Activity Rate
• Appropriate Return to Baseline when Motion Removed
• Automatic Gain | |
| Pacing Characteristics | • Rate Hysteresis
• Rate Repetitive Hysteresis
• Rate Scan Hysteresis
• AV Hysteresis
• AV Repetitive Hysteresis
• AV Scan Hysteresis
• Refractory Period
• Atrial Upper Rate
• Biventricular Synchronization | • Rate Fading
• Night Mode
• PMT Prevention and Termination
• Mode Switching
• Atrial Upper Rate
• AF Classification
• Common Mode Rejection |
| Battery Monitoring | • Internal Battery Impedance Measurement
• Charge Accumulation
• Battery Capacity | |
| Programming Wand | • Programming and Interrogation Distances
• Magnet Response at Various Distances
• Response Under Magnet Application | |
| Home Monitoring | • Service Distance
• Transmission and Schedule of Trend Message
• Transmission and Schedule of Event Message
• Transmission and Schedule of Patient Message
• Transmission Behavior in ERI Mode
• Effectiveness of the Home Monitoring “Bug Fix” for Trend Errors | |

## iii. Electronic Module Testing

Electronic Module validation testing was designed to confirm the overall functionality of the electronic circuits utilized in the Stratos LV/LV-T CRT-Ps. The Stratos LV/LV-T electronic module successfully passed all test requirements. Validation testing was performed to verify that the Stratos LV/LV-T electronic module functioned as specified during and after exposure to a variety of external conditions and origins. The acceptance criteria for testing of the Stratos LV/LV-T firmware were based on internal BIOTRONIK specifications and all test data was acceptable.

| Table 4: Electronic Module Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Visual Inspection and Dimensions Before and After Life Test | The test was conducted over 1000 hours at 125°C and rated voltages were taken. Visual and dimensional inspection is performed according to internal BIOTRONIK specifications. | Pass |
| Final Acceptance Test (FAT) After Temperature Cycles | Testing performed according to military standards, MIL-STD-883E⁶ M.1010.7 C.A and MIL-STD-883E M.1005.8. | Pass |
| Shear Test Initial | Testing performed according to military standard, MIL-STD-883⁶, M2019.5. | Pass |
| Bond Pull Test | Testing performed according to military standard, MIL-STD-883E⁶ M.2011.4D. | Pass |

⁶ MIL-STD 883E: Test Method Standard, Microcircuits

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| Table 4: Electronic Module Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Mechanical Stability of Substrate During Point Load | The test specification was at orienting measurement, Fmax >50N. | Pass |
| Constant Acceleration (2000g) | Testing performed according to military standard, MIL-STD-883^{6} M2001. | Pass |
| Mechanical Shock Test | Testing performed according to European Standard, EN 45502-1^{1}, Sect. 23.7. | Pass |

## iv. Electromagnetic Interference (EMI) Testing

BIOTRONIK has performed a comprehensive set of electromagnetic interference testing of the Stratos LV/LV-T CRT-Ps according to two separate industry standards, including the DIN VDE 0750, and EN 45502-2-1². All EMI susceptibility testing has successfully passed the criteria for medical implantable devices.

The purpose of testing to these standards was to assure that both European and U.S. concerns were satisfied for both conducted and radiated measurements over a wide frequency spectrum. Tests were performed at certified EMI laboratories CETECOM in Germany, as well as at BIOTRONIK facilities. All testing passed the requirements presented in standard EN 45502-2-1².

| Table 5: Electromagnetic Interference (EMI) Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Safety during EMI, Induced Electrical Currents in the Pacing Leads | Testing performed according to European Standard EN 45502-2-1: 2003, Sect. 27.2. | Pass |
| Safety during EMI, Non-modulated Electromagnetic Signals | Testing performed according to European Standard EN 45502-2-1: 2003, Sect. 27.3 | Pass |
| Safety during EMI, Modulated Electromagnetic Signal | Testing performed according to European Standard. EN 45502-2-1: 2003, Sect. 27.4. | Pass |
| Immunity from EMV Signals in the Range of 16.6 Hz to 10 MHz | Testing according to European Standard, EN 45502-2-1:2003, Sect. 27.5.1; Sect. 27.5.2 | Pass |
| Immunity from EMV Signals in the Range of 10 MHz to 450 MHz | Testing according to European Standard, EN 45502-2-1:2003, Sect. 27.5.3 | Pass |
| Immunity from EMV Signals in the Range of 450 MHz to 3000 MHz | Testing according to European Standard, EN 45502-2-1:2003, Sect. 27.5.4 | Pass |
| Immunity from Time-Variable Magnetic Fields | Testing according to European Standard, EN 45502-2-1:2003, Sect. 27.8 | Pass |
| Radio Permit Test of the NF Telemetry | Testing according to European Standard, EN 300330^{7} (1995-05) and ETSI EN 300 220-3^{8} V 1.1.1 (2000-09). | Pass |
| Effect of Static Magnetic Field | Exposure to magnetic field strength of 1 mT. Testing performed according to European Standard EN 45502-2-1:1998 Sect. 27.5 & Sect. 27.6. | Pass |
| Demodulation Product | Testing performed according to internal BIOTRONIK procedures. | Pass |

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| Table 5: Electromagnetic Interference (EMI) Validation Testing (Stratos LV / LV-T) | | |
| --- | --- | --- |
| Test | Acceptance Criteria | Test Results (Pass/Fail) |
| Application of a Cautery Device on a Specimen in Physiologic Sodium Solution | Interrogation must be possible; there must be no changes in the characteristic parameters. | Pass |
| Programming Response During EMI Disturbances | Testing performed according to internal BIOTRONIK procedures to guarantee the programmability of pacemakers under the influence of EMU disturbances, as well as communication with the programmer via a minimum coverage range. | Pass |
| Radio Approval Measurement, EMC for Radio Equipment and Services, and Risk Control: Transmission Power vs. Tissue Damage | Testing according to European Standards, ETSI EN 301 839-2^{9} V 1.1.1 (2002-06), ETSI EN 301 489-27^{10} (2004-03), and EN 50371:2002^{11} Abs. 4.1. | Pass |

## B. NON-CLINICAL LABORATORY STUDIES – COROX OTW(-S) BP LEADS

The following tables summarize the validation testing (safety and performance) conducted on the components of BIOTRONIK's Corox OTW(-S) BP Leads, including performance testing, packaging, shelf life and biocompatibility tests. Validation has been performed according to the appropriate European, International and National standards, in addition to internal BIOTRONIK specifications. In the tables below, "Pass" denotes that the results satisfy the company's design specifications.

| Table 6 Corox OTW(-S) BP Validation Testing | |
| --- | --- |
| Test Performed | Test Results (Pass/Fail) |
| Biocompatibility and Sterilization | |
| Hemocompatibility (final product) according to ISO 10993-4^{12} | Pass |
| Cell Toxicity (final product) according to ISO 10993-5: 1999^{13} | Pass |
| Proof of Absence of Pyrogens with the Limulus Amoebocyte Lysate Test (LAL Test) | Pass |
| Proof of Bioburden on Medical Products / Determination of the Correction Factor according to DIN EN 1174-1: 1996^{14} | Pass |
| Proof of Sterilization Success according to EN 550: 1994^{15} | Pass |
| Residual Gas Analysis: Ethylene Oxide and Ethylene Chlorohydrin according to ISO 10993-7: 1995^{16} | Pass |
| Final Product | |
| Electrical Continuity and DC Resistance according to FDA Lead Guidance* | Pass |
| Leakage Current according to FDA Lead Guidance* | Pass |
| Strength of Lead (bonds) (of Complete Lead, Weld and Crimp Connections) according to FDA Lead Guidance* | Pass |
| Leak Proof (Isotonic Saline at 37°C) according to FDA Lead Guidance* | Pass |
| Corrosion Resistance of Conductors according to FDA Lead Guidance* | Pass |

9 ETSI EN 301 839-2: Electromagnetic compatibility and Radio spectrum Matters (ERM); Radio equipment in the frequency range 402 MHz to 405 MHz for Ultra Low Power Active Medical Implants and Accessories; Part 2: Harmonized EN covering essential requirements of article 3.2 of the R&TTE Directive
10 ETSI EN 301 489-27: Electromagnetic compatibility and Radio spectrum Matters (ERM); EMC standard for radio equipment and services; Part 27: Specific conditions for Ultra Low Power Active Medical Implants (ULP-AMI) and related peripheral devices (ULP-AMI-P)
11 EN 50371: Generic standard to demonstrate the compliance of low power electronic and electrical apparatus with the basic restrictions related to human exposure to electromagnetic fields (10 MHz - 300 GHz). General public
12 ISO 10993-4: Biological evaluation of medical devices. Part 4: Selection of tests for interactions with blood
13 ISO 10993-5: Biological evaluation of medical devices. Part 5: Tests for in-vitro cytotoxicity
14 DIN EN 1174-1: Sterilization of medical devices - Estimation of the population of micro-organisms on product - Part 1: Requirements
15 EN 550: Sterilization of medical devices - Validation and routine control of ethylene oxide sterilization
16 ISO 10993-7: Biological evaluation of medical devices. Part 7: Ethylene oxide sterilization residuals

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| Table 6 Corox OTW(-S) BP Validation Testing | |
| --- | --- |
| Test Performed | Test Results (Pass/Fail) |
| Stylet Performance according to FDA Lead Guidance* | Pass |
| Fatigue Test (Bending Fatigue Test on Lead Body and on Connector) according to FDA Lead Guidance* | Pass |
| Connector Testing to ISO 5841-3^{5} (IS-1) (on Lead Body between Connector and Tip/Ring, at Connector Transition) | Pass |
| Anchoring Sleeve Performance according to FDA Lead Guidance* | Pass |
| Lead Tip Pressure (Compression Behavior: Determination of Pressure Exerted on Projected Area of Distal End) according to FDA Lead Guidance* | Pass |
| Labeling on Sales and Sterile Package according to EN 45502-1^{1} | Pass |
| Visual, Electrical & Dimensional Inspection of Complete Lead and Inspection of Markings according to EN 45502-1: 1998-07 and EN 45502-2-1: 2002-4^{2} | Pass |
| Area Calculation of Tip Electrode according to Internal BIOTRONIK Specification; Leads were checked for conformance with the dimensions detailed in BIOTRONIK design specifications. The surface areas of the tip and ring electrodes were calculated from the design specifications to verify the electrodes had the specified surface area (A = 5.0 ± 0.2 mm^{2} and 8.0 mm^{2}, respectively) | Pass |
| Abrasion Resistance of Complete Lead according to Internal BIOTRONIK Specification; The number of shaft revolutions required to completely rub through the tubing must meet the following criteria: The lower limit of the 95% confidence interval of the population mean must be greater than 7500 revolutions. If the test was aborted before all specimens were completely rubbed through, then this statistic shall be calculated only with those specimens that were rubbed through. Each individual value must be ≥ 5000 revolutions. | Pass |
| X-Ray Visibility of Complete Lead according to DIN 13273-7: 1996-12^{17} | Pass |
| Simulated Fixation of Distal End of Lead in Blood Vessel according to Internal BIOTRONIK Specification; Helix fixation at the distal end of the lead (immersed in NaCl solution at 37 °C) was inserted in a straight glass tube with inner diameter of 3.2 mm. The retention force when pulled axially out of the tube must be ≥ 0.05 N. | Pass |
| Steroid | |
| Test of Identification, Purity and Content of DXA in the Collar and Collar Subassemblies according to Internal BIOTRONIK Specification: Identity: the retention time of the DXA peak in the HPLC chromatograph must be comparable with the retention time of the standard substance peak. Purity: no peak more than 0.5% and the sum of all impurity peaks not more than 1% of main peak. Content of DXA must be 0.5 mg ± 30% per collar. | Pass |
| Liberation of DXA from the Collar and Lead Assemblies –Determination of the Elution Rate according to Internal BIOTRONIK Specification; There must be more than 4 μg DXA released after two and more than 7 μg DXA released after 4 days for the collar and 4 – 8 μg DXA after two and 7 – 13 μg DXA after 4 days for the lead tip assemblies. | Pass |
| Accessories | |
| Use of Corox OTW(-S) BP with Implantation Tool ScoutPro 7F and 8F – Introduction and Retraction of the Lead according to Internal BIOTRONIK Specification; The lead was introduced to and retracted from the implantation tool five times. There must be no problem with handling and no damage to the lead, introducer or hemostatic valve. The friction force during advancement of the lead within the sheath must be less than 1 N (less than 2 N for the 7F). | Pass |

17 DIN 13273-7: Catheters for medical use - Part 7: Determination of the x-ray attenuation of catheters; Requirements and testing

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| Table 6 Corox OTW(-S) BP Validation Testing | |
| --- | --- |
| Test Performed | Test Results (Pass/Fail) |
| Use of Corox OTW with Anchoring Sleeve EFH-16 (Straight Slitted) according to Internal BIOTRONIK Specification; A tensile load was applied at both ends of the thread until the thread breaks. No damage may occur to the lead or EFH at the maximum constriction force (which is equal to the tensile strength of the ligature). A normal manual force of 8 N was applied as knots are tied in the thread. The EFH may not shift at a tensile force up to 5 N. | Pass |
| Use of Corox OTW(-S) BP with Stylets S xx-K OTW and S xx-G OTW according to Internal BIOTRONIK Specification; The retention force of the stylet wire within connector pin (clamping function) was determined to verify that the insertion and extraction force is between 1.0 N and 5.0 N No damage may occur to the lead (including the distal seal) or the stylet. The stylet must maintain continuous movement. The stylet may not protrude from the distal end of the lead. | Pass |
| Use of Corox OTW(-S) BP with Torque Wrench for Guide Wire according to Internal BIOTRONIK Specification; The handling of the torque wrench was assessed. The torque wrench must easily tighten and loosen. The wrench must be threaded over 0.36 mm guidewire and tightened. The tightened wrench must not be moved on a 0.3 mm wire when a 2 N axial force is applied. | Pass |
| Use of Corox OTW(-S) BP with Cannula for Introducing Guide Wire into Introducer or Hemostatic Valve of Implantation Tool according to Internal BIOTRONIK Specification; The cannula was introduced into the hemostatic valve and introducer. The guidewire was inserted into the cannula and then removed. The testing was performed with four different samples. There must be no problem with handling and no damage to the lead, introducer or hemostatic valve. | Pass |
| Use of Corox OTW(-S) BP with Guide wire 0.36 mm: Handling, Insertion, Maneuverability, Friction Force according to Internal BIOTRONIK Specification; The maneuverability and handling of the guidewire were assessed after the guidewire was completely inserted into the lead from both ends. The friction forces were determined during advancement and retreat of the lead to verify that the forces were not greater than 0.5 N. No damage may occur to the lead or the guidewire. The guidewire must maintain continuous movement. | Pass |

* Guidance for the Submission of Research and Marketing Applications for Permanent Pacemaker Leads and for Pacemaker Lead Adaptor 510(k) Submissions dated November 1, 2000

## C. PROGRAMMER SOFTWARE

Validation of the programmer software presented in this PMA application was performed using automated or manual testing techniques. Testing was performed using BIOTRONIK's EVALUATOR™ automatic testing setup for evaluating the programmer screens and functional displays. All features and characteristics that could not be tested with the EVALUATOR system were tested manually (user). Results of the validation substantiate that the software used for interrogating and programming BIOTRONIK implants functions as designed.

## D. BIOCOMPATIBILITY TESTING

All tissue-contacting materials of BIOTRONIK's CRT-Ps are currently utilized in BIOTRONIK products market-released in the US. Biocompatibility testing of all tissue-contacting materials utilized in BIOTRONIK's CRT-Ps has been successfully completed.

All tissue-contacting materials of BIOTRONIK's Corox OTW(-S) BP Left Ventricular Lead are currently utilized in BIOTRONIK products market-released in the US. Biocompatibility testing of all tissue-contacting materials utilized in BIOTRONIK's leads has been successfully completed.

The biocompatibility results demonstrated that the requirements of ISO 10993 were fulfilled and the Stratos LV/LV-T CRT-Ps and Corox OTW(-S) BP leads bear no additional biological risks.

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# E. SHELF LIFE

A 18-month expiration date, "Use Before Date" (UBD), has been established for the Stratos LV/LV-T CRT-Ps based on device longevity and internal battery characteristics. The use before date is assigned as the last date of the eighteenth month after battery connection is made during the manufacturing process.

A 24-month expiration date, "Use Before Date" (UBD), has been established for the Corox OTW(-S) BP Left Ventricular Lead based on sterility and long-term storage testing. The use before date is assigned as the last date of the twenty-fourth month after sterilization.

# F. CONCLUSION CONCERNING NON-CLINICAL LABORATORY TESTING

BIOTRONIK conducted risk analyses on all new features and critical components and then conducted testing to evaluate these and other device characteristics. All test results were found to be acceptable to support reasonable safety to begin clinical trials.

# X. SUMMARY OF CLINICAL STUDIES

The subsequent sections summarize the following four clinical studies that were used to support the safety and effectiveness of the Stratos LV/LV-T CRT-Ps and/or Corox OTW(-S) BP Left Ventricular Leads.

- The AVAIL CLS/CRT clinical study
- The OVID clinical study (OUS)
- The OPTION CRT/ATx clinical study
- The everest clinical study (OUS)

Two of the studies, AVAIL CLS/CRT and OVID, collected significant safety data supporting use of the Stratos LV/LV-T CRT-P system. The third study, OPTION CRT/ATx, supports the effectiveness of cardiac resynchronization therapy (CRT). The OPTION CRT/ATx study was conducted on a device that delivers CRT but, in addition, also offers defibrillation therapy (CRT-D).

The everest clinical investigation assessed the clinical safety and effectiveness of Corox OTW(-S) BP bipolar left ventricular leads.

# A. STRATOS LV CLINICAL STUDY – AVAIL CLS/CRT

## i. Study Design

The AVAIL CLS/CRT was a multi-center, prospective, randomized, blinded clinical study designed to support approval for cardiac resynchronization therapy for a Heart Failure (HF) patient population not requiring back up defibrillation and that are indicated for an ablate and pace procedures. All patients enrolled into the clinical study were randomly assigned to one of three groups using a 2:2:1 ratio for randomization.

- Patients assigned to Group 1 received biventricular pacing with CLS-based rate adaptive pacing using BIOTRONIK's Protos DR/CLS, which is a dual-chamber pulse generator with CLS-based rate adaptive pacing. During this study, the Protos DR/CLS devices were implanted with two ventricular leads: the right ventricular lead was connected to the ventricular port, and the left ventricular lead was connected to the atrial port. Protos DR/CLS was included in this study to evaluate biventricular pacing with a different type of rate adaptive sensor technology.
- Patients assigned to Group 2 received biventricular pacing with accelerometer-based rate adaptive pacing using the Stratos LV.
- Patients assigned to Group 3 (control group) received right ventricular pacing with accelerometer-based rate adaptive pacing using the Stratos LV. Therefore, 60% of the patients received a Stratos LV device.

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Primarily, the study evaluated and compared the functional benefits of CRT between the three randomized groups using a composite endpoint consisting of a six-minute walk test (meters walked) and quality of life measurement (assessed using the Minnesota Living with Heart Failure Questionnaire). Relevant measurements were completed twice for each patient: once at the Baseline evaluation (prior to implant and ablation) and again at a six-month follow-up evaluation. The data collected during this clinical study was used to demonstrate superiority of CRT to RV only pacing. This study also evaluated the safety of both the Protos DR/CLS and Stratos LV devices through an analysis of the complication-free rate through six months. Secondarily, the study also evaluated the superiority of CRT with CLS rate adaptation compared to CRT with accelerometer rate adaptation.

## ii. Clinical Inclusion and Exclusion Criteria

### a. Clinical Inclusion Criteria

To support the objectives of this investigation, patients were required to meet the following inclusion criteria prior to enrollment:

- Meet the indications for therapy
- Persistent (documented for more than 7 days), symptomatic AF with poorly controlled rapid ventricular rates or permanent, (documented for more than 30 days with failed cardioversion, or longstanding AF of 6 months or more) symptomatic AF with poorly controlled rapid ventricular rates.
- Eligible for AV nodal ablation and permanent pacemaker implantation
- NYHA Class II or III heart failure
- Age ≥ 18 years
- Understand the nature of the procedure
- Ability to tolerate the surgical procedure required for implantation
- Give informed consent
- Able to complete all testing required by the clinical protocol
- Available for follow-up visits on a regular basis at the investigational site

### b. Clinical Exclusion Criteria

To support the objectives of this investigation, the exclusion criteria at the time of patient enrollment included the following:

- Meet one or more of the contraindications
- Have a life expectancy of less than six months
- Expected to receive heart transplantation within six months
- Enrolled in another cardiovascular or pharmacological clinical investigation
- Patients with an ICD, or being considered for an ICD
- Patients with previously implanted biventricular pacing systems
- Patients with previously implanted single or dual chamber pacing system with >50% documented ventricular pacing
- Patients with previous AV node ablation
- Six-minute walk test distance greater than 450 meters
- Any condition preventing the patient from being able to perform required testing
- Presence of another life-threatening, underlying illness separate from their cardiac disorder
- Conditions that prohibit placement of any of the lead systems

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# iii. Follow-Up Schedule

At the enrollment screening, the physician evaluated the patient to verify that all inclusion/exclusion criteria have been met in accordance to the protocol and the patient has signed the informed consent. After successful enrollment, all patients were implanted with either a Stratos LV CRT-P or Protos DR/CLS device. Evaluations at the Four Week, Three and Six Month follow-ups included NYHA classification, medications, and percentage of ventricular pacing.

# iv. Clinical Endpoints

## a. Primary Endpoint: Complication-free Rate (Safety)

The safety of the Stratos LV was evaluated based on complications (adverse events that require additional invasive intervention to resolve) related to the implanted CRT system which includes the Stratos LV, the right ventricular, the left ventricular lead, lead ventricular lead adapters (if used) and the implant procedure. The target complication-free rate at six months is 85%.

## b. Primary Endpoint: Six Minute Walk Test & QOL (Effectiveness)

The purpose of Primary Endpoint 1 was to evaluate the effectiveness of the CRT (Groups 1 and 2) compared to RV only (Group 3) pacing as measured by the average composite rate of improvement in six minute walk test and QOL.

# v. Accountability of PMA Cohorts

After randomization and enrollment, 23 patients (8 in Group 1, 8 in Group 2 and 7 in Group 3) did not receive an implant. The reasons for patients not receiving an implant are outlined in Figure 1. Two additional patients in Group 1 had an unsuccessful first implant attempt (unable to implant the LV lead), but follow up data was not received.

Figure 1: Patient Accountability

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vi. Demographics and Baseline Parameters

Table 7 provides a summary of the patient demographics at enrollment. There were no statistical differences in enrollment demographics between the 3 groups.

Table 7: Patient Demographics at Enrollment

| Characteristic | Group1 | Group 2 | Group 3 | P-value |
| --- | --- | --- | --- | --- |
| Age at Enrollment (Years) | N=42 | N=50 | N=25 | |
| Mean ± SE | 73.7 ± 1.3 | 72.3 ± 1.2 | 71.5 ± 1.6 | 0.534* |
| Range | 56 to 90 | 51 to 86 | 52 to 85 | |
| Gender | N=42 | N=50 | N=25 | |
| Male | 18 (42.9%) | 19 (38.0%) | 13 (52.0%) | 0.553** |
| Female | 24 (57.1%) | 31 (62.0%) | 12 (48.0%) | |
| Six-Minute Walk Distance (meters) | N=42 | N=50 | N=25 | |
| Mean ± SE | 262.7 ± 15.1 | 283.6 ± 13.8 | 267.8 ± 22.9 | 0.395* |
| Range | 78 to 420 | 37 to 438 | 23 to 420 | |
| New York Heart Association Class | N=42 | N=50 | N=25 | |
| Class II | 23 (54.8%) | 18 (36.0%) | 10 (40.0%) | 0.189** |
| Class III | 19 (45.2%) | 32 (64.0%) | 15 (60.0%) | |
| Underlying Heart Disease | N=42 | N=49 | N=25 | |
| Dilated Cardiomyopathy | 8 (19.0%) | 11 (22.4%) | 1 (4.0%) | 0.125** |
| Hypertrophic Cardiomyopathy | 4 (9.5%) | 1 (2.0%) | 2 (8.0%) | 0.216** |
| Valvular Heart Disease | 12 (28.6%) | 12 (24.5%) | 5 (20.0%) | 0.792** |
| Coronary Artery Disease | 19 (45.2%) | 28 (57.7%) | 6 (24.0%) | 0.031** |
| Hypertension | 37 (88.1%) | 37 (75.5%) | 19 (76.0%) | 0.348** |
| No underlying structural heart disease | 3 (7.1%) | 2 (4.1%) | 7 (28.0%) | 0.007** |
| Other Medical History | N=29 | N=36 | N=17 | |
| Diabetes | 13 (44.8%) | 9 (25.0%) | 4 (23.5%) | 0.287** |
| Chronic Lung Disease | 7 (24.1%) | 16 (44.4%) | 7 (41.2%) | 0.211** |
| Thyroid Disease | 12 (41.4%) | 12 (33.3%) | 5 (29.4%) | 0.791** |
| Chronic Kidney Disease | 4 (13.8%) | 5 (13.9%) | 1 (5.9%) | 0.836** |
| Prior Ischemic Stroke or TIA | 7 (24.1%) | 10 (27.8%) | 6 (35.3%) | 0.726** |
| Prior Embolic Events (non-cerebrovascular) | 1 (2.3%) | 3 (6.0%) | 2 (8.0%) | 0.653** |

*One-way ANOVA, **Chi-Square test (2-sided)

Table 8 provides a summary of the AF medical history. Table 9 provides a summary of cardiac medications patients were taking at the time of enrollment. Please note some categories may equal more than 100% as several categories allow more than one response. In some cases, complete demographic data was not provided for all patients. There were no statistical differences in AF medical history and cardiac medication at enrollment between the 3 groups.

Table 8: Atrial Fibrillation Demographics at Enrollment

| Characteristic | Group 1 | Group 2 | Group 3 | P-value* |
| --- | --- | --- | --- | --- |
| Classification of Atrial Fibrillation | N=42 | N=50 | N=24 | |
| Persistent AF | 10 (23.8%) | 17 (34%) | 6 (25%) | 0.537 |
| Permanent AF | 32 (76.2%) | 33 (66%) | 18 (75%) | |
| Classification of Symptoms Related to AF | N=42 | N=49 | N=25 | |
| Palpitations | 32 (76.2%) | 34 (69.4%) | 14 (56.0%) | 0.236 |
| Chest Pain | 6 (14.3%) | 7 (14.3%) | 3 (12.0%) | 1.000 |
| Dyspnea or shortness of breath | 36 (85.7%) | 40 (81.6%) | 19 (76.0%) | 0.568 |
| Fatigue | 34 (81.0%) | 45 (91.8%) | 18 (72.0%) | 0.149 |
| Lightheadedness or syncope | 17 (40.5%) | 13 (26.5%) | 9 (36.0%) | 0.329 |
| Other | 9 (21.4%) | 11 (22.4%) | 10 (40.0%) | 0.205 |
| Previous AF Ablation | N=42 | N=50 | N=25 | |
| No | 37 (88.1%) | 47 (94.0%) | 21 (84.0%) | 0.354 |
| Yes | 5 (11.9%) | 3 (6.0%) | 4 (16.0%) | |

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| Characteristic | Group 1 | Group 2 | Group 3 | P-value* |
| --- | --- | --- | --- | --- |
| Past Medications for Rate or Rhythm Control | N=41 | N=48 | N=24 | |
| Amiodarone | 12 (29.3%) | 10 (20.8%) | 10 (41.7%) | 0.192 |
| Digoxin | 17 (41.5%) | 22 (45.8%) | 13 (54.2%) | 0.683 |
| Diltiazem | 17 (41.5%) | 23 (47.9%) | 12 (50.0%) | 0.804 |
| Disopyramide | 0 (0.0%) | 3 (6.3%) | 0 (0.0%) | 0.228 |
| Dofetilide | 4 (9.8%) | 3 (6.3%) | 2 (8.3%) | 0.895 |
| Flecanide | 5 (12.2%) | 5 (10.4%) | 1 (4.2%) | 0.656 |
| Ibutilide | 0 (0.0%) | 0 (0.0%) | 1 (4.2%) | 0.215 |
| Procainamide | 0 (0.0%) | 2 (4.2%) | 0 (0.0%) | 0.506 |
| Propafenone | 2 (4.9%) | 4 (8.3%) | 0 (0.0%) | 0.423 |
| Sotolol | 9 (22.0%) | 10 (20.8%) | 2 (8.3%) | 0.389 |
| Verapamil | 5 (12.2%) | 8 (16.7%) | 3 (12.5%) | 0.829 |
| Metoprolol | 19 (46.3%) | 28 (58.3%) | 10(41.7%) | 0.382 |
| Propranolol | 0 (0.0%) | 0 (0.0%) | 1 (4.2%) | 0.215 |
| Other Beta-Blockers | 7 (17.1%) | 15 (31.3%) | 4 (16.7%) | 0.248 |
| Other Medications | 5 (12.2%) | 5 (10.4%) | 1 (4.2%) | 0.656 |
| Rate Control Medication, Reasons for Discontinuation | N=17 | N=20 | N=12 | |
| Ineffective | 10 (58.8%) | 13 (65.0%) | 9 (75.0%) | 0.558 |
| Not tolerated | 8 (47.1%) | 7 (35.0%) | 3 (25.0%) | 0.760 |
| Other | 1 (5.9%) | 2 (10.0%) | 0 (0.0%) | 0.800 |
| Rhythm Control Medication, Reasons for Discontinuation | N=22 | N=25 | N=13 | |
| Ineffective | 17 (77.3%) | 20 (80.0%) | 8 (61.5%) | 0.759 |
| Not tolerated | 6 (27.3%) | 7 (28.0%) | 6 (46.2%) | 0.530 |
| Other | 1 (4.5%) | 1 (4.0%) | 2 (15.4%) | 0.430 |
| Cardioversion History | N=42 | N=49 | N=25 | |
| Successful prior electrical cardioversion | 13 (31.0%) | 16 (32.7%) | 10 (40.0%) | 0.760 |
| Transthoracic | 13 (100.0%) | 15 (93.8%) | 10 (100.0%) | 0.808 |
| Transvenous | 0 (0.0%) | 1 (6.3%) | 0 (0.0%) | |
| Unsuccessful prior electrical cardioversion | 15 (35.7%) | 14 (28.6%) | 7 (28.0%) | 0.680 |
| Transthoracic | 15 (100.0%) | 14 (93.3%) | 7 (100.0%) | 0.741 |
| Transvenous | 0 (0.0%) | 2 (13.3%) | 0 (0.0%) | |
| No electrical cardioversion attempted | 17 (40.5%) | 20 (40.8%) | 9 (36.0%) | 0.936 |
| Successful prior pharmacological cardioversion | 5 (11.9%) | 3 (6.1%) | 3 (12.0%) | 0.547 |
| Unsuccessful prior pharmacological cardioversion | 8 (19.0%) | 11 (22.4%) | 7 (28.0%) | 0.678 |
| No pharmacological cardioversion attempted | 23 (54.8%) | 29 (59.2%) | 15 (60.0%) | 0.915 |

*Chi-Square test (2-sided)

Table 9: Current Cardiac Medications at Enrollment

| Drug Category | Group 1
N=42 | Group 2
N=50 | Group 3
N=25 | P-value* |
| --- | --- | --- | --- | --- |
| Anti-Arrhythmics | 12 (28.6%) | 10 (20.4%) | 4 (16.0%) | 0.480 |
| Rate Control Medications | 32 (76.2%) | 43 (87.8%) | 20(80.0%) | 0.462 |
| Anti-thrombic Agents | 17 (40.5%) | 19(38.8%) | 11 (44.0%) | 0.863 |
| Anti-Coagulants | 36 (85.7%) | 40 (81.6%) | 22 (88.0%) | 0.686 |
| ACE Inhibitors | 16 (38.1%) | 16 (32.7%) | 8 (32.0%) | 0.848 |
| Angiotensin-Receptor Blockers | 10 (23.8%) | 7 (14.3%) | 4 (16.0%) | 0.491 |
| Diuretics | 30 (71.4%) | 34 (69.4%) | 13 (52.0%) | 0.255 |
| Inotropes | 1 (2.4%) | 2 (4.1%) | 0 (0.0%) | 0.803 |
| Nitrates | 3 (7.1%) | 6 (12.2%) | 2 (8.0%) | 0.714 |
| Beta-Blockers for CHF | 6 (14.3%) | 9 (18.4%) | 4 (16.0%) | 0.947 |
| Other | 23 (54.8%) | 26 (53.1%) | 14 (56.0%) | 0.941 |

*Chi-Square test (2-sided)

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# vii. Safety and Effectiveness Results

A total of 118 patients were enrolled in the AVAIL CLS/CRT clinical study at 20 sites:

There were 43 Group 1, 50 Group 2, and 25 Group 3 patients in this prospective, multi-center, randomized clinical study. For Group 1, there were 33 successful implants (76.7%) of the Protos DR/CLS system. For Groups 2 and 3, there were 44 and 21 successful implants (88.0% and 84.0%), respectively, of the Stratos LV CRT-P system.

- The study was designed to enroll 265 patients. However, the study was evaluated early due to slow patient enrollment. There were no safety issues involved in the early evaluation decision. Due to the lack of patient data, the AVAIL CLS/CRT study alone was insufficient to support CRT pacing effectiveness or an ablate and pace indication.
- The cumulative enrollment duration was 416.7 months with a mean duration of 9.7 months for Group 1, 522.4 months with a mean duration of 10.4 months for Group 2, and 261.1 months with a mean duration of 10.4 months for Group 3. 73 (61.9%) of the study patients had enrollment durations greater than 6 months.
- There were 158 adverse events (115 observations in 68 patients and 43 complications in 34 patients). There were no unanticipated adverse device effects reported.
- The overall protocol violation non-compliance rate is 0.4% in Group 1, 0.5% in Group 2, and 0.4% in Group 3. The overall follow-up compliance rate is 99.8% in all groups.
- There were 3 patient deaths reported, two in Group 2 and one in Group 3. The clinical investigators and clinical events committee determined that none of these deaths were related to the study devices.
- Both the CRT pacing and the RV pacing only groups showed improvements in the primary composite endpoint of quality of life and six-minute walk distance between the baseline evaluation and the six-month follow-up. In addition, there was a trend towards improvement between the combined CRT pacing groups compared to the RV pacing only group at six months.

## a. Primary Endpoint: Complication-free Rate (Safety)

The safety of the Stratos LV was evaluated based on complications (adverse events that require additional invasive intervention to resolve) related to the implanted CRT system which includes the Stratos LV, the right ventricular, the left ventricular lead, lead ventricular lead adapters (if used) and the implant procedure. The target complication-free rate at six months is 85%.

13 complications in these categories were seen in 11 patients with cumulative enrollment duration of 783.5 months (64.4 patient-years). 14.7% of the patients had a reported complication in these categories. The rate of complications per patient-year is 0.20. Details of the Stratos LV complications in the AVAIL CLS/CRT study are listed in Table 10.

| Table 10: AVAIL CLS/CRT Complication-Free Rate at Six Months – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complication per patient-year |
| Device-Related | | | | |
| Pocket Infection/Pain | 1 | 1.3% | 2 | 0.03 |
| Total Device-Related | 1 | 1.3% | 2 | 0.03 |
| LV Lead Related | | | | |
| High Threshold/No Capture | 1 | 1.3% | 1 | 0.02 |
| Diaphragmatic Stimulation | 1 | 1.3% | 1 | 0.02 |
| Dislodgement | 2 | 2.7% | 2 | 0.03 |
| Total LV Lead-Related | 4 | 5.3% | 4 | 0.06 |
| RV Lead Related | | | | |
| High Threshold/No Capture | 4 | 5.3% | 4 | 0.06 |
| Total RV Lead-Related | 4 | 5.3% | 4 | 0.06 |
| Procedure | | | | |
| Pneumothorax | 1 | 1.3% | 1 | 0.02 |

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| Table 10: AVAIL CLS/CRT Complication-Free Rate at Six Months – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complication per patient-year |
| User error | 1 | 1.3% | 1 | 0.02 |
| Hematoma | 1 | 1.3% | 1 | 0.02 |
| Total Procedure | 3 | 4.0% | 3 | 0.05 |
| Total Lead and Procedure Related | 11 | 14.7% | 13 | 0.20 |
| Other Medical | | | | |
| Worsening CHF | 2 | 2.7% | 2 | 0.03 |
| Repeat Ablation | 3 | 4.0% | 3 | 0.05 |
| Non-CHF cardiac symptoms | 3 | 4.0% | 3 | 0.05 |
| Other Medical | 3 | 4.0% | 3 | 0.05 |
| Total Other Medical | 10 | 13.3% | 11 | 0.17 |
| Total—All Patients and Categories | 19 | 25.3% | 24 | 0.37 |

Number of Patients = 75 Number of Patient-Years = 64.4

The freedom from Stratos LV system-related and procedure-related complications was 85.33% with a one-sided lower 95% confidence bound of 76.89%. Therefore, the procedure, lead and device related complication-free rate at 6 months met the pre-specified acceptance criterion of equivalence (non-inferiority) within 10% of 85% (p = 0.0196).

## b. Observed Adverse Events

Adverse events are classified as either observations or complications. Observations are defined as clinical events that do not require additional invasive intervention to resolve. Complications are defined as clinical events that require additional invasive intervention to resolve.

Of the 104 adverse events reported in the Stratos LV study groups, there have been 76 observations in 45 patients and 28 complications in 20 patients with a cumulative enrollment duration of 64.4 patient-years. 26.7% of the enrolled Stratos LV patients have experienced a complication. The rate of complications per patient-year is 0.43. 60.0% of the enrolled study patients have a reported observation. The rate of observations per patient-year is 1.18.

Complications and observations for the Stratos LV study groups are summarized in Table 11 and Table 12. The total number of patients may not equal the sum of the number of patients listed in each category, as an individual patient may have experienced more than one complication or observation.

| Table 11: Summary of Complications – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| Device-Related | | | | |
| Pocket Infection or Pain | 2 | 2.7% | 3 | 0.05 |
| Total | 2 | 2.7% | 3 | 0.05 |
| LV Lead-Related | | | | |
| High Threshold/No Capture | 1 | 1.3% | 1 | 0.02 |
| Diaphragmatic Stimulation | 1 | 1.3% | 1 | 0.02 |
| Dislodgement | 2 | 2.7% | 2 | 0.03 |
| Total | 4 | 5.3% | 4 | 0.06 |
| RV Lead Related | | | | |
| High Threshold/No Capture | 4 | 5.3% | 4 | 0.06 |
| Total | 4 | 5.3% | 4 | 0.06 |

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| Table 11: Summary of Complications – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| Procedure | | | | |
| Pneumothorax | 1 | 1.3% | 1 | 0.02 |
| User error | 1 | 1.3% | 1 | 0.02 |
| Hematoma | 1 | 1.3% | 1 | 0.02 |
| Total | 3 | 4.0% | 3 | 0.05 |
| Total Lead and Procedure Related | 11 | 14.7% | 14 | 0.22 |
| Other Medical | | | | |
| Worsening CHF | 2 | 2.7% | 2 | 0.03 |
| Non-CHF cardiac symptoms | 5 | 6.7% | 5 | 0.08 |
| Repeated ablation | 3 | 4.0% | 3 | 0.05 |
| Lead addition | 1 | 1.3% | 1 | 0.02 |
| Other medical | 3 | 4.0% | 3 | 0.05 |
| Total | 12 | 16.0% | 14 | 0.22 |
| Total—All Patients and Categories | 20 | 26.7% | 28 | 0.43 |

Number of Patients = 75, Number of Patient-Years = 64.4

| Table 12: Summary of Observations – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| LV Lead-Related | | | | |
| High Threshold/No Capture | 1 | 1.3% | 1 | 0.02 |
| Diaphragmatic Stimulation | 13 | 17.3% | 13 | 0.20 |
| Total LV | 14 | 18.7% | 14 | 0.22 |
| Device Related | | | | |
| Pocket Infection or pain | 5 | 6.7% | 5 | 0.08 |
| Total | 5 | 6.7% | 5 | 0.08 |
| Procedure | | | | |
| Pneumothorax | 1 | 1.3% | 1 | 0.02 |
| Atrial edema | 1 | 1.3% | 1 | 0.02 |
| User error | 1 | 1.3% | 1 | 0.02 |
| Total | 3 | 4.0% | 3 | 0.05 |
| Total Lead, Device and Procedure Related | 19 | 25.3% | 22 | 0.34 |
| Other Medical | | | | |
| Dizziness | 3 | 4.0% | 3 | 0.05 |
| Other Medical | 24 | 32.0% | 34 | 0.53 |
| Worsening CHF | 8 | 10.7% | 8 | 0.12 |
| Ventricular arrhythmias | 2 | 2.7% | 2 | 0.03 |
| Shortness of Breath | 5 | 6.7% | 5 | 0.08 |
| Stroke/TIA | 1 | 1.3% | 1 | 0.02 |

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| Table 12: Summary of Observations – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| Non-CHF cardiac symptoms | 1 | 1.3% | 1 | 0.02 |
| Total | 35 | 46.7% | 54 | 0.84 |
| Total—All Patients and Categories | 45 | 60.0% | 76 | 1.18 |

Number of Patients = 75 Number of Patient-Years = 64.4

There have been 3 patient deaths reported for the Stratos LV groups (out of 75 Stratos LV patients). None of the deaths were related to the implanted CRT-P system. Table 13 provides a summary of reported patient deaths.

Table 13: Summary of Patient Deaths

| | Stratos LV Patients (N = 75) |
| --- | --- |
| Sudden Cardiac | 1 |
| Non-Cardiac | 2 |
| All Causes | 3 |

## c. Primary Endpoint: Six Minute Walk Test & QOL (Effectiveness)

The purpose of Primary Endpoint 1 was to evaluate the effectiveness of the CRT (Groups 1 and 2) compared to RV only (Group 3) pacing as measured by the average composite rate of improvement in six minute walk test and QOL.

- Stratos LV Effectiveness (Group 2 compared to Group 3): The average composite rate for Group 2 (N=30) was 48.1% with a standard error of 12.3%. The average composite rate for Group 3 (N=15) was 33.0% with a standard error of 12.3%. The difference in the mean composite rate between Group 2 and Group 3 is 15.1%. The p value for superiority is 0.442.
- Protos DR/CLS Effectiveness (Group 1 compared to Group 3): The average composite rate for the Group 1 (N=23) is 36.8% with a standard error of 7.9%. The average composite rate for Group 3 (N=15) is 33.0% with a standard error of 12.3%. The difference in the mean composite rate between Group 1 and Group 3 is 3.8%. The p value for superiority is 0.788.

Table 14 presents the average composite rate of improvement in six minute walk test distance and QOL score, the average 6-minute walk test distance and the average QOL score at Baseline and at the Six-Month follow-up, as well as the average difference in 6-minute walk test distance and QOL score between Baseline and the Six-Month follow-up for the CRT (Groups 1 and 2) and RV only (Group 3) for those patients with six minute walk test data and complete QOL data at both Baseline and the Six-Month follow-up.

| Table 14: Composite of Six Minute Walk Test and QOL (Effectiveness) | | | |
| --- | --- | --- | --- |
| Category | CRT (Group 1 & 2) (N = 53) Mean ± SE | RV only Group 3 (N = 15) Mean ± SE | p value * (student's t-test, 2-sided) |
| Distance Walked at Baseline | 262.8 ± 13.7 | 288.5 ± 22.4 | 0.369 * |
| Distance Walked at Six-Months | 312.8 ± 14.6 | 345.8 ± 30.0 | 0.303 * |
| Δ Distance Walked (meters) | 50.0 ± 12.2 | 57.2 ± 26.7 | 0.790 * |
| Δ Distance Walked (%) | 39.0% ± 13.1% | 25.7% ± 15.0% | 0.610 * |
| QOL Score at Baseline | 58.5 ± 2.9 | 49.3 ± 5.5 | 0.137 * |
| QOL Score at Six-Months | 30.1 ± 3.2 | 27.7 ± 6.5 | 0.731 * |
| Δ in QOL Score | 28.4 ± 3.4 | 21.6 ± 7.7 | 0.367 * |

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| Table 14: Composite of Six Minute Walk Test and QOL (Effectiveness) | | | |
| --- | --- | --- | --- |
| Category | CRT (Group 1 & 2) (N = 53) Mean ± SE | RV only Group 3 (N = 15) Mean ± SE | p value * (student's t-test, 2-sided) |
| Δ in QOL Score (%) | 47.4% ± 5.1% | 40.4% ± 11.1% | 0.537 * |
| Composite Rate | 43.2% ± 7.7% | 33.0% ± 12.3% | 0.525 * |

* p value is provided for informational purposes to show trends only; clinical significance is not indicated by p values for analyses that were not prespecified.

## d. Primary Effectiveness Endpoint Analysis and Conclusions

The primary effectiveness endpoint evaluated CRT effectiveness (Groups 1 and 2) compared to RV only effectiveness (Group 3), as measured by the composite rate of the six minute walk test and QOL improvement from Baseline to the Six-Month follow-up (Table 14). For this analysis, both six minute walk test and QOL were equally weighted at 50%. Due to the small number of patients with data available for the analysis of the primary endpoint, the results lack power to demonstrate that biventricular pacing with either the Protos DR/CLS or Stratos LV device is statistically different from RV only pacing with the Stratos LV device in patients undergoing an "ablate and pace" procedure.

## e. Multi-site Poolability and Gender Analysis

The AVAIL CLS/CRT clinical report included data from multiple centers with centralized coordination, data processing, and reporting at BIOTRONIK. All of the clinical centers followed the requirements of an identical clinical protocol, and all of the clinical centers used the same methods to collect and report the clinical data, including New York Heart Association evaluation, six-minute walk test, Minnesota Living with Heart Failure questionnaire, and echocardiographic measurements. In order to justify pooling of the data from multiple centers, several analyses were completed. All of the centers were divided into two groups (Small and Large sites) based on implant volume. Comparisons were then made between the patient populations based on the results of the safety and effectiveness endpoints. Additionally, analyses were performed on the data collected in the AVAIL clinical investigation in order to compare results between males and females. The first type of analysis compared enrollment by patient gender in each of the study groups. The second type of analysis compared effectiveness and safety outcomes in each gender.

The results of these analyses demonstrated poolability of the data between sites. There were no significant differences in the primary safety or effectiveness endpoints between high and low volume implant centers.

The gender distribution in this clinical investigation was consistent within the study groups and included a representative proportion of enrolled female participants (57.2% versus 42.7% male). There were no significant differences in the primary safety or effectiveness endpoints between the male and female population.

## B. STRATOS LV CLINICAL STUDY – OVID STUDY

The OVID clinical study collected significant safety data supporting the Stratos LV/LV-T CRT-P System.

## i. Study Design

BIOTRONIK conducted the Corox Over-the-Wire Lead Evaluation (OVID) prospective registry outside the United States (OUS) of the Corox OTW Steroid LV lead in a multi-center trial with legally marketed CRT-D and CRT-P pulse generators that provide biventricular pacing therapy. Data from this registry is presented in the following sections to support the safety of the Stratos LV CRT-P.

The multi-center investigation was designed to validate the safety of the Corox OTW Steroid LV lead through a comparison of successfully implanted LV leads against a pre-defined success rate threshold, when no anatomical restrictions prevent access to the coronary sinus. The evaluation of safety is based on the analysis of the incidence of adverse events, defined as any complications or observations judged by the investigator to be in probable relationship with Corox OTW Steroid LV lead system. Additionally, the effectiveness of the leads was evaluated using lead parameter data, including sensing amplitudes, pacing thresholds, and impedance values.

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In the OVID study, enrolled patients could be implanted with any legally marketed CRT-P or CRT-D device. There were 121 patients enrolled in the OVID clinical study, and 89 patients were implanted with a Stratos LV device.

## ii. Clinical Inclusion and Exclusion Criteria

### a. Clinical Inclusion Criteria

To support the objectives of this investigation, patients were required to meet the following inclusion criteria prior to enrollment:

- Meet the indications for bi-ventricular pacing
- Age ≥ 18 years
- Receiving optimal drug therapy for Congestive Heart Failure treatment
- Give informed consent

### b. Clinical Exclusion Criteria

To support the objectives of this investigation, the exclusion criteria at the time of patient enrollment included the following requirements:

- Myocardial infarction or unstable angina pectoris
- Acute myocarditis
- Life expectancy ≤ 6 months
- Planned cardiac surgical procedures or interventional measures within the next 6 months
- Pregnancy

## iii. Follow-Up Schedule

All patients were implanted with the Corox OTW/Steroid LV lead system and a CRT-P or CRT-D pulse generator capable of providing bi-ventricular pacing for the treatment of CHF. The specific study procedures were performed at:

- Pre-operative Visit
- Implantation
- Pre-discharge follow-up
- One-month follow-up
- Three-month follow-up
- Six-month follow-up
- Twelve-month follow-up

## iv. Clinical Endpoints

The safety of the Stratos LV was evaluated based on complications (adverse events that require additional invasive intervention to resolve) related to the implanted CRT system which includes the Stratos LV device, the atrial lead, the right ventricular lead the left ventricular lead and the implant procedure. The target complication-free rate at six months was 85%.

## v. Accountability of PMA Cohorts

During the OVID study, 84 patients were implanted with the Stratos LV CRT-P and Corox OTW/Steroid LV lead system. Additionally, 5 other patients were implanted with a Stratos LV CRT-P device following an unsuccessful Corox OTW/Steroid LV lead implant attempt. Of these 5 patients, three were not implanted with any LV pacing lead, one was implanted with a non-study LV pacing lead and one was implanted with a BIOTRONIK Elox P 60 BP placed in the RV outflow tract for bi-focal ventricular pacing. These 5 patients were excluded from the OVID study at 1 month post-implant, because the primary endpoint of the OVID study was the evaluation of the safety and effectiveness of the Corox OTW/Steroid lead.

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vi. Demographics and Baseline Parameters

Table 15 provides a summary of the patient demographics and medical history for the 89 enrolled patients implanted with a Stratos LV. The typical patient implanted with a Stratos LV CRT-P was a 68 year old male with NYHA Class III heart failure, Left Bundle Branch Block (LBBB), a mean QRS duration of 160 ms, and non-ischemic cardiomyopathy.

Table 15: Patient Demographics

| Characteristic | Results |
| --- | --- |
| Age at Implant (Years) | n=88 |
| Mean ± SD | 68 ± 10 |
| Range | 34 to 84 |
| Gender | n=89 |
| Male | 66 (74%) |
| Female | 23 (26%) |
| QRS-width (ms) | n=70 |
| Mean ± SD | 160 ± 23 |
| Range | 110 to 210 |
| Etiology of Heart Failure | n=87 |
| Ischemic | 32 (37%) |
| Non-Ischemic | 55 (63%) |
| New York Heart Association (NYHA) Classification | n=87 |
| Class III | 73 (84%) |
| Class IV | 14 (16%) |
| Atrial Tachyarrhythmias | N=87 |
| None | 48 (55%) |
| Atrial flutter | 5 (5.7%) |
| Paroxysmal atrial fibrillation | 19 (22%) |
| Persistent atrial fibrillation | 10 (11.5%) |
| Other | 5 (5.7%) |
| Ventricular Tachyarrhythmias | N=87 |
| None | 80 (92%) |
| Ventricular fibrillation | - |
| Sustained or non-sustained VT | 5 (5.7%)^{1)} |
| Other VT | 2 (2.3%)^{2)} |
| Existing/chronic leads prior to Corox OTW/Steroid | n=88 |
| None | 73 (83%) |
| Yes, due to previous pacemaker therapy | 15 (17%) |

1) non-sustained VT (n=4); no further information available (n=1); 2) VES (n=2)

vii. Safety and Effectiveness Results

- The cumulative implant duration was 760 months with a mean duration of 9.2 months. Sixty-five (77%) of the patients had implant durations greater than 6 months.
- The implant success rate for the Stratos LV CRT-P was 100% (89 out of 89). The implant success of the Stratos LV CRT-P in combination with the Corox OTW/Steroid LV lead was 94.4% (84 out of 89).
- The mean LV pacing threshold at implant was 0.9 and at 6-months was 0.9 volts.
- The mean R-wave at implant was 15.7 mV.
- The mean LV lead impedance at implant was 729 ohms and at 6-months was 603 ohms.
- There were 29 adverse events (18 observations in 17 patients and 11 complications in 10 patients). There were no unanticipated adverse device effects reported.

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- There were 10 patient deaths reported in the OVID study. The clinical investigators have determined that no deaths were related to the Stratos LV CRT-P system.
- The overall follow-up compliance rate for the OVID study is 93%.

## a. Primary Endpoint—Complication-free Rate (Safety)

The safety of the Stratos LV was evaluated based on complications (adverse events that require additional invasive intervention to resolve) related to the implanted CRT system which includes the Stratos LV device, the atrial lead, the right ventricular lead the left ventricular lead and the implant procedure. The target complication-free rate at six months was 85%.

Ten (10) complications in these categories were seen in 10 patients with cumulative implant duration of 760 months (63.3 patient-years). 11.2% of the patients had a reported complication in these categories. The rate of complications per patient-year was 0.16. Details of the Stratos LV complications in the AVAIL CLS/CRT study are listed in Table 16.

| Table 16: OVID Complication-Free Rate at Six Months – Stratos LV | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| Corox OTW/Steroid Lead-Related | | | | |
| Loss of capture | 2 | 2.2% | 2 | 0.03 |
| Phrenic nerve stimulation | 1 | 1.1% | 1 | 0.02 |
| Total | 3 | 3.3% | 3 | 0.05 |
| Atrial Lead Related | | | | |
| Loss of capture | 1 | 1.1% | 1 | 0.02 |
| Total | 1 | 1.1% | 1 | 0.02 |
| RV Lead Related | | | | |
| Loss of capture | 3 | 3.3% | 3 | 0.05 |
| Elevated Pacing thresholds | 2 | 2.2% | 2 | 0.03 |
| Total | 5 | 5.6% | 5 | 0.08 |
| Device Related | | | | |
| Pocket infection | 1 | 1.1% | 1 | 0.02 |
| Total | 1 | 1.1% | 1 | 0.02 |
| Total System Related | 10 | 11.2% | 10 | 0.16 |
| Other Medical | | | | |
| Arrhythmias | 1 | 1.1% | 1 | 0.02 |
| Total | 1 | 1.1% | 1 | 0.02 |
| Overall Complication Totals | 10 | 11.2% | 11 | 0.17 |

Number of Patients = 89, Number of Patient-Years = 63.3

The freedom from Stratos LV system-related and procedure-related complications was 88.76% with a one sided lower 95% confidence bound of 81.69%. Therefore, the null hypothesis was rejected, and it was concluded that the complication-free rate at 6 months is equivalent to 85% within 10% (p = 0.0014).

## b. Observed Adverse Events

Adverse events are classified as either observations or complications. Observations are defined as clinical events that do not require additional invasive intervention to resolve. Complications are defined as clinical events that require additional invasive intervention to resolve.

Of the 29 adverse events reported, there were 18 observations and 11 complications in a total of 89 patients. Table 17 and Table 18 provide a summary by category of each type of adverse event (complications and observations).

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| Table 17: Summary of Complications at Six Months | | | | |
| --- | --- | --- | --- | --- |
| Category | Number of Patients | % of Patients | Number of Complications | Complications per patient-year |
| Corox OTW/Steroid Lead-Related | | | | |
| Loss of capture | 2 | 2.2% | 2 | 0.03 |
| Phrenic nerve stimulation | 1 | 1.1% | 1 | 0.02 |
| Total | 3 | 3.3% | 3 | 0.05 |
| Atrial Lead Related | | | | |
| Loss of capture | 1 | 1.1% | 1 | 0.02 |
| Total | 1 | 1.1% | 1 | 0.02 |
| RV Lead Related | | | | |
| Loss of capture | 3 | 3.3% | 3 | 0.05 |
| Elevated Pacing thresholds | 2 | 2.2% | 2 | 0.03 |
| Total | 5 | 5.6% | 5 | 0.08 |
| Device Related | | | | |
| Pocket infection | 1 | 1.1% | 1 | 0.02 |
| Total | 1 | 1.1% | 1 | 0.02 |
| Total System Related | 10 | 11.2%…