← Product Code MRM · P050023

# TUPOS LV/ATX & KRONOS LV-T CRT-D & COROX OWT STEROID LV PACING LEAD (P050023)

_Biotronik, Inc. · MRM · Aug 10, 2006 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P050023

## Device Facts

- **Applicant:** Biotronik, Inc.
- **Product Code:** MRM
- **Decision Date:** Aug 10, 2006
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic

## Intended Use

The Tupos LV/ATx and Kronos LV-T CRT-Ds are indicated for use in patients with all of the following conditions: - Indicated for ICD therapy - Receiving optimized and stable Congestive Heart Failure (CHF) drug therapy - Symptomatic CHF (NYHA Class III/IV and LVEF ≤35%); and - Intraventricular conduction delay (QRS duration ≥130 ms) The Tupos LV/ATx is also indicated for patients who, in addition to an indication for a CRT-D device, have atrial tachyarrhythmias or are at risk of developing atrial tachyarrhythmias. Corox OTW Steroid LV Leads The Corox OTW Steroid leads are intended for implantation via the coronary veins to provide long term cardiac pacing when used in conjunction with a compatible pulse generator.

## Device Story

Tupos LV/ATx and Kronos LV-T are implantable cardioverter defibrillators (ICDs) providing cardiac resynchronization therapy (CRT) and standard ICD therapy; inputs include cardiac signals via RV and LV leads; transforms inputs using Smart Detection algorithm to discriminate ventricular from supraventricular tachyarrhythmias; produces biphasic shocks (1-30J) and antitachycardia pacing (ATP); used in clinical settings by physicians; Kronos includes Home Monitoring for automatic transmission of diagnostic data; Corox OTW Steroid LV leads are transvenous, steroid-eluting leads (0.5 mg dexamethasone acetate) for long-term pacing; output affects clinical decision-making by providing therapy for life-threatening arrhythmias and heart failure; benefits include improved functional capacity and reduced heart failure symptoms.

## Clinical Evidence

Evidence includes three clinical studies: OPTION (prospective, randomized, multi-center, N=200) for Tupos LV/ATx, HOME-CARE (observational, N=45) for Kronos LV-T, and OVID (registry, N=132) for Corox leads. OPTION met primary effectiveness endpoint (composite 6-minute walk/QOL, p=0.030) but missed primary safety endpoint (complication-free rate); post-hoc analysis showed safety profile comparable to other CRT-Ds. OVID demonstrated 91.7% implant success rate. No deaths were device-related across studies.

## Technological Characteristics

Pulse generators: Tupos/Kronos CRT-Ds. Leads: Corox OTW Steroid (silicone/polyurethane, 0.5 mg dexamethasone acetate, platinum/iridium fractal tip). Sensing/pacing: Biventricular pacing, biphasic shocks. Connectivity: Wireless Home Monitoring (Kronos). Sterilization: EtO. Software: Embedded firmware for device control and Smart Detection algorithm.

## Predicate Devices

- Tachos ATx ICD ([P000009](/device/P000009.md)/S4)
- Belos DR ICD ([P000009](/device/P000009.md)/S05)

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA

I. GENERAL INFORMATION

Device Generic Name: Implantable Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy (CRT) and Left Ventricular (LV) Pacing Leads

Device Trade Name: Tupos LV/ATx CRT-D Kronos LV-T CRT-D 505.U Programmer Software for the ICS 3000 A-K00.7.U Programmer Software for the EPR/TMS 1000PLUS Corox OTW Steroid 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: P050023

Date of Notice of Approval to Applicant: AUG 10 2006

II. INDICATIONS

Tupos LV/ATx and Kronos LV-T CRT-Ds

The Tupos LV/ATx and Kronos LV-T CRT-Ds are indicated for use in patients with all of the following conditions:

- Indicated for ICD therapy
- Receiving optimized and stable Congestive Heart Failure (CHF) drug therapy
- Symptomatic CHF (NYHA Class III/IV and LVEF ≤35%); and
- Intraventricular conduction delay (QRS duration ≥130 ms)

The Tupos LV/ATx is also indicated for patients who, in addition to an indication for a CRT-D device, have atrial tachyarrhythmias or are at risk of developing atrial tachyarrhythmias.

Corox OTW Steroid LV Leads

The Corox OTW Steroid leads are intended for implantation via the coronary veins to provide long term cardiac pacing when used in conjunction with a compatible pulse generator.

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# III. CONTRAINDICATIONS

## Tupos LV/ATx and Kronos LV-T CRT-Ds

The Tupos LV/ATx and Kronos LV-T CRT-Ds are contraindicated for use in patients with the following conditions:

- Patients whose ventricular tachyarrhythmias may have transient or reversible causes such as:
- Acute myocardial infarction
- Digitalis intoxication
- Drowning
- Electrocution
- Electrolyte imbalance
- Hypoxia
- Sepsis

- Patients with incessant Ventricular fibrillation (VF) and ventricular tachycardia (VT)
- Patients whose only disorder is bradyarrhythmias or atrial arrhythmias

## Corox OTW Steroid LV Leads

The use of the Corox OTW Steroid lead is 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 0.65 mg of dexamethasone acetate (DXA)

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Tupos LV/ATx CRT-D, Kronos LV-T CRT-D and Corox OTW Steroid Lead technical manuals.

# V. SYSTEM DESCRIPTION

The Tupos LV/ATx and Kronos LV-T System are implantable Cardioverter Defibrillators (ICDs) designed to provide cardiac resynchronization therapy (CRT) or biventricular pacing and standard ICD therapy. The systems consist of the pulse generators (Tupos and Kronos) commercially available leads and/or the Corox OTW Steroid Left Ventricular Lead and the 505.U and A-K00.7.U Programmer Software.

The Tupos and Kronos provide CRT in a “shared-ring” configuration with both the RV and LV outputs tied together and are only programmable to a single value for both outputs. These devices also provide therapy for ventricular tachyarrhythmias with a range of programmable antitachycardia pacing (ATP) and/or defibrillation therapy, which is identical to therapies provided by standard ICDs. Both devices provide biphasic shocks with programmable energies from 1.0 to 30 Joules. The devices also provide enhanced ventricular tachyarrhythmia discrimination through the Smart Detection™ algorithm. The SMART Detection™ algorithm is specifically designed to detect and treat ventricular tachycardias while withholding therapy for supraventricular tachyarrhythmias. In addition, the Tupos provides therapy for atrial

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tachyarrhythmias (AT and AF) with a range of ATP, high frequency (HF) burst pacing, and/or defibrillation therapy.

The Tupos and Kronos also are designed to collect diagnostic data to aid the physician's assessment of a patient's condition and the performance of the implanted device. Unlike the Tupos, the Kronos can provide triggered ventricular pacing in response to ventricular sensed events (VVT pacing) and Home Monitoring. VVT triggered pacing ensures that biventricular pacing occurs when a RV signal is sensed. Home Monitoring allows the automatic transmission of diagnostic patient data from the device to the physician at any time. The device uses wireless communication technology to provide the physician with daily patient monitoring and trend analysis information between follow-up visits.

## COROX OTW STEROID LEAD

BIOTRONIK's Corox OTW Steroid 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 unipolar (UP) IS-1 connector configuration. The lead can be positioned in the target vein using either the over-the-wire technique or a stylet.

The leads are constructed with multifilar conductors insulated with medical grade silicone and coated with polyurethane. The distal end of the lead is helix shaped at the lead tip, which facilitates attachment of the lead to the coronary vein.

The distal tip of the Corox OTW Steroid lead consists of a steroid-eluting collar, containing 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 Steroid lead features a tip electrode 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 Steroid leads are available in the following configurations: Corox OTW 75-UP Steroid (77 cm length) and Corox OTW 85-UP Steroid (87 cm length).

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

Patients who require an ICD and also have heart failure are routinely treated with a legally marketed ICD 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-Ds. Alternative therapies for the treatment of life-threatening ventricular arrhythmias as deemed appropriate by the physician are based upon electrophysiology (EP) testing and other diagnostic evaluations. These include the use of antiarrhythmic medication, electrical ablation, cardiac surgery, pacemakers and other commercially available implantable cardioverter defibrillators or a combination thereof.

## VII. MARKETING HISTORY

### Tupos LV/ATx CRT-D

Tupos LV/ATx received CE certification (number I7020610275211) on June 28, 2002 and has been marketed outside of the United States since that time. The Tupos LV/ATx has been legally marketed outside the United States, with greater than 707 of systems sold as of June 6, 2005. In April 2003, BIOTRONIK announced a voluntary recall of 186 Tupos LV/ATx as part of a larger worldwide recall of the Tachos Family of ICDs. The recall involved a premature increase of

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internal impedance in the high voltage (6V) battery due to a change in raw materials. This issue was resolved in future products with a return to the original raw material. No other adverse events associated with the use of this system have been reported to competent authorities outside the US as of May 2, 2006.

The Tupos LV/ATx has been distributed in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Cyprus, Czech Republic, France, Germany, Great Britain, Hungary, Israel, Italy, Lebanon, Mexico, Netherland, Poland, Russia, Slovakia, Spain, Switzerland, Turkey, Uruguay, and Venezuela.

## Kronos LV-T CRT-D

The Kronos LV-T received CE certification (I7 00 11 10275 168) on August 11, 2004 and has been marketed outside of the United States since that time. The Kronos LV-T has been legally marketed outside the United States, with greater than 1555 systems sold as of May 2, 2006. Two adverse events associated with the use of this system have been reported to competent authorities as of May 2, 2006. The adverse events included one case of intermittent oversensing at implant exhibited as a lack of pacing (5-7 second gaps in pacing) with no clear root cause identified and one case reported of a device in backup mode, after receipt this device was determined to be functioning completely within specification, but that it had been reset out of the backup mode on the date it was explanted. The stored error code indicated a temporary drop in supply voltage, resulting in backup mode. Further analysis was able to reproduce the failure when applying pressure to one of the internal integrated circuits, however a definitive root cause could not be determined.

The Kronos LV-T has been distributed in the following countries: Argentina, Australia, Austria, Belgium, China, Cyprus, Czech Republic, Egypt, France, Germany, Great Britain, Hungary, Israel, Italy, Lebanon, Mexico, Netherlands, Panama, Poland, Portugal, Spain, Switzerland, Uruguay, and Venezuela

## Corox OTW Steroid LV Lead

BIOTRONIK received approval of the Corox OTW Steroid leads in Europe on 10-17-2003 (CE number I7 03 10 10275 005) by the Notified Body TÜV Product Service GmbH.

BIOTRONIK has distributed over 4277 Corox OTW Steroid leads outside the United States as of May 2, 2006. No adverse events or incidents associated with these leads have been reported to date.

The Corox OTW Steroid has been distributed in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Chile, China, Cyprus, Czech Republic, Denmark, Egypt, Finland, France, Germany, Great Britain, Hungary, India, Iran, Israel, Italy, Latvia, Lebanon, Lithuania, Malta, Netherlands, Panama, Poland, Portugal, Romania, Russia, Slovakia, South Africa, Spain, Switzerland, Turkey, Uruguay, and Venezuela. The Corox OTW lead has not been withdrawn from marketing for any reason relating to the safety and effectiveness of the device.

## VIII. POTENTIAL AND OBSERVED EFFECTS OF THE DEVICE ON HEALTH

### A. POTENTIAL ADVERSE EVENTS

#### Tupos LV/ATx and Kronos LV-T CRT-Ds

The following are possible adverse events that may occur relative to the implant procedure and chronic implant of the Tupos LV/ATx and Kronos LV-T CRT-Ds:

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- Air embolism
- Allergic reactions to contrast media
- Arrhythmias
- Bleeding
- Body rejection phenomena
- Cardiac tamponade
- Chronic nerve damage
- Damage to heart valves
- Device migration
- Elevated pacing thresholds
- Extrusion
- Fluid accumulation
- Hematoma
- 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
- Thromboembolism
- Undersensing of intrinsic signals
- Venous occlusion
- Venous or cardiac perforation

In addition, patients implanted with the CRT-D system may have the following risks. These are the same risks relate with implantation of any CRT-D system:

- Acceleration of arrhythmias (speeding up heart rhythm caused by the CRT-D)
- Dependency
- Depression
- Fear of premature battery depletion (fear that battery will stop working before predicted time)
- Fear of shocking while awake
- Fear that shocking ability may be lost
- Anxiety about the CRT-D resulting from frequent shocks

- Imagined shock (phantom shock)
- Inappropriate detection of ventricular arrhythmias
- Inappropriate shocks
- Potential death due to inability to defibrillate or pace
- Shunting current or insulating myocardium during defibrillation with external or internal paddles

There may be other risks associated with this device that are currently unforeseeable.

## Corox OTW Steroid 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  |

## B. OBSERVED ADVERSE EVENTS

There were 3 clinical trials conducted that contributed to this analysis of adverse events: The OPTION CRT/ATx Study, the HOME-CARE Study, and the OVID Study. The adverse events associated with each of these are described below.

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.

## Tupos LV/ATx CRT-Ds – Summary of Adverse Events in the OPTION CRT/ATx Study

The OPTION CRT/ATx study was a prospective, randomized, multi-center study to demonstrate the safety and effectiveness of the investigational Tupos LV/ATx Cardiac Resynchronization Therapy Defibrillator (CRT-D) in patients with congestive heart failure (CHF) and atrial tachyarrhythmias. All patients enrolled into the clinical study were randomly assigned to either the study group or the control group at a 2 to 1 ratio. Patients in the study group were implanted with the Tupos LV/ATx. Patients in the control group were implanted with a legally marketed ICD that provides CRT.

Of the 278 adverse events reported in the Tupos LV/ATx study group, there have been 210 observations in 104 patients and 68 complications in 50 patients with a cumulative implant duration of 1240.4 months (101.9 patient-years). 37.6% of the enrolled study patients have experienced a complication. The rate of complications per patient-year is 0.67. 78.2% of the enrolled study patients have a reported observation. The rate of observations per patient-year is 2.06.

Complications and observations for the Tupos LV/ATx study group are summarized in Table 2 and Table 3. 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.

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Table 2: Summary of Complications – Tupos LV/ATx

|  Category | Number of Patients | Percentage of Patients | Number of Complications | Complications per patient-year  |
| --- | --- | --- | --- | --- |
|  Procedure Related  |   |   |   |   |
|  Hematoma | 4 | 3.01% | 4 | 0.04  |
|  Pneumothorax | 2 | 1.50% | 2 | 0.02  |
|  Total | 6 | 4.51% | 6 | 0.06  |
|  Atrial Lead Related  |   |   |   |   |
|  Dislodgement | 3 | 2.26% | 3 | 0.03  |
|  Total | 3 | 2.26% | 3 | 0.03  |
|  ICD Lead Related  |   |   |   |   |
|  High threshold/ No capture | 2 | 1.50% | 2 | 0.02  |
|  Diaphragmatic/ Intercostal stimulation (RV) | 1 | 0.75% | 1 | 0.01  |
|  Total | 3 | 2.26% | 3 | 0.03  |
|  LV Lead Related  |   |   |   |   |
|  High threshold/ Intermittent biventricular capture/ No capture | 11 | 8.27% | 12 | 0.12  |
|  Unable to implant lead via coronary sinus | 11 | 8.27% | 11 | 0.11  |
|  Dislodgement | 4 | 3.01% | 4 | 0.04  |
|  Diaphragmatic/ Intercostal stimulation | 1 | 0.75% | 2 | 0.02  |
|  Total | 27 | 20.30% | 29 | 0.28  |
|  Device Related  |   |   |   |   |
|  Infection | 3 | 2.26% | 7 | 0.07  |
|  Device migration | 4 | 3.01% | 4 | 0.04  |
|  Elective replacement indicator | 4 | 3.01% | 4 | 0.04  |
|  Inductions and conversions | 1 | 0.75% | 1 | 0.01  |
|  Unable to interrogate device* | 1 | 0.75% | 1 | 0.01  |
|  Total | 12 | 9.02% | 17 | 0.17  |
|  Total Procedure, Lead and Device Related | 43 | 32.33% | 58 | 0.57  |
|  Other Medical Related  |   |   |   |   |
|  Non-CHF Cardiac Symptoms | 4 | 3.01% | 4 | 0.04  |
|  Ventricular arrhythmias | 2 | 1.50% | 3 | 0.03  |
|  Other medical | 2 | 1.50% | 2 | 0.02  |
|  Atrial arrhythmia | 1 | 0.75% | 1 | 0.01  |
|  Total | 9 | 6.77% | 10 | 0.10  |
|  Total – All Patients and Categories | 50 | 37.59% | 68 | 0.67  |

Number of Patients = 133, Number of Patient-Years = 101.9
* 1 Unanticipated Adverse Device Effect (UADE) occurred with a Tupos LV/ATx CRT-D during the OPTION clinical study. The device was explanted after it was unable to be interrogated with the programmer software and no pacing output was evident. The analysis showed an appropriately depleted battery and no anomalies with the IC module. The battery depletion strongly suggests that the high voltage circuit was activated over a prolonged period due to a single-bit execution path failure. The current programmer software with Automatic Battery Management (ABM) would have prevented the battery from becoming completely depleted. There were no other instances of this failure mechanism in Tupos LV/ATx devices.

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Table 3: Summary of Observations – Tupos LV/ATx

|  Category | Number of Patients with Observations | Percentage of Patients with Observations | Number of Observations | Observations per patient-year  |
| --- | --- | --- | --- | --- |
|  Procedure Related  |   |   |   |   |
|  Hematoma | 10 | 7.52% | 10 | 0.10  |
|  Cardiac arrest | 2 | 1.50% | 2 | 0.02  |
|  Unable to implant system | 1 | 0.75% | 1 | 0.01  |
|  Total | 13 | 9.77% | 13 | 0.13  |
|  Atrial Lead Related  |   |   |   |   |
|  Dislodgement | 1 | 0.75% | 1 | 0.01  |
|  High threshold | 1 | 0.75% | 1 | 0.01  |
|  Total | 2 | 1.50% | 2 | 0.02  |
|  ICD Lead Related  |   |   |   |   |
|  High threshold/No capture | 1 | 0.75% | 1 | 0.01  |
|  Total | 1 | 0.75% | 1 | 0.01  |
|  LV Lead Related  |   |   |   |   |
|  High threshold/ Intermittent biventricular capture/ No capture | 24 | 18.05% | 24 | 0.24  |
|  Diaphragmatic / Intercostal stimulation | 8 | 6.02% | 8 | 0.08  |
|  Total | 30 | 22.56% | 32 | 0.31  |
|  Device Related  |   |   |   |   |
|  Infection | 1 | 0.75% | 1 | 0.01  |
|  Inductions and conversions | 6 | 4.51% | 6 | 0.06  |
|  Inappropriate sensing | 20 | 15.04% | 20 | 0.20  |
|  Symptomatic with biventricular pacing | 2 | 1.50% | 2 | 0.02  |
|  Total | 25 | 18.80% | 29 | 0.28  |
|  Total Procedure, Lead and Device Related | 61 | 45.86% | 77 | 0.76  |
|  Other Medical Related  |   |   |   |   |
|  Non-CHF Cardiac Symptoms | 21 | 15.79% | 21 | 0.21  |
|  Ventricular arrhythmias | 11 | 8.27% | 11 | 0.11  |
|  Other medical | 26 | 19.55% | 32 | 0.31  |
|  Atrial arrhythmia | 14 | 10.53% | 14 | 0.14  |
|  Dizziness | 4 | 3.01% | 4 | 0.04  |
|  Medication | 5 | 3.76% | 5 | 0.05  |
|  Worsening CHF | 46 | 34.59% | 46 | 0.45  |
|  Total | 82 | 61.65% | 133 | 1.31  |
|  Total – All Patients and Categories | 104 | 78.20% | 210 | 2.06  |

Number of Patients = 133 Number of Patient-Years = 101.9

There have been 4 patient deaths reported for the control group (out of 67 total control patients) and 10 patient deaths have been reported for the study group (out of 133 total study patients). None of the deaths were related to the implanted CRT-D system. One patient in the control group died prior to receiving a biventricular device implant. There is no significant difference between

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the number of deaths in the study group versus the control group (p = 0.777, Fisher's Exact Test, 2 sided). Table 4 provides a summary of reported patient deaths and Table 5 provides survival percentages by follow-up interval during the first 12 months of study participation.

Table 4: Summary of Patient Deaths
|   | Study Patients (N = 133) | Control Patients (N = 67)  |
| --- | --- | --- |
|  Sudden Cardiac | 1 | 1  |
|  Non-Sudden Cardiac | 5 | 2  |
|  Non-Cardiac | 4 | 1  |
|  All Causes | 10 | 4  |

Figure 1 shows the associated Kaplan-Meier survival curves for the study and control groups. The significance level for the difference between the two study groups based on a Log Rank test was p = 0.795.

![img-0.jpeg](img-0.jpeg)
Figure 1: Kaplan-Meier Survival Curves

Table 5 Survival Table
|  Study Group (n = 133) |   |   | Control Group (n = 66)  |   |
| --- | --- | --- | --- | --- |
|   | Number | % | Number | %  |
|  Enrollment | 133 | 100.00% | 67 | 100.00%  |
|  3-month | 131 | 98.50% | 63 | 94.03%  |
|  6-month | 127 | 95.49% | 63 | 94.03%  |
|  12-month | 123 | 92.48% | 63 | 94.03%  |

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# Kronos LV-T CRT-Ds – Summary of Adverse Events in the HOME-CARE Study

The HOME-CARE Observational study, conducted outside the US on the Kronos LV-T cardiac resynchronization defibrillator (CRT-D) in patients with congestive heart failure (CHF), involved 45 devices implanted with a cumulative implant duration of 202 months (mean implant duration of 4.5 months).

Of the 31 adverse events reported, there were 26 observations in 23 patients and 5 complications in 3 patients with a cumulative implant duration of 202 months (16.8 patient-years). 6.7% of the enrolled patients experienced a complication with 2 patients experiencing 2 separate complications. The rate of complications per patient-year is 0.30. 51% of the enrolled study patients had a reported observation with 3 patients having more than 1 observation. The rate of observations per patient-year was 1.54. Complications and observations for the patient group are summarized in Table 6 and Table 7, respectively.

Table 6: Summary of Complications – Kronos LV-T

|  Category | Number of Patients | % of Patients | Number | Per patient-year  |
| --- | --- | --- | --- | --- |
|  Left Ventricular Lead Related  |   |   |   |   |
|  Dislodgement | 1 | 2.2% | 1 | 0.06  |
|  No Capture | 1 | 2.2% | 1 | 0.06  |
|  Total | 2 | 4.4% | 2 | 0.12  |
|  ICD Lead Related  |   |   |   |   |
|  Dislodgement | 1 | 2.2% | 1 | 0.06  |
|  Elevated Pacing Threshold | 1 | 2.2% | 1 | 0.06  |
|  Total | 2 | 4.4% | 2 | 0.12  |
|  Unrelated to CRT-D or Leads  |   |   |   |   |
|  Hemathorax | 1 | 2.2% | 1 | 0.06  |
|  Total | 1 | 2.2% | 1 | 0.06  |
|  Overall Complication Totals | 3 | 6.7% | 5 | 0.30  |

Number of Patients = 45, Number of Patient-Years = 16.8

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Table 7: Summary of Observations – Kronos LV-T

|  Category | Number of Patients | % of Patients | Number | per patient-year  |
| --- | --- | --- | --- | --- |
|  Unsuccessful LV lead implant | 8 | 17.8% | 8 | 0.48  |
|  Elevated LV pacing threshold | 5 | 11.1% | 5 | 0.30  |
|  Phrenic nerve stimulation | 3 | 6.7% | 3 | 0.18  |
|  Elevated DFT measurement | 2 | 4.4% | 2 | 0.12  |
|  T-wave oversensing | 2 | 4.4% | 2 | 0.12  |
|  Worsening CHF | 2 | 4.4% | 2 | 0.12  |
|  Elevated RV pacing threshold | 1 | 2.2% | 1 | 0.06  |
|  Hepatitis | 1 | 2.2% | 1 | 0.06  |
|  Arrhythmias | 1 | 2.2% | 1 | 0.06  |
|  Cardiac Decompensation | 1 | 2.2% | 1 | 0.06  |
|  All Observations | 23 | 51.1% | 26 | 1.54  |

Number of Patients = 45, Number of Patient-Years = 16

Two patient deaths were reported during the HOME-CARE Observational Study. One death resulted from worsening heart failure and the second death resulted from cardiogenic shock due to ischemic cardiomyopathy. None of the deaths were related to the implanted CRT-D system. There were no device explants during the HOME-CARE Observational Study.

## Corox OTW Steroid LV Leads – Summary of Adverse Events in the OVID Study

An outside the US clinical evaluation of the Corox OTW Steroid (OVID) involved a total of 132 patients meeting indications for biventricular pacing. The coronary sinus was accessed in all patients, and of these, 121 were successfully implanted with the Corox OTW Steroid LV lead. The cumulative implant duration was 1145 months with a mean duration of 9.6 months. Ninety-six (79%) of the patients have implant durations greater than 6 months.

Of the 44 adverse events reported, there were 28 observations and 16 complications in a total of 132 patients. Table 8 and Table 9 provide a summary by category of each type of adverse event (complications and observations).

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Table 8: Summary of Complications

|  Category | # of Pts | Percentage of Patients | # of Complications | Complication per pt-year  |
| --- | --- | --- | --- | --- |
|  Corox OTW Steroid Lead-Related  |   |   |   |   |
|  Loss of capture | 5 | 3.8% | 5 | 0.05  |
|  Phrenic nerve stimulation | 2 | 1.5% | 2 | 0.02  |
|  Total LV Lead Related | 7 | 5.3% | 7 | 0.07  |
|  Atrial Lead Related  |   |   |   |   |
|  Loss of capture | 2 | 1.5% | 2 | 0.02  |
|  Total Atrial Lead Related | 2 | 1.5% | 2 | 0.02  |
|  RV Lead Related  |   |   |   |   |
|  Loss of capture | 3 | 2.3% | 3 | 0.03  |
|  Elevated Pacing thresholds | 2 | 1.5% | 2 | 0.02  |
|  Total RV Lead Related | 5 | 3.8% | 5 | 0.05  |
|  Medical  |   |   |   |   |
|  Arrhythmias | 1 | 0.8% | 1 | 0.01  |
|  Pocket infection | 1 | 0.8% | 1 | 0.01  |
|  Total Medical | 2 | 1.5% | 2 | 0.02  |
|  Overall Complication Totals | 13 | 9.8% | 16 | 0.17  |

Number of Patients = 132; Number of Patient-Years = 94.1

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Table 9: Summary of Observations

|  Category | # of Pts | Percentage of Patients | # of Observations | Observations per pt-year  |
| --- | --- | --- | --- | --- |
|  Corox OTW Steroid Lead-Related  |   |   |   |   |
|  Implant failure | 11 | 8.3% | 11 | 0.12  |
|  Phrenic nerve stimulation | 4 | 3.0% | 4 | 0.04  |
|  Total LV Lead-Related | 15 | 11.4% | 15 | 0.16  |
|  Atrial Lead Related  |   |   |   |   |
|  Loss of capture | 1 | 0.8% | 1 | 0.01  |
|  Elevated Pacing thresholds | 1 | 0.8% | 1 | 0.01  |
|  Total Atrial Lead Related | 2 | 1.5% | 2 | 0.02  |
|  RV Lead Related  |   |   |   |   |
|  Elevated Pacing thresholds | 2 | 1.5% | 2 | 0.02  |
|  Total RV Lead Related | 2 | 1.5% | 2 | 0.02  |
|  Medical  |   |   |   |   |
|  Arrhythmias | 2 | 1.5% | 2 | 0.02  |
|  Pocket infection/ Pericardial Effusion | 2 | 1.5% | 2 | 0.02  |
|  Chest pain | 1 | 0.8% | 1 | 0.01  |
|  Shortness of breath, palpitations | 1 | 0.8% | 1 | 0.01  |
|  Total Medical | 6 | 4.5% | 6 | 0.06  |
|  Miscellaneous  |   |   |   |   |
|  Malfunction of hemostatic valve | 2 | 1.5% | 2 | 0.02  |
|  Improper Lead preparation | 1 | 0.8% | 1 | 0.01  |
|  Total Miscellaneous | 3 | 2.3% | 3 | 0.03  |
|  Overall Observation Totals | 26 | 19.7% | 28 | 0.30  |

Number of Patients = 132; Number of Patient-Years = 94.1

There were a total of 12 patient deaths reported in the OVID study. The clinical investigators determined that no deaths were related to the Corox OTW Steroid LV lead.

## IX. SUMMARY OF PRE-CLINICAL STUDIES

### A. NON-CLINICAL LABORATORY STUDIES - TUPOS LV/ATx CRT-Ds

Based on the design of the Tupos LV/ATx and the results of BIOTRONIK’s clinical testing, the effective pacing voltage (at the lead tip) will be slightly lower for the Tupos LV/ATx when compared to commercially available CRT-Ds. However, there is no clinically significant difference (<0.5V) in the pacing thresholds between the Tupos LV/ATx CRT-D and other commercially available CRT-Ds. The results of the non-clinical testing showing the different programmed voltage levels is detailed in Table 10.

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Table 10 Effective Pacing Voltage Summary (Tupos LV/ATx)

|  Programmed Pacing Amplitude in Volts | Effective Pacing Amplitude (Tupos LV/ATx) | Effective Pacing Amplitude at 600 ohms in True Triple Chamber Configuration (current commercially available CRT-Ds)  |
| --- | --- | --- |
|  2.0 | 1.4 | 1.8  |
|  2.5 | 1.8 | 2.2  |
|  3.0 | 2.2 | 2.6  |
|  3.5 | 2.5 | 3.1  |
|  4.0 | 2.9 | 3.5  |

The service times for the Tupos LV/ATx from beginning of service (BOS) to elective replacement indication (ERI) are listed in Table 11. All estimates assume pacing rate of 50 ppm, atrial pulse amplitude of 2.4 V at 0.5 ms and a biventricular pulse amplitude of 4.0 V at 0.5 ms and 500 ohm pacing impedance for both the atrial and ventricles with periodic capacitor reformations and active use of the Automated Battery Management (ABM) functionality. The use before dating is 9 months after the battery is connected during the manufacturing process. It is assumed that the shocks are equally spaced throughout the life of the CRT-D. The estimates associated with 0% pacing support assume the CRT-D is sensing an intrinsic sinus rhythm at a rate of 70 bpm. These estimates are based on actual current consumption measurement made during testing of the electronic modules for the Tupos LV/ATx CRT-D.

Table 11: Longevity Estimates

|  100% DDD Pacing Support | Shocks per Year | Longevity in Years  |
| --- | --- | --- |
|  100 % | 12 | 2.9  |
|   |  8 | 3.0  |
|   |  4 | 3.2  |
|   |  0 | 3.4  |
|  50 % | 12 | 3.2  |
|   |  8 | 3.4  |
|   |  4 | 3.6  |
|   |  0 | 3.9  |
|  0 % | 12 | 3.5  |
|   |  8 | 3.8  |
|   |  4 | 4.1  |
|   |  0 | 4.4  |

The Tupos LV/ATx CRT-D is a derivation of BIOTRONIK's legally marketed Tachos ATx ICD (P000009/S4) with biventricular pacing capabilities added to provide cardiac resynchronization therapy (CRT). Nearly all of the components used for the Tupos LV/ATx are identical to those used for the Tachos ATx ICD. Because many of the performance requirements and pass / fail criteria for the Tachos ATx ICD and Tupos LV/ATx are identical, the successfully completed validation testing of the Tupos LV/ATx CRT-D was also supported by testing of the Tachos ATx ICD.

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2.3

|  Component | Comparison to Tachos ATx ICD | Qualification Basis | Qualification Result  |
| --- | --- | --- | --- |
|  Header | The header is formed from HYSOL EE 0079/HD 0070 epoxy, a liquid, two-component, unfilled epoxy system. The epoxy is used to form the lead connector ports of the CRT-D's header to facilitate placement and consistent connections between the CRT-D and leads. | Finished device qualification testing of Tachos to Tupos LV/ATx including dimensional and visual inspection, temperature shock and header shear testing. Similar to Tachos ATx with additional LV connector port (IS-1 Standard). | Specifications met, qualification testing passed.  |
|  Batteries (2) | One battery, lithium-iodine type (pacemaker battery), for supplying power to the control hybrid portion of the Tupos LV/ATx electronic module, and the second battery, Lithium Manganese Dioxide (high voltage battery), supplies power to the portion of the electronic module that generates the high energy defibrillation and cardioversion shocks. | Previously qualified for the Tachos ICD Family due to identical ICD batteries as the Tupos LV/ATx. Qualification tests included humidity storage, pressure resistance, mechanical shock, mechanical loading of pins, temperature shock and vibration tests, charge voltage as a function of temperature, high temperature storage and rapid battery discharge tests. | Specifications met, qualification testing passed.  |
|  High Energy Shock Capacitors (2) | The capacitors are aluminum electrolytic construction having a triple anode foil configuration housed in a cylindrical shape providing high energy density and lightweight construction. The electrical interface is comprised of two lugs that form a solid mechanical connection with very low impedance and minimal energy loss. | Previously qualified for the Tachos ICD Family as they are identical to the Tupos LV/ATx shock capacitors. Qualification tests included solderability after aging, thermal stability when soldering, long-term voltage, outgassing response, capacitance and dissipation factor, leakage current, mechanical characterization, cyclic charge-discharge testing, formation response, temperature storage, helium overpressure storage, electrolytic recombination, leakage current for excess voltage. Mechanical testing included vibration tests, temperature cycle, vacuum load and humidity storage. | Specifications met, qualification testing passed.  |

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|  Table 12 Tupos LV/ATx Qualification Summary  |   |   |   |
| --- | --- | --- | --- |
|  Component | Comparison to Tachos ATx ICD | Qualification Basis | Qualification Result  |
|  Feedthrough | Ceramic feedthroughs are used to connect the internal circuitry of the CRT-Ds to the connector ports located in the header of each CRT-D. Identical to Tachos ATx ICD feedthroughs. | Qualification testing including temperature shock, helium leak and insulation testing as well as dimensional inspections and pin tensile strength test same as for earlier versions of BIOTRONIK ICDs., e.g., Tachos and Belos. | Specifications met, qualification testing passed.  |
|  Electronic Module | The Tupos LV/ATx CRT-D uses the identical layout as the legally marketed Tachos ATx ICD with activation of biventricular pacing circuitry through a simple jumper. The control logic for Cardiac Resynchronization Therapy is in the Tachos ATx ICD although inactive.
The entire electronic module is fabricated on a single hybrid substrate. The hybrid substrate consists of four (4) layers of laminated rigid and flexible polyamide materials in a symmetrical stack. The hybrid substrate utilizes wide copper traces (for minimum resistance) for shock delivery and battery current paths that provide maximum power delivery. | Qualified for the Tachos ATx ICD, which has an electronic module that is identical to the Tupos LV/ATx. Qualification tests included physical dimensions, mechanical stress (temperature cycle), element shear, outgassed materials, constant acceleration, 250 and 1000 shock dump test, spacer insertion test, folding test, visual and electrical inspection, mechanical shock, vibration / variable frequency, 184 hour, 150c, life test as well as visual inspection and physical dimension changes. | Specifications met, qualification testing passed.  |

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|  Table 12 Tupos LV/ATx Qualification Summary  |   |   |   |
| --- | --- | --- | --- |
|  Component | Comparison to Tachos ATx ICD | Qualification Basis | Qualification Result  |
|  Firmware | The CRT-Ds require embedded software to provide basic instructions for operating the device microcontroller. This software is contained in the RAM memory within the CRT-D and is not accessible by the user. | Qualified for the Tachos ATx ICD because of identical firmware when compared to the Tupos LV/ATx. Qualification testing included Defibrillation Strength, Demodulation of Product, ESD Resistance, Electrical Neutrality, High Rate Protection, Testing of the Input Protection against High Voltages generated during Shock, Rate Limit by UTR, Input Impedance, Input Filter Characteristics, Pace Pulses as a Function of Load and Pacing Parameters, Shock Output as a Function of Load, Programmed Shock Energy, Battery Voltage and Temperature, Parameters as a Function of Temperature, Attack and Decay Times, Motion Sensor tests, Switch-On Behavior, Expanded Test for the Influence of Interference caused by HF Surgical Devices, Operation Voltage Measurement, Battery Management, Magnet Distances, IEGM Transmission and Signal Noise, and numerous tests for crosstalk. | Specifications met, qualification testing passed.  |

## Finished Device Testing – Tupos LV/ATx CRT-D

The Tupos LV/ATx finished device has been subjected to validation testing according to the Biotronik’s validation plans. The Tupos LV/ATx CRT-Ds have passed all in vitro laboratory validation tests with acceptance based on Tupos LV/ATx product specifications.

|  Table 13 Tupos LV/ATx Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  Visual Inspection | Visual inspection is performed according to European Standards EN 45502-1:1998 and EN 45502-2-1:1998 | 1 | Pass  |

25

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|  Table 13 Tupos LV/ATx Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  Transportation / Drop Test | This test was performed according to DIN IEC 68 T.2-55, Procedure A in conjunction with the Drop Test according to European Standards DIN EN 45502-1: 1998-07, Section 10.1; and EN 60068-2-32: 3/95. | 6 | Pass  |
|  Humidity and Vacuum Storage | Protection from Temperature and Humidity Changes according to European Standard DIN EN 45502-1: 1998-07, Section 10.2, | 3 | Pass  |
|  Wipe Test, Abrasion Test, and Bonding Strength of the Blister Label | The wipe test, abrasion test, and bonding strength test are verified per European Standard EN 45502-1:1998, Section 10.3 | 5 | Pass  |
|  Sterilization Process | Three devices were inoculated under the dummy plug with 100 μL Bacillus subtilis spore suspension in the connector opening and on the surface. The products were dried under the laminar flow and sealed in double PETG blisters. Then they were sterilized with the half-cycle method (sterilization time of 60 min.) and tested for growth of Bacillus subtilis, no bacillus subtilis is allowed on the samples under test. | 3 | Pass  |
|  Protection of the Patient or the User from Injury Caused by External Physical Properties or by Heat | The ICD casting was inspected per European Standards EN 45502-1:1998 Section 15.2 and prEN 45502-2-2:1998, Sec. 17.1. | 4 | Pass  |
|  Ultrasonic Resistance | Exposure to Ultrasound according to European Standard pr EN 45502-1, 1996 D, Section 22.1 | 1 | Pass  |
|  Vibration Test | Exposure to Vibration according to European Standard EN 45502-2-2, Sec. 23.2. | 5 | Pass  |
|  Mechanical Shock Test | Exposure to Mechanical Shock according to European Standard prEN 45502-2-2 03.98 Section 23.7 | 5 | Pass  |
|  Protection from Damage caused by Air Pressure or Temperature Changes | Exposure to Air Pressure and Temperature Changes according to European Standard EN 45502-1 Sec. 25.1 and Sec. 26.2. | 6 | Pass  |

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|  Table 13 Tupos LV/ATx Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  EtO Residual Gas Analysis | Residual Gas Analysis of Ethylene Oxide, Ethylene Chlorohydrine, Ethylene Glycol according to ISO 10993-7 | 5 | Pass  |
|  Microbial Impermeability of the Sealed Seam | Neither colonies of Staphylococcus aureus nor colonies of Bacillus subtilis shall grow on any of the 40 tested Rodak plates. With this, it is guaranteed that the PETG blister material is adequately impermeable. In principle, the test method is based on contaminating the test material on one side with microorganisms for a defined period of time. Afterwards, it is tested whether the microorganisms have penetrated through the test material to the underside. No penetrations are allowed. | 2 | Pass  |
|  Microbiology: Bio-Burden and Pyrogen Test | The endotoxin limit for medical devices in indicated in EU/ml. The warning limit is 5 EU/Device and the intervention limit is 20 EU/Device. No gelation may occur in a 40 ml extract solution and a lysate sensitivity of 0.125 EU/ml. The final cleaning procedure must be tested if the limits are exceeded. The microbe load must be less than the specified maximum values (20 EU/Device). The pyrogenicity must be 0% after EtO sterilization. | 3 | Pass  |
|  Dimensional and Visual Inspection of the Header/ Feedthroughs | The validation standard refers to ISO 11318: 05'92 (DF-1) and ISO 5841-3:12'92 (IS-1) for the header ports and internal BIOTRONIK specification for the other header characteristics. | 3 | Pass  |
|  Temperature Shock | The validation standard refers to the requirements from the norm DIN IEC 68-2-14: 6'87, Section 1 (Temperature Change) and MIL-STD 883D, Method 1011.9 (Thermal Shock). | 5 | Pass  |
|  Header Shear Test | The housing is mounted firmly and the header is stressed on its upper edge till it breaks. The test is passed if the mean shear value of five units > to 1.5 N/mm2. | 5 | Pass  |
|  Visual Inspection of the Inner Construction | The units were inspected to ensure proper arrangement of the subassembly and parts in terms of function and further processing. | 2 | Pass  |

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|  Table 13 Topos LV/ATx Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  In-Vitro Test 2000 Hours | The ICD is required to function within all electrical and mechanical specifications and with identical programming values before and after the 2000 hour In Vitro Test. | 3 | Pass  |
|  Life-Time Calculation / Use Before Time | The individual service periods of both batteries (LI 12100 & LIS3482) are calculated to achieve the total service life. The longevity is calculated based on measurement of twenty-five electronic circuits to estimate the total service life. The service life calculation is required according to prEN 45502-2-2: 1998, Par. 28.19, the average period of longevity must be determined for numerous patient use scenarios. | 25 | Specification met, results accepted.  |

# B. NON-CLINICAL LABORATORY STUDIES - KRONOS LV-T CRT-Ds

The Kronos LV-T CRT-D is a derivation of BIOTRONIK's legally marketed Belos DR ICD (P000009/S05) with biventricular pacing capabilities added to provide cardiac resynchronization therapy (CRT). Nearly all of the components used for the Kronos LV-T are identical to those used for the Belos DR ICD. Because many of the performance requirements and pass / fail criteria for the Belos DR ICD and Kronos LV-T are identical, the successfully completed validation testing of the Kronos LV-T CRT-D was also supported by testing of the Belos DR ICD.

|  Table 14 Kronos LV-T Qualification Summary  |   |   |   |
| --- | --- | --- | --- |
|  Component | Comparison to Belos DR ICD | Qualification Basis | Qualification Result  |
|  Header | The header is formed from HYSOL EE 0079/HD 0070 epoxy, a liquid, two-component, unfilled epoxy system. The epoxy is used to form the lead connector ports of the CRT-D's header to facilitate placement and consistent connections between the CRT-D and leads. | Finished device qualification testing of Kronos LV-T including dimensional and visual inspection, temperature shock and header shear testing. Similar to Belos DR-T with additional LV connector port (IS-1 Standard). | Specifications met, qualification testing passed.  |

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|  Table 14 Kronos LV-T Qualification Summary  |   |   |   |
| --- | --- | --- | --- |
|  Component | Comparison to Belos DR ICD | Qualification Basis | Qualification Result  |
|  Battery | One, Lithium Manganese Dioxide battery supplies power to the electronic module for all system functions. | Previously qualified for the Belos ICD Family due to the battery being identical to Kronos LV-T battery. Qualification testing included pressure resistance, vacuum stability, mechanical shock, vibration test, high temperature test, temperature shock, high and low temperature storage, accelerated pulse testing, load stress dependent on temperature, rapid discharge, short circuit test, charging test, high energy discharge, thin pin impression, stamp impression, destruction test, verification of safe weld seam. | Specifications met, qualification testing passed.  |
|  High Energy Shock Capacitors (2) | The capacitors are aluminum electrolytic construction having a four layer anode foil configuration housed in a cylindrical shape providing high energy density and lightweight construction. The electrical interface is comprised of two lugs that form a solid mechanical connection with very low impedance and minimal energy loss. | Previously qualified for the Belos ICD Family due to the capacitors being identical to Kronos LV-T CRT-D capacitors. Qualification testing included capacity and dissipation factor, leakage current, cyclic charge-discharge test, mechanical characterization, vibration and temperature cycle testing, humidity storage, leakage current, vacuum load, soldering after conditioning, thermal stability when soldering, outgassing, electrolytic recombination, formation response, response during long-term helium pressurized and temperature storage. | Specifications met, qualification testing passed.  |

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|  Table 14 Kronos LV-T Qualification Summary  |   |   |   |
| --- | --- | --- | --- |
|  Component | Comparison to Belos DR ICD | Qualification Basis | Qualification Result  |
|  Feedthrough | Ceramic feedthroughs are used to connect the internal circuitry of the CRT-Ds to the connector ports located in the header of each CRT-D. | Qualification testing including temperature shock, helium leak and insulation testing as well as dimensional inspections and pin tensile strength test same as for earlier versions of BIOTRONIK ICDs, e.g., Tachos and Belos. | Specifications met, qualification testing passed.  |
|  Electronic Module | The Kronos LV-T CRT-D uses the identical layout as the legally marketed Belos DR ICD with activated of biventricular pacing circuitry.
The entire electronic module is fabricated on a single hybrid substrate.
The hybrid substrate consists of four (4) layers of laminated rigid and flexible polyamide materials in a symmetrical stack. The hybrid substrate utilizes wide copper traces (for minimum resistance) for shock delivery and battery current paths | Qualified for the Belos DR-T ICD, which has an electronic module that is identical to the Kronos LV-T. Qualification tests included temperature cycling, physical dimension tests, element shear test, constant acceleration, 250 shock dumps and 1000 shock testing, numerous mechanical tests after high temperature storage, transportation and drop tests in the circuit packaging, 184 hour, 150c, life test, visual inspection and physical dimensions / shrinkage changes. | Specifications met, qualification testing passed.  |

## Finished Device Testing – Kronos LV-T CRT-D

The Kronos LV-T finished device has been subjected to thorough validation testing according to the validation plans. The Kronos LV-T CRT-Ds have passed all in vitro laboratory validation tests with acceptance based on Kronos LV-T product specifications.

|  Table 15 Kronos LV-T Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  Visual Inspection | Visual inspection is performed according to European Standards EN 45502-1:1998 and EN 45502-2-1:1998 | 1 | Pass  |

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|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
| --- | --- | --- | --- |
|  Transportation / Drop Test | This test was performed according to DIN IEC 68 T.2-55, Procedure A in conjunction with the Drop Test according to European Standards DIN EN 45502-1: 1998-07, Section 10.1; and EN 60068-2-32: 3/95. | 5 | Pass  |
|  Humidity and Vacuum Storage | Protection from Temperature and Humidity Changes according to European Standard DIN EN 45502-1: 1998-07, Section 10.2, | 1 | Pass  |
|  Wipe Test, Abrasion Test, and Bonding Strength of the Blister Label | The wipe test, abrasion test, and bonding strength test are verified per European Standard EN 45502-1:1998, Section 10.3 | 5 | Pass  |
|  Sterilization Process | Three devices were inoculated under the dummy plug with 100 μL Bacillus subtilis spore suspension in the connector opening and on the surface. The products were dried under the laminar flow and sealed in double PETG blisters. Then they were sterilized with the half-cycle method (sterilization time of 60 min.) and tested for growth of Bacillus subtilis. No bacillus subtilis is allowed on the samples under test. | 3 | Pass  |
|  Protection of the Patient or the User from Injury Caused by External Physical Properties or by Heat | The ICD casting was inspected per European Standards EN 45502-1:1998 Section 15.2 and prEN 45502-2-2:1998, Sec. 17.1. | 2 | Pass  |
|  Ultrasonic Resistance | Exposure to Ultrasound according to European Standard pr EN 45502-1, 1996 D, Section 22.1 | 1 | Pass  |
|  Vibration Test | Exposure to Vibration according to European Standard EN 45502-2-2, Sec. 23.2. | 4 | Pass  |
|  Mechanical Shock Test | Exposure to Mechanical Shock according to European Standard prEN 45502-2-2 03.98 Section 23.7 | 4 | Pass  |

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|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
| --- | --- | --- | --- |
|  Protection from Damage caused by Air Pressure or Temperature Changes | Exposure to Air Pressure and Temperature Changes according to European Standard EN 45502-1 Sec. 25.1 and Sec. 26.2. | 6 | Pass  |
|  EtO Residual Gas Analysis | Residual Gas Analysis of Ethylene Oxide, Ethylene Chlorohydrine, Ethylene Glycol according to ISO 10993-7 | 4 | Pass  |
|  Microbial Impermeability of the Sealed Seam | Neither colonies of Staphylococcus aureus nor colonies of Bacillus subtilis shall grow on any of the 40 tested Rodak plates. With this, it is guaranteed that the PETG blister material is adequately impermeable. | 3 | Pass  |
|  Microbiology: Bio-Burden and Pyrogen Test | The endotoxin limit for medical devices in indicated in EU/ml. The warning limit is 5 EU/Device and the intervention limit is 20 EU/Device. No gelation may occur in a 40 ml extract solution and a lysate sensitivity of 0.125 EU/ml. The final cleaning procedure must be tested if the limits are exceeded. The microbe load must be less than the specified maximum values (20 EU/Device). The pyrogenicity must be 0% after EtO sterilization. | 1 | Pass  |
|  Dimensional and Visual Inspection of the Header/ Feedthroughs | The validation standard refers to ISO 11318: 05'92 (DF-1) and ISO 5841-3:12'92 (IS-1) for the header ports and internal BIOTRONIK specification for the other header characteristics. | 3 | Pass  |
|  Temperature Shock | The validation standard refers to the requirements from the norm DIN IEC 68-2-14: 6'87, Section 1 (Temperature Change) and MIL-STD 883D, Method 1011.9 (Thermal Shock). | 1 | Pass  |
|  Header Shear Test | The housing is mounted firmly and the header is stressed on its upper edge till it breaks. The test is passed if the mean shear value of five units > to 1.5 N/mm2. | 3 | Pass  |
|  In-Vitro Test 2000 Hours | The ICD is required to function within specifications and with identical programming values before and after the 2000 hour In Vitro Test. | 5 | Pass  |

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|  Table 15 Kronos LV-T Finished Device Validation Testing  |   |   |   |
| --- | --- | --- | --- |
|  Test Performed | Acceptance Criteria | Sample Size | Test Results (Pass/Fail)  |
|  Life-Time Calculation / Use Before Time | The individual service periods are calculated based on measurement of twenty electronic circuits to estimate the total service life. The service life calculation is required according to prEN 45502-2-2: 1998, Par. 28.19, the average period of longevity must be determined for numerous patient use scenarios. | 20 | Specification met, results accepted.  |

## Firmware

Embedded Software validation testing was designed to confirm the overall safety and functionality of the Kronos LV-T CRT-Ds. The Kronos LV-T embedded software successfully passed all test requirements. Validation testing was performed to verify that the Kronos 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 Kronos LV-T firmware were based on internal BIOTRONIK specifications and all test data was acceptable.

|  Table 16 Kronos LV-T Firmware Validation Testing  |   |
| --- | --- |
|  Firmware Tests | Successfully Performed  |
|  Exposure to External Influences+ | - Defibrillation Stability,
- Demodulation of Product,
- Electrostatic Discharge Susceptibility
- Effect of HF Electrosurgery
- Temperature Changes  |
|  Exposure to Internal Influences | - Test of the Input Protection against High Voltages Emitted during a Shock,
- High Rate Protection
- Timing Based on Age of Crystal
- High Voltage Strength of Inner Assembly
- Risk of HV Switch or Capacitor Failure
- Risk of HV Generation
- Influences on Device during RF Telemetry  |
|  Elective Replacement Indication (ERI) and End of Service (EOS) | - Long-term 100% BiV Pacing
- Measurement of Current Consumption
- EOS Behavior with Low Battery Voltage
- Service Life Calculations / Use Before Date  |

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|  Table 16 Kronos LV-T Firmware Validation Testing  |   |
| --- | --- |
|  Firmware Tests | Successfully Performed  |
|  Electrical Characteristics | - Electric Neutrality
- Measurement of Input Impedance
- Common Mode Rejection Ratio (CMRR)
- Input Filter Response,
- Battery Voltage
- Switch-On Response
- Latch-up Stability
- Response to Reset
- Non-Rate Adaptive Pacing Mode Appropriateness
- VF Detection
- VF Redetection
- Emergency Shocks
- Crosstalk of Feedthroughs
- Brady and Tachy Default Programs
- Pacing Impedance Measurements
- Shock Impedance Measurements
- P/R Wave Measurements
- DFT Testing
- ATP Testing
- Pacing Threshold Testing
- Retrograde Conduction Testing  |
|  Sensor Response Threshold | - Only Affected by Frequencies Between 2 and 10 Hz
- Appropriate Return to Baseline when Motion Removed
- Response During Patient Activity
- Automatic Gain  |
|  Characteristics of Pacing Terminal (Input/Output) Pulse Response Based on: | - Temperature
- Pacemaker
- ATP
- HF Burst
- Shock
- Trigger Time after Pulse Generation
- Battery Voltage
- Pacemaker
- ATP
- HF Burst
- Shock
- Pacing Load
- Atrial, LV and RV Pulse Widths
- Various Pulse Amplitudes  |
|  Intra-Electrograms (IEGM) | - IEGM Transmission – Pulse Generator to Programmer
- Far-Field IEGM  |

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|  Table 16 Kronos LV-T Firmware Validation Testing  |   |
| --- | --- |
|  Firmware Tests | Successfully Performed  |
|  Battery Management | • During Capacitor Charging – Direct Mode
• During Capacitor Charging – Substrate Charge Pump Switching
• Current Consumption During Various Cardiac Rhythms
• Pacing Behavior During Capacitor Reformations
• Pacing Behavior During Reset  |
|  Programming Wand | • Programming and Interrogation Distances
• Magnet Response at Various Distances
• Wand Location / Orientation
• Telemetry Circuit Behavior and Current Draw
• Programming Depending on Load
• Impact of Programmer from other Manufacturers
• Communication Protocols
• Response Under Magnet Application  |
|  Emergency Functions | • Emergency Brady Pacing
• Emergency Shock  |
|  Home Monitoring | • Crosstalk – Detailed Investigation
• Automatic Measurement Functions  |

## EMI Testing

BIOTRONIK has performed a comprehensive set of electromagnetic interference testing of the Tupos LV/ATx CRT-D according to three separate industry standards, including the DIN VDE 0750, EN 45502-2-2, and the AAMI standard PC-69. 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 standards EN 45502-2-2, and the AAMI standard PC-69.

|  Table 17 EMI Testing of CRT-Ds  |   |   |
| --- | --- | --- |
|  Test Performed | Sample Size | Test Results (Pass/Fail)  |
|  Safety During EMI: EMI-Induced currents | 1 | Pass  |
|  Safety During EMI: Static Fields | 1 | Pass  |
|  Test of the Safety Against Malfunction Caused by Outside Electromagnetic Fields | 1 | Pass  |
|  Safety Against Malfunction Caused by Unmodulated Electromagnetic Influence | 1 | Pass  |
|  Protection Against Detecting Modulated EMI | 1 | Pass  |
|  EMI Resistance Measurements according to AAMI PC69 in the Range 450 MHz to 3 GHz | 1 | Pass  |
|  Use of a Cautery on an ICD in Saline Solution | 1 | Pass  |

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|  Table 17 EMI Testing of CRT-Ds  |   |   |
| --- | --- | --- |
|  Test Performed | Sample Size | Test Results (Pass/Fail)  |
|  HF Surgery Test | 9 | Pass  |
|  Influence of Alternating Magnetic Fields | 1 | Pass  |
|  Programming Behavior at EMI | 1 | Pass  |

## C. COROX OTW STEROID LEAD

The following tables summarize the validation testing (safety and performance) conducted on the components of BIOTRONIK's Corox OTW Steroid Lead, 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 18 Corox OTW Steroid Validation Testing  |   |
| --- | --- |
|  Test Performed | Test Results (Pass/Fail)  |
|  Biocompatibility and Sterilization  |   |
|  Biocompatibility (of Pellethane 2363-55DE) according to ISO 10993-1 | Pass  |
|  Hemocompatibility (final product) according to ISO 10993:4 | Pass  |
|  Cell Toxicity (final product and Polyurethane Pellethane 2363-55 DE) according to ISO 10993-5: 1999 | 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 | Pass  |
|  Proof of Sterilization Success according to EN 550: 1994 | Pass  |
|  Residual Gas Analysis: Ethylene Oxide and Ethylene Chlorohydrin according to ISO 10993-7: 1995 | 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  |
|  Stylet Performance according to FDA Lead Guidance* | Pass  |
|  Fatigue Test (Bending Fatigue Test on Lead Body between Connector and Tip, at Connector Transition, at Transitions in Distal Section of Lead: Head Proximally) according to FDA Lead Guidance* | Pass  |
|  Connector Testing to ISO 5841-3 (IS-1) (on Lead Body between Connector and Tip, at Connector Transition) | Pass  |
|  Anchoring Sleeve Performance according to FDA Lead Guidance* | Pass  |

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37

|  Table 18 Corox OTW Steroid Validation Testing  |   |
| --- | --- |
|  Test Performed | Test Results (Pass/Fail)  |
|  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 | 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 | Pass  |
|  Area Calculation of Tip Electrode according to Internal BIOTRONIK Specification; Leads were checked for conformance with the dimensions detailed in BIOTRONIK’s drawing 346049. The surface areas of the tip electrodes were calculated from the design specifications to verify the electrodes had the specified surface area (A = 5.0 ± 0.2 mm²) | 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 | 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%. | Pass  |
|  Liberation of DXA from the Collar and Lead Tip 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  |

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|  Table 18 Corox OTW Steroid Validation Testing  |   |
| --- | --- |
|  Test Performed | Test Results (Pass/Fail)  |
|  Accessories  |   |
|  Use of Corox OTW 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  |
|  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 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 with Torque 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 0.36mm 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 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 test 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 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

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## D. 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).

## E. BIOCOMPATIBILITY TESTING

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

All tissue-contacting materials of BIOTRONIK’s Corox OTW Steroid Left Ventricular Lead are currently utilized in BIOTRONIK products market-released in the US, except for Pellethane 2363-55DE. Biocompatibility testing of Pellethane 2363-55DE as well as all tissue-contacting materials utilized in BIOTRONIK’s Corox OTW Steroid has been successfully completed in accordance with ISO 10993-1, “Biological Evaluation of Medical Devices.”

## F. SHELF LIFE

A 9-month expiration date, "Use Before Date" (UBD), has been established for the Tupos LV/ATx and Kronos LV-T CRT-Ds based on device longevity and internal battery characteristics. The use before date is assigned as the last date of the ninth month after battery connection is made during the manufacturing process. It is guaranteed that the projected longevity of the device remains valid until implantation.

A 24-month expiration date, "Use Before Date" (UBD), has been established for the Corox OTW Steroid 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.

## G. ANIMAL STUDIES

BIOTRONIK conducted an animal study in foxhound dogs to evaluate the safety, electrical performance, and biocompatibility of the Corox OTW unipolar leads. A total of 12 dogs were randomized into two study groups: steroid or non-steroid Corox OTW leads. In the steroid eluting model of the Corox OTW leads, the steroid effectively reduced any pacing threshold increases compared to the non-steroid lead model. The complication rates for all dogs were clinically acceptable for the animal model. Therefore, the Corox OTW LV pacing lead animal study supported the safety and effectiveness of the Corox OTW-UP (both steroid and non-steroid models).

## 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

### TUPOS LV/ATx CLINICAL IDE STUDY – OPTION CRT/ATx

#### Study Overview

The purpose of the prospective, randomized, multi-center OPTION CRT/ATx study was to demonstrate the safety and effectiveness of the investigational Tupos LV/ATx Cardiac

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Resynchronization Therapy Defibrillator (CRT-D) in patients with congestive heart failure (CHF) and atrial tachyarrhythmias. Patients in the study group were implanted with a BIOTRONIK Tupos LV/ATx. Patients in the control group were implanted with any legally marketed CRT-D. Patients in both the study and control groups were implanted with a legally marketed left ventricular lead.

## Methods

Primarily, the study evaluates and compares the functional benefits of CRT between the two 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 (two-week post implant follow-up) and again at a six-month follow-up evaluation. The data collected during this clinical study was used to demonstrate equivalent treatment of CHF in both the study and control groups. This study also evaluated other outcomes including: the effectiveness of atrial therapy to automatically convert atrial tachyarrhythmias, the percentage of time CRT is delivered, and other measures of CHF status including NYHA classification, peak oxygen consumption during metabolic exercise testing, and the rate of hospitalization for CHF.

## Inclusion Criteria

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

- Stable, symptomatic CHF status
- NYHA Class III or IV congestive heart failure
- Left ventricular ejection fraction ≤ 35% (measured within six-months prior to enrollment)
- Intraventricular conduction delay (QRS duration greater than or equal to 130 ms)
- For patients with an existing ICD, optimal and stable CHF drug regimen including ACE-inhibitors and beta-blockers unless contraindicated (stable is defined as changes in dosages less than 50% during the last 30 days)
- Indicated for ICD therapy
- History or significant risk of atrial tachyarrhythmias
- Willing to receive possibly uncomfortable atrial shock therapy for the treatment of atrial tachyarrhythmias
- Able to understand the nature of the study and give informed consent
- Ability to tolerate the surgical procedure required for implantation
- Ability to complete all required testing including the six-minute walk test and cardiopulmonary exercise testing
- Available for follow-up visits on a regular basis at the investigational site
- Age greater than or equal to 18 years

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# Exclusion Criteria

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

- Previously implanted CRT device
- ACC/AHA/NASPE indication for bradycardia pacing (sinus node dysfunction)
- Six-minute walk test distance greater than 450 meters
- Chronic atrial tachyarrhythmias refractory to cardioversion shock therapy
- Receiving intermittent, unstable intravenous inotropic drug therapy (patients on stable doses of positive inotropic outpatient therapy for at least one-month are permitted)
- Enrolled in another cardiovascular or pharmacological clinical investigation
- Expected to receive a heart transplant within 6 months
- Life expectancy less than 6 months
- Presence of another life-threatening, underlying illness separate from their cardiac disorder
- Acute myocardial infarction, unstable angina or cardiac revascularization within the last 30 days prior to enrollment
- Conditions that prohibit placement of any of the lead systems

# Summary of Clinical Results

A total of 200 patients were enrolled in the OPTION CRT/ATx clinical study at 25 sites:

There were 133 study patients and 67 active control patients in this prospective, multi-center, randomized clinical study. For the study group, there were 129 successful implants (91.4%) of the Tupos LV/ATx CRT-D system. For the active control group, there were 64 successful implants (92.2%) of the legally marketed CRT-D systems.

# Patient Accountability

After randomization and enrollment, 7 patients (4 in the study group and 3 in the control group) did not receive an implant. The reasons for patients not receiving an implant are outlined in Figure 2.

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Figure 2: Patient Accountability

![img-1.jpeg](img-1.jpeg)

# Overall Results

- There were 192 endocardial and 19 epicardial leads implanted in 193 patients. Investigators were allowed to choose among any legally marketed LV lead according to their familiarity with the lead and patient anatomy. The Tupos LV/ATx CRT-D was implanted with 7 endocardial and 4 epicardial lead models from 6 different manufacturers. There were no adverse events reported attributable to lead-generator incompatibility.
- The cumulative implant duration is 1240.4 months with a mean duration of 9.6 months for the study group. The cumulative implant duration is 596.5 months with a mean duration of 9.3 months for the control group.
- For the study group, there have been 278 adverse events (210 observations in 104 patients and 68 complications in 50 patients). There has been one unanticipated adverse device effect reported.

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- For the control group, there have been 105 adverse events (81 observations in 44 patients and 24 complications in 19 patients). There have been no unanticipated adverse device effects reported.
- The overall protocol compliance rate is 79.2% in the study group and 85.9% in the control group. The overall follow-up compliance rate is 99.4% in the study group and 98.3% in the control group.
- There have been 10 patient deaths reported in the study group and 4 patient deaths reported in the control group. The clinical investigators have determined that no deaths were related to the study device.

## Primary Endpoint 1: Six Minute Walk Test & QOL (Effectiveness)

The purpose of Primary Endpoint 1 is to evaluate the effectiveness of the Tupos LV/ATx system in providing CRT as measured by the average composite rate of improvement in six minute walk test and QOL.

**Table 19** 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 Study and Control Groups for those patients with six minute walk test data and complete QOL data at both Baseline and the Six-Month follow-up.

**Table 19: Composite of Six Minute Walk Test and QOL (Effectiveness)**

|  Category | Study Group (N = 74)
Mean ± SE | Control Group (N = 38)
Mean ± SE | P-value*  |
| --- | --- | --- | --- |
|  Distance Walked at Baseline | 310.51 ± 10.89 | 288.76 ± 15.37 | 0.249  |
|  Distance Walked at Six-Months | 340.77 ± 12.32 | 301.84 ± 17.02 | 0.067  |
|  Δ Distance Walked | 30.26 ± 10.40 | 13.08 ± 13.05 | 0.322  |
|   |  17.27% ± 5.59% | 8.71% ± 5.26% | 0.326  |
|  QOL Score at Baseline | 44.39 ± 2.78 | 45.53 ± 4.13 | 0.817  |
|  QOL Score at Six-Months | 28.68 ± 2.66 | 33.95 ± 4.35 | 0.279  |
|  Δ in QOL Score** | 15.72± 2.83 | 11.58 ± 3.45 | 0.376  |
|   |  19.08% ± 12.21% | -13.42% ± 34.54% | 0.281  |
|  Composite Rate*** | 18.18% ± 7.07% | -2.36% ± 17.73% | 0.030  |

*The calculated p-values are associated with a Student's t-test (2-sided) of the equality of means in the two groups, except for the p-value of the composite rate, which is associated with a test of equivalence (non-inferiority).
**Δ in QOL Score is calculated as the average of the individual differences between Baseline and Six-Months for each patient. Negative values for mean Δ QOL in percent are possible when positive mean values for absolute changes in QOL are recorded. In some cases, small, negative changes in absolute QOL scores resulted in relatively large percentage changes.
***The Composite Rate (= (Δ Distance Walked (%) + Δ QOL Score (%)) / 2) is calculated for each patient and then averaged to obtain the Composite Rates. For all calculations, a positive number represents improvement from Baseline to Six-Months.

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# Primary Effectiveness Endpoint Analysis and Conclusions

A composite rate of six minute walk test and QOL improvement from Baseline to the Six-Month follow-up is evaluated as a measure of CRT effectiveness. For this analysis both six minute walk test and QOL are equally weighted at 50%.

The mean difference in the composite rate between study and control group was 20.53% with an associated one-sided, 95% confidence bound of (-6.10%). The p-value for non-inferiority within 10% is 0.030. The analysis of the composite rate in six minute walk test distance and QOL score demonstrates that the study group is non-inferior to the control group and that the primary effectiveness endpoint was met (p=0.030).

# Primary Endpoint 2: Complication-Free Rate (Safety)

The purpose of Primary Endpoint 2 was to evaluate complications (adverse events that require additional invasive intervention to resolve) related to the implanted CRT system which includes the Tupos LV/ATx, the right atrial lead, the right ventricular ICD lead, the left ventricular lead, and the implant procedure. The target complication-free rate at Six-Months is 85%.

Table 20 provides the categorized complication rates at 6-months for the study and the control group as well as a comparison between the study and the control group.

Table 20: Complications at 6-Month – Study and Control

|  Category | Study
N = 133 | Control
N = 67 | Study versus Control Comparison  |   |   |
| --- | --- | --- | --- | --- | --- |
|   |   |   |  Difference | 95% CI | P-value  |
|  Procedure Related | 6 (4.51%) | 1 (1.49%) | 3.02% | [-3.64%, 8.45%] | 0.428  |
|  Atrial Lead Related | 3 (2.26%) | 1 (1.49%) | 0.76% | [-5.74%, 5.37%] | 1.000  |
|  ICD Lead Related | 3 (2.26%) | 0 (0%) | 2.26% | [-3.03%, 6.53%] | 0.552  |
|  LV Lead Related | 26 (19.55%) | 9 (13.43%) | 6.12% | [-5.50%, 16.45%] | 0.329  |
|  Device Related | 7 (5.26%) | 5 (7.46%) | -2.20% | [-11.42%, 4.77%] | 0.541  |
|  Other Medical
Related | 9 (…

---

**Source:** [https://fda.innolitics.com/device/P050023](https://fda.innolitics.com/device/P050023)

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