Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Reddy VY, Exner DV, Cantillon DJ, et al. Percutaneous implantation of an entirely intracardiac leadless pacemaker. N Engl J Med 2015;373: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes.

3 TABLE OF CONTENTS A. Study Protocols 1. Original Protocol Revision D: first FDA approved protocol version that was implemented at study centers 2. Final Protocol Revision H 3. Summary of Protocol Changes Revision H (section1, pages 2-4) B. Statistical Analysis Plan 1. Original Statistical Analysis Plan Revision D (section 6.2, pages 14-26) 2. Final Statistical Analysis Plan Revision H (section 6.2, pages 15-27) 3. Changes to Statistical Analysis Plan detailed in Revision H (section 1, pages 2-4)!!!

4 INVESTIGATION PLAN The LEADLESS II Study Nanostim s safety and effectiveness trial for a leadless cardiac pacemaker system DC Rev D November 1, 2013 IDE Number: G The LEADLESS II Study Page 1 November 1, 2013

5 DC Rev D 1.0 Revision Change History Revision # DC Rev A DC Rev B DC Rev C DC Rev D Reason for Revision First doc controlled version of investigation plan submitted to FDA Conformance to remarks in FDA letter of for G Conformance to remarks in FDA letter of for G Conformance to remarks in FDA of for G The LEADLESS II Study Page 2 November 1, 2013

6 Table of Contents Investigation Plan DC Rev D 1.0 REVISION CHANGE HISTORY CLINICAL INVESTIGATION PLAN SYNOPSIS ABBREVIATIONS INTRODUCTION PURPOSE CLINICAL PROTOCOL STUDY DESIGN AND SCOPE STUDY OBJECTIVE AND ENDPOINTS Primary Endpoints Primary Safety Endpoint Primary Effectiveness Endpoint Data Analysis of Primary Safety and Effectiveness Endpoints Adaptive Sample Size Re-estimation Pooling of Regions and Sites Missing Data Subgroup Analyses Conditional Probability of Meeting 1-Year Primary Endpoints Secondary Endpoint Supplementary Endpoints Supplementary Safety Endpoint Evaluation at 12 Months Supplementary Effectiveness Endpoint Evaluation at 12 Months Data Analysis of Supplementary Safety and Effectiveness Endpoints Additional data Definitions used in LEADLESS II study SUBJECT SELECTION Inclusion Criteria Exclusion Criteria STUDY PROCEDURES Enrollment Requirements Recruitment and Enrollment Subject Numbering Baseline Assessment Medications Implant Procedure Femoral Vein Assessment and Access LCP Preparation and Implant LCP Assessment and Programming LCP Repositioning and/or Release Unsuccessful Implant LCP Retrievals and Replacement Post-procedure Assessments Access-site Management During Hospital Stay Pre-Discharge Assessment week and 6-week follow-up visits Month Visit Month Follow-up Visit Follow-up Visit Every Subsequent 6-Months until Study Completion Unscheduled Follow-up Visits PROTOCOL DEVIATIONS ADVERSE EVENTS The LEADLESS II Study Page 3 November 1, 2013

7 DC Rev D 9.0 DEATHS COMMITTEES AND CORE LABORATORIES DATA AND SAFETY MONITORING BOARD (DSMB) CLINICAL EVENTS COMMITTEE (CEC) HOLTER CORE LABORATORY WITHDRAWALS RISK ANALYSIS PRODUCT-RELATED RISKS CLINICAL RISKS ANTICIPATED CLINICAL BENEFITS BENEFIT/RISK ASSESSMENT CONCLUSIONS FROM PRE-CLINICAL RISK EVALUATION DESCRIPTION OF DEVICE IDENTIFICATION OF THE DEVICE: PROPRIETARY AND CODE NAMES DESCRIPTION OF THE DEVICE AND ITS INTENDED APPLICATION Leadless cardiac pacemaker (LCP) Delivery catheter Programmer Link F introducer kit Retrieval catheters CONFIGURATIONS AND VARIANTS INVESTIGATOR INFORMATION MONITORING PROCEDURES FDA INSPECTIONS LABELING CONSENT MATERIALS IRB INFORMATION OTHER INSTITUTIONS RECORDS AND REPORTS CUSTODY RETENTION PERIOD PUBLICATIONS APPENDICES APPENDIX A: GRADED EXERCISE TEST (CAEP PROTOCOL) BIBLIOGRAPHY The LEADLESS II Study Page 4 November 1, 2013

8 2.0 Clinical Investigation Plan Synopsis Investigation Plan DC Rev D Title Investigational Device Regulatory Classification of the Investigational Device Number of Institutions Nanostim safety and effectiveness trial for a leadless cardiac pacemaker system The LEADLESS II Study Leadless cardiac pacemaker (LCP) system Class III Up to 50 investigation sites in the United States, Canada and Europe Number of Subjects Up to 667. At least 50% of the subjects recruited from sites located in the United States. Trial Population Schedule of Assessments Study Design Study Objective Primary Safety Endpoint Primary Effectiveness Endpoint Secondary Endpoint Subjects who are at least 18 years old, and who are indicated for a VVI(R) pacemaker. Enrollment, Implant, Pre-Discharge, 2-week, 6-week, 3-month, 6- month follow-up, and every 6 months thereafter until study completion. Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Prospective, non-randomized, single-arm, international multicenter, clinical safety and effectiveness investigation. The primary objectives of this study are to evaluate the clinical safety and effectiveness of the LCP system in patients who are indicated for VVI(R) pacemaker. The primary safety endpoint evaluates the 6-month complicationfree rate. The primary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 6 months post-implant. The secondary endpoint evaluates an appropriate and proportional rate response during graded exercise testing (CAEP protocol), performed any time at or after the 3-month follow-up visit. The LEADLESS II Study Page 5 November 1, 2013

9 DC Rev D PMA Application Study continuation and supplementary analyses after PMA application Inclusion Criteria A PMA application will be submitted to FDA upon successful demonstration of the 6-month primary safety and effectiveness objectives. These 6-month data will be sufficient for FDA to review the PMA and make a determination of the safety and effectiveness of the device and the approvability of the PMA. The study will continue under IDE until evaluation of 1-year supplementary safety and effectiveness objectives, or until PMA approval, whichever comes first. If PMA approval occurs before evaluation of the 1-year supplementary safety and effectiveness objectives, the study will continue as a short-term post-approval study, until evaluation of the 1-year supplementary safety and effectiveness objectives. All patients in the IDE study and this short-term post-approval study will consent to continue annual follow-ups each year until 7 years after implant, in a long-term post-approval study. Eligible subjects will meet all of the following: 1. Subject must have one of the clinical indications in adherence with Medicare, ACC/AHA/HRS/ESC single chamber pacing guidelines including: Chronic and/or permanent atrial fibrillation with 2 or 3 AV or bifascicular bundle branch block (BBB block), including slow ventricular rates (with or without medication) associated with atrial fibrillation; or Normal sinus rhythm with 2 or 3 AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year); or Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings; and 2. Subject 18 years of age; and 3. Subject has life expectancy of at least one year; and 4. Subject is not enrolled in another clinical investigation; and 5. Subject is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams; and 6. Subject has been informed of the nature of the study, agrees to its provisions and has provided written informed consent, approved by the IRB; and 7. Subject is not pregnant and does not plan to get pregnant during the course of the study. The LEADLESS II Study Page 6 November 1, 2013

10 Clinical Investigation Synopsis continued Exclusion Criteria Investigation Plan DC Rev D Subjects will be excluded if they meet any of the following: 1. Subject has pacemaker syndrome, has retrograde VA conduction or suffers a drop in arterial blood pressure with the onset of ventricular pacing; or 2. Subject is allergic or hypersensitive to <1 mg of dexamethasone sodium phosphate; or 3. Subject has a mechanical tricuspid valve prosthesis; or 4. Subject has a pre-existing pulmonary arterial (PA) hypertension (PA systolic pressure exceeds 40 mmhg or RV systolic pressure (RVSP) as estimated by echo exceeds 40 mmhg), or significant physiologically-impairing lung disease; or 5. Subject has a pre-existing pacing or defibrillation leads; or 6. Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT); or 7. Subject has an implanted vena cava filter; or 8. Subject has evidence of thrombosis in one of the veins used for access during the procedure; or 9. Subject has an implanted leadless cardiac pacemaker. Enrollment Subjects who sign an IRB-approved informed consent and have an attempted or successful implant will be considered enrolled in the study. Estimated Schedule First subject enrolled: January 2014 Last subject enrolled: February 2015 Last subject visit: February 2016 The LEADLESS II Study Page 7 November 1, 2013

11 Clinical Investigation Synopsis continued Investigation Plan DC Rev D Schedule of Assessments Pre-procedure Assessments Inclusion/exclusion criteria Informed consent Pregnancy assessment 12-lead ECG Medical history Medications 1 Implant Assessments Femoral vein assessment and access Procedure details LCP implant LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs Post-procedure Assessments Access-site assessment 12-lead ECG X-ray of pacemaker LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 2-week Visit LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 1 Data are collected for anti-arrhythmic, anti-coagulant, and anti-platelet medications only, at all visits. The LEADLESS II Study Page 8 November 1, 2013

12 Clinical Investigation Synopsis continued Schedule of Assessments (continued) Investigation Plan DC Rev D 6-week Visit LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 3-month Visit LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 24-hour Holter monitor with diary (first 30 subjects) Graded exercise test (CAEP protocol for first 30 subjects) 6-month Visit LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs Every 6-month Visits LCP assessment and programming Assess for changes in medications or change in therapy Assess for AEs The LEADLESS II Study Page 9 November 1, 2013

13 Pre-procedure Assessments Table 1: Schedule of Assessments Procedure Assessment Post-procedure Assessments Investigational Plan DC Rev. A Every Postprocedure Follow-up Follow-up Follow-up Follow-up 2-week 6-week 3-month 6-month Screen & 6-months Additional Baseline Implant Enroll Assessment Visit 1 Visit 1 Visit 2 Visit 2 until study Visits Activity completion 3 Inclusion Exclusion Informed Consent Pregnancy Assessment/Test Medical History Baseline Assessment Procedure Post-procedure Pre-discharge LCP Assessment and Programming 12-lead ECG X-ray of a pacemaker Follow-up Visit 24-hour Holter monitor with diary 4 Graded exercise test CAEP Protocol 5 Additional CRFs (when applicable) Adverse Event Medications Deviation Study Withdrawal Product Out of Service System Revision Death Hospitalization 1 ±7 days 2 ±30 days The LEADLESS II Study Page 10 November 1, 2013

14 3 ±45 days 4 All capable patients are asked to wear a 24-hour Holter and complete a diary, until 30 patients provide data contributing to the analysis. The test may be performed any time at or after the 3- month follow-up visit. 5 All capable patients are asked to perform a CAEP treadmill test until 30 patients provide data contributing to the analysis. The test may be performed any time at or after the 3- month follow-up visit. Investigation Plan DC Rev D The LEADLESS II Study Page 11 November 1, 2013

15 Investigational Plan DC Rev. A 3.0 Abbreviations Abbreviation Definition Abbreviation Definition 2 Second degree eptfe Expanded poly tetra fluoro ethylene 3 Third degree ESC European Society of Cardiology ABS Acrylonitrile butadiene styrene FEP Fluorinated ethylene propylene ACC American College of Cardiology ICD Implantable cardioverter defibrillator ACT Activated clotting time IFU Instructions for use ADL Activities of daily living INR International normalized ratio AE Adverse event IRB Independent or institutional review board AHA American Heart Association LCP Leadless cardiac pacemaker AIMD Active implantable medical device MRI Magnetic resonance imaging AV Atrioventricular PA Pulmonary arterial BBB Bifascicular bundle branch PEEK Polyether ether ketone CAEP Chronotropic assessment PTFE Poly tetra fluoro ethylene exercise protocol CFR Complication free rate PtIr Platinum Iridium CIP Clinical investigation plan PVC Poly(vinyl chloride) (also referred to as clinical protocol) CRF Case report form RR Rate response CRO Clinical research RV Right ventricular organization CRT Cardiac resynchronization SAE Serious adverse event therapy EC/MEC Ethics committee/medical TiN Titanium nitride ethics committee ECG Electrocardiogram UADE Unanticipated adverse device effect EP Electrophysiology The LEADLESS II Study Page 12 November 1, 2013

16 4.0 Introduction Investigation Plan DC Rev D Sponsor has developed a leadless cardiac pacemaker (LCP) system to eliminate leads, pockets, and connectors required by conventional pacemakers and to eliminate associated complications. This concept could improve patient comfort by replacing a surgical procedure with a percutaneous one, eliminating the visible lump and scar at a conventional pacemaker s pectoral implant site, and removing the need for activity restrictions to prevent dislodgement after implantation of a conventional lead. Finally, the concept could permit pacemaker patients to undergo magnetic resonance imaging (MRI) with specified machines, although this is not being evaluated under this protocol. Nanostim s LCP system consists of a pacemaker and its accessories: a programmer, introducer, delivery catheter, and retrieval catheters. The accessories are not intended for use alone or with any device other than the Nanostim pacemaker. The pacemaker and all accessories, except the programmer, are single-use devices and are supplied sterile. 5.0 Purpose The intent of this IDE study is to evaluate the safety and effectiveness of the implanted Nanostim Leadless Cardiac Pacemaker for treatment of bradycardia. A Nanostim LINK, also investigational, will be used in conjunction with the LCP. The LINK is a programming device that when connected to the St. Jude Medical Merlin Patient Care System (Model 3650) allows the user to communicate with the LCP. 6.0 Clinical Protocol 6.1 Study Design and Scope This is a prospective, non-randomized, multi-center, international clinical study designed to evaluate the safety and effectiveness of the Nanostim Leadless Cardiac Pacemaker System in a patient population indicated for a VVI(R) pacemaker. Sponsor will conduct the study at up to 50 centers in the United States, Canada and Europe. To meet study endpoints, the Sponsor expects to enroll up to 667 subjects in 14 months, based on a model accounting for up to 10% attrition over the 1-year follow-up evaluation period. Sponsor will allow a maximum of 100 (15% of the total) enrollments per center and expects, on average, approximately 1.75 enrollments per center per month. At least 50% of subjects will be recruited from sites located in the United States. Enrollment in the LEADLESS II clinical study is expected to take approximately 14 months. Sponsor anticipates the duration of study participation to be approximately 26 months. All eligible subjects will undergo implant attempt with a Nanostim LCP. All patients will The LEADLESS II Study Page 13 November 1, 2013

17 DC Rev D consent to continue annual follow-ups each year until 7 years after implant, in a long-term post-approval study. The following study evaluations will occur after implant: Pre-discharge assessment 2-week follow-up visit (in-office or clinic) 6-week follow-up visit (in-office or clinic) 3-month follow-up visit (in-office or clinic) 6-month follow-up visit (in-office or clinic) Every 6 months thereafter until study completion Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Follow-up schedules will be calculated from the date of successful implant. 6.2 Study Objective and Endpoints The primary objectives of this study are to assess the safety and effectiveness of the Nanostim device from implant through 6-months in a patient population indicated for a VVI(R) pacemaker. Primary Safety Endpoint The primary safety endpoint evaluates a 6-month complication-free rate. Primary Effectiveness Endpoint The primary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 6 months post-implant. Secondary Endpoint The secondary effectiveness endpoint evaluates an appropriate and proportional rate response during graded exercise testing (CAEP protocol). Supplementary Safety Endpoint The supplementary safety endpoint evaluates a 1-year complication-free rate. Supplementary Effectiveness Endpoint The supplementary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 1 year post-implant. The LEADLESS II Study Page 14 November 1, 2013

18 6.2.1 Primary Endpoints Investigation Plan DC Rev D A PMA application will be submitted to FDA upon successful demonstration of the 6-month primary safety and effectiveness endpoints. These 6-month data will be sufficient for FDA to review the PMA and make a determination of the safety and effectiveness of the device and the approvability of the PMA Primary Safety Endpoint The goal of the primary safety endpoint evaluation is to demonstrate an acceptable complication-free rate (CFR), including any complication that prevents initial implantation. From a literature review of conventional pacemakers and leads (Nanostim document RC ), and from experience in the prior clinical investigation of the Nanostim system (Nanostim document RC-02181), the expected 6-month CFR is 92% and the 1-year CFR for the Nanostim system is 89%. Given these assumptions, the study hypotheses are stated below. Subjects whose initial implantation procedure was not successful will not be eligible for reimplantation attempts with the investigational device at a later date. Subjects who leave the study before their 6-month visit will be censored at the time they leave the study. So, any complications that occur in patients that leave the study before their 6 month visit will be included in this analysis. Primary Safety Endpoint Evaluation at 6 Months H 0 : CFR 86% vs. H 1 : CFR > 86% A sample size of 300 evaluable subjects will have a 90% probability of establishing a twosided 95% confidence interval for CFR, with a lower bound exceeding 86%, based on an exact binomial distribution. Since the LCP device is unique both in its design and delivery, there is no precedent for estimating an expected or acceptable complication rate based on prior clinical studies for other pacemaker devices reported in the literature. Nanostim has conducted a pilot study where the actual CFR was estimated to be 96.88% (31/32) at 3 months. Assuming this to be a random event, the estimated CFR rate would be expected to be the same between the first three months and the second 3 months. Therefore, the estimated CFR rate at 6 months would be 93.75% (30/32), with an associated exact 95% confidence interval of (79.19%, 99.23%). Nanostim has used a planning estimate for the expected CFR at 6 months of 92.0%, which exceeds the midpoint of the 95% confidence interval for the estimated rate at 6 months based on pilot data (89.2%). An observed CFR of 92.0% or higher would be needed to demonstrate The LEADLESS II Study Page 15 November 1, 2013

19 DC Rev D superiority to the proposed Performance Goal of 86% with a sample of 300 evaluable subjects. A Performance Goal of higher than 86% would lead to substantially larger sample size requirements (for example, 88% would require a doubling of the sample size to 600 subjects). The proposed study will collect sufficient information both on the number of complications and their type, to assess the risk/benefit profile for this new technology Primary Effectiveness Endpoint The composite primary effectiveness endpoint will be used to evaluate pacing thresholds and R-wave amplitudes at the 6-month visit and to document the percentage of subjects with acceptable sensing and pacing performance. Pacing thresholds and R-wave amplitudes will be collected, tabulated for each visit, and also displayed as frequency plots. Acceptable ranges for sensing and pacing are shown in the table below. Parameter Pacing voltage R Sensitivity Acceptable test values Pacing threshold < 2.0 V at 0.4 ms R-wave amplitude > 5.0 mv or value at implant Success Criteria: A subject will be considered to have met the primary effectiveness endpoint if the pacing threshold voltage is 2.0 V at 0.4 ms and the sensed R-wave amplitude is either 5.0 mv at the 6-month visit or the value at implant. In a previous Nanostim pilot study (n = 32, 3-month follow-up period), the maximum observed pacing threshold voltage occurring in the period from hospital discharge to 3 months was 1.75 V, and the minimum observed R-wave was 4.0 mv. Based on these prior data, the success rate (Rate) for the Nanostim device at 6 months is expected to be 91.5% or higher, and 89.5% or higher at 12 months. A prespecified performance goal is set at 85.0% for both evaluation periods. The inability to sense or pace within the programmable range available in the Nanostim device, resulting in device repositioning, replacement, or removal will be captured in the associated safety endpoints. Primary Effectiveness Endpoint Evaluation at 6 Months H 0 : Rate 85.0% vs. H 1 : Rate > 85.0% A sample size of 300 subjects will have at least a 90% probability of establishing a two-sided 95% confidence interval for conformance with the above-referenced criteria for pacing threshold and R-wave amplitude, with a lower bound exceeding 85.0%, based on an exact binomial distribution. The LEADLESS II Study Page 16 November 1, 2013

20 Data Analysis of Primary Safety and Effectiveness Endpoints The following analysis populations are defined for the study: Investigation Plan DC Rev D Intent-to-Treat (ITT): Subjects who meet the enrollment criteria, provide signed Informed Consent, and who have an attempted or successful implant are considered enrolled in the study and part of the ITT population. Per Protocol (PP): The Per Protocol population at 6 months includes all enrolled subjects who have 6-month safety and effectiveness evaluations. The PP population at 12 months includes all enrolled subjects who have 12-month safety and effectiveness evaluations. It excludes subjects, for example, who withdrew informed consent, were lost to follow-up prior to the scheduled evaluations, or missed evaluation visits, but includes those subjects who contributed events to the primary endpoints prior to withdrawal or the scheduled visits. There are no other major protocol deviations which define the PP population or would exclude subjects from analysis. The primary analysis population for the Primary Safety Endpoint will be the ITT population. The Primary Effectiveness Endpoint will be evaluated in both the ITT and PP populations. The primary safety and effectiveness endpoints must be met at the 6-month evaluations for the study to be considered an appropriate basis for PMA approval. All primary safety and effectiveness endpoints will be tested against the pre-specified performance goals at 6 months with exact, binomial tests. Interim Analysis and Adaptive Sample Size Re-estimation A single interim analysis will be performed at the point that 50% of the 300 evaluable subjects required for the 6-month evaluation have been assessed (150 subjects). This analysis will be limited to primary safety endpoint data for this 50% cohort. If it is determined at the interim analysis that the study will not achieve its original design objective of 90% unconditional power at the 6-month evaluation, then the study size will be increased to regain that power. Otherwise, the sample size will remain at the original 300 evaluable subjects. There will be no provision for reducing the study sample size or early stopping of the study, other than for emergent safety concerns. The maximum allowable increase in the sample size for the 6-month evaluation will be twice the original estimated number of 300 subjects (that is, a total of 600 evaluable subjects for the 6-month evaluation). Since there are no plans for early termination of the study, adjustments to the alpha requirements for the safety endpoint are not required. If the sample size is increased, then the Type I error level for both primary safety and effectiveness endpoints will be preserved using the method of Cui et al (Cui L, Hung HMJ, and Wang SJ, 1999, Modification of Sample Size in Group Sequential Trials, Biometrics, 55: ). The LEADLESS II Study Page 17 November 1, 2013

21 DC Rev D The interim analysis and any potential sample size recommendation made to the sponsor will be the responsibility of the study DSMB Adaptive Sample Size Re-estimation A pre-specified adaptive design will ensure that the study has adequate power in case the complication-free rate is lower than expected. The purpose of an adaptive design would be to increase sample size if the study does not meet the requirements of the 6-month endpoint with 300 evaluable patients. If an increase in the sample size is required for the 6-month evaluation then that increment will be added to the original sample size of 600 estimated for the 12-month evaluation (that is, a maximum of 900 evaluable subjects for the 12-month evaluation) Pooling of Regions and Sites All baseline and demographic characteristics between study regions and individual sites will be examined using statistics appropriate to the variable examined: Chi-square or Fisher's Exact tests for categorical variables, and Student's t-tests or ANOVAs for continuous variables. The consistency of results for the primary safety and effectiveness endpoints across (1) Regions: US vs. OUS and (2) Sites will be examined using Chi-square or Fisher-Freeman- Halton tests, with associated p-values of 0.15 or less considered evidence of potential heterogeneity in outcomes. If evidence is found of heterogeneity in safety or effectiveness outcomes across regions or sites, then additional analyses will be performed to determine if differences in the distributions of baseline factors account for the region or site differences Missing Data All attempts will be made to ensure patient retention in the study to minimize the amount of missing data. Reasons for withdrawals will be documented and assessed relative to possible relationships to study primary endpoints. In the evaluation of the Primary Safety Endpoint, the last known status (LOCF) of patients who withdraw from the study will be used in the primary analysis for the intent-to-treat (ITT) population. As previously stated, patients who had experienced an event prior to withdrawal are included in the analysis. For those subjects who withdraw for reasons unrelated to complications (e.g., withdrawal of consent), the LOCF assumption is not the most conservative approach but is considered a more unbiased approach to estimating the complication-free rate. To evaluate the potential impact of any missing data on the Primary Safety Endpoint, the following sensitivity analyses will also be performed: o Evaluation in the Per Protocol (PP) population The LEADLESS II Study Page 18 November 1, 2013

22 DC Rev D o Assume that no complications occur in patients who withdraw (best case) o Assume that all withdrawals would have experienced a complication (worst case) o Kaplan-Meier survival estimates of the complication-free rate at 6 months and associated 95% confidence interval, using the 6-month cumulative survival and its estimated standard error (Peto method) In the evaluation of the Primary Effectiveness Endpoint, the last known status (LOCF) regarding success or failure in achieving acceptable sensing and pacing performance at the 6- month visit will be used in the ITT primary analysis. To evaluate the potential impact of any missing data on the Primary Effective Endpoint, the following sensitivity analyses will also be performed: o Evaluation in the Per Protocol (PP) population o Assume that successful sensing and pacing would have occurred at 6 months in patients who withdraw (best case) o Assume that unsuccessful sensing or pacing would have occurred at 6 months in patients who withdraw (worst case) o Estimated success for sensing and pacing at 6 months, based on linear regressions of pacing thresholds and R-wave amplitudes from available data prior to withdrawal Subgroup Analyses Additional exploratory analyses will be performed to examine the consistency of primary safety and effectiveness outcomes across study subgroups, including gender and age. All patient and baseline factors that have a univariate association with outcomes resulting in a p- value of 0.15 or less will be identified. The analyses for association will be appropriate to the factor being examined: for example, Chi-square and Fisher's Exact tests for categorical variables, and Student's t-tests and ANOVAs for continuous variables. These analyses may also include logistic multivariable regressions to determine the independent contributions of patient and baseline factors identified as having univariate associations Conditional Probability of Meeting 1-Year Primary Endpoints The conditional probabilities for the primary safety and effectiveness endpoints will be calculated using the procedure for estimating conditional power of one proportion tests based on the method of Chang (Chang, M, Classical and Adaptive Clinical Trial Designs, 2008, John Wiley & Sons. Hoboken, New York) implemented in the PASS 12 software package (Version , NCSS). The current estimated 1-year complication-free rate (CFR) is 89% (Section Primary Safety Endpoint) and the estimated 1-year success rate is 89.5% (Section Primary Effectiveness Endpoint). The conditional power for each endpoint will be calculated based The LEADLESS II Study Page 19 November 1, 2013

23 DC Rev D on these assumed values, adjusted for the actual differences observed between the observed and expected rates at 6 months. The expected 6-month rates are 92% for the Primary Safety Endpoint and 91.5% for the Primary Effectiveness Endpoint. For example, if the observed 6- month CFR is 93%, then the assumed 1-year rate for purposes of calculating the conditional power will be 89% + (93% - 92%) = 90%. In general, the one-sided conditional power at look k (0,...,k,...,K) using the proposed method is given by: CP k (θ) = Φ { [ Z k (Ι k ) 1/2 - z 1-α (Ι k ) 1/2 + θ (Ι K - Ι k ) ] / (Ι K - Ι k ) 1/2 } Where, k = the look number (here, there is one look at n = 300, and a final look at n= 600) θ = P 1 - P 0 P 0 = proportion under the null hypothesis P 1 = proportion under the alternative hypothesis Z k = (p k - P 0 ) (Ι k ) 1/2, is the test statistic Ι k = n k / σ 2 x, the information level p k = the observed proportion at look k σ 2 = variance of p k, estimated by [P (1 - P) ] 1/2, and P = (P 1 + P 0 ) / 2 n k = sample size at look k Secondary Endpoint The secondary endpoint includes evaluation of a CAEP exercise protocol. If both the Primary Safety and Primary Effectiveness Endpoints are met, then the following hypotheses will be hierarchically evaluated: Secondary CAEP Endpoint H 0 : Mean Slope is Not Equivalent to 100% Slope - 100% δ H 1 : Mean Slope is Equivalent to 100% Slope - 100% < δ Where, δ = equivalence margin, equal to 35% CAEP exercise protocol All capable patients will be asked to perform a CAEP exercise protocol to demonstrate an appropriate and proportional response of sensor-indicated rate in graded exercise tests, until 30 patients provide data contributing to the analysis. A sample of 30 should be The LEADLESS II Study Page 20 November 1, 2013

24 DC Rev D representative of the population and should result in at least 8 subjects showing >50% pacing during the CAEP protocol 2, otherwise, additional subjects may need to be added. The analysis of these exercise test data will provide an estimate of the slope of the normalized increase in sensor-indicated rate versus normalized CAEP workload for each subject. An analysis of these data will also estimate the 95% confidence interval for the mean slope across subjects, which has a pre-specified success criterion requiring that this confidence interval must fall between slopes of 65% and 135%. Based on recently reported studies of marketed rate-responsive pacemakers the expected slope for similar devices, including the Nanostim device, is estimated to be approximately 77%, with an associated standard deviation of 14%. It is estimated based on these data that a sample size of 8 subjects would be sufficient to demonstrate that the lower and upper 95% confidence bounds meet the success criterion, based on a normally distributed random variable. To ensure that a robust cross-section of subjects is evaluated, however, a total of 30 subjects will undergo this assessment. The analysis will provide individual graphs for each subject, displaying: Exercise level (Y1 in METs), sensor-indicated rate (Y2 in min -1 ), intrinsic rate (Y3 in min -1 ), and heart rate (Y4 in min -1 ), as a function of time (X in minutes) since start of exercise. Normalized increase in sensor-indicated rate (Y = 0 to 100 %) versus normalized CAEP workload (X = 0 to 100 %). o Y = (SIR BAS)/(MHR BAS), where SIR = sensor-indicated rate, BAS = basic rate, and MHR = 80 % * (220-age), all in min -1. o X = (MET-RST)/(MAX-RST), where MET is the actual workload, MAX is the maximum achieved workload, and RST is the resting workload (1), all in METs. The CAEP test will be performed any time after the beginning of the 3-month visit window to ensure maturity of the tissue interface Supplementary Endpoints The following supplementary endpoints will be evaluated at 12 months after implant Supplementary Safety Endpoint Evaluation at 12 Months H 0 : CFR 84.5% vs. H 1 : CFR > 84.5% A sample size of 600 evaluable subjects will have a 90% probability of establishing a twosided 95% confidence interval for CFR, with a lower bound exceeding 84.5%, based on an exact binomial distribution. 2 This estimate is based on data from the preliminary European Leadless clinical trial, in which 27% of subjects demonstrated >50% pacing during the 6 minute hallwalk test at the 6-week follow-up. The LEADLESS II Study Page 21 November 1, 2013

25 DC Rev D Patients who leave the study before their 1 year visit will be censored at the time they leave the study. Therefore, any complications occurring in patients who depart the study prior to their 1 year visit will be included in this analysis. Based on the above assumptions, the total enrollment is expected to be 667 subjects, including an adjustment for potential 10% annual attrition. Successful demonstration of an 86 % CFR at six months does not preclude 84.5 % CFR at one year Supplementary Effectiveness Endpoint Evaluation at 12 Months H 0 : Rate 85.0% vs. H 1 : Rate > 85.0% A sample size of 600 subjects will have at least a 90% probability of establishing a two-sided 95% confidence interval for successful sensing and pacing, with a lower bound exceeding 85.0%, based on an exact binomial distribution. The inability to sense or pace within the programmable range available in the Nanostim device, resulting in device repositioning, replacement, or removal will also be captured in the associated safety endpoints Data Analysis of Supplementary Safety and Effectiveness Endpoints The supplementary safety and effectiveness endpoints must be met at the 1-year evaluations, although this is not a criterion for approval of the original PMA application. All supplementary safety and effectiveness endpoints will be tested against the pre-specified performance goals at 12 months with exact binomial tests Additional data The following additional data will be recorded and reported: All adverse events, and whether or not each is device-related or procedure-related Implant success rate Number of device repositionings at time of implantation Implant duration, fluoro duration, and time from implant to hospital discharge Demographics: gender, age, ethnicity, race, indication for pacemaker implant Medical history Use of anti-coagulation, anti-arrhythmic, and anti-platelet medications A table and histogram across all patients of remaining longevity at the six-month and 1-year visits, as displayed by the programmer based on delivered therapy, programmed settings, percent pacing, and measured pacing impedance. Average pacing rate, impedance, pulse amplitude, pulse duration and percentage pacing will also be reported for all visits. The LEADLESS II Study Page 22 November 1, 2013

26 Holters Investigation Plan DC Rev D All capable patients will be asked to wear a 24-hour Holter monitor and complete a diary, until 30 patients provide data contributing to the analysis. The test may be performed any time after the beginning of the 3-month visit window. These data will be examined for appropriate sensing, pacing and activities of daily living for each subject. The investigational plan does not require inclusion of pacer-dependent subjects to assess device s pacing capabilities because it is expected that at least a third of subjects will have >50% pacing, based on data from preliminary European data (for 31 subjects at 6 week follow-up), provided below: Histogram of percentage pacing at 6 month follow-up visit (from preliminary European data): Percent pacing Percentage of subjects 0-25% 42% 26-50% 26% 51-75% 23% >75% 10% Sponsor will provide an IDE interim report to FDA within one month of completion of the 30 th patient Holter monitor. The IDE interim report will include the following for each subject. Minimum, maximum and average heart rate Percent pacing A telemetry strip of the minimum heart rate and a telemetry strip during pacing (the pacing strip may be the same as the minimum heart rate strip, but does not have to be). Number of pauses seen (defined as RR interval greater than or equal to 2 sec) All telemetry strips of a pause greater than the cycle length that corresponds to the programmed lower rate limit after accounting for any hysteresis programming All telemetry strips showing evidence of oversensing, undersensing, or loss of capture Programmed parameters (which are necessary to assess if the pauses or minimum heart rate seen on Holter are appropriate or not) Definitions used in LEADLESS II study Adverse Event: Any unfavorable clinical event which impacts, or has the potential to impact the health or safety of a patient caused by or associated with a study device or intervention. Complication: A device- or procedure-related serious adverse event, including any adverse event that prevents initial implantation. The LEADLESS II Study Page 23 November 1, 2013

27 DC Rev D Cardiac Tamponade: Confirmed or suspected accumulation of fluid in the pericardial space. Cardiac Perforation: An excursion of the LCP through the cardiac muscle. Signs and symptoms of a perforation by an LCP may include radiographic evidence of excursion of the LCP into the pericardial sac, abnormal echocardiography indicative of a perforation, the accumulation of fluid in the pericardium, cardiac tamponade, or subject symptoms such as chest pain and discomfort. Device-malfunction: the failure of a device to meet its performance specifications or otherwise perform as intended. Performance specifications include all claims made in the labeling for the device. The intended performance of a device refers to the intended use for which the device is labeled or marketed. Diaphragmatic/Phrenic Nerve Stimulation: Electrical activation of the diaphragm muscle by the device output pulse. The abrupt diaphragmatic contraction is noted clinically as hiccups associated with each pacing stimulus. The pacing stimulus may stimulate the diaphragm either directly or indirectly via the phrenic nerve. Dislodgement: The movement of the LCP from its originally implanted position resulting in elevated pacing thresholds or a decrease in sensing. Elevated Pacing Thresholds: Pacing thresholds > 2.5 V at 0.4 ms at implant. Following lead maturation at 6-8 weeks, an increase in pacing thresholds of 1.2 V at 0.4 ms or greater between visits. This definition is intended to serve as a guideline and it is understood that individual subjects may have unique situations. Implant procedure duration: Defined as the time from delivery catheter and LCP insertion to removal. Implant success rate: Defined as the number of subjects leaving the implant procedure with an implanted and functioning LCP device, divided by the number of subjects in whom implantation is attempted. Loss of Capture: The inability of the device s output pulse to result in depolarization and contraction of the ventricle. Causes include insufficient stimulus strength, separation of the electrode from the myocardium and placement of the stimulating electrode in contact with a non-responsive portion of the myocardium such as scar tissue. Delivery of an output pulse at a time when the myocardium is physiologically refractory is not loss of capture, since capture is not physiologically feasible. Loss of Sensing: A condition in which the pulse generator is unable to sense intrinsic cardiac signals. The LEADLESS II Study Page 24 November 1, 2013

28 DC Rev D Oversensing: The detection of inappropriate electrical signals by the pulse generator s sense amplifier. These signals, such as myopotentials, electromagnetic interference, or T waves must be of sufficient duration to interfere with normal device function. Procedure duration: Defined as the time from 18F femoral introducer insertion to removal. Serious Adverse Event (SAE): Any untoward medical occurrence that: a. Led to death, b. Led to serious deterioration in the health of the subject, that either resulted in 1. A life-threatening illness or injury, or 2. A permanent impairment of a body structure or a body function, or 3. In-patient or prolonged hospitalization, or 4. Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, or requires an invasive strategy to remedy, c. Led to fetal distress, fetal death or a congenital abnormality or birth defect. NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration in health, is not considered a serious adverse event. Sponsor understands that the following items meet the definition of serious adverse event if they require hospitalization or prolong hospitalization, even though an invasive approach may not be necessary to resolve: AV fistula, pseudoaneurysm, blood transfusions, tricuspid valve damage, pericardial effusion, pulmonary embolus, device dislodgement, right ventricular perforation, thrombus formation on the device, ventricular arrhythmias even if not associated with an invasive strategy to remedy Non-invasive means such as device re-programming do not meet the criteria for medical or surgical intervention. Time to discharge: Defined as the time from introducer sheath removal to discharge. Unanticipated adverse device effect (UADE): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of patients. [21 CFR 812.3(s)] Unavoidable adverse event: An unavoidable AE is defined as an adverse event related to the implant procedure that is expected to occur for a projected duration in all subjects. The LEADLESS II Study Page 25 November 1, 2013

29 DC Rev D Undersensing: The failure of the pulse generator to sense R-waves, causing delivery of inappropriately timed, asynchronous or competitive output pulses. Undersensing can sometimes be corrected by programming the device to a more sensitive setting, i.e., decreasing the millivolt value. 6.3 Subject Selection The inclusion and exclusion criteria are consistent with recommendations of the European Society of Cardiology, 1 American College of Cardiology, American Heart Association, and the Heart Rhythm Society. 2 Additionally, sponsor has included investigator input. Eligibility for implant is based on conformance to all prospectively defined inclusion and exclusion criteria Inclusion Criteria Eligible subjects will meet all of the following. 1. Subject must have one of the clinical indications in adherence with Medicare, ACC/AHA/HRS/ESC single chamber pacing guidelines including: Chronic and/or permanent atrial fibrillation with 2 or 3 AV or bifascicular bundle branch block (BBB block), including slow ventricular rates (with or without medication) associated with atrial fibrillation; or Normal sinus rhythm with 2 or 3 AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year); or Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings; and 2. Subject is 18 years of age; and 3. Subject has a life expectancy of at least one year; and 4. Subject is not be enrolled in another clinical investigation; and 5. Subject is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams; and 6. Subject has been informed of the nature of the study, agrees to its provisions and has provided a signed written informed consent, approved by the IRB; and 7. Subject is not pregnant and does not plan to get pregnant during the course of the study Exclusion Criteria Subjects will be excluded if they meet any of the following. 1. Subject has pacemaker syndrome, has retrograde VA conduction, or suffers a drop in arterial blood pressure with the onset of ventricular pacing; or 2. Subject is allergic or hypersensitive to < 1 mg of dexamethasone sodium phosphate (DSP); The LEADLESS II Study Page 26 November 1, 2013

30 DC Rev D 3. Subject has a mechanical tricuspid valve prosthesis; or 4. Subject has a pre-existing pulmonary arterial (PA) hypertension (PA systolic pressure exceeds 40 mmhg or RV systolic pressure (RVSP) as estimated by echo exceeds 40 mmhg), or significant physiologically-impairing lung disease; or 5. Subject has a pre-existing pacing or defibrillation leads; or 6. Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device; or 7. Subject has an implanted vena cava filter; or 8. Subject has evidence of thrombosis in one of the veins used for access during the procedure; or 9. Subject has an implanted leadless cardiac pacemaker. 6.4 Study Procedures This section provides a description of all the clinical-investigation-related procedures that subjects undergo during the clinical investigation. Figure 1 illustrates study flow and Table 1 lists a summary of scheduled assessments. Refer to Figure 1 and Table 1 for an overview of the required study procedures at each interval or study visit. The clinical-investigation-related procedures do not require additional radiation compared to a traditional VVIR lead implant and conform to standard of care for pacemaker patient management with the exception of the following: Femoral vein access instead of subclavian artery access Addition of Treadmill tests Addition of 24 hour Holter monitor Sponsor representatives may assist the investigator in assessing pacemaker effectiveness (for example pacing, sensing, and rate response effectiveness), downloading diagnostic information and programming pacemaker parameters. Sponsor representatives may also assist the team in equipment setup prior to and during a procedure. The LEADLESS II Study Page 27 November 1, 2013

31 Figure 1: Study Flow Diagram Investigation Plan DC Rev D Informed Consent Implant Attempt (enrollment) YES Implant Successful? NO Follow Patient for 30 Days, then Withdraw Pre-Discharge Visit 2 Week Post Implant Visit Includes 12-lead EKG, chest x-ray and magnet mode assessment 6 Week Post Implant Visit 3 Month Post Implant 30 patients: Includes 24-hour Holter monitor 30 patients: Includes CAEP Protocol 6 Month Post Implant Every 6 Months Post Implant until Study Completion After Study Completion, yearly until 7 years post implant The LEADLESS II Study Page 28 November 1, 2013

32 Investigational Plan DC Rev. A Enrollment Requirements Recruitment and Enrollment Candidates for this clinical investigation include patients indicated for a VVI(R) pacemaker. Pre-enrollment records will include evidence of diagnosis indicating need for VVI(R) pacemaker. For the Leadless II study, it is the sponsor s intention that the enrolled patient population be as representative as possible of the eligible population. Physician investigators are strongly encouraged to evaluate all consecutive eligible patients for participation in the study and, if inclusion and exclusion criteria are met, to approach all eligible patients, regardless of gender. Centers will be selected for participation in the study based on their ability to screen and enroll eligible patients, and perform the required study procedures. The sponsor will attempt to have a diversified group of centers participating in the study, including academic and non-academic institutions, and anticipates participation to be in the order of approximately percent from academic institutions. To ensure a widespread distribution of data and minimize site bias, a maximum of approximately 15% of the total enrollment will be allowed at a single site. Screen subjects as outlined by the inclusion/exclusion criteria. Obtain informed consent from the subject. Collect data on the subject, including gender, age, ethnicity, race, cardiac disease history, cardiac medications (anti-platelets, anti-arrhythmics, anti-coagulants), arrhythmia history, and indication for pacemaker implant. Subjects who sign an IRBapproved informed consent and have an attempted or successful implant will be considered enrolled in the study. Once eligibility screening is completed, subject provides informed consent, and the investigator implants the Nanostim LCP or attempts to implant complete and submit the forms listed under the Implant Procedures to sponsor Subject Numbering An identification (ID) number will identify enrolled subjects. The format of this ID number is a combination of the site number and a sequential number assigned by the site Baseline Assessment Investigator will record subject s medical history on the Enrollment Form. Investigator will record specific cardiac medications (anti-coagulants, anti-platelets, anti-arrhythmics) given to the subject during the same hospital stay as the procedure, as well as during the follow-up period. All subjects will undergo standard laboratory assessment per site s standard of care. For female subjects of childbearing age, investigator will document a pregnancy assessment, which may include a obtaining a blood sample for conducting a pregnancy test. Investigator will not start any study-specific procedures or alterations of patient care until the informed consent process has been completed and investigator obtains a signed Informed The LEADLESS II Study Page 29 November 1, 2013

33 DC Rev D Consent Form. To determine eligibility, some screening procedures may be necessary. If any of these tests do not fall within the investigator s standard clinical practice, they will be required for subjects to be enrolled in the clinical investigation Medications Investigator will administer all medications per hospital standard of care for pacemaker implant and femoral venous catheterization procedures. Use of anticoagulation medications is not required with the implantation of the LCP. Investigator will record anti-coagulants, anti-platelets, anti-arrhythmics given during procedure Implant Procedure Femoral Vein Assessment and Access Turi (2005, 2008), Abu-Fadel et al (2009), Seto et al (2010), and Fitts et al (2008) have shown that physicians can minimize access-site complications by using ultrasound guidance or fluoroscopic guidance when accessing vessels in the groin. 3-7 Although sponsor supports using either technique for assessing femoral vein access-site location, size and presence of disease, investigator will use medical judgment and follow institutional standard of care when accessing the femoral vein during catheter-based procedures. The ideal puncture site should be located below the inguinal ligament and above the bifurcation (Refer to Figure 2). 5,8-10 Penetrate the skin and puncture the femoral vein using the Seldinger technique. Due to the introducer sheath size, investigator may need to nick and spread the tissue at the access-site location to allow for easier transition of the introducer sheath through the tissue tract. The LEADLESS II Study Page 30 November 1, 2013

34 DC Rev D Figure 2. Location of femoral vein in relation to femoral artery, inguinal ligament and femoral head LCP Preparation and Implant Investigator will prepare and implant the LCP in accordance with the manufacturer s instructions for use (IFU). Consult the IFU for implantation guidelines and general handling information. Only approved investigators will be responsible for performing the implant procedure, including placement of the LCP. Investigator will follow standard institutional catheter-based and pacemaker-lead implantation procedures, guidelines, and precautions LCP Assessment and Programming Investigator and/or sponsor will interrogate the LCP using the market-approved St. Jude Medical Merlin Patient Care System (Model 3650) with the Nanostim Link. Investigator will measure and record the following parameters. Capture threshold at (0.4 msec)* Impedance R-wave amplitude* Battery voltage and Estimated time to RRT Cumulative paced and sensed event counters * R-wave amplitude measurements are not required if the subject s intrinsic rate has been established to be below 30 beats per minute. Capture thresholds are not required if a high ventricular rate is present. Confirm at least three consecutive beats have capture before recording the capture threshold results. The LEADLESS II Study Page 31 November 1, 2013

35 DC Rev D To avoid potential complications associated with under-sensing, Investigator shall program a sensing margin of at least two times the intrinsic cardiac amplitude (e.g., for an intrinsic R- wave of 4 mv, program the R-sensitivity <2 mv). To avoid potential complications associated with loss of pacing capture, Investigator shall maintain pulse amplitude margin of at least two times the pacing threshold (e.g., for a pacing threshold of 0.5V, program the pulse amplitude >1.0V) LCP Repositioning and/or Release Once the investigator implants the LCP and successfully demonstrates acute effectiveness, the investigator may release the LCP. Investigator may reposition LCP, if necessary. For release and repositioning procedures, refer to the IFU. Once the LCP has been released, investigator will use a retrieval catheter for removal, if needed (Refer to Retrieval Catheter IFU). Once the LCP has been removed, investigator may attempt to implant another LCP, or instead, choose to implant a market-approved pacemaker. When the investigator has released the LCP, s/he will use fluoroscopy to assess positioning of the implanted LCP Unsuccessful Implant Investigators will follow subjects who have an unsuccessful implant for a period of 30 days to evaluate for adverse events. At the end of the 30 days, the investigator will withdraw the subject. The investigator must document the nature of the unsuccessful implant on the Procedure Form. Data Submission Once information has been collected and required testing has been completed at the implant visit, complete and submit the forms listed below to sponsor. Enrollment Form Implant Form LCP Assessment and Programming Form Medications Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable LCP Retrievals and Replacement When considering LCP retrieval and replacement, investigators will refer to the respective IFUs. The LEADLESS II Study Page 32 November 1, 2013

36 DC Rev D Under normal operating conditions, the LCP battery is expected to last for approximately 8.4 years. In the event a Nanostim LCP must be removed during the clinical study follow-up period, investigators may opt to replace LCPs in the following ways: Retrieve the first Nanostim pacemaker with a special catheter and implant a new Nanostim pacemaker, Deactivate the first Nanostim pacemaker and implant a second Nanostim pacemaker in close proximity to the first one, or Deactivate the first Nanostim pacemaker and implant a traditional pacemaker with a lead. Complete and submit the forms listed below to sponsor. Implant Form LCP Assessment and Programming Form, if applicable Medications, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Death Form, if applicable If the subject has the Nanostim LCP removed at any time during the study, and the subject will not receive a replacement Nanostim LCP, follow the subject for 30 days, and withdraw the subject from the study. Complete and submit the forms listed below to sponsor. Study Withdrawal Form Product Out of Service Form LCP Assessment and Programming Form, if applicable Medications, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Death Form, if applicable Post-procedure Assessments The follow-up period is sufficient to demonstrate safety and effectiveness. Additionally, during this 6-month follow-up period, sponsor will identify any residual risks and complications. Subjects will be seen at the following intervals: Pre-discharge assessment 2-week follow-up visit (in-office or clinic) 6-week follow-up visit (in-office or clinic) The LEADLESS II Study Page 33 November 1, 2013

37 3-months follow-up visit (in-office or clinic) 6-months follow-up visit (in-office or clinic) Investigation Plan DC Rev D After completing 6-month follow-up assessment, subjects will return every 6 months until study completion Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Table 3: Follow-up Assessment Windows Post Implant (Pre-Discharge) 2-week follow-up 6-week follow-up 0-2days 14 ± 7 days 42 ± 7 days 3-month followup 6-month follow-up 90 ± 30 days 180 ± 30 days Every 6 months post 1-year until study completion Every 180 ± 45 days Access-site Management During Hospital Stay Investigator will manage vascular-access sites per standard of care. Investigator will assess and document any post-procedural access-site bleeding event based on the following grading system. ACCESS-SITE OOZING: Superficial bleeding of a cutaneous or subcutaneous origin characterized by diffuse localized bleeding and controlled with minimal care (e.g., application of manual pressure, application of sandbag). ACCESS-SITE HEMATOMA: A localized collection of extravasated blood in subcutaneous tissue at the access site that does not require intervention. A metric ruler should be used to measure the widest portion of the hematoma. ACCESS-SITE HEMATOMA REQUIRING INTERVENTION: A localized collection of extravasated blood in subcutaneous tissue at the access site that is considered life threatening The LEADLESS II Study Page 34 November 1, 2013

38 DC Rev D and requires emergency wound exploration (e.g., acutely expanding hematoma, acute leg pain/numbness/swelling) and/or prolongation of hospital stay. ACCESS-SITE RE-BLEEDING: Localized bleeding at the access site that occurs after hospital discharge. These bleeds are typically associated with an event (e.g., fall, attempted suture removal, physical activity) Pre-Discharge Assessment Investigator will assess all subjects at the implant center prior to hospital discharge, or within 2-days post implant, whichever is shorter. Investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; Assess magnet mode; Program LCP; Obtain a 12-lead electrocardiogram (ECG) with pacing ON; Obtain a posterior/anterior (P/A) and lateral view chest x-ray to assess final LCP position; Investigator will use medical judgment and provide institutional standard of care for post-pacemaker-implant monitoring. Data Submission Once information has been collected and required testing has been completed at the implant visit, complete and submit the forms listed below to sponsor. Pre-Discharge Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Hospitalization Form, if applicable The LEADLESS II Study Page 35 November 1, 2013

39 DC Rev D week and 6-week follow-up visits All subjects will return to the investigation site for a 14-day and 42-day (±7 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; Program LCP and adjust programmable parameters of LCP, as needed. Data Submission Once information has been collected and required testing has been completed at the visit, complete and submit the forms listed below to sponsor. Follow-up Visit Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Hospitalization Form, if applicable Month Visit All subjects will return to the investigation site for a 90-day (±30 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; Program LCP and adjust programmable parameters of LCP, as needed; Holter Data Collection 3 3 Holter data collection can be done any time at or after the 3- month follow-up visit. The LEADLESS II Study Page 36 November 1, 2013

40 DC Rev D o Connect each capable subject to 24-hour Holter monitor (until 30 subjects contribute to the analysis); set LCP to VVIR mode, if indicated. CAEP Protocol 4 o Administer CAEP protocol with rate-response feature in VVIR ON mode (refer to CAEP protocol this test may be performed between 3 and 6 months post-implant). o After completing CAEP protocol, program LCP and adjust programmable parameters of LCP, as needed. Data Submission Once information has been collected and required testing has been completed at the visit, complete and submit the forms listed below to sponsor. Follow-up Visit Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Holter Form, if applicable Graded Exercise Test Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Hospitalization Form, if applicable Month Follow-up Visit All subjects will return to the investigation site for a 180-day (±30 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; 4 Administration of the CAEP protocol can be done any time at or after the 3- month follow-up visit, (until 30 subjects contribute to the analysis). The LEADLESS II Study Page 37 November 1, 2013

41 DC Rev D Data Submission Once information has been collected and required testing has been completed at the visit, complete and submit the forms listed below to sponsor. Follow-up Visit Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Hospitalization Form, if applicable Follow-up Visit Every Subsequent 6-Months until Study Completion All subjects will return to the investigation site every 180-days (±45 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; Program LCP and adjust programmable parameters of LCP, as needed. Data Submission Once information has been collected and required testing has been completed at the visit, complete and submit the forms listed below to sponsor. Follow-up Visit Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable The LEADLESS II Study Page 38 November 1, 2013

42 DC Rev D Hospitalization Form, if applicable Unscheduled Follow-up Visits If a subject returns to the investigation site for a clinically-warranted unscheduled visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in cardiac medications and adjunct cardiac medical therapies; Measure and record LCP performance, as described in LCP Assessment and Programming ; Program LCP and adjust programmable parameters of LCP, as needed. Data Submission Once information has been collected and required testing has been completed at the visit, complete and submit the forms listed below to sponsor. Follow-up Visit Form LCP Assessment and Programming Form Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Hospitalization Form, if applicable 7.0 Protocol Deviations Investigators are required to adhere to the investigation plan, signed Investigator s Agreement, applicable federal or state/local, laws and regulations, and any conditions required by the IRB, or FDA. A protocol deviation is used to describe situations in which the investigation plan was not followed. Investigator must report all deviations from the investigational to sponsor per 21 CFR In addition, investigator must report all deviations to the reviewing IRB per the IRB s reporting requirements. The LEADLESS II Study Page 39 November 1, 2013

43 DC Rev D Investigator must notify sponsor and the reviewing IRB of any deviation from the investigation plan to protect the life or physical well-being of a subject in an emergency as soon as possible, but not later than 5-working days after the deviation has occurred, or no later than 5-working days after the investigator becomes aware of the deviation. 8.0 Adverse Events A Clinical Events Committee (CEC) will review and adjudicate all Adverse Events. The CEC will base their final adjudication on the information provided on the case report forms, medical records, and their clinical knowledge and experience. Investigator will document all AEs on the Adverse Event Form, including (at a minimum) a description of the event, date of onset, relationship to the investigational device, required interventions, duration, and outcome. Investigator will monitor all AEs until they are resolved, determined to be a chronic condition or the subject is lost to follow-up. Investigator will report all AEs regardless of whether it is anticipated or unanticipated and regardless of classification, seriousness, outcome or causality. Should an AE occur, complete an Adverse Event Form and submit to sponsor. If an adverse event occurs between scheduled visits, report the event at the next scheduled visit. Report the adverse event to the IRB/MEC per the IRB/MEC policy. Investigator will return any retrieved devices to sponsor for analysis. Unavoidable AEs are not reportable unless the condition worsens or continues beyond the time frame listed below. Unavoidable AEs, listed below, do not need to be reported if they are resolved within the time frame specified. Table 2: Unavoidable AEs related to the Implant Procedure Event Time Frame post-implant Anesthesia related nausea/vomiting <24 hours Low-grade fever (<100 degree Fahrenheit fever or < < 48 hours 37.8 degree Celsius Percutaneous access pain < 72 hours Mild to moderate bruising/ecchymosis at < 72 hours percutaneous access site Sleep problems (insomnia) < 72 hours Back pain related to laying on the table < 72 hours If an UNANTICIPATED ADVERSE DEVICE EFFECT occurs, the investigator must notify sponsor and the IRB/MEC immediately, but no later than 10 working days of the investigator s knowledge of the event, as required by 21 CFR Sponsor will take any steps necessary to investigate the event, and will be responsible for notifying FDA and all other participating IRBs/MECs and investigators. The LEADLESS II Study Page 40 November 1, 2013

44 DC Rev D Should sponsor determine, either through physician reports or in-house testing, that an unanticipated adverse event presents an unreasonable risk to participating subjects, sponsor will suspend the clinical investigation and notify all participating investigators, IRBs/MECs and FDA. Sponsor will provide to FDA on a quarterly basis an interim safety and adverse event report. The LEADLESS II Study Page 41 November 1, 2013

45 DC Rev D Table 4: List of foreseeable adverse events and anticipated adverse device effects Air embolism Induced ventricular ectopy or arrhythmias Angina pectoris Infection, local at access site, or systemic Arterial puncture Insufficient cardiac output AV fistula Intermittent capture Bladder puncture Interruption of desired pacemaker function due to electrical interference, either electromyogenic or electromagnetic Blood transfusion Keloid formation Blunted or poor sensor response Loss of normal device function due to battery failure or component malfunction Body rejection phenomena Muscle and nerve stimulation Bowel penetration Myocardial damage Cardiac arrhythmias Myocardial infarction Cardiac dissection Myocardial irritability Cardiac perforation Oversensing Cardiac tamponade Pacemaker syndrome Chronic nerve damage Palpitations Damage to vessels Pericardial effusion or rub Death Pericarditis Device dislodgment Phrenic nerve/diaphragmatic stimulation Dizziness Pneumothorax Dyspnea Premature battery depletion Embolism Programmer/software anomaly Endocarditis Pseudoaneurysm formation Excessive Bleeding Psoas abscess Exit block Reaction to contrast Failure to capture/loss of capture Septic arthritis Femoral nerve injury with Seroma resulting paresthesias Fluid accumulation Syncope Hematoma formation, including Threshold elevation retroperitoneal hematoma/hemorrhage High impedance Thromboemboli Inability to interrogate or Thrombosis program due to programmer or device malfunction The LEADLESS II Study Page 42 November 1, 2013

46 DC Rev D Table 4: List of foreseeable adverse events and anticipated adverse device effects (continued) Undersensing Venous perforation Valve damage Ventricular ectopy Venous occlusion Ventricular tachycardia A right ventriculogram carries risk, most notably, allergic reaction to contrast media. 9.0 Deaths In the event of subject death, the investigator should provide sponsor and monitor with access to source documents. If source documents are not available, investigator should provide a letter to the sponsor summarizing the subject s course since enrollment in the study and the details of death with the following information, if available. Date and time of death Place death occurred (e.g. hospital, nursing home, subject s home) If death was witnessed Identification of the rhythm at the time of death, if known (include any available documentation) Cause of death Any other circumstances surrounding the death Approximate time interval to death from the initiating event Autopsy report (if performed) Whether it was device and/or procedure related Whether it was related to the study If any of the above information is not available, investigator will provide an explanation in the death narrative of what attempts (and how many) were made to obtain the information, and the outcome of those attempts. At a minimum, investigator will place two (2) phone calls, followed by a certified letter, to the subject s next of kin and provide clinical notes and witness statements. If possible, interrogate the pacemaker. Retrieve and print all episode diagnostics, and programmed parameters. If applicable, the pacemaker should then be programmed OFF. Attempt to explant the pacemaker and return any explanted devices to sponsor for analysis promptly. Clearly state on Case Report Form the reason the pacemaker is not being returned to sponsor. The LEADLESS II Study Page 43 November 1, 2013

47 10.0 Committees and Core Laboratories Investigation Plan DC Rev D 10.1 Data and safety monitoring board (DSMB) Sponsor will establish an independent DSMB to review safety data. The DSMB will consist of at least 3 members with study-related backgrounds. Members will include at least one statistician and two cardiologists with pacemaker experience. Nanostim will appoint members of the DSMB and the chairperson. Nanostim may provide administrative support to DSMB meetings, but will not be a voting member and will not be present during closed portions of the meeting. Non-DSMB members are not allowed to be present during DSMB closed meetings. Refer to DSMB Charter, RC Sponsor will provide to FDA within 10 working days of receipt copies of written communication from the DSMB that relates to safety concerns, or changes to the study plan, procedures or informed consent document. Sponsor will provide the DSMB within 10 working days copies of any letter from FDA that relates to safety concerns, or changes to the study plan, procedures or informed consent document Clinical events committee (CEC) Sponsor will establish an independent CEC to review all adverse events. The CEC s role is to determine relationship of event to device and or procedure. The CEC will consist of at least 3 members with study-related backgrounds. Members will include clinicians with relevant experience. Nanostim will appoint members of the CEC and the chairperson. Nanostim may supply study information and provide administrative support for CEC meetings, but will not be a voting member. Refer to CEC Charter, RC Holter core laboratory Sponsor will establish an independent core laboratory to review all 24-hour Holter monitors. The core laboratory s role is to evaluate and report Holter findings Withdrawals Withdrawal is defined as termination of a subject s participation from the clinical trial. All reasonable efforts should be made to retain the subject in the clinical trial until completion of the clinical trial. All reasons for withdrawal will be documented. Reasons for withdrawal include, but are not limited to the following: Subject Death Subject and/or Family Request representing withdrawal of consent Subject Lost to Follow-Up: Subject will be considered lost to follow-up after a minimum of 2 documented phone calls by personnel at the investigational center to The LEADLESS II Study Page 44 November 1, 2013

48 DC Rev D the subject or emergency contact and a certified letter is sent to the last known address Subject Participation terminated by investigator based on the best medical interest of the study subject Pacemaker explanted Unsuccessful Implant. A Study Withdrawal Form will be completed by clinical sites and sent to sponsor Risk Analysis Nanostim addresses the risk of poor usability of the programmer through a usability engineering process complying with EN 62366:2007. Nanostim has implemented a risk management process in conformance with EN ISO 14971:2012. The application of this risk management process to the leadless pacemaker system is documented in a risk management file. The risk management file also includes a risk management plan (Nanostim s standard operating procedure for risk management). This risk management process includes risk analysis, risk evaluation, and risk control. These are documented for the leadless pacemaker system in a top-down system hazard analysis; bottom-up failure mode effects analyses for the pacemaker, catheters, programmer and introducer; software safety analyses for the pacemaker and programmer; annual reviews of post-production information on similar devices; and a system risk management report. These bottom-up analyses provide risk analysis for single component failure as required by EN : Product-related risks Nanostim conducted system hazard analysis for the LCP system. This analysis found that the system employed state of the art therapy and materials. Failure-mode-effects analyses of each device in the system confirmed that the level of risk is as expected for pacing systems. Thus, the risk assessment focused on the potential influence of novel design features: implantation procedure; access site; fixation characteristics; absence of lead, connector, and antenna; device retrieval; and conductive communication with programmer (Link). Nanostim s risk assessment identified uncertainties relating to product-specific risks, such as those associated with percutaneous delivery via a femoral vein, and dislodgement or migration. The need for product-specific risk-control measures was identified, such as fixation optimization and exclusion of subjects with pulmonary arterial hypertension or lung disease Clinical risks Nanostim s risk assessment following the system hazard analysis concluded that the patient population and delivered therapy are essentially the same as those of existing VVIR therapy. The LEADLESS II Study Page 45 November 1, 2013

49 DC Rev D Thus, existing clinical evidence addresses proof of concept of therapy and supports the view that clinical risks should be the same as those seen with comparable existing products. The follow-up period of 6-12 months is consistent with the follow-up duration of comparable devices in studies for regulatory approval, which in turn was determined by the well-known maturation time of the interface between the electrode and myocardium, which is typically reached by three months 5. Animal study, human clinical trial results and feedback from physicians indicate that the delivery, implantation and retrieval procedures will not expose the subject, the physician or third parties to radiation in excess to that from implantation of a conventional single chamber pacemaker and lead Anticipated clinical benefits Implantation of the LCP for cardiac pacing could offer certain advantages as compared to a conventional pacemaker. Specifically, the benefits that are associated with the use of the LCP could include: Precise and repeatable procedure; Percutaneous procedure (potential outpatient procedure); Eliminates the need for lead (no risk of lead fracture, lowers risk of infection); Eliminates the need for a pocket (lowers risk of infection, no need for scar and/or lump); Eliminates the need for connectors (eliminates connector complications); Eliminates the visible lump and scar at a conventional pacemaker s pectoral implant site; Could lessen the need for activity restrictions after implantation; 12.4 Benefit/risk assessment It is concluded from preclinical data (risk analysis and literature review) that clinical risks are comparable to those associated with currently available therapy. Uncertainty exists in relation to risks associated with novel features (percutaneous delivery via a femoral vein and the possibility dislodgement or migration). These residual risks cannot be estimated with confidence without data from a clinical investigation. Taking into account the nature of the possible harm that could arise from these device-related risks and the assurance provided by pre-clinical data, the risk-benefit balance associated with the use of the LCP in a clinical trial is considered to be favourable Conclusions from pre-clinical risk evaluation Clinical investigation needs to confirm safety and performance of novel design features. The basis for design of this investigation may be summarized as follows: 5 Hayes DL, Friedman PA, Cardiac pacing, defibrillation, and resynchronization: a clinical approach, Wiley 2011, The LEADLESS II Study Page 46 November 1, 2013

50 DC Rev D Most design features are equivalent to existing products and will have been verified by pre-clinical evaluation. Literature shows that for conventional pacemakers, approximately 96% of patients are event-free at 6-months. Risk analysis indicates novel features should not be associated with significant residual risks or complications. It is not possible to design a clinical investigation to investigate low-level or unexpected risks, on the basis of a statistical analysis. The objective should be to identify a flaw in the pre-clinical risk analysis, exposing the minimum number of subjects to the risk. It is concluded that the results of the pre-clinical evaluation justify the design of the clinical investigation to determine whether the Nanostim LCP is suitable for the purpose and the population for which it is intended. The clinical investigation has been designed to ensure that the results obtained have clinical relevance and scientific validity, and address the clinical investigation objectives. The LEADLESS II Study Page 47 November 1, 2013

51 13.0 Description of Device Investigation Plan DC Rev D 13.1 Identification of the device: proprietary and code names The Nanostim leadless cardiac pacemaker system consists of these items: Name in Nanostim s Name on labels on product lifecycle the device and its management system S1DLCP System 1, leadless cardiac pacemaker S1LINK System 1, communications link for SJM Merlin programmer S1S18F System 1, 18 French introducer, 30 cm length S1RSIN S1RTRI System 1, single-loop retrieval catheter System 1, tri-loop retrieval catheter packaging Notes Acronym System 1, leadless LCP cardiac pacemaker S1LINK 18F Introducer Kit System 1 Retrieval Catheter, Single Loop System 1 Retrieval Catheter, Triple Loop 13.2 Description of the device and its intended application Includes pacemaker and catheter for delivering the pacemaker For interrogating and programming the pacemaker after implant For use with pacemaker, delivery catheter, or retrieval catheters For retrieving an implanted pacemaker with a single-loop snare For retrieving an implanted pacemaker with a tri-loop snare PRG INT RET RET The Nanostim LCP system consists of the Nanostim LCP and its accessories listed in The intended application of the LCP is implant in the right ventricle, with permanent duration (greater than 30 days). The intended application of the delivery catheter, retrieval catheters, and introducer is external communicating, circulating blood contact, with limited duration (less than 24 hours). The intended application of the communications link is external, with skin contact via a CE-marked cable and ECG electrodes. The devices in the system achieve their intended purposes as described in the subsections below: Leadless cardiac pacemaker (LCP) The LCP provides bradycardia pacing as a pulse generator with built-in battery and electrodes, for permanent implantation in the apex of the right ventricle. As a leadless pacemaker, it does not need a connector, pacing lead, or pulse generator pocket. A distal non-retractable, single-turn helix affixes the LCP to the endocardium. Sensing, pacing and communication with the external programmer occur between a distal electrode near the helix The LEADLESS II Study Page 48 November 1, 2013

52 DC Rev D and the external can of the LCP. The tip electrode is a titanium-nitride coated platinumiridium disc located at the center of the fixation helix, with a geometric surface area of 2 mm 2. The tip electrode includes 0.1 to 0.7 mg of dexamethasone sodium phosphate, intended to reduce inflammation. The ring electrode is the uncoated part of the titanium pacemaker case, with a geometric surface area >500 mm2. The inter-electrode distance is >10 mm. The maximum depth of penetration of the fixation mechanism in tissue is 1.3 mm. The pacemaker s proximal end has a feature for docking to delivery and retrieval catheters, which provides for repositioning capability. The pacemaker communicates bi-directionally with the programmer via electrical signals conducted between the implanted LCP s electrodes and skin electrodes applied to the patient s chest and connected to the programmer. Consequently the pacemaker transmits signals using circuits and electrodes already provided for pacing, with data encoded in pulses delivered during the heart s refractory period. The pacemaker senses right-ventricular blood temperature to provide an increase in pacing rate with increased metabolic demand. Otherwise, the LCP has the same operating principles as a conventional cardiac pacemaker. For further information refer to DC-01470, Instructions for use, S1DLCP (pacemaker and delivery catheter). The drawing below shows mechanical characteristics of the LCP. Pacemaker length = 42 mm. Pacemaker outer diameter (max) = 6.15 mm. Key: A. Docking Interface button with cables. B. Ring electrode. C. Insulated header. D. MP35N fixation helix. E. Titanium nitride (TiN) coated platinum-iridium (Ptlr) electrode with steroid (proximal to helix) Delivery catheter The delivery catheter provides a means for a single operator to: Advance the LCP from an access site in the groin (utilizing minimally invasive techniques) through the femoral vein to the apex of the right ventricle, Protect the LCP helix and electrode during delivery, Position the LCP and rotate it to affix the helix, Undock the LCP from the delivery catheter leaving the LCP tethered to the delivery catheter, to measure thresholds without force from the catheter. Re-dock to the catheter, unscrew and reposition the LCP if necessary for acceptable thresholds. The LEADLESS II Study Page 49 November 1, 2013

53 DC Rev D Undock from the LCP, leaving it implanted, and disconnect it from the tether. Apart from the docking mechanism, the delivery catheter and its control system (handle) have the same operating principle as a conventional steerable catheter and control system. The system includes an introducer, one or more pre-shaped guide catheters, and an eptfe sleeve to protect the fixation helix and electrode. For further information refer to DC-01470, Instructions for use, S1DLCP (pacemaker and delivery catheter). The drawing below shows mechanical characteristics of the delivery catheter: Catheter effective length = 128 cm Catheter maximum outer diameter = 4.6 mm (0.178 inch) Programmer Link The programmer displays the patient s electrocardiogram and the status of the implanted LCP, and it sends commands to change LCP parameter settings as directed by a user. The programmer transmits signals to an implanted LCP via conducted communication with subliminal 250 khz pulses applied to the skin electrodes. Apart from this conducted communication, it has the same operating principle as a conventional pacemaker programmer. The Nanostim programmer uses a St. Jude Medical Merlin Patient Care System Programmer (Model 3650) with a USB interface to a Nanostim external module (Nanostim link). The module uploads Nanostim software to the Merlin programmer and provides an interface between the programmer and standard ECG electrodes placed on the subject s torso, for twoway communication with the implanted pacemaker and display of the surface ECG. For further information refer to DC-01471, Instructions for use, S1LINK programmer. The LEADLESS II Study Page 50 November 1, 2013

54 The photographs below show mechanical characteristics of the Link: Top view Bottom view Investigation Plan DC Rev D 1. LED lights will illuminate when the S1LINK is receiving appropriate power 2. Patient connector. Connect to the patient using the patient cable and skin electrodes. 3. USB connector. Connect to the St. Jude Merlin programmer using the USB cable. 4. Auxiliary power connector. Not required in normal use 1. The mating slot in the middle of the S1LINK is designed to slide on top of a mount that is affixed via glue to the back of a St Jude Merlin programmer. 2. The S1LINK is approximately 4.5 x 9.5 x 1.5. Its case is made of plastic. The S1LINK weighs approximately one pound F introducer kit The system includes an 18F introducer kit consisting of a sheath introducer and dilator. The introducer provides access to the venous vasculature and operates compatibly with the Nanostim pacemaker and catheters. For further information, refer to DC-01469, instructions for use, S1S18F (18F introducer kit). The LEADLESS II Study Page 51 November 1, 2013

55 The drawing below shows mechanical characteristics of the 18F introducer kit: Investigation Plan DC Rev D LN = length ID = inner diameter OD = outer diameter = inches Retrieval catheters The retrieval catheters use a snare to engage the docking feature on the proximal end of the LCP, mate the retrieval catheter with the docking cap, unscrew it, and retrieve it. Consequently, the retrieval catheter provides means for a single operator to: Mate with the proximal button of the LCP from an access site in the groin through the femoral vein to the right ventricle. Dock to the LCP, Rotate the LCP to unscrew the helix from the endocardium, Protect the LCP helix and electrode during retrieval Extract the LCP through the access site in the groin. Apart from the accessing, and docking features, the retrieval system has the same operating principle as a conventional steerable catheter and control system (handle). For additional information, refer to DC-01468, Instructions for use, retrieval catheters. The drawings below show mechanical characteristics for the single-loop and tri-loop retrieval catheters: Catheter effective length = 128 cm, catheter outer diameter (max) = 4.6 mm (0.181 inch). The LEADLESS II Study Page 52 November 1, 2013

56 DC Rev D Single-loop snare for S1RSIN Loop inner diameter = 19 mm (0.748 inch) Single-loop snare for S1RTRI Snare loop inner diameter = 20 mm (0.787 inch) 13.3 Configurations and Variants In this clinical investigation, Nanostim includes only one variant each of the leadless pacemaker and delivery catheter, and two variants of the retrieval catheter. Nanostim may incorporate a validated change to the LCP implant and/or programmer software, when necessary, to correct observed non-conformance with intended device operation Investigator Information This clinical investigation will be conducted by investigators with experience and/or willingness to be trained in the use of the device therapy for the treatment of bradyarrhythmias. An investigator should have experience in and/or will be responsible for: Conducting the clinical investigation in accordance with the signed agreement with sponsor, the investigation plan, all applicable FDA regulations (21 CFR Parts 50, 54, 56, 812), GCP guidelines, and any conditions of approval imposed by the IRB/MEC Providing signed Investigator s Agreement, RC Providing signed Financial Disclosure Form Providing IRB/MEC-approved Informed Consent Collection and archiving of data obtained pursuant to the requirements of the investigation plan during the course of the study and after the study has been completed Strict adherence to the investigation plan testing requirements Screening and selecting appropriate subjects. The LEADLESS II Study Page 53 November 1, 2013

57 DC Rev D It is acceptable for the principal investigator to delegate one or more of the above functions to an associate or co-investigator, however, the principal investigator remains responsible for the proper conduct of the clinical investigation, complying with the investigation plan and collecting all required data. In clinical investigations involving active implantation of an investigational product, the investigation is not transferable to other implant centers attended by the investigator unless prior approval is obtained from sponsor Monitoring Procedures Nanostim, Inc. will serve as the sponsor of the LEADLESS II clinical investigation. It is the responsibility of Nanostim, Inc. as the sponsor of the study to ensure proper monitoring of the investigation and to see that all the clinical requirements are met. Prior to beginning the study, sponsor personnel will contact the investigator or designee to discuss the investigation plan and to review the data requirements in detail. A monitor will visit the investigator or designee periodically during the study to monitor progress, to assist in gathering the required data and to answer any questions. During these visits, the clinical monitor will review the subject s records to verify that all records and files are up to date, and to assure compliance with all requirements of the protocol and FDA regulations. The investigator will make subject and study records available to the clinical monitor for periodic inspection. Clinical monitoring will be conducted in accordance with the Monitoring Plan, RC Responsibility for overall study management will be held by the VP, Global Clinical Studies, St. Jude Medical. Clinical Studies Department St. Jude Medial IESD Valley View Court Sylmar, CA TEL: +1 (818) FAX: +1 (800) FDA Inspections The investigator and/or designee should contact sponsor within 24 hours upon being notified of an impending FDA inspection. A clinical monitor may assist and review study documentation with the investigator and/or designee to prepare for the audit. An investigator shall permit authorized FDA employees, at reasonable times and in a reasonable manner, to enter and inspect any establishment where investigational devices are used and to inspect and copy all records relating to an investigation. The LEADLESS II Study Page 54 November 1, 2013

58 DC Rev D An investigator shall permit authorized FDA employees to inspect and copy records that identify subjects, upon notice that FDA has reason to suspect that adequate informed consent was not obtained, or that reports required to be submitted by the investigator to the sponsor or IRB have not been submitted or are incomplete, inaccurate, false, or misleading Labeling Sponsor will provide all implants and accessories with labels in USA stating, CAUTION-- Investigational device. Limited by Federal (or United States) law to investigational use. Sponsor will also provide implants and accessories for use in Canada with appropriate Canadian labeling. Sponsor will provide all implants and catheters as sterile units, and the packaging lists the method of sterilization, manufacturing date, manufacturer name and address, use before date, that devices are single use only, model number, and lot or serial number. The programmer and accessories labels contain the company name, location and phone number, model number, and lot or serial number. Software versions are displayed on the programmer screen and in printed or saved reports. Validated changes to implant and programmer software are allowed during the study, when necessary, to correct an observed nonconformance with intended device operation. Nanostim implants, catheters and programmers will be stored in a clean, dry, secure location at room temperature prior to shipment to the clinical site Consent Materials All subjects will be consented for seven-year follow-up, so that they can additionally contribute to post-approval studies. Refer to sample consent form, Patient Informed Consent, RC Failure to obtain informed consent from a subject prior to study enrollment should be reported to sponsor within 5 working days and to the reviewing IRB consistent with the IRB s reporting requirements IRB Information IRB approval for the study and informed consent will be required prior to beginning the study. A copy of the IRB approval and corresponding informed consent must be forwarded to sponsor prior to authorization of the institution to begin the study. Any withdrawal of IRB approval should be reported to sponsor within 5 working days of the withdrawal of approval. A list of IRBs for Institutions participating in the clinical investigation will be provided upon request. The LEADLESS II Study Page 55 November 1, 2013

59 19.0 Other Institutions Investigation Plan DC Rev D The name and address of each institution, at which a part of the investigation may be conducted, that has not been identified under IRB information, will be provided upon request Records and Reports Clinical investigators are required to maintain all study records, prepare and submit reports, and permit FDA Bioresearch Monitoring Inspections relating to the investigator s participation in and conduct of the study, as described in 21 CFR Sponsor will provide study data to the FDA on an annual basis or as requested by the FDA. Sponsor will provide to FDA on a quarterly basis an interim safety and adverse event report. Sponsor will provide an IDE interim report to FDA within one month of completion of the 30 th patient Holter monitor Custody An investigator may withdraw from the responsibility to maintain records for the period required and transfer custody of the records to any other person who will accept responsibility for them as described, including the requirements regarding FDA inspection. Notice of transfer shall be given to sponsor and FDA no later than ten working days after transfer occurs Retention Period Investigator is required to maintain records during the investigation and for a period of two years after the date on which the investigation is terminated or completed. Sponsor will maintain records until they are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol Publications This study will be posted on ClinicalTrials.gov and results will be posted on ClinicalTrials.gov as required. The LEADLESS II Study Page 56 November 1, 2013

60 DC Rev D 22.0 Appendices 22.1 Appendix A: Graded Exercise Test (CAEP Protocol) The Chronotropic Assessment Exercise Protocol (CAEP) Stage Speed (MPH) Grade (%) Time (min) Cumulative time METs Warm-up (0) Source Hamilton D KM, Sharp C, Haennel R. Cardiac Pacemakers and Exercise Rehabiliation. In: Jobin J, ed. Advancing the frontiers of cardiopulmonary rehabilitation:2002:83. The LEADLESS II Study Page 57 November 1, 2013

61 23.0 Bibliography Investigation Plan DC Rev D 1. Vardas PE, Auricchio A, Blanc JJ, et al. Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association. European heart journal. Sep 2007;28(18): Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Journal of the American College of Cardiology. May ;51(21):e Turi ZG. An evidence-based approach to femoral arterial access and closure. Reviews in cardiovascular medicine. Winter 2008;9(1): Turi ZG. Fluoroscopy guided vascular access: asking the right question, but getting the wrong answer? Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Oct ;74(4): Schnyder G, Sawhney N, Whisenant B, Tsimikas S, Turi ZG. Common femoral artery anatomy is influenced by demographics and comorbidity: implications for cardiac and peripheral invasive studies. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Jul 2001;53(3): Abu-Fadel MS, Sparling JM, Zacharias SJ, et al. Fluoroscopy vs. traditional guided femoral arterial access and the use of closure devices: a randomized controlled trial. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Oct ;74(4): Seto AH, Abu-Fadel MS, Sparling JM, et al. Real-time ultrasound guidance facilitates femoral arterial access and reduces vascular complications: FAUST (Femoral Arterial Access With Ultrasound Trial). JACC. Cardiovascular interventions. Jul 2010;3(7): Fitts J, Ver Lee P, Hofmaster P, Malenka D, Northern New England Cardiovascular Study G. Fluoroscopy-guided femoral artery puncture reduces the risk of PCI-related vascular complications. Journal of interventional cardiology. Jun 2008;21(3): Turi ZG. Optimizing vascular access: routine femoral angiography keeps the vascular complication away. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Jun 2005;65(2): Sherev DA, Shaw RE, Brent BN. Angiographic predictors of femoral access site complications: implication for planned percutaneous coronary intervention. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. Jun 2005;65(2): The LEADLESS II Study Page 58 November 1, 2013

62 INVESTIGATION PLAN The LEADLESS II Study A safety and effectiveness trial for a leadless pacemaker system /Rev H DC-02374/ Rev H July 18, 2014 IDE Number: G The LEADLESS II Study Page 1 July 18, 2014

63 1.0 Revision Change History Investigation Plan DC-02374/ Rev H /Rev H Revision # Reason for Revision DC Rev A First doc controlled version of investigation plan submitted to FDA DC Rev B Conformance to remarks in FDA letter of for G DC Rev C Conformance to remarks in FDA letter of for G DC Rev D Conformance to remarks in FDA of for G and c DC Rev E Changes of sponsor and study-device names. Section Secondary endpoint clarification: - Deleted intrinsic rate Y3 and heart rate Y4 and replaced with heart rate Y3, because Y2 sensor-indicated rate plotted with Y3 intrinsic rate provides information about status of subject s heart rate. - Clarification on statistical methods used to calculate the mean slope of the normalized increase in sensor-indicated rate versus normalized CAEP workload and the test statistic for evaluation of the CAEP endpoint. Modification of the up to 50 investigation sites in USA, Canada, Europe to worldwide with up to 50 investigation sites in USA Additional clarification to the following inclusion/exclusion criteria: - Addition of the words before device implant in the first inclusion criterion. - Addition of the word known in the first exclusion criterion. - Defined significant physiologically-impairing lung disease to be severe pulmonary disease producing frequent hospitalizations for respiratory distress or requiring continuous home oxygen Updated abbreviations (section 3.0).Clarified the definition of subjects lost to followup to Subject will be considered lost to follow-up after a minimum of 2 documented phone calls by personnel at the investigational center to the subject or emergency contact, a certified letter is sent to the last known address and two consecutive visits pass without the investigator receiving data. EQ-5D patient survey will be collected at 4 different visits. Hospitalization Form has been renamed to Healthcare Utilization Form Medications Form is deleted. Information about medications will be captured on the enrollment, implant, pre-discharge and follow-up forms. A window between 3-months and 6-months post-implant has been specified for the Holter test and CAEP exercise test. Under additional data, reason for unsuccessful implant and device handling characteristics, final leadless pacemaker placement, hospitalizations and mortality have been added. Subject numbering format has been updated. A statement has been added about submitting case report forms and device printouts using the St. Jude Medical Electronic Data Capture (EDC) system. Assessment of cardiac medications has been made specific to anti-platelets, anticoagulants and anti-arrhythmics. The LEADLESS II Study Page 2 July 18, 2014

64 DC Rev E continued A section on hospitalizations has been added. The death section has been updated. Investigation Plan DC-02374/ Rev H /Rev H DC Rev F An instruction to collect Product Out of Service and Healthcare Utilization Forms has been added at certain visits, if applicable. Clarification on the total number of sites was modified to this statement: Sponsor will conduct the study at up to 60 centers worldwide with up to 50 centers in the United States Date collection regarding medications: In addition to anticoagulant, antiplatelet and antiarrhythmic, the following medications will also be reported: beta blocker, ACE (ace inhibitor) and ARB (angiotensin II receptor blocker) at enrollment and all scheduled follow-up visits. Added exclusion criteria: Subject had recent cardiovascular or peripheral vascular surgery within 30 days of enrollment DC Rev G Replaced patient with subject to be consistent throughout IP Clinical Investigation Plan Synopsis: Secondary Endpoint- Changed assessment window from any time after 3-month visit to between 3-6 month visit Schedule of Assessment-3-month: Removed first in front of 30 patients for CAEP and Holter Monitor test(s) IP Section 2.0-Secondary Endpoint: Clarification of CAEP treadmill: Individual slope calculations sets y-intercept to zero Data from subjects unable to complete at least 4 stages of the exercise protocol will be excluded from analysis Thirty subjects will provide data contributing to the analysis. Appendix A: Warm-up phase name changed to stage 0 and limited to 2 minutes IP Section Modified # 5 exclusion criteria to: Subject has a pre-existing endocardial pacing or defibrillation leads IP Section Clarified #9 exclusion criteria: Recent cardiovascular or peripheral vascular surgery within 30 days of enrollment Recent cardiovascular or peripheral vascular surgery within 30 days of enrollment is defined as the following: (see next page) The LEADLESS II Study Page 3 July 18, 2014

65 DC Rev G continued Investigation Plan DC-02374/ Rev H /Rev H Percutaneous valvular correction 30 days Femoral or abdominal vascular procedure involving incisional access 30 days Peripheral or arterial endovascular procedure or surgery 30 days Cardiac surgery 72 hrs, ongoing mediastinal drainage, or re-do sternotomy attributed to bleeding 30 days Any endovascular procedure with specified complication 30 days - Femoral access site-vascular complication including hematoma requiring transfusion, surgical intervention or prolongation of hospitalization, arterio-venous fistula, pseudoaneurysm or tear - New pericardial effusion more than trivial/mild, or requiring percutaneous/surgical drainage Acute deep venous thrombosis IP Section 6.4- Typographical error: Changed femoral artery to femoral vein IP Section Added screening procedure to determine eligibility (i.e. echocardiogram for subjects with pulmonary arterial hypertension) IP Section Added billing information as part of data collection at pre-discharge assessment IP Section Modified Unscheduled follow up visit: Should only apply to visits associated with interrogation and reprogramming of the leadless pacemaker IP Section 7.0- Hospitalizations-specified types of visits that would require billing information. UB04 billing information should be limited to cardiac events. IP Section 9.0-AE Table: Removed Fluid accumulation and added- Heart Failure Added Access site bleeding event to be consistent with section DC Rev H IP Section Added- members in CEC will include cardiologists with pacemaker experience IP Section #9 exclusion criteria: Recent cardiovascular or peripheral vascular surgery within 30 days of enrollment Minor edit to definition (see below) Percutaneous valvular correction 30 days Femoral or abdominal vascular procedure involving incisional access 30 days Peripheral or arterial endovascular procedure or surgery 30 days Cardiac surgery 72 hrs with ongoing complications, ongoing mediastinal drainage, or re-do sternotomy attributed to bleeding 30 days Tricuspid valve replacement or annuloplasty 30 days Any endovascular procedure with specified complication 30 days - Femoral access site-vascular complication including hematoma requiring transfusion, surgical intervention or prolongation of hospitalization, arterio-venous fistula, pseudoaneurysm or tear - New pericardial effusion more than trivial/mild, or requiring percutaneous/surgical drainage Acute deep venous thrombosis I.P. Section Redefined Unscheduled visit definition to include when the subject returns to the investigational site for a visit that is related to the device or implant procedure. The LEADLESS II Study Page 4 July 18, 2014

66 DC-02374/ Rev H /Rev H Table of Contents 1.0 REVISION CHANGE HISTORY CLINICAL INVESTIGATION PLAN SYNOPSIS ABBREVIATIONS INTRODUCTION PURPOSE CLINICAL PROTOCOL STUDY DESIGN AND SCOPE STUDY OBJECTIVE AND ENDPOINTS Primary Endpoints Primary Safety Endpoint Primary Effectiveness Endpoint Data Analysis of Primary Safety and Effectiveness Endpoints Adaptive Sample Size Re-estimation Pooling of Regions and Sites Missing Data Subgroup Analyses Conditional Probability of Meeting 1-Year Primary Endpoints Secondary Endpoint Supplementary Endpoints Supplementary Safety Endpoint Evaluation at 12 Months Supplementary Effectiveness Endpoint Evaluation at 12 Months Data Analysis of Supplementary Safety and Effectiveness Endpoints Additional data Definitions used in LEADLESS II study SUBJECT SELECTION Inclusion Criteria Exclusion Criteria STUDY PROCEDURES Enrollment Requirements Recruitment and Enrollment Subject Numbering Baseline Assessment Medications Implant Procedure Femoral Vein Assessment and Access Nanostim LP Preparation and Implant Nanostim LP Assessment and Programming Nanostim LP Repositioning and/or Release Unsuccessful Implant Nanostim LP Retrievals and Replacement Post-procedure Assessments Access-site Management During Hospital Stay Pre-Discharge Assessment week and 6-week follow-up visits Month Visit Month Follow-up Visit Follow-up Visit Every Subsequent 6-Months until Study Completion Unscheduled Follow-up Visits The LEADLESS II Study Page 5 July 18, 2014

67 DC-02374/ Rev H /Rev H 7.0 HOSPITALIZATIONS PROTOCOL DEVIATIONS ADVERSE EVENTS DEATHS COMMITTEES AND CORE LABORATORIES DATA AND SAFETY MONITORING BOARD (DSMB) CLINICAL EVENTS COMMITTEE (CEC) HOLTER CORE LABORATORY WITHDRAWALS RISK ANALYSIS PRODUCT-RELATED RISKS CLINICAL RISKS ANTICIPATED CLINICAL BENEFITS BENEFIT/RISK ASSESSMENT CONCLUSIONS FROM PRE-CLINICAL RISK EVALUATION DESCRIPTION OF DEVICE IDENTIFICATION OF THE DEVICE: PROPRIETARY AND CODE NAMES DESCRIPTION OF THE DEVICE AND ITS INTENDED APPLICATION Nanostim LP Delivery catheter Nanostim Programmer Link Nanostim 18F introducer kit Nanostim Retrieval catheters CONFIGURATIONS AND VARIANTS INVESTIGATOR INFORMATION MONITORING PROCEDURES FDA INSPECTIONS LABELING CONSENT MATERIALS IRB INFORMATION OTHER INSTITUTIONS RECORDS AND REPORTS CUSTODY RETENTION PERIOD PUBLICATIONS APPENDICES APPENDIX A: GRADED EXERCISE TEST (CAEP PROTOCOL) BIBLIOGRAPHY The LEADLESS II Study Page 6 July 18, 2014

68 2.0 Clinical Investigation Plan Synopsis Investigation Plan DC-02374/ Rev H /Rev H Title A safety and effectiveness trial for a leadless pacemaker system The LEADLESS II Study Investigational Device Regulatory Classification of the Investigational Device Number of Institutions Nanostim Leadless Pacemaker (LP) Class III Up to sixty sites worldwide with up to 50 investigation sites in the United States. Number of Subjects Up to 667. At least 50% of the subjects recruited from sites located in the United States. Trial Population Schedule of Assessments Study Design Study Objective Primary Safety Endpoint Primary Effectiveness Endpoint Secondary Endpoint Subjects who are at least 18 years old, and who are indicated for a VVI(R) pacemaker. Enrollment, Implant, Pre-Discharge, 2-week, 6-week, 3-month, 6- month follow-up, and every 6 months thereafter until study completion. Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Prospective, non-randomized, single-arm, international multicenter, clinical safety and effectiveness investigation. The primary objectives of this study are to evaluate the clinical safety and effectiveness of the Nanostim LP system in subjects who are indicated for VVI(R) pacemaker. The primary safety endpoint evaluates the 6-month complicationfree rate. The primary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 6 months post-implant. The secondary endpoint evaluates an appropriate and proportional rate response during graded exercise testing (CAEP protocol), performed between 3-month and 6- month visit. The LEADLESS II Study Page 7 July 18, 2014

69 PMA Application Study continuation and supplementary analyses after PMA application Inclusion Criteria Investigation Plan DC-02374/ Rev H /Rev H A PMA application will be submitted to FDA upon successful demonstration of the 6-month primary safety and effectiveness objectives. These 6-month data will be sufficient for FDA to review the PMA and make a determination of the safety and effectiveness of the device and the approvability of the PMA. The study will continue under IDE until evaluation of 1-year supplementary safety and effectiveness objectives, or until PMA approval, whichever comes first. If PMA approval occurs before evaluation of the 1-year supplementary safety and effectiveness objectives, the study will continue as a short-term post-approval study, until evaluation of the 1-year supplementary safety and effectiveness objectives. All subjects in the IDE study and this short-term post-approval study will consent to continue annual follow-ups each year until 7 years after implant, in a long-term post-approval study. Eligible subjects will meet all of the following: 1. Subject must have one of the clinical indications before device implant in adherence with Medicare, ACC/AHA/HRS/ESC single chamber pacing guidelines including: Chronic and/or permanent atrial fibrillation with 2 or 3 AV or bifascicular bundle branch block (BBB block), including slow ventricular rates (with or without medication) associated with atrial fibrillation; or Normal sinus rhythm with 2 or 3 AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year); or Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings; and 2. Subject 18 years of age; and 3. Subject has life expectancy of at least one year; and 4. Subject is not enrolled in another clinical investigation; and 5. Subject is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams; and 6. Subject has been informed of the nature of the study, agrees to its provisions and has provided written informed consent, approved by the IRB; and 7. Subject is not pregnant and does not plan to get pregnant during the course of the study. The LEADLESS II Study Page 8 July 18, 2014

70 Clinical Investigation Synopsis continued Exclusion Criteria Investigation Plan DC-02374/ Rev H /Rev H Subjects will be excluded if they meet any of the following: 1. Subject has known pacemaker syndrome, has retrograde VA conduction or suffers a drop in arterial blood pressure with the onset of ventricular pacing; or 2. Subject is allergic or hypersensitive to <1 mg of dexamethasone sodium phosphate; or 3. Subject has a mechanical tricuspid valve prosthesis; or 4. Subject has a pre-existing pulmonary arterial (PA) hypertension (PA systolic pressure exceeds 40 mmhg or RV systolic pressure (RVSP) as estimated by echo exceeds 40 mmhg), or significant physiologically-impairing lung disease (have severe pulmonary disease producing frequent hospitalizations for respiratory distress or requiring continuous home oxygen); or 5. Subject has a pre-existing endocardial pacing or defibrillation leads; or 6. Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT); or 7. Subject has an implanted vena cava filter; or 8. Subject has evidence of thrombosis in one of the veins used for access during the procedure; or 9. Subject had recent cardiovascular or peripheral vascular surgery within 30 days of enrollment; or 10. Subject has an implanted leadless cardiac pacemaker. Enrollment Subjects who sign an IRB-approved informed consent and have an attempted or successful implant will be considered enrolled in the study. Estimated Schedule First subject enrolled: January 2014 Last subject enrolled: February 2015 Last subject visit: February 2016 The LEADLESS II Study Page 9 July 18, 2014

71 Clinical Investigation Synopsis continued Investigation Plan DC-02374/ Rev H /Rev H Schedule of Assessments Pre-procedure Assessments Inclusion/exclusion criteria Informed consent Pregnancy assessment 12-lead ECG Medical history Medications 1 Implant Assessments Femoral vein assessment and access Procedure details Nanostim LP implant Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs Post-procedure Assessments Access-site assessment 12-lead ECG X-ray of pacemaker Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 2-week Visit Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 1 Data are collected for beta blocker, ACE, ARB, anti-arrhythmic, anti-coagulant, and anti-platelet medications, at all visits. The LEADLESS II Study Page 10 July 18, 2014

72 Clinical Investigation Synopsis continued Schedule of Assessments (continued) Investigation Plan DC-02374/ Rev H /Rev H 6-week Visit Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 3-month Visit Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs 24-hour Holter monitor with diary (30 subjects) Graded exercise test (CAEP protocol) until 30 subjects provide data contributing to the analysis) 6-month Visit Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs Every 6-month Visits Nanostim LP assessment and programming Assess for changes in medications or change in therapy Assess for AEs The LEADLESS II Study Page 11 July 18, 2014

73 Activity Pre-procedure Assessments Screen & Enroll Baseline Table 1: Schedule of Assessments Procedure Assessment Implant Postprocedure Assessment 2-week Follow-up Visit 1 Post-procedure Assessments 6-week Follow-up Visit 1 3-month Follow-up Visit 2 6-month Follow-up Visit 2 Investigational Plan DC Rev. H /Rev H Every 6-months until study completion 3 Additional Visits Inclusion Exclusion Informed Consent Pregnancy Assessment/Test Medical History Baseline Assessment Procedure Post-procedure Pre-discharge Nanostim LP Assessment and Programming 12-lead ECG X-ray of a pacemaker Follow-up Visit 24-hour Holter monitor with diary 4 Graded exercise test CAEP Protocol 5 EQ-5D patient survey Additional CRFs (when applicable) Adverse Event Deviation Study Withdrawal Product Out of Service System Revision Death Healthcare Utilization 1 ±7 days 2 ±30 days 3 ±45 days 4 All capable subjects are asked to wear a 24-hour Holter and complete a diary, until 30 subjects provide data contributing to the analysis. The preferred window to perform the 24 hour Holter test is between the 3-month and 6-month visit. 5 All capable subjects are asked to perform a CAEP treadmill test until 30 subjects provide data contributing to the analysis. The preferred window to perform the CAEP treadmill test is between the 3-month and 6-month visit. The LEADLESS II Study Page 12 July 18, 2014

74 Investigational Plan DC Rev. H /Rev H 3.0 Abbreviations Abbreviation Definition Abbreviation Definition 2 Second degree EP Electrophysiology 3 Third degree ESC European Society of Cardiology ACC American College of Cardiology ICD Implantable cardioverter defibrillator ACT Activated clotting time IFU Instructions for use ADL Activities of daily living INR International normalized ratio AE Adverse event IRB Independent or institutional review board AHA American Heart LP Leadless pacemaker Association AV Atrioventricular MRI Magnetic resonance imaging BBB Bifascicular bundle branch PA Pulmonary arterial CAEP Chronotropic assessment PtIr Platinum Iridium exercise protocol CFR Complication free rate RR Rate response CIP Clinical investigation plan RV Right ventricular (also referred to as clinical protocol) CRF Case report form SAE Serious adverse event CRT Cardiac resynchronization TiN Titanium nitride therapy ECG Electrocardiogram UADE Unanticipated adverse device effect The LEADLESS II Study Page 13 July 18, 2014

75 4.0 Introduction Investigation Plan DC-02374/ Rev H /Rev H Sponsor has developed a leadless pacemaker system (Nanostim LP) to eliminate leads, pockets, and connectors required by conventional pacemakers and to eliminate associated complications. This concept could improve patient comfort by replacing a surgical procedure with a percutaneous one, eliminating the visible lump and scar at a conventional pacemaker s pectoral implant site, and removing the need for activity restrictions to prevent dislodgement after implantation of a conventional lead. Finally, the concept could permit pacemaker patients to undergo magnetic resonance imaging (MRI) with specified machines, although this is not being evaluated under this protocol. St. Jude Medical s Nanostim LP system consists of a pacemaker and its accessories: a programmer, introducer, delivery catheter, and retrieval catheters. The accessories are not intended for use alone or with any device other than the Nanostim LP. The pacemaker and all accessories, except the programmer, are single-use devices and are supplied sterile. 5.0 Purpose The intent of this IDE study is to evaluate the safety and effectiveness of the implanted Nanostim LP for treatment of bradycardia. A Nanostim Programmer Link also investigational, will be used in conjunction with the Nanostim LP. The Nanostim Programmer Link is a programming device that when connected to the St. Jude Medical Merlin Patient Care System (Model 3650) allows the user to communicate with the Nanostim LP. 6.0 Clinical Protocol 6.1 Study Design and Scope This is a prospective, non-randomized, multi-center, international clinical study designed to evaluate the safety and effectiveness of the Nanostim LP System in a subject population indicated for a VVI(R) pacemaker. Sponsor will conduct the study at up to 60 centers worldwide with up to 50 centers in the United States. To meet study endpoints, the Sponsor expects to enroll up to 667 subjects in 14 months, based on a model accounting for up to 10% attrition over the 1-year follow-up evaluation period. Sponsor will allow a maximum of 100 (15% of the total) enrollments per center and expects, on average, approximately 1.75 enrollments per center per month. At least 50% of subjects will be recruited from sites located in the United States. Enrollment in the LEADLESS II clinical study is expected to take approximately 14 months. Sponsor anticipates the duration of study participation to be approximately 26 months. All eligible subjects will undergo implant attempt with a Nanostim LP. The LEADLESS II Study Page 14 July 18, 2014

76 DC-02374/ Rev H /Rev H All subjects will consent to continue annual follow-ups each year until 7 years after implant, in a long-term post-approval study. The following study evaluations will occur after implant: Pre-discharge assessment 2-week follow-up visit (in-office or clinic) 6-week follow-up visit (in-office or clinic) 3-month follow-up visit (in-office or clinic) 6-month follow-up visit (in-office or clinic) Every 6 months thereafter until study completion Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Follow-up schedules will be calculated from the date of successful implant. 6.2 Study Objective and Endpoints The primary objectives of this study are to assess the safety and effectiveness of the Nanostim device from implant through 6-months in a subject population indicated for a VVI(R) pacemaker. Primary Safety Endpoint The primary safety endpoint evaluates a 6-month complication-free rate based on CEC adjudication of the adverse event. Primary Effectiveness Endpoint The primary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 6 months post-implant. Secondary Endpoint The secondary effectiveness endpoint evaluates an appropriate and proportional rate response during graded exercise testing (CAEP protocol). Supplementary Safety Endpoint The supplementary safety endpoint evaluates a 1-year complication-free rate based on CEC adjudication of the adverse event. Supplementary Effectiveness Endpoint The supplementary effectiveness endpoint evaluates pacing thresholds and R-wave amplitudes within the therapeutic range through 1 year post-implant. The LEADLESS II Study Page 15 July 18, 2014

77 6.2.1 Primary Endpoints Investigation Plan DC-02374/ Rev H /Rev H A PMA application will be submitted to FDA upon successful demonstration of the 6- month primary safety and effectiveness endpoints. These 6-month data will be sufficient for FDA to review the PMA and make a determination of the safety and effectiveness of the device and the approvability of the PMA Primary Safety Endpoint The goal of the primary safety endpoint evaluation is to demonstrate an acceptable complication-free rate (CFR); including any complication that prevents initial implantation. From a literature review of conventional pacemakers and leads (sponsor s document RC ), and from experience in the prior clinical investigation of the Nanostim LP system (sponsor s document RC-02181), the expected 6-month CFR is 92% and the 1-year CFR for the Nanostim LP system is 89%. Given these assumptions, the study hypotheses are stated below. Subjects whose initial implantation procedure was not successful will not be eligible for reimplantation attempts with the investigational device at a later date. Subjects who leave the study before their 6-month visit will be censored at the time they leave the study. So, any complications that occur in subjects that leave the study before their 6 month visit will be included in this analysis. Primary Safety Endpoint Evaluation at 6 Months H 0 : CFR 86% vs. H 1 : CFR > 86% A sample size of 300 evaluable subjects will have a 90% probability of establishing a twosided 95% confidence interval for CFR, with a lower bound exceeding 86%, based on an exact binomial distribution. Since the Nanostim LP device is unique both in its design and delivery, there is no precedent for estimating an expected or acceptable complication rate based on prior clinical studies for other pacemaker devices reported in the literature. Nanostim conducted a pilot study where the actual CFR was estimated to be 96.88% (31/32) at 3 months. Assuming this to be a random event, the estimated CFR rate would be expected to be the same between the first three months and the second 3 months. Therefore, the estimated CFR rate at 6 months would be 93.75% (30/32), with an associated exact 95% confidence interval of (79.19%, 99.23%). St. Jude Medical has used a planning estimate for the expected CFR at 6 months of 92.0%, which exceeds the midpoint of the 95% confidence interval for the estimated rate at 6 months based on pilot data (89.2%). An observed CFR of 92.0% or higher would be needed to The LEADLESS II Study Page 16 July 18, 2014

78 DC-02374/ Rev H /Rev H demonstrate superiority to the proposed Performance Goal of 86% with a sample of 300 evaluable subjects. A Performance Goal of higher than 86% would lead to substantially larger sample size requirements (for example, 88% would require a doubling of the sample size to 600 subjects). The proposed study will collect sufficient information both on the number of complications and their type, to assess the risk/benefit profile for this new technology Primary Effectiveness Endpoint The composite primary effectiveness endpoint will be used to evaluate pacing thresholds and R-wave amplitudes at the 6-month visit and to document the percentage of subjects with acceptable sensing and pacing performance. Pacing thresholds and R-wave amplitudes will be collected, tabulated for each visit, and also displayed as frequency plots. Acceptable ranges for sensing and pacing are shown in the table below. Parameter Pacing voltage R Sensitivity Acceptable test values Pacing threshold < 2.0 V at 0.4 ms R-wave amplitude > 5.0 mv or value at implant Success Criteria: A subject will be considered to have met the primary effectiveness endpoint if the pacing threshold voltage is 2.0 V at 0.4 ms and the sensed R-wave amplitude is either 5.0 mv at the 6-month visit or the value at implant. In a previous Nanostim pilot study (n = 32, 3-month follow-up period), the maximum observed pacing threshold voltage occurring in the period from hospital discharge to 3 months was 1.75 V, and the minimum observed R-wave was 4.0 mv. Based on these prior data, the success rate (Rate) for the Nanostim LP device at 6 months is expected to be 91.5% or higher, and 89.5% or higher at 12 months. A prespecified performance goal is set at 85.0% for both evaluation periods. The inability to sense or pace within the programmable range available in the Nanostim LP device, resulting in device repositioning, replacement, or removal will be captured in the associated safety endpoints. Primary Effectiveness Endpoint Evaluation at 6 Months H 0 : Rate 85.0% vs. H 1 : Rate > 85.0% A sample size of 300 subjects will have at least a 90% probability of establishing a two-sided 95% confidence interval for conformance with the above-referenced criteria for pacing threshold and R-wave amplitude, with a lower bound exceeding 85.0%, based on an exact binomial distribution. The LEADLESS II Study Page 17 July 18, 2014

79 Data Analysis of Primary Safety and Effectiveness Endpoints The following analysis populations are defined for the study: Investigation Plan DC-02374/ Rev H /Rev H Intent-to-Treat (ITT): Subjects who meet the enrollment criteria, provide signed Informed Consent, and who have an attempted or successful implant are considered enrolled in the study and part of the ITT population. Per Protocol (PP): The Per Protocol population at 6 months includes all enrolled subjects who have 6-month safety and effectiveness evaluations. The PP population at 12 months includes all enrolled subjects who have 12-month safety and effectiveness evaluations. It excludes subjects, for example, who withdrew informed consent, were lost to follow-up prior to the scheduled evaluations, or missed evaluation visits, but includes those subjects who contributed events to the primary endpoints prior to withdrawal or the scheduled visits. There are no other major protocol deviations which define the PP population or would exclude subjects from analysis. The primary analysis population for the Primary Safety Endpoint will be the ITT population. The Primary Effectiveness Endpoint will be evaluated in both the ITT and PP populations. The primary safety and effectiveness endpoints must be met at the 6-month evaluations for the study to be considered an appropriate basis for PMA approval. All primary safety and effectiveness endpoints will be tested against the pre-specified performance goals at 6 months with exact, binomial tests. Interim Analysis and Adaptive Sample Size Re-estimation A single interim analysis will be performed at the point that 50% of the 300 evaluable subjects required for the 6-month evaluation have been assessed (150 subjects). This analysis will be limited to primary safety endpoint data for this 50% cohort. If it is determined at the interim analysis that the study will not achieve its original design objective of 90% unconditional power at the 6-month evaluation, then the study size will be increased to regain that power. Otherwise, the sample size will remain at the original 300 evaluable subjects. There will be no provision for reducing the study sample size or early stopping of the study, other than for emergent safety concerns. The maximum allowable increase in the sample size for the 6-month evaluation will be twice the original estimated number of 300 subjects (that is, a total of 600 evaluable subjects for the 6-month evaluation). Since there are no plans for early termination of the study, adjustments to the alpha requirements for the safety endpoint are not required. If the sample size is increased, then the Type I error level for both primary safety and effectiveness endpoints will be preserved using the method of Cui et al (Cui L, Hung HMJ, and Wang SJ, 1999, Modification of Sample Size in Group Sequential Trials, Biometrics, 55: ). The interim analysis and any potential sample size recommendation made to the sponsor will be the responsibility of the study DSMB. The LEADLESS II Study Page 18 July 18, 2014

80 Adaptive Sample Size Re-estimation Investigation Plan DC-02374/ Rev H /Rev H A pre-specified adaptive design will ensure that the study has adequate power in case the complication-free rate is lower than expected. The purpose of an adaptive design would be to increase sample size if the study does not meet the requirements of the 6-month endpoint with 300 evaluable subjects. If an increase in the sample size is required for the 6-month evaluation then that increment will be added to the original sample size of 600 estimated for the 12-month evaluation (that is, a maximum of 900 evaluable subjects for the 12-month evaluation) Pooling of Regions and Sites All baseline and demographic characteristics between study regions and individual sites will be examined using statistics appropriate to the variable examined: Chi-square or Fisher's Exact tests for categorical variables, and Student's t-tests or ANOVAs for continuous variables. The consistency of results for the primary safety and effectiveness endpoints across (1) Regions: US vs. OUS and (2) Sites will be examined using Chi-square or Fisher-Freeman- Halton tests, with associated p-values of 0.15 or less considered evidence of potential heterogeneity in outcomes. If evidence is found of heterogeneity in safety or effectiveness outcomes across regions or sites, then additional analyses will be performed to determine if differences in the distributions of baseline factors account for the region or site differences Missing Data All attempts will be made to ensure subject retention in the study to minimize the amount of missing data. Reasons for withdrawals will be documented and assessed relative to possible relationships to study primary endpoints. In the evaluation of the Primary Safety Endpoint, the last known status (LOCF) of subjects who withdraw from the study will be used in the primary analysis for the intent-to-treat (ITT) population. As previously stated, subjects who had experienced an event prior to withdrawal are included in the analysis. For those subjects who withdraw for reasons unrelated to complications (e.g., withdrawal of consent), the LOCF assumption is not the most conservative approach but is considered a more unbiased approach to estimating the complication-free rate. To evaluate the potential impact of any missing data on the Primary Safety Endpoint, the following sensitivity analyses will also be performed: o Evaluation in the Per Protocol (PP) population o Assume that no complications occur in subjects who withdraw (best case) o Assume that all withdrawals would have experienced a complication (worst case) The LEADLESS II Study Page 19 July 18, 2014

81 DC-02374/ Rev H /Rev H o Kaplan-Meier survival estimates of the complication-free rate at 6 months and associated 95% confidence interval, using the 6-month cumulative survival and its estimated standard error (Peto method) In the evaluation of the Primary Effectiveness Endpoint, the last known status (LOCF) regarding success or failure in achieving acceptable sensing and pacing performance at the 6- month visit will be used in the ITT primary analysis. To evaluate the potential impact of any missing data on the Primary Effective Endpoint, the following sensitivity analyses will also be performed: o Evaluation in the Per Protocol (PP) population o Assume that successful sensing and pacing would have occurred at 6 months in subjects who withdraw (best case) o Assume that unsuccessful sensing or pacing would have occurred at 6 months in subjects who withdraw (worst case) o Estimated success for sensing and pacing at 6 months, based on an average of the observed and available 2 week, 6 week, and 3 month data for pacing thresholds and R-wave amplitudes prior to withdrawal. o Missing 6 month pacing thresholds and R-wave amplitudes will be imputed by substituting the average of the observed 2 week, 6 week, and 3 month data for the missing 6 month data. If the imputed values for a subject at 6 months from this methodology meet the success criteria outlined in Section of the protocol, then the subject will be classified as a success for the primary effectiveness endpoint; otherwise, a failure. Subjects with missing 6-month evaluations who have their outcome status imputed in this manner will be added to the set of subjects with observed 6-month assessments, and the hypotheses for the primary effectiveness endpoint will be evaluated with this expanded data set Subgroup Analyses Additional exploratory analyses will be performed to examine the consistency of primary safety and effectiveness outcomes across study subgroups, including gender and age. All subject and baseline factors that have a univariate association with outcomes resulting in a p- value of 0.15 or less will be identified. The analyses for association will be appropriate to the factor being examined: for example, Chi-square and Fisher's Exact tests for categorical variables, and Student's t-tests and ANOVAs for continuous variables. These analyses may also include logistic multivariable regressions to determine the independent contributions of subject and baseline factors identified as having univariate associations Conditional Probability of Meeting 1-Year Primary Endpoints The conditional probabilities for the primary safety and effectiveness endpoints will be calculated using the procedure for estimating conditional power of one proportion tests based The LEADLESS II Study Page 20 July 18, 2014

82 DC-02374/ Rev H /Rev H on the method of Chang (Chang, M, Classical and Adaptive Clinical Trial Designs, 2008, John Wiley & Sons. Hoboken, New York) implemented in the PASS 12 software package (Version , NCSS). The current estimated 1-year complication-free rate (CFR) is 89% (Section Primary Safety Endpoint) and the estimated 1-year success rate is 89.5% (Section Primary Effectiveness Endpoint). The conditional power for each endpoint will be calculated based on these assumed values, adjusted for the actual differences observed between the observed and expected rates at 6 months. The expected 6-month rates are 92% for the Primary Safety Endpoint and 91.5% for the Primary Effectiveness Endpoint. For example, if the observed 6- month CFR is 93%, then the assumed 1-year rate for purposes of calculating the conditional power will be 89% + (93% - 92%) = 90%. In general, the one-sided conditional power at look k (0,...,k,...,K) using the proposed method is given by: CP k () = { [ Z k ( k ) 1/2 - z 1- ( k ) 1/2 + ( K - k ) ] / ( K - k ) 1/2 } Where, k = the look number (here, there is one look at n = 300, and a final look at n= 600) = P 1 - P 0 P 0 = proportion under the null hypothesis P 1 = proportion under the alternative hypothesis Z k = (p k - P 0 ) ( k ) 1/2, is the test statistic k = n k / 2 x, the information level p k = the observed proportion at look k 2 = variance of p k, estimated by [P (1 - P) ] 1/2, and P = (P 1 + P 0 ) / 2 n k = sample size at look k Secondary Endpoint The secondary endpoint includes evaluation of a CAEP exercise protocol. If both the Primary Safety and Primary Effectiveness Endpoints are met, then the following hypotheses will be hierarchically evaluated: Secondary CAEP Endpoint H 0 : Mean Slope is Not Equivalent to 100% Slope - 100% H 1 : Mean Slope is Equivalent to 100% Slope - 100% < Where, = equivalence margin, equal to 35% The LEADLESS II Study Page 21 July 18, 2014

83 DC-02374/ Rev H /Rev H CAEP exercise protocol All capable subjects will be asked to perform a maximal effort CAEP exercise protocol to demonstrate an appropriate and proportional response of sensor-indicated rate in graded exercise tests. Data from subjects unable to complete at least stage 3 of the exercise protocol (3.6 METS) will be excluded from the analysis, although their results will still be reported. Thirty subjects will provide data contributing to the analysis. A sample of 30 should be representative of the population and should result in at least 8 subjects showing >50% pacing during the CAEP protocol 2, otherwise, additional subjects may need to be added. The analysis of these exercise test data will provide an estimate of the slope of the normalized increase in sensor-indicated rate versus normalized CAEP workload for each subject. An analysis of these data will also estimate the 95% confidence interval for the mean slope across subjects, which has a pre-specified success criterion requiring that this confidence interval must fall between slopes of 65% and 135%. Based on recently reported studies of marketed rate-responsive pacemakers the expected slope for similar devices, including the Nanostim device, is estimated to be approximately 77%, with an associated standard deviation of 14%. It is estimated based on these data that a sample size of 8 subjects would be sufficient to demonstrate that the lower and upper 95% confidence bounds meet the success criterion, based on a normally distributed random variable. To ensure that a robust cross-section of subjects is evaluated, however, a total of 30 subjects will undergo this assessment. The analysis will provide individual graphs for each subject, displaying: Exercise level (Y1 in METs), sensor-indicated rate (Y2 in min -1 ), and heart rate (Y3 in min -1 ), as a function of time (X in minutes) since start of exercise. Normalized increase in sensor-indicated rate (Y = 0 to 100 %) versus normalized CAEP workload (X = 0 to 100 %), with data points taken at the end of every completed CAEP stage as follows: o Y = (SIR BAS)/(MHR BAS), where SIR = sensor-indicated rate (Y2), BAS = basic rate, and MHR = 80 % * (220-age), all in min -1. o X = (MET-RST)/(MAX-RST), where MET is the actual workload, MAX is the maximum achieved workload, and RST is the resting workload (1), all in METs. For each subject (i), a slope will be estimated using data points (Yij) on Xij, where j= individual paired values for subject (i). The estimate of the slope for data from subject (i) is given by: Slope i = (X ij ) (Y ij ) / (X ij ) 2 2 This estimate is based on data from the preliminary European Leadless clinical trial, in which 27% of subjects demonstrated >50% pacing during the 6 minute hall walk test at the 6-week follow-up. The LEADLESS II Study Page 22 July 18, 2014

84 DC-02374/ Rev H /Rev H Where, the summations are across individual paired values (j) for subject (i) taken at the end of every completed CAEP stage. The mean slope (SlopeMean) is estimated by the average slope across N subjects: SlopeMean = Slope i / N Where the summation is over i = 1,..., N, with N equal to the number of subjects. The standard error of the mean slope is estimated in the usual manner: SE (SlopeMean) = [ (Slope i - SlopeMean) 2 / N (N-1) ] 1/2 The test statistic for evaluation of the CAEP endpoint becomes: Test Statistic = [ SlopeMean - 100% - 35% ] / SE (SlopeMean) The boundary of the critical zone for the above test statistic is equal to [ - t 0.025, N-1 ], associated with a one-sided Student's t-test, an alpha value equal to 0.025, and (N-1) degrees of freedom. The CAEP test will be performed any time after the beginning of the 3-month visit window to ensure maturity of the tissue interface. The preferred window to perform the CAEP test is between the 3-month and 6-month visit Supplementary Endpoints The following supplementary endpoints will be evaluated at 12 months after implant Supplementary Safety Endpoint Evaluation at 12 Months H 0 : CFR 84.5% vs. H 1 : CFR > 84.5% A sample size of 600 evaluable subjects will have a 90% probability of establishing a twosided 95% confidence interval for CFR, with a lower bound exceeding 84.5%, based on an exact binomial distribution. Subjects who leave the study before their 1 year visit will be censored at the time they leave the study. Therefore, any complications occurring in subjects who depart the study prior to their 1 year visit will be included in this analysis. Based on the above assumptions, the total enrollment is expected to be 667 subjects, including an adjustment for potential 10% annual attrition. The LEADLESS II Study Page 23 July 18, 2014

85 DC-02374/ Rev H /Rev H Successful demonstration of an 86 % CFR at six months does not preclude 84.5 % CFR at one year Supplementary Effectiveness Endpoint Evaluation at 12 Months H 0 : Rate 85.0% vs. H 1 : Rate > 85.0% A sample size of 600 subjects will have at least a 90% probability of establishing a two-sided 95% confidence interval for successful sensing and pacing, with a lower bound exceeding 85.0%, based on an exact binomial distribution. The inability to sense or pace within the programmable range available in the Nanostim device, resulting in device repositioning, replacement, or removal will also be captured in the associated safety endpoints Data Analysis of Supplementary Safety and Effectiveness Endpoints The supplementary safety and effectiveness endpoints must be met at the 1-year evaluations, although this is not a criterion for approval of the original PMA application. All supplementary safety and effectiveness endpoints will be tested against the pre-specified performance goals at 12 months with exact binomial tests Additional data The following additional data will be recorded and reported: All adverse events, and whether or not each is device-related or procedure-related Implant success rate and reasons for unsuccessful implant Device handling characteristics at implant Number of device repositioning at time of implantation Implant duration, fluoro duration, and time from implant to hospital discharge Final LP placement Demographics: gender, age, ethnicity, race, indication for pacemaker implant Medical history Use of beta blocker, ACE, ARB, anti-coagulation, anti-arrhythmic, and anti-platelet medications A table and histogram across all subjects of remaining longevity at the six-month and 1-year visits, as displayed by the programmer based on delivered therapy, programmed settings, percent pacing, and measured pacing impedance. Average pacing rate, impedance, pulse amplitude, pulse duration and percentage pacing will also be reported for all visits. Hospitalizations Mortality Holters All capable subjects will be asked to wear a 24-hour Holter monitor and complete a diary, until 30 subjects provide data contributing to the analysis. The test may be The LEADLESS II Study Page 24 July 18, 2014

86 DC-02374/ Rev H /Rev H performed any time after the beginning of the 3-month visit window. The preferred window to perform the 24 hour Holter test is between the 3-month and 6-month visit. These data will be examined for appropriate sensing, pacing and activities of daily living for each subject. The investigational plan does not require inclusion of pacer-dependent subjects to assess device s pacing capabilities because it is expected that at least a third of subjects will have >50% pacing, based on data from preliminary European data (for 31 subjects at 6 week follow-up), provided below: Histogram of percentage pacing at 6 month follow-up visit (from preliminary European data): Percent pacing Percentage of subjects 0-25% 42% 26-50% 26% 51-75% 23% >75% 10% Sponsor will provide an IDE interim report to FDA within one month of completion of the 30 th subject Holter monitor. The IDE interim report will include the following for each subject. Minimum, maximum and average heart rate Percent pacing A telemetry strip of the minimum heart rate and a telemetry strip during pacing (the pacing strip may be the same as the minimum heart rate strip, but does not have to be). Number of pauses seen (defined as RR interval greater than or equal to 2 sec) All telemetry strips of a pause greater than the cycle length that corresponds to the programmed lower rate limit after accounting for any hysteresis programming All telemetry strips showing evidence of oversensing, undersensing, or loss of capture Programmed parameters (which are necessary to assess if the pauses or minimum heart rate seen on Holter are appropriate or not) Definitions used in LEADLESS II study Adverse Event: Any unfavorable clinical event which impacts, or has the potential to impact the health or safety of a subject caused by or associated with a study device or intervention. Complication: A device- or procedure-related serious adverse event, including any adverse event that prevents initial implantation. Cardiac Tamponade: Confirmed or suspected accumulation of fluid in the pericardial space. The LEADLESS II Study Page 25 July 18, 2014

87 DC-02374/ Rev H /Rev H Cardiac Perforation: An excursion of the Nanostim LP through the cardiac muscle. Signs and symptoms of a perforation by Nanostim LP may include radiographic evidence of excursion of the LP into the pericardial sac, abnormal echocardiography indicative of a perforation, the accumulation of fluid in the pericardium, cardiac tamponade, or subject symptoms such as chest pain and discomfort. Device-malfunction: the failure of a device to meet its performance specifications or otherwise perform as intended. Performance specifications include all claims made in the labeling for the device. The intended performance of a device refers to the intended use for which the device is labeled or marketed. Diaphragmatic/Phrenic Nerve Stimulation: Electrical activation of the diaphragm muscle by the device output pulse. The abrupt diaphragmatic contraction is noted clinically as hiccups associated with each pacing stimulus. The pacing stimulus may stimulate the diaphragm either directly or indirectly via the phrenic nerve. Dislodgement: The movement of the Nanostim LP from its originally implanted position resulting in elevated pacing thresholds or a decrease in sensing. Elevated Pacing Thresholds: Pacing thresholds > 2.5 V at 0.4 ms at implant. Following lead maturation at 6-8 weeks, an increase in pacing thresholds of 1.2 V at 0.4 ms or greater between visits. This definition is intended to serve as a guideline and it is understood that individual subjects may have unique situations. Implant procedure duration: Defined as the time from delivery catheter and Nanostim LP insertion to removal. Implant success rate: Defined as the number of subjects leaving the implant procedure with an implanted and functioning Nanostim LP device, divided by the number of subjects in whom implantation is attempted. Loss of Capture: The inability of the device s output pulse to result in depolarization and contraction of the ventricle. Causes include insufficient stimulus strength, separation of the electrode from the myocardium and placement of the stimulating electrode in contact with a non-responsive portion of the myocardium such as scar tissue. Delivery of an output pulse at a time when the myocardium is physiologically refractory is not loss of capture, since capture is not physiologically feasible. Loss of Sensing: A condition in which the pulse generator is unable to sense intrinsic cardiac signals. Oversensing: The detection of inappropriate electrical signals by the pulse generator s sense amplifier. These signals, such as myopotentials, electromagnetic interference, or T waves must be of sufficient duration to interfere with normal device function. The LEADLESS II Study Page 26 July 18, 2014

88 DC-02374/ Rev H /Rev H Procedure duration: Defined as the time from 18F femoral introducer insertion to removal. Serious Adverse Event (SAE): Any untoward medical occurrence that: a. Led to death, b. Led to serious deterioration in the health of the subject, that either resulted in 1. A life-threatening illness or injury, or 2. A permanent impairment of a body structure or a body function, or 3. In-patient or prolonged hospitalization, or 4. Medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, or requires an invasive strategy to remedy, or c. Led to fetal distress, fetal death or a congenital abnormality or birth defect. NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration in health, is not considered a serious adverse event. Sponsor understands that the following items meet the definition of serious adverse event if they require hospitalization or prolong hospitalization, even though an invasive approach may not be necessary to resolve: AV fistula, pseudoaneurysm, blood transfusions, tricuspid valve damage, pericardial effusion, pulmonary embolus, device dislodgement, right ventricular perforation, thrombus formation on the device, ventricular arrhythmias even if not associated with an invasive strategy to remedy. Non-invasive means such as device re-programming do not meet the criteria for medical or surgical intervention. Time to discharge: Defined as the time from introducer sheath removal to discharge. Unanticipated adverse device effect (UADE): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. [21 CFR 812.3(s)] Unavoidable adverse event: An unavoidable AE is defined as an adverse event related to the implant procedure that is expected to occur for a projected duration in all subjects. Undersensing: The failure of the pulse generator to sense R-waves, causing delivery of inappropriately timed, asynchronous or competitive output pulses. Undersensing can sometimes be corrected by programming the device to a more sensitive setting, i.e., decreasing the millivolt value. The LEADLESS II Study Page 27 July 18, 2014

89 6.3 Subject Selection Investigation Plan DC-02374/ Rev H /Rev H The inclusion and exclusion criteria are consistent with recommendations of the European Society of Cardiology, 1 American College of Cardiology, American Heart Association, and the Heart Rhythm Society. 2 Additionally, sponsor has included investigator input. Eligibility for implant is based on conformance to all prospectively defined inclusion and exclusion criteria Inclusion Criteria Eligible subjects will meet all of the following. 1. Subject must have one of the clinical indications before device implant in adherence with Medicare, ACC/AHA/HRS/ESC single chamber pacing guidelines including: Chronic and/or permanent atrial fibrillation with 2 or 3 AV or bifascicular bundle branch block (BBB block), including slow ventricular rates (with or without medication) associated with atrial fibrillation; or Normal sinus rhythm with 2 or 3 AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year); or Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings; and 2. Subject is 18 years of age; and 3. Subject has a life expectancy of at least one year; and 4. Subject is not be enrolled in another clinical investigation; and 5. Subject is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams; and 6. Subject has been informed of the nature of the study, agrees to its provisions and has provided a signed written informed consent, approved by the IRB; and 7. Subject is not pregnant and does not plan to get pregnant during the course of the study Exclusion Criteria Subjects will be excluded if they meet any of the following. 1. Subject has known pacemaker syndrome, has retrograde VA conduction, or suffers a drop in arterial blood pressure with the onset of ventricular pacing; or 2. Subject is allergic or hypersensitive to < 1 mg of dexamethasone sodium phosphate (DSP); 3. Subject has a mechanical tricuspid valve prosthesis; or 4. Subject has a pre-existing pulmonary arterial (PA) hypertension (PA systolic pressure exceeds 40 mmhg or RV systolic pressure (RVSP) as estimated by echo exceeds 40 mmhg), or significant physiologically-impairing lung disease (have severe The LEADLESS II Study Page 28 July 18, 2014

90 DC-02374/ Rev H /Rev H pulmonary disease producing frequent hospitalizations for respiratory distress or requiring continuous home oxygen); or 5. Subject has a pre-existing endocardial pacing or defibrillation leads; or 6. Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device; or 7. Subject has an implanted vena cava filter; or 8. Subject has evidence of thrombosis in one of the veins used for access during the procedure; or 9. *Subject had recent cardiovascular or peripheral vascular surgery within 30 days of enrollment; or 10. Subject has an implanted leadless cardiac pacemaker *Recent cardiovascular or peripheral vascular surgery within 30 days of enrollment is defined as the following: Percutaneous valvular correction 30 days Femoral or abdominal vascular procedure involving incisional access 30 days Peripheral or arterial endovascular procedure or surgery 30 days Cardiac surgery 72 hrs with ongoing complications, ongoing mediastinal drainage, or re-do sternotomy attributed to bleeding 30 days Tricuspid valve replacement or annuloplasty 30 days Any endovascular procedure with specified complication 30 days - Femoral access site-vascular complication including hematoma requiring transfusion, surgical intervention or prolongation of hospitalization, arterio-venous fistula, pseudoaneurysm or tear - New pericardial effusion more than trivial/mild, or requiring percutaneous/surgical drainage Acute deep venous thrombosis 6.4. Study Procedures This section provides a description of all the clinical-investigation-related procedures that subjects undergo during the clinical investigation. Figure 1 illustrates study flow and Table 1 lists a summary of scheduled assessments. Refer to Figure 1 and Table 1 for an overview of the required study procedures at each interval or study visit. The clinical-investigation-related procedures do not require additional radiation compared to a traditional VVIR lead implant and conform to standard of care for pacemaker patient management with the exception of the following: The LEADLESS II Study Page 29 July 18, 2014

91 Femoral vein access instead of subclavian vein access Addition of Treadmill tests Addition of 24 hour Holter monitor Investigation Plan DC-02374/ Rev H /Rev H Sponsor representatives may assist the investigator in assessing pacemaker effectiveness (for example pacing, sensing, and rate response effectiveness), downloading diagnostic information and programming pacemaker parameters. Sponsor representatives may also assist the team in equipment setup prior to and during a procedure. The LEADLESS II Study Page 30 July 18, 2014

92 Figure 1: Study Flow Diagram Investigation Plan DC-02374/ Rev H /Rev H Informed Consent Implant Attempt (enrollment) YES Implant Successful? NO Follow Patient for 30 Days, then Withdraw Pre-Discharge Visit 2 Week Post Implant Visit Includes 12-lead EKG, chest x-ray and magnet mode assessment 6 Week Post Implant Visit 3 Month Post Implant 30 patients: Includes 24-hour Holter monitor 30 patients: Includes CAEP Protocol 6 Month Post Implant Every 6 Months Post Implant until Study Completion After Study Completion, yearly until 7 years post implant The LEADLESS II Study Page 31 July 18, 2014

93 Investigational Plan DC Rev. H /Rev H Enrollment Requirements Recruitment and Enrollment Candidates for this clinical investigation include patients indicated for a VVI(R) pacemaker. Pre-enrollment records will include evidence of diagnosis indicating need for VVI(R) pacemaker. For the Leadless II study, it is the sponsor s intention that the enrolled subject population be as representative as possible of the eligible population. Physician investigators are strongly encouraged to evaluate all consecutive eligible subjects for participation in the study and, if inclusion and exclusion criteria are met, to approach all eligible subjects, regardless of gender. Centers will be selected for participation in the study based on their ability to screen and enroll eligible subjects, and perform the required study procedures. The sponsor will attempt to have a diversified group of centers participating in the study, including academic and non-academic institutions, and anticipates participation to be in the order of approximately percent from academic institutions. To ensure a widespread distribution of data and minimize site bias, a maximum of approximately 15% of the total enrollment will be allowed at a single site. Screen subjects as outlined by the inclusion/exclusion criteria. Obtain informed consent from the subject. Collect data on the subject, including gender, age, ethnicity, race, cardiac disease history, cardiac medications (beta blockers, ACE, ARB, anti-platelets, antiarrhythmics, anti-coagulants), arrhythmia history, and indication for pacemaker implant. Subjects who sign an IRB-approved informed consent and have an attempted or successful implant will be considered enrolled in the study. Once eligibility screening is completed, subject provides informed consent, and the investigator implants the Nanostim LP or attempts to implant complete and submit the forms listed under the Implant Procedures to sponsor Subject Numbering An identification (ID) number will identify enrolled subjects. The format of this ID number is a combination of the study number, subject number assigned by SJM and a subject ID assigned by the site Baseline Assessment Investigator will record subject s medical history on the Enrollment Form. Investigator will record specific cardiac medications (beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-arrhythmics) given to the subject during the same hospital stay as the procedure, as well as during the follow-up period. All subjects will undergo standard laboratory assessment per site s standard of care. For female subjects of childbearing age, investigator will document a pregnancy assessment, which may include a obtaining a blood sample for conducting a pregnancy test. Investigator will not start any study-specific procedures or alterations of patient care until the informed consent process has been completed and investigator obtains a signed The LEADLESS II Study Page 32 July 18, 2014

94 DC-02374/ Rev H /Rev H Informed Consent Form. To determine eligibility, some screening procedures may be necessary (i.e. transthoracic echocardiogram for subjects with a medical history of pulmonary arterial hypertension). If any of these tests do not fall within the investigator s standard clinical practice, they will be required for subjects to be enrolled in the clinical investigation Medications Investigator will administer all medications per hospital standard of care for pacemaker implant and femoral venous catheterization procedures. Use of anticoagulation medications is not required with the implantation of the Nanostim LP. Investigator will record beta blockers, ACE, ARB, anti-coagulants, anti-platelets, anti-arrhythmics given during procedure Implant Procedure Femoral Vein Assessment and Access Turi (2005, 2008), Abu-Fadel et al (2009), Seto et al (2010), and Fitts et al (2008) have shown that physicians can minimize access-site complications by using ultrasound guidance or fluoroscopic guidance when accessing vessels in the groin. 3-7 Although sponsor supports using either technique for assessing femoral vein access-site location, size and presence of disease, investigator will use medical judgment and follow institutional standard of care when accessing the femoral vein during catheter-based procedures. The ideal puncture site should be located below the inguinal ligament and above the bifurcation (Refer to Figure 2). 5,8-10 Penetrate the skin and puncture the femoral vein using the Seldinger technique. Due to the introducer sheath size, investigator may need to nick and spread the tissue at the access-site location to allow for easier transition of the introducer sheath through the tissue tract. The LEADLESS II Study Page 33 July 18, 2014

95 DC-02374/ Rev H /Rev H Figure 2. Location of femoral vein in relation to femoral artery, inguinal ligament and femoral head Nanostim LP Preparation and Implant Investigator will prepare and implant the Nanostim LP in accordance with the manufacturer s instructions for use (IFU). Consult the IFU for implantation guidelines and general handling information. Only approved investigators will be responsible for performing the implant procedure, including placement of the Nanostim LP. Investigator will follow standard institutional catheter-based and pacemaker-lead implantation procedures, guidelines, and precautions Nanostim LP Assessment and Programming Investigator and/or sponsor will interrogate the Nanostim LP using the market-approved St. Jude Medical Merlin Patient Care System (Model 3650) with the Nanostim Programmer Link. Investigator will measure and record the following parameters. Capture threshold at (0.4 msec)* Impedance R-wave amplitude* Battery voltage and Estimated time to RRT Cumulative paced and sensed event counters * R-wave amplitude measurements are not required if the subject s intrinsic rate has been established to be below 30 beats per minute. Capture thresholds are not required if a high ventricular rate is present. Confirm at least three consecutive beats have capture before recording the capture threshold results. The LEADLESS II Study Page 34 July 18, 2014

96 DC-02374/ Rev H /Rev H To avoid potential complications associated with under-sensing, Investigator shall program a sensing margin of at least two times the intrinsic cardiac amplitude (e.g., for an intrinsic R-wave of 4 mv, program the R-sensitivity <2 mv). To avoid potential complications associated with loss of pacing capture, Investigator shall maintain pulse amplitude margin of at least two times the pacing threshold (e.g., for a pacing threshold of 0.5V, program the pulse amplitude >1.0V) Nanostim LP Repositioning and/or Release Once the investigator implants the Nanostim LP and successfully demonstrates acute effectiveness, the investigator may release the Nanostim LP. Investigator may reposition Nanostim LP, if necessary. For release and repositioning procedures, refer to the IFU. Once the Nanostim LP has been released, investigator will use a retrieval catheter for removal, if needed (Refer to Retrieval Catheter IFU). Once the Nanostim LP has been removed, investigator may attempt to implant another Nanostim LP, or instead, choose to implant a market-approved pacemaker. When the investigator has released the Nanostim LP, s/he will use fluoroscopy to assess positioning of the implanted Nanostim LP Unsuccessful Implant Investigators will follow subjects who have an unsuccessful implant for a period of 30 days to evaluate for adverse events. At the end of the 30 days, the investigator will withdraw the subject. The investigator must document the nature of the unsuccessful implant on the Implant Form. Data Submission Once information has been collected and required testing has been completed at the implant visit, complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Enrollment Form (includes medications) Implant Form (includes medications) Nanostim LP Assessment and Programming Form Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Death Form, if applicable Product Out of Service Form, if applicable Nanostim LP Retrievals and Replacement When considering Nanostim LP retrieval and replacement, investigators will refer to the respective IFUs. The LEADLESS II Study Page 35 July 18, 2014

97 DC-02374/ Rev H /Rev H Under normal operating conditions, the Nanostim LP battery is expected to last for approximately 8.4 years. In the event a Nanostim LP must be removed during the clinical study follow-up period, investigators may opt to replace LCPs in the following ways: Retrieve the first Nanostim LP with a special catheter and implant a new Nanostim LP, Deactivate the first Nanostim LP and implant a second Nanostim LP in close proximity to the first one, or Deactivate the first Nanostim LP and implant a traditional pacemaker with a lead. Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. System Revision Form Healthcare Utilization Form Nanostim LP Assessment and Programming Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Death Form, if applicable Study Withdrawal Form, if applicable Product out of Service Form, if applicable If the subject has the Nanostim LP removed at any time during the study, and the subject will not receive a replacement Nanostim LP, follow the subject for 30 days, and withdraw the subject from the study. Complete and submit the following case report forms to St. Jude Medical, IESD Sylmar, CA using the EDC system. Study Withdrawal Form Product Out of Service Form Nanostim LP Assessment and Programming Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Death Form, if applicable Post-procedure Assessments The follow-up period is sufficient to demonstrate safety and effectiveness. Additionally, during this 6-month follow-up period, sponsor will identify any residual risks and complications. Subjects will be seen at the following intervals: The LEADLESS II Study Page 36 July 18, 2014

98 Pre-discharge assessment 2-week follow-up visit (in-office or clinic) 6-week follow-up visit (in-office or clinic) 3-months follow-up visit (in-office or clinic) 6-months follow-up visit (in-office or clinic) Investigation Plan DC-02374/ Rev H /Rev H After completing 6-month follow-up assessment, subjects will return every 6 months until study completion Subjects consent to continue in post-approval studies and will have follow-ups at one year and each year thereafter until seven years after implant. Table 3: Follow-up Assessment Windows Post Implant (Pre-Discharge) 2-week follow-up 6-week follow-up 0-2days 14 7 days 42 7 days 3-month followup 6-month follow-up days days Every 6 months post 1-year until study completion Every days Access-site Management During Hospital Stay Investigator will manage vascular-access sites per standard of care. Investigator will assess and document any post-procedural access-site bleeding event based on the following grading system. ACCESS-SITE OOZING: Superficial bleeding of a cutaneous or subcutaneous origin characterized by diffuse localized bleeding and controlled with minimal care (e.g., application of manual pressure, application of sandbag). ACCESS-SITE HEMATOMA: A localized collection of extravasated blood in subcutaneous tissue at the access site that does not require intervention. A metric ruler should be used to measure the widest portion of the hematoma. ACCESS-SITE HEMATOMA REQUIRING INTERVENTION: A localized collection of extravasated blood in subcutaneous tissue at the access site that is considered life threatening The LEADLESS II Study Page 37 July 18, 2014

99 DC-02374/ Rev H /Rev H and requires emergency wound exploration (e.g., acutely expanding hematoma, acute leg pain/numbness/swelling) and/or prolongation of hospital stay. ACCESS-SITE RE-BLEEDING: Localized bleeding at the access site that occurs after hospital discharge. These bleeds are typically associated with an event (e.g., fall, attempted suture removal, physical activity) Pre-Discharge Assessment Investigator will assess all subjects at the implant center prior to hospital discharge, or within 2-days post implant, whichever is shorter. Investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics ; Measure and record Nanostim LP performance, as described in Nanostim LP Assessment and Programming; Assess magnet mode; Program Nanostim LP per physician discretion; Obtain a 12-lead electrocardiogram (ECG) with pacing ON; Obtain a posterior/anterior (P/A) and lateral view chest x-ray to assess final LP position; Investigator will use medical judgment and provide institutional standard of care for post-pacemaker-implant monitoring. Collect medical billing information for implant (i.e. UB04 billing form) Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Pre-Discharge Form (includes medication changes) Nanostim LP Assessment and Programming Form EQ-5D patient survey Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable The LEADLESS II Study Page 38 July 18, 2014

100 week and 6-week follow-up visits Investigation Plan DC-02374/ Rev H /Rev H All subjects will return to the investigation site for a 14-day and 42-day (±7 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics ; Measure and record LP performance, as described in Nanostim LP Assessment and Programming; Program Nanostim LP and adjust programmable parameters of Nanostim LP, as needed. Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Follow-up Visit Form (includes medication changes) Nanostim LP Assessment and Programming Form EQ-5D patient survey Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Healthcare Utilization Form, if applicable Month Visit All subjects will return to the investigation site for a 90-day (±30 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics ; Measure and record Nanostim LP performance, as described in Nanostim LP Assessment and Programming; The LEADLESS II Study Page 39 July 18, 2014

101 DC-02374/ Rev H /Rev H Program Nanostim LP and adjust programmable parameters of Nanostim LP, as needed; Holter Data Collection 3 o Connect each capable subject to 24-hour Holter monitor (until 30 subjects contribute to the analysis); set Nanostim LP to VVIR mode, if indicated (This test may be performed between 3 and 6 months post-implant). CAEP Protocol 4 o Administer CAEP protocol (until 30 subjects contribute to the analysis); with rate-response feature in VVIR ON mode (refer to CAEP protocol this test may be performed between 3 and 6 months post-implant). o After completing CAEP protocol, program Nanostim LP and adjust programmable parameters of Nanostim LP, as needed. Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Follow-up Visit Form (includes medication changes) Nanostim LP Assessment and Programming Form EQ-5D patient survey Medications, if any changes Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Graded Exercise Test Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Healthcare Utilization Form, if applicable Month Follow-up Visit All subjects will return to the investigation site for a 180-day (±30 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; 3 Holter data collection can be done any time between the 3- month and 6-month follow-up visit. 4 Administration of the CAEP protocol can be done any time between the 3- month and 6-month follow-up visit, (until 30 subjects contribute to the analysis). The LEADLESS II Study Page 40 July 18, 2014

102 Investigation Plan DC-02374/ Rev H /Rev H Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics ; Measure and record Nanostim LP performance, as described in Nanostim LP Assessment and Programming. Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Follow-up Visit Form (includes medication changes) Nanostim LP Assessment and Programming Form Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Healthcare Utilization Form, if applicable Follow-up Visit Every Subsequent 6-Months until Study Completion All subjects will return to the investigation site every 180-days (±45 days) follow-up visit. During this visit, investigation team will: Assess for adverse events and deviations from investigation plan; Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics ; Measure and record Nanostim LP performance, as described in Nanostim LP Assessment and Programming; Program Nanostim LP and adjust programmable parameters of Nanostim LP, as needed. Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Follow-up Visit Form (includes medication changes) Nanostim LP Assessment and Programming Form Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable The LEADLESS II Study Page 41 July 18, 2014

103 Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Healthcare Utilization Form, if applicable Investigation Plan DC-02374/ Rev H /Rev H Unscheduled Follow-up Visits If a subject returns to the investigational site for a visit that is related to the device or implant procedure, the research team will: Assess for adverse events and deviations from investigation plan; Assess for changes in beta blockers, ACE, ARB, anti-coagulants, anti-platelets, antiarrhythmics; As applicable, measure and record Nanostim LP performance, as described in Nanostim LP Assessment and Programming; Program Nanostim LP and adjust programmable parameters of Nanostim LP, as needed. Data Submission Complete and submit the following case report forms and device print outs to St. Jude Medical, IESD Sylmar, CA using the EDC system. Follow-up Visit Form (includes medication changes) Nanostim LP Assessment and Programming Form Study Withdrawal Form, if applicable Adverse Event Form, if applicable Deviation Form, if applicable Product Out of Service Form, if applicable System Revision Form, if applicable Death Form, if applicable Healthcare Utilization Form, if applicable 7.0 Hospitalizations All hospitalizations, outpatient services, emergency room and urgent care visits that are related to heart failure, cardiac/ non-cardiac reasons and Nanostim LP implant/retrieval/replacement procedure(s) must be reported to St. Jude Medical via a Healthcare Utilization Form within 10 working days of the center becoming aware of the subject s admission to the hospital. The investigation team will submit the Healthcare Utilization Form and supporting documentation (i.e., Admission/Discharge Summary) to St. Jude Medical, IESD Sylmar, CA using the EDC system. The UB04 billing record will The LEADLESS II Study Page 42 July 18, 2014

104 DC-02374/ Rev H /Rev H be required for hospitalizations and emergency room visits that are cardiac related. 8.0 Protocol Deviations Investigators are required to adhere to the investigation plan, signed Investigator s Agreement, applicable federal or state/local, laws and regulations, and any conditions required by the IRB, or FDA. A protocol deviation is used to describe situations in which the investigation plan was not followed. Investigator must report all deviations from the investigational to sponsor per 21 CFR In addition, investigator must report all deviations to the reviewing IRB per the IRB s reporting requirements. Investigator must notify sponsor and the reviewing IRB of any deviation from the investigation plan to protect the life or physical well-being of a subject in an emergency as soon as possible, but not later than 5-working days after the deviation has occurred, or no later than 5-working days after the investigator becomes aware of the deviation. 9.0 Adverse Events A Clinical Events Committee (CEC) will review and adjudicate all Adverse Events. The CEC will base their final adjudication on the information provided on the case report forms, medical records, and their clinical knowledge and experience. Investigator will document all AEs on the Adverse Event Form, including (at a minimum) a description of the event, date of onset, relationship to the investigational device, required interventions, duration, and outcome. Investigator will monitor all AEs until they are resolved, determined to be a chronic condition or the subject is lost to follow-up. Investigator will report all AEs regardless of whether it is anticipated or unanticipated and regardless of classification, seriousness, outcome or causality. Should an AE occur, complete an Adverse Event Form and submit to sponsor. If an adverse event occurs between scheduled visits, report the event at the next scheduled visit. Report the adverse event to the IRB/MEC per the IRB/MEC policy. Investigator will return any retrieved devices to sponsor for analysis. Unavoidable AEs are not reportable unless the condition worsens or continues beyond the time frame listed below. Unavoidable AEs, listed below, do not need to be reported if they are resolved within the time frame specified. The LEADLESS II Study Page 43 July 18, 2014

105 Table 4: Unavoidable AEs related to the Implant Procedure Event Time Frame post-implant Anesthesia related nausea/vomiting <24 hours Low-grade fever (<100 degree Fahrenheit fever or < < 48 hours 37.8 degree Celsius Percutaneous access pain < 72 hours Mild to moderate bruising/ecchymosis at < 72 hours percutaneous access site Sleep problems (insomnia) < 72 hours Back pain related to laying on the table < 72 hours Investigation Plan DC-02374/ Rev H /Rev H If an UNANTICIPATED ADVERSE DEVICE EFFECT occurs, the investigator must notify sponsor and the IRB/MEC immediately, but no later than 10 working days of the investigator s knowledge of the event, as required by 21 CFR Sponsor will take any steps necessary to investigate the event, and will be responsible for notifying FDA and all other participating IRBs/MECs and investigators. Should sponsor determine, either through physician reports or in-house testing, that an unanticipated adverse event presents an unreasonable risk to participating subjects, sponsor will suspend the clinical investigation and notify all participating investigators, IRBs/MECs and FDA. Sponsor will provide to FDA on a quarterly basis an interim safety and adverse event report. The LEADLESS II Study Page 44 July 18, 2014

106 DC-02374/ Rev H /Rev H Table 5: List of foreseeable adverse events and anticipated adverse device effects *Access site bleeding event Air embolism Induced ventricular ectopy or arrhythmias Angina pectoris Infection, local at access site, or systemic Arterial puncture Insufficient cardiac output AV fistula Bladder puncture Blood transfusion Blunted or poor sensor response Body rejection phenomena Bowel penetration Cardiac arrhythmias Cardiac dissection Cardiac perforation Cardiac tamponade Chronic nerve damage Damage to vessels Death Device dislodgment Dizziness Dyspnea Embolism Endocarditis Excessive Bleeding Exit block Failure to capture/loss of capture Femoral nerve injury with resulting paresthesias Heart Failure Hematoma formation, including retroperitoneal hematoma/hemorrhage High impedance Inability to interrogate or program due to programmer or device malfunction Intermittent capture Interruption of desired pacemaker function due to electrical interference, either electromyogenic or electromagnetic Keloid formation Loss of normal device function due to battery failure or component malfunction Muscle and nerve stimulation Myocardial damage Myocardial infarction Myocardial irritability Oversensing Pacemaker syndrome Palpitations Pericardial effusion or rub Pericarditis Phrenic nerve/diaphragmatic stimulation Pneumothorax Premature battery depletion Programmer/software anomaly Pseudoaneurysm formation Psoas abscess Reaction to contrast Septic arthritis Seroma Syncope Threshold elevation Thromboemboli Thrombosis The LEADLESS II Study Page 45 July 18, 2014

107 DC-02374/ Rev H /Rev H Table 5: List of foreseeable adverse events and anticipated adverse device effects (continued) Undersensing Venous perforation Valve damage Ventricular ectopy Venous occlusion Ventricular tachycardia *Access site bleeding event is defined in section A right ventriculogram carries risk, most notably, allergic reaction to contrast media Deaths All subject deaths that occur during this study must be reported to St. Jude Medical within 10 working days of the center being notified. Notification of a death should include a detailed statement of the pertinent events and be signed by the investigator in addition to the completion of the appropriate forms (Death form, Withdrawal form, and Product Out of Service form) and submitted to St. Jude Medical, IESD Sylmar, CA using the EDC system. It is the investigator s responsibility to notify the IRB per the IRB policy. Date and time of death Place death occurred (e.g. hospital, nursing home, subject s home) If death was witnessed Identification of the rhythm at the time of death, if known (include any available documentation) Cause of death Any other circumstances surrounding the death Approximate time interval to death from the initiating event Autopsy report (if performed) Whether it was device and/or procedure related Whether it was related to the study If any of the above information is not available, investigator will provide an explanation in the death narrative of what attempts (and how many) were made to obtain the information, and the outcome of those attempts. At a minimum, investigator will place two (2) phone calls, followed by a certified letter, to the subject s next of kin and provide clinical notes and witness statements. If possible, interrogate the pacemaker. Retrieve and print all episode diagnostics, and programmed parameters. If applicable, the pacemaker should then be programmed OFF. Attempt to explant the pacemaker and return any explanted devices to sponsor for analysis promptly. Clearly state on Case Report Form the reason the pacemaker is not being returned to sponsor. The LEADLESS II Study Page 46 July 18, 2014

108 11.0 Committees and Core Laboratories Investigation Plan DC-02374/ Rev H /Rev H 11.1 Data and safety monitoring board (DSMB) Sponsor will establish an independent DSMB to review safety data. The DSMB will consist of at least 3 members with study-related backgrounds. Members will include at least one statistician and two cardiologists with pacemaker experience. St. Jude Medical will appoint members of the DSMB and the chairperson. St. Jude Medical may provide administrative support to DSMB meetings, but will not be a voting member and will not be present during closed portions of the meeting. Non-DSMB members are not allowed to be present during DSMB closed meetings. Refer to DSMB Charter, RC Sponsor will provide to FDA within 10 working days of receipt copies of written communication from the DSMB that relates to safety concerns, or changes to the study plan, procedures or informed consent document. Sponsor will provide the DSMB within 10 working days copies of any letter from FDA that relates to safety concerns, or changes to the study plan, procedures or informed consent document Clinical events committee (CEC) Sponsor will establish an independent CEC to review all adverse events. The CEC s role is to determine relationship of event to device and or procedure. The CEC will consist of at least 3 members with study-related backgrounds. Members will include cardiologists with pacemaker experience. St. Jude Medical will appoint members of the CEC and the chairperson. St. Jude Medical may supply study information and provide administrative support for CEC meetings, but will not be a voting member. Refer to CEC Charter, RC Holter core laboratory Sponsor will establish an independent core laboratory to review all 24-hour Holter monitors. The core laboratory s role is to evaluate and report Holter findings Withdrawals Withdrawal is defined as termination of a subject s participation from the clinical trial. All reasonable efforts should be made to retain the subject in the clinical trial until completion of the clinical trial. All reasons for withdrawal will be documented. Reasons for withdrawal include, but are not limited to the following: Subject Death Subject and/or Family Request representing withdrawal of consent Subject Lost to Follow-Up: Subject will be considered lost to follow-up after a minimum of 2 documented phone calls by personnel at the investigational center to The LEADLESS II Study Page 47 July 18, 2014

109 Investigation Plan DC-02374/ Rev H /Rev H the subject or emergency contact, a certified letter is sent to the last known address and two consecutive visits pass without the investigator receiving data. Subject Participation terminated by investigator based on the best medical interest of the study subject Nanostim LP explanted and not reimplanted Unsuccessful Implant. A Withdrawal Form will be completed and submitted to St. Jude Medical, IESD Sylmar, CA using the EDC system Risk Analysis St. Jude Medical addresses the risk of poor usability of the programmer through a usability engineering process complying with EN 62366:2007. St. Jude Medical (formerly Nanostim) has implemented a risk management process in conformance with EN ISO 14971:2012. The application of this risk management process to the leadless pacemaker system is documented in a risk management file. The risk management file also includes a risk management plan (St. Jude Medical s standard operating procedure for risk management). This risk management process includes risk analysis, risk evaluation, and risk control. These are documented for the leadless pacemaker system in a top-down system hazard analysis; bottom-up failure mode effects analyses for the pacemaker, catheters, programmer and introducer; software safety analyses for the pacemaker and programmer; annual reviews of post-production information on similar devices; and a system risk management report. These bottom-up analyses provide risk analysis for single component failure as required by EN : Product-related risks St. Jude Medical conducted system hazard analysis for the Nanostim LP system. This analysis found that the system employed state of the art therapy and materials. Failure-mode-effects analyses of each device in the system confirmed that the level of risk is as expected for pacing systems. Thus, the risk assessment focused on the potential influence of novel design features: implantation procedure; access site; fixation characteristics; absence of lead, connector, and antenna; device retrieval; and conductive communication with Nanostim programmer Link. St. Jude Medical s risk assessment identified uncertainties relating to product-specific risks, such as those associated with percutaneous delivery via a femoral vein, and dislodgement or migration. The need for product-specific risk-control measures was identified, such as fixation optimization and exclusion of subjects with pulmonary arterial hypertension or lung disease Clinical risks St. Jude Medical s risk assessment following the system hazard analysis concluded that the subject population and delivered therapy are essentially the same as those of The LEADLESS II Study Page 48 July 18, 2014

110 DC-02374/ Rev H /Rev H existing VVIR therapy. Thus, existing clinical evidence addresses proof of concept of therapy and supports the view that clinical risks should be the same as those seen with comparable existing products. The follow-up period of 6-12 months is consistent with the follow-up duration of comparable devices in studies for regulatory approval, which in turn was determined by the well-known maturation time of the interface between the electrode and myocardium, which is typically reached by three months 5. Animal study, human clinical trial results and feedback from physicians indicate that the delivery, implantation and retrieval procedures will not expose the subject, the physician or third parties to radiation in excess to that from implantation of a conventional single chamber pacemaker and lead Anticipated clinical benefits Implantation of the Nanostim LP for cardiac pacing could offer certain advantages as compared to a conventional pacemaker. Specifically, the benefits that are associated with the use of the Nanostim LP could include: Precise and repeatable procedure; Percutaneous procedure (potential outpatient procedure); Eliminates the need for lead (no risk of lead fracture, lowers risk of infection); Eliminates the need for a pocket (lowers risk of infection, no need for scar and/or lump); Eliminates the need for connectors (eliminates connector complications); Eliminates the visible lump and scar at a conventional pacemaker s pectoral implant site; Could lessen the need for activity restrictions after implantation; 13.4 Benefit/risk assessment It is concluded from preclinical data (risk analysis and literature review) that clinical risks are comparable to those associated with currently available therapy. Uncertainty exists in relation to risks associated with novel features (percutaneous delivery via a femoral vein and the possibility dislodgement or migration). These residual risks cannot be estimated with confidence without data from a clinical investigation. Taking into account the nature of the possible harm that could arise from these device-related risks and the assurance provided by pre-clinical data, the risk-benefit balance associated with the use of the Nanostim LP in a clinical trial is considered to be favourable. 5 Hayes DL, Friedman PA, Cardiac pacing, defibrillation, and resynchronization: a clinical approach, Wiley 2011, The LEADLESS II Study Page 49 July 18, 2014

111 13.5 Conclusions from pre-clinical risk evaluation Investigation Plan DC-02374/ Rev H /Rev H Clinical investigation needs to confirm safety and performance of novel design features. The basis for design of this investigation may be summarized as follows: Most design features are equivalent to existing products and will have been verified by pre-clinical evaluation. Literature shows that for conventional pacemakers, approximately 96% of subjects are event-free at 6-months. Risk analysis indicates novel features should not be associated with significant residual risks or complications. It is not possible to design a clinical investigation to investigate low-level or unexpected risks, on the basis of a statistical analysis. The objective should be to identify a flaw in the pre-clinical risk analysis, exposing the minimum number of subjects to the risk. It is concluded that the results of the pre-clinical evaluation justify the design of the clinical investigation to determine whether the Nanostim LP is suitable for the purpose and the population for which it is intended. The clinical investigation has been designed to ensure that the results obtained have clinical relevance and scientific validity, and address the clinical investigation objectives. The LEADLESS II Study Page 50 July 18, 2014

112 14.0 Description of Device Investigation Plan DC-02374/ Rev H /Rev H 14.1 Identification of the device: proprietary and code names The Nanostim leadless pacemaker system consists of these items: Name in sponsor Name on labels on product lifecycle the device and its management system S1DLCP System 1, leadless cardiac pacemaker S1LINK System 1, communications link for SJM Merlin programmer S1S18F System 1, 18 French introducer, 30 cm length S1RSIN S1RTRI System 1, single-loop retrieval catheter System 1, tri-loop retrieval catheter packaging Notes Acronym Nanostim Leadless LP Pacemaker Nanostim Programmer Link Nanostim Introducer Kit Nanostim Retrieval Catheter - Single Loop Snare Nanostim Retrieval Catheter - Triple Loop Snare Includes pacemaker and catheter for delivering the pacemaker For interrogating and programming the pacemaker after implant For use with pacemaker, delivery catheter, or retrieval catheters For retrieving an implanted pacemaker with a single-loop snare For retrieving an implanted pacemaker with a tri-loop snare 14.2 Description of the device and its intended application PRG INT RET RET The Nanostim LP system consists of the Nanostim LP and its accessories listed in The intended application of the Nanostim LP is implant in the right ventricle, with permanent duration (greater than 30 days). The intended application of the delivery catheter, retrieval catheters, and introducer is external communicating, circulating blood contact, with limited duration (less than 24 hours). The intended application of the communications link is external, with skin contact via a CE-marked cable and ECG electrodes. The devices in the system achieve their intended purposes as described in the subsections below: Nanostim LP The Nanostim LP provides bradycardia pacing as a pulse generator with built-in battery and electrodes, for permanent implantation in the apex of the right ventricle. As a leadless pacemaker, it does not need a connector, pacing lead, or pulse generator pocket. A distal non-retractable, single-turn helix affixes the Nanostim LP to the endocardium. Sensing, pacing and communication with the external programmer occur The LEADLESS II Study Page 51 July 18, 2014

113 DC-02374/ Rev H /Rev H between a distal electrode near the helix and the external can of the Nanostim LP. The tip electrode is a titanium-nitride coated platinum-iridium disc located at the center of the fixation helix, with a geometric surface area of 2 mm 2. The tip electrode includes 0.1 to 0.7 mg of dexamethasone sodium phosphate, intended to reduce inflammation. The ring electrode is the uncoated part of the titanium pacemaker case, with a geometric surface area >500 mm2. The inter-electrode distance is >10 mm. The maximum depth of penetration of the fixation mechanism in tissue is 1.3 mm. The pacemaker s proximal end has a feature for docking to delivery and retrieval catheters, which provides for repositioning capability. The pacemaker communicates bi-directionally with the programmer via electrical signals conducted between the implanted Nanostim LP s electrodes and skin electrodes applied to the patient s chest and connected to the programmer. Consequently the pacemaker transmits signals using circuits and electrodes already provided for pacing, with data encoded in pulses delivered during the heart s refractory period. The pacemaker senses right-ventricular blood temperature to provide an increase in pacing rate with increased metabolic demand. Otherwise, the Nanostim LP has the same operating principles as a conventional cardiac pacemaker. For further information refer to DC-01470, Instructions for use, S1DLCP (pacemaker and delivery catheter). The drawing below shows mechanical characteristics of the LP. Pacemaker length = 42 mm. Pacemaker outer diameter (max) = 6.15 mm. Key: A. Docking Interface button with cables. B. Ring electrode. C. Insulated header. D. MP35N fixation helix. E. Titanium nitride (TiN) coated platinum-iridium (Ptlr) electrode with steroid (proximal to helix) Delivery catheter The delivery catheter provides a means for a single operator to: Advance the Nanostim LP from an access site in the groin (utilizing minimally invasive techniques) through the femoral vein to the apex of the right ventricle, Protect the Nanostim LP helix and electrode during delivery, Position the Nanostim LP and rotate it to affix the helix, Undock the Nanostim LP from the delivery catheter leaving the Nanostim LP tethered to the delivery catheter, to measure thresholds without force from the catheter. The LEADLESS II Study Page 52 July 18, 2014

114 Investigation Plan DC-02374/ Rev H /Rev H Re-dock to the catheter, unscrew and reposition the Nanostim LP if necessary for acceptable thresholds. Undock from the Nanostim LP, leaving it implanted, and disconnect it from the tether. Apart from the docking mechanism, the delivery catheter and its control system (handle) have the same operating principle as a conventional steerable catheter and control system. The system includes an introducer, one or more pre-shaped guide catheters, and an eptfe sleeve to protect the fixation helix and electrode. For further information refer to DC-01470, Instructions for use, S1DLCP (pacemaker and delivery catheter). The drawing below shows mechanical characteristics of the delivery catheter: Catheter effective length = 128 cm Catheter maximum outer diameter = 4.6 mm (0.178 inch) Nanostim Programmer Link The programmer displays the patient s electrocardiogram and the status of the implanted Nanostim LP, and it sends commands to change Nanostim LP parameter settings as directed by a user. The programmer transmits signals to an implanted LCP via conducted communication with subliminal 250 khz pulses applied to the skin electrodes. Apart from this conducted communication, it has the same operating principle as a conventional pacemaker programmer. The Nanostim Programmer Link uses a St. Jude Medical Merlin Patient Care System Programmer (Model 3650) with a USB interface to an external module (Nanostim Programmer Link). The module uploads St. Jude Medical Nanostim software to the Merlin programmer and provides an interface between the programmer and standard ECG electrodes placed on the subject s torso, for two-way communication with the implanted pacemaker and display of the surface ECG. For further information refer to DC-01471, Instructions for use, S1LINK programmer. The LEADLESS II Study Page 53 July 18, 2014

115 DC-02374/ Rev H /Rev H The photographs below show mechanical characteristics of the Nanostim Programmer Link: Top view Bottom view 1. LED lights will illuminate when the S1LINK is receiving appropriate power 2. Patient connector. Connect to the patient using the patient cable and skin electrodes. 3. USB connector. Connect to the St. Jude Merlin programmer using the USB cable. 4. Auxiliary power connector. Not required in normal use 1. The mating slot in the middle of the S1LINK is designed to slide on top of a mount that is affixed via glue to the back of a St Jude Merlin programmer. 2. The S1LINK is approximately 4.5 x 9.5 x 1.5. Its case is made of plastic. The S1LINK weighs approximately one pound Nanostim 18F introducer kit The system includes an 18F introducer kit consisting of a sheath introducer and dilator. The introducer provides access to the venous vasculature and operates compatibly with the Nanostim pacemaker and catheters. For further information, refer to DC-01469, instructions for use, S1S18F (18F introducer kit). The LEADLESS II Study Page 54 July 18, 2014