Medtronic MC1AVR1 Clinical Study / Summary

Micra™ Atrial TRacking Using A Ventricular AccELerometer 2 (MARVEL 2) Study

Summary of clinical results and adverse events

Clinical study

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Micra™ Atrial TRacking Using A Ventricular

AccELerometer 2 (MARVEL 2) Study

Summary of Clinical Results

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Table of Contents

1 Summary of Clinical Results ......................................................................... 4

2 Study Purpose............................................................................................... 4

3 Study Scope, Design, and Methods .............................................................. 4

4 Subject Inclusion and Exclusion Criteria ....................................................... 6

5 Primary Objectives ........................................................................................ 6

6 Secondary Objectives ................................................................................... 7

7 Results .......................................................................................................... 7

8 Adverse Events Summary ........................................................................... 30

9 Death Summary .......................................................................................... 30

10 Clinical Study Conclusion ............................................................................ 30

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Table 1: Baseline Characteristics .................................................................................................... 9

Table 2: Baseline Physical Exam and Testing Results ................................................................. 10

Table 3: Primary Pacing Indication ............................................................................................ 11

Table 4: General Cardiovascular History .................................................................................... 12

Table 5: Cardiovascular Surgical and Intervention History ........................................................ 13

Table 6: Arrhythmia History ........................................................................................................ 14

Table 7: AV Junctional and Atrioventricular Block History ....................................................... 15

Table 8: Other Medical History ................................................................................................... 15

Table 9. Summary of Subjects and Holter Recordings Evaluated for the Primary Safety

Objective. ...................................................................................................................................... 16

Table 10: Long Cardiac Cycles Identified for Assessment…………………………………….. 17

Table 11: Episodes Exceeding 100 BPM Identified for Further Assessment ............................... 18

Table 12: AV Synchrony Status by Pacing Mode (Primary Efficacy Cohort n=40) .................... 19

Table 13: Summary of Intrinsic Conduction Mode Switching ..................................................... 23

Table 14: Summary of Activity Mode Switching ....................................................................... 25

Table 15: Predominant Rhythm by Study Visit for de novo Subjects .......................................... 27

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1 Summary of Clinical Results

The MARVEL 2 Clinical Study Report provides the full data and analyses related to the MARVEL 2 study objectives. All primary safety and efficacy objectives were met. No unanticipated adverse events or new risks were identified during the course of the trial.

A total of 77 subjects were enrolled at 12 centers in Hong Kong, Malaysia, Europe, and the United States. Of the 77 enrolled subjects, 75 had the MARVEL 2 software downloaded, and all 75 had Holter files with readable ventricular events files and were included in the analysis of the primary safety objective. The predominant heart rhythm during the Holter monitoring period was persistent 3rd degree AV block with normal sinus function in 40 of the 75 subjects with Holter data. All 40 of these subjects had at least 500 evaluable beats during the auto setup phase (VVI pacing) and during the resting period (VDD pacing) and were included in the analysis of the primary objective.

Among the 40 subjects with a predominant rhythm of persistent 3

degree AV block and normal sinus function, 38 (95.0%) had >70% AV synchrony during rest compared to 0% during VVI pacing (P<0.001) with average AV synchrony percentage improving from 26.8% during VVI pacing to 89.2% during mechanical sensing based VDD pacing. In these same subjects, stroke volume, as measured by LVOT VTI increased from 22.7 cm during VVI pacing to 24.5 cm (P=0.002) during VDD pacing as measured by blinded echocardiogram assessment.

There were no safety concerns identified during the study among all 75 subjects regardless of predominant heart rhythm exposed to the study algorithm. The study algorithm performed as intended. There were no algorithm related adverse events and review of all Holter recordings revealed no cardiac pauses and no instances of oversensing induced tachycardia exceeding three minutes.

2 Study Purpose

The purpose of the MARVEL 2 study was to demonstrate safe and effective operation of an accelerometer based atrial sensing algorithm providing AV synchronous pacing in patients with normal sinus node function and AV block. The MARVEL 2 algorithm provides VDD pacing by mechanically sensing atrial contractions using the Micra device’s 3-axis accelerometer. In addition, the algorithm incorporates an intrinsic conduction mode-switch (i.e. switch to VVI-40 pacing) during periods of intact AV conduction and an activity mode switch to VVIR pacing when the sensor pacing rate is significantly faster than the VDD rate. The results from the MARVEL 2 clinical study provide pivotal evidence to support market approval of the Micra AV device for expanding the use of transcatheter pacing systems into patients with normal sinus node function and AV node block where an atrial lead placement is considered difficult, high risk, or not deemed necessary for effective therapy.

3 Study Scope, Design, and Methods

The MARVEL 2 study was an acute, prospective, global, multi-center, software-download clinical study. The study enrolled 77 subjects at 12 centers in the US, Europe, and Asia. Following enrollment, the investigational MARVEL 2 software was downloaded into a subject’s Micra device to allow the performance of the new algorithm to be assessed in subjects where a Micra device had already been chosen as most appropriate for the subject. Following download the subject performed a series of posture maneuvers and exercises including an approximately 20-minute resting period while data were collected for the study’s primary objectives. Echocardiograms were performed in accordance with the study echo protocol to assess the effect of the MARVEL 2 algorithm on echocardiographic measures including stroke volume (LVOT VTI) and mitral valve filling patterns.

Most enrolled subjects completed the study procedure during a single study visit. However, subjects who enrolled in the study at the time of their Micra implant (de novo subjects; n=10) had the investigational algorithm downloaded following Micra implant, prior to hospital discharge, and approximately 1-month post-implant. Evaluation of the algorithm’s performance in these subjects allowed the MARVEL 2 features to be tested at multiple points in the device life cycle.

Since the downloaded algorithm running in a Micra device significantly increases current drain, a 2-4 hour acute study was used to limit the reduction in device longevity. Following each subject’s participation, the

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MARVEL 2 software was removed from the subject’s device. Note that for de novo subjects, the MARVEL 2 software was removed following each evaluation time point.

Figure 1: MARVEL 2 Study Flow

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4 Subject Inclusion and Exclusion Criteria

Subjects who satisfied all inclusion and no exclusion criteria were eligible to participate in the study.

Inclusion criteria

• Subject has been implanted with a Micra TPS (Model MC1VR01) with remaining device longevity of 6 years or more or is expected to be implanted with a Micra TPS.

• Subject has history of AV block*

• Subject is ≥ 18 years old and as per required local law.

• Subject (and/or witness as applicable per local regulations) provides signed and dated

authorization and/or consent per institution and local requirements.

• Subject is willing and able to comply with the protocol.

*This included subjects with normal sinus function and persistent 3rd degree AV block and subjects with other forms of AV block.

Exclusion criteria

• Subject is currently enrolled or planning to participate in a potentially confounding drug or device trial during the study. Co-enrollment in concurrent trials is only allowed when documented preapproval is obtained from the Medtronic Clinical Research Specialist.

• Subject is pregnant (if required by local law, women of child-bearing potential must undergo a pregnancy test within seven days prior to MARVEL 2 study procedures).

• Subject meets any exclusion criteria required by local law (age or other).

5 Primary Objectives

There is one primary safety objective and one primary efficacy objective. In order for the study to be considered successful, the study needed to meet both primary objectives.

Primary Safety Objective

The primary safety objective was to demonstrate that the MARVEL 2 features provided pacing as intended.

The primary safety endpoint was defined as freedom from:

• Pauses lasting longer than two cardiac cycles (where cardiac cycle length was defined by the programmed lower rate interval), AND

• Episodes of oversensing induced tachycardia exceeding 3-minutes, defined as oversensing of the accelerometer signal leading to a heart rate exceeding 100 bpm.

Primary Efficacy Objective

The primary efficacy objective was to demonstrate the superiority of the MARVEL 2 features to provide atrioventricular synchronous pacing relative to Micra VVI pacing in subjects with normal sinus node function and persistent 3rd degree AV node block during rest.

The primary efficacy endpoint was defined as a paced or ventricular beat within 300 ms following an ECG confirmed P-wave for at least 70% of ECG confirmed P-waves. The primary efficacy endpoint was evaluated during the MARVEL 2 setup phase (VDI pacing which is effectively VVI pacing) and during the 20-minute resting period in which the MARVEL 2 features were enabled.

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6 Secondary Objectives

The following secondary objectives were prospectively defined:

Secondary Objective:

Demonstrate an increase in stroke volume, as measured by left ventricular outflow tract (LVOT) velocity time integral (VTI), with the MARVEL 2 software relative to VVI pacing in subjects with normal sinus node function and persistent 3rd degree AV block.

The secondary endpoint was LVOT VTI as obtained from echocardiogram while the MARVEL 2 features were in adaptive mode (VDD pacing) and while the MARVEL 2 features were in monitor mode (VDI pacing which is effectively VVI pacing). LVOT was measured by an echo core laboratory blinded to subject and pacing mode.

7 Results

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Figure 2: Disposition of Subjects for Primary Efficacy Objective Analysis

Subject Accountability

Of the 77 enrolled subjects, 74 (96%) completed the study procedures. Of the 3 subjects not completing the study, two exited the study prior to the MARVEL 2 software download and one (3004192011) exited after MARVEL 2 software download, but prior to completing the echocardiogram. Specifically, this subject completed testing for the primary efficacy objective and all posture testing but had a non-sustained VT while programmed to VDI pacing mode with a lower rate of 50 bpm during echo testing. The result of this premature exit was that this subject was missing echo data for analysis of the secondary objective.

Subject Demographics

Subject demographics and medical history were collected at the time of enrollment into the MARVEL 2 study. Tables for key baseline demographic, pacing indication, and medical history characteristics are provided below for all enrolled subjects, all subjects where the MARVEL 2 software was downloaded, and for the 40 subjects with persistent 3rd degree AV block and normal sinus function that contributed to the primary efficacy analysis cohort. Among the 77 enrolled subjects, 31 (40%) were female, and the average age was 77.6 years (range: 21 – 94 years). The Micra device had been implanted for a median of 9.7 months with a range from the day of implant (de novo subjects) to 62.1 months post-implant.

Of note there were 10 subjects enrolling on the day of their Micra implant (de novo subjects), and 10 subjects that also participated in the original MARVEL study.

The most common primary pacing indication among the 77 enrolled subjects was 3rd degree AV block without atrial arrhythmias (61%)

Baseline Characteristics are described in Table 1.

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