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Confidential Next Generation INCEPTA ICD and CRT-D Field Following Study: Respiratory Rate Trend Evaluation in Heart Failure Patients NOTICE-HF (NOTICE-HF) Final report Study Device: -INCEPTA (DR and VR) ICD system / Models F160, F161, F162, F163 -INCEPTA CRT-D system / Models P162, P163, P165 Sponsor or Sponsor’s Representative: Ljubomir Manola Clinical Project Manager Guidant Europe, a Boston Scientific Company Green Square, Lambroekstraat 5D, 1831 Diegem, Belgium Tel: +32 241 67219 Coordinating Principal Investigator(s): PD Dr. med. Stephan Goetze Deutsches Herzzentrum Berlin (German Heart Center Berlin) Klinik für Innere Medizin - Kardiologie (Dept. Of Internal Medicine - Cardiology) AugustenburgerPlatz 1 13353 Berlin, Germany CIP Identification: NOTICE-HF 0410 ClinicalTrial.gov Registration: NCT01227785 Date of Report: 23 May 2012 Report Author(s)/ Contact: Lancy Wang Principal Clinical Scientist Boston Scientific Proprietary and Confidential THESE DOCUMENTS ARE THE PROPERTY OF BOSTON SCIENTIFIC CORP. AND SHALL NOT BE REPRODUCED, DISTRIBUTED, DISCLOSED, OR USED FOR MANUFACTURE OR SALE OF APPARATUS WITHOUT THE EXPRESS WRITTEN CONSENT OF BOSTON SCIENTIFIC CORP. This study was conducted in accordance with ISO 14155, etc. that ensured adherence to Good Clinical Practices and protection of the subjects, as required by the directives in operation at the time. THESE DOCUMENTS ARE THE PROPERTY OF BOSTON SCIENTIFIC CORP. AND SHALL NOT BE REPRODUCED, DISTRIBUTED, DISCLOSED OR USED FOR MANUFACTURE OR SALE OF APPARATUS WITHOUT THE EXPRESS WRITTEN CONSENT OF BOSTON SCIENTIFIC CORP. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 1 of 44 Confidential 2. 1. Table of Contents TITLE PAGE ......................................................................................................................... 1 2. TABLE OF CONTENTS .......................................................................................................... 2 2.1. Index of Figures ........................................................................................................ 5 2.2. Index of Tables ......................................................................................................... 5 3. SUMMARY ............................................................................................................................ 7 4. INTRODUCTION ................................................................................................................... 8 5. STUDY DEVICE AND METHODS ........................................................................................... 9 5.1. Study Device Description......................................................................................... 9 5.1.1. Intended Use and/or Indication for Use of Study Device .......................... 10 5.1.2. Changes to the Study Device During the Study ........................................ 10 5.1.2.1. Software .................................................................................... 10 5.2. Clinical Investigational Plan ................................................................................. 10 5.2.1. Study Objectives ........................................................................................ 10 5.2.2. Study Design .............................................................................................. 11 5.2.2.1. Type of Study ............................................................................ 12 5.2.2.2. Study Endpoints ........................................................................ 12 5.2.3. Ethical Considerations ............................................................................... 12 5.2.4. Data Quality Assurance ............................................................................. 13 5.2.5. Study Subject Population ........................................................................... 13 5.2.5.1. Inclusion/Exclusion Criteria ..................................................... 13 5.2.5.2. Sample Size ............................................................................... 14 5.2.6. Treatment and Treatment Allocation Schedule ......................................... 14 5.2.7. Duration of Follow-up ............................................................................... 16 5.2.8. Statistical Analysis..................................................................................... 16 5.2.8.1. Study Hypotheses...................................................................... 16 5.2.8.2. Sample Size Calculation ........................................................... 16 5.2.8.3. Statistical Analysis Methods ..................................................... 17 6. RESULTS ............................................................................................................................ 18 6.1. Study Initiation Date .............................................................................................. 18 6.2. Study Completion ................................................................................................... 18 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 2 of 44 Confidential 6.3. Subject Disposition ................................................................................................. 18 6.4. Subject Demographics ........................................................................................... 19 6.5. CIP Compliance ..................................................................................................... 21 6.5.1. CIP Deviations ........................................................................................... 21 6.6. Analysis ................................................................................................................... 22 6.6.1. Device Technical Performance .................................................................. 22 6.7. Study Endpoint Results ......................................................................................... 23 6.7.1. Purpose I .................................................................................................... 23 6.7.1.1. Pacing thresholds (V) ................................................................ 23 6.7.1.2. Sensed Amplitude (mV) ........................................................... 25 6.7.1.3. Pacing Impedance (Ohms) ........................................................ 27 6.7.1.4. VT/VF detection & conversion ................................................. 29 6.7.1.5. Wanded and Wireless Telemetry .............................................. 31 6.7.2. Purpose II ................................................................................................... 32 6.7.3. Summary of Adverse Events ..................................................................... 33 6.7.4. Death Summary ......................................................................................... 35 7. BIBLIOGRAPHY/PUBLICATIONS ........................................................................................ 36 7.1. References Cited in the Report ............................................................................. 36 7.2. Publications Based on the Study ........................................................................... 38 8. DISCUSSION AND OVERALL CONCLUSIONS ...................................................................... 38 9. ABBREVIATED TERMS AND DEFINITIONS ......................................................................... 39 9.1. Abbreviated Terms ................................................................................................ 39 10. INVESTIGATORS AND ADMINISTRATIVE STRUCTURE ...................................................... 40 10.1. List of Investigators ............................................................................................... 40 10.2. Sponsor(s) or Representative(s) ............................................................................ 40 11. SIGNATURE PAGE .............................................................................................................. 41 11.1. Signature of the Coordinating Investigator ......................................................... 41 11.2. Signature of the Sponsor ....................................................................................... 42 12. ANNEX ............................................................................................................................... 43 12.1. List of Principal Investigators and Sites .............................................................. 43 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 3 of 44 Confidential 12.1.1. Summary of Qualifications or CVs ........................................................... 43 12.2. List of Monitors ...................................................................................................... 44 12.3. List of ECs............................................................................................................... 44 12.4. Tabulation of Data Sets ......................................................................................... 44 12.4.1. CIP Deviations ........................................................................................... 44 12.4.2. Adverse Events .......................................................................................... 44 12.4.3. Withdrawal and Discontinued Subjects ..................................................... 44 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 4 of 44 Confidential 2.1. Index of Figures Figure 1: Schematic of Study Design .......................................................................... 11 Figure 2: Subject Disposition in NOTICE HF Study .................................................. 18 2.2. Index of Tables Table 1 New or modified features of the INCEPTA ICD and CRT-D:........................ 9 Table 2: Inclusion Criteria ........................................................................................... 13 Table 3: Exclusion Criteria .......................................................................................... 14 Table 4 Data Collection and Testing Summary .......................................................... 15 Table 5: Duration of Follow-up Post-implant .............................................................. 19 Table 6 : Withdrawal ................................................................................................... 19 Table 7: Baseline Demographic and Clinical Characteristics...................................... 20 Table 8: Classification of Deviation ............................................................................ 21 Table 9: Deviations Class ............................................................................................ 22 Table 10: Product Experience frequency ..................................................................... 22 Table 11: Pacing thresholds (V) – Purpose I ............................................................... 23 Table 12: Pacing thresholds (V) – All data .................................................................. 24 Table 13: Sensing Amplitude (mV) – Purpose I.......................................................... 25 Table 14: Sensing Amplitude (mV) – All Data ........................................................... 26 Table 15: Pacing impedance (Ohms) – Purpose I ........................................................ 27 Table 16: Pacing impedance (Ohms) – All data .......................................................... 28 Table 17: Induced episodes – Purpose I ...................................................................... 29 Table 18: Induced episodes – All Data ........................................................................ 29 Table 19: Induced episodes detection time – Purpose I ............................................... 30 Table 20: Induced episodes detection time – All Data ................................................ 30 Table 21: Spontaneous Episodes – Purpose I .............................................................. 31 Table 22: Spontaneous Episodes – All Data ................................................................ 31 Table 23: Results for Telemetry – Purpose I ............................................................... 31 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 5 of 44 Confidential Table 24: Results for Telemetry – All Data ................................................................. 32 Table 25: Changes in Respiratory Rate ....................................................................... 33 Table 26: Adverse Events by ISO 14155 Classification .............................................. 35 Table 27: Patient Deaths ............................................................................................. 35 Table 28: Abbreviation ............................................................................................... 39 Table 29: Enrollments by Investigational Center ........................................................ 43 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 6 of 44 Confidential 3. Summary Study Title Next Generation INCEPTA ICD and CRT-D Field Following Study: Respiratory Rate Trend Evaluation in Heart Failure Patients (NOTICE-HF) Introduction This was a prospective, multi-center, field following study. Purpose Study purpose I: To evaluate and document appropriate clinical performance of the INCEPTA (DR and VR) implantable cardioverter defibrillator (ICD) system and the INCEPTA cardiac resynchronization therapy ICD (CRTD) system and associated application software. Study purpose II: Demonstrate the clinical relevance of chronic ambulatory daily median Respiratory Rate Trend (RRT) in HF patients Study Population Patients were selected from the investigator’s general population indicated for an ICD or CRT-D implantation. Investigators were responsible for screening patients and selecting those who met study eligibility criteria. Methods This was a prospective, multi-center, single arm, field following study. 121 patients who met all of the inclusion and none of the exclusion criteria were enrolled. Patients were enrolled at implant and had followups at pre-discharge, 1 month, 3 months, 6 months, and 9 months. Results For study purpose I, the clinical performance of the INCEPTA ICDs and CRT-Ds were analyzed and compared to historical data for the protocol defined subset of patients. The clinical performance of the INCEPTA ICDs and CRT-Ds at implant, pre-discharge, and 1 month were consistent with historical data. Threshold, sensing, and impedance tests were within acceptable performance ranges. The VT/VF conversion rate for induced and spontaneous episodes was 100%. For study purpose II, a statistically significant increase in the daily median RRT was not observed with the pre-specified duration window (P = 0.361). Conclusions The performance of the INCEPTA ICDs and CRT-Ds were consistent with historical data. A larger study is warranted to demonstrate the statistical significance of daily respiratory rate trends in HF patient management. Initiation Date The first patient was enrolled on 05 November 2010 Completion Date The last study follow up visit was completed on 28 December, 2011. The database was locked on 29 February 2012. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 7 of 44 Confidential 4. Introduction The use of implantable cardioverter defibrillator (ICD) therapy has enabled important achievements in the therapy of patients suffering from cardiac arrhythmias. Considerable technical developments in this medical device therapy have been made over the last decade. In the past decades, heart disease has become the number one killer in the US1. Sudden Cardiac Death (SCD) accounts for almost half of all coronary heart disease deaths and affects 450,000 people each year in the US2. The current approach for primary prevention of SCD is to stratify patients at high risk and to provide prophylactic intervention with either antiarrhythmic drugs or ICDs or both. The benefit of ICD therapy over antiarrhythmic drugs was demonstrated in patients with ischemic heart disease, low ejection fraction (EF), and a history of sustained VT/VF (AVID )3 and in patients with ischemic heart disease, non-sustained VT, low EF, and a positive EP test (MADIT)4. Large randomized trials showed that patients with heart failure (HF) implanted with a cardiac resynchronize therapy (CRT) device showed an improvement in exercise tolerance and symptoms of heart failure and quality of life. In addition, evidence of reverse remodeling of the heart as well as a reduction in HF mortality and morbidity were demonstrated in clinical trials5-8 . Research has shown that between 20 and 30% of patients with HF implanted with a cardiac resynchronization therapy ICD (CRT-D) device receive appropriate ICD therapy. The COMPANION trial showed that while both CRT pacemakers and CRT-D devices significantly increased composite primary endpoint (all cause of death or hospitalization), only CRT-D reached significance on the mortality endpoint when compared to the medication control group9. Wilkoff et al.10 reported recently that patients with HF and a CRT-D device had 0.09 episodes/ month if their ICD indication was for primary prevention and 0.43 episodes/ month if it was for secondary prevention. These data show that in order to provide a full treatment and protection for patients with HF, a CRT device with defibrillation back up may be a more desirable option. While a number of studies are currently underway to evaluate the feasibility of detecting early signs of pulmonary edema using implanted sensors11, 12, the NOTICEHF study was designed to evaluate the changes in daily median Respiratory Rate (RR) trends before HF events. The ADHERE registry (n = 187,565) showed that the most common presenting symptom at HF admission is dyspnea, i.e., shortness of breath, presented in 89% of patients13. Schiff et al. reported that patients hospitalized with acute decompensated HF began to develop symptoms of dyspnea 8.4 ± 0.9 days before prior to admission14. Extensive research has demonstrated, using an external respiratory monitor, that breathing is usually rapid (i.e., elevated respiratory rate) and shallow (i.e., reduced tidal volume) in patients with HF15-20. A retrospective analysis by Maurizio Landolina et al21 used minute ventilation along with activity to develop a Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 8 of 44 Confidential prediction model for acute HF events 14±10 days in advance of a hospitalization. Da Cunha et al. reported that daily median RR elevated 14.8±3.5 days prior to clinical signs of worsening HF in a canine HF model 22. All of these studies suggest that respiratory distress precedes HF hospitalization and monitoring of respiratory rate may help early identification of worsening HF. The NOTICE-HF study was thus designed to gather information on the performance of the INCEPTA ICDs and CRT-Ds, and evaluate changes in respiratory rate prior to HF events. 5. Study Device and Methods 5.1. Study Device Description The new INCEPTA CRT-D and ICD products are extensions to the original and currently commercially available product range of COGNIS/TELIGEN 100 pulse generators. Minimal hardware enhancements were applied to the design of these devices. New or modified features are presented in Table 1. Table 1 New or modified features of the INCEPTA ICD and CRT-D: New/modified Feature Respiratory Rate Trend INCEPTA ICD √* INCEPTA CRT-D √* Rhythm ID with RhythmMatch Wireless ECG HF diagnostics (in ICDs) ApneaScan RYTHMIQ Inductive telemetry frequency √* √ √*** √ √*** √* √* √ √* √ N/A √* 副: new 副*: available but not new 副**: modified version in comparison with the legacy COGNIS/TELIGEN 100 devices. 副***: DR model only All devices in this study were CE marked and available for distribution at centers participating in the study. The INCEPTA ICD device is a standard ICD. The INCEPTA CRT-D device combines CRT and an ICD. • INCEPTA Implantable Cardioverter Defibrillator (ICD) Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 9 of 44 Confidential o All models have RF telemetry. Model Numbers: F160 (VR, DF-4), F161 (VR, DF-1), F162 (DR, DF-4, IS-1) F163 (DR, DF-1, IS-1). INCEPTA 160 Cardiac Resynchronization Therapy ICD (CRT-D) • o All models have RF telemetry. Model Numbers: P162 (DF-4, IS-1, IS1), P163 (DF-1, IS-1, IS-1), P165 (DF-1, IS-1, LV-1). 5.1.1. Intended Use and/or Indication for Use of Study Device The INCEPTA CRT-Ds and ICDs used in this study were CE marked available for use under normal standard of care. 5.1.2. Changes to the Study Device During the Study 5.1.2.1. Software There was a software maintenance release (SMR) for software application model 2868 version 2.04 during the NOTICE-HF study in May 2011. Included in this SMR was a change to the manual shock lead impedance algorithm. During the NOTICE-HF study, a higher than expected rate of “Noise” was observed during Manual Shock Lead Impedance measurements. “Noise” in this case means environmental electrical interference that prohibits the device from returning a valid impedance value. It was concluded that the manual shock lead impedance algorithm in the INCEPTA ICD and CRT-Ds was too sensitive to such noise. In single-coil or coil-to-coil configurations, the algorithm collected multiple lead impedance samples and calculated an average for the impedance result. However, if any of the samples collected indicated “Noise”, no average was calculated and instead the measurement result displayed to the user was “Noise”. In the SMR, the manual shock lead impedance algorithm was changed to make it less susceptible to environmental electrical noise. Multiple lead impedance samples are still collected however, not all of the samples are required for a numeric measurement result (not “Noise”) to be calculated and returned. 5.2. Clinical Investigational Plan 5.2.1. Study Objectives The study had two primary objectives or purposes: For purpose I, the objective was to collect data on the performance of the INCEPTA ICD and INCEPTA CRT-D devices during standard clinical use at implant, predischarge and at a 1 month post-implant device evaluation. For purpose II, the objective was to show that daily median respiratory rate increased more in the patients who experience a HF-event (Group 1) than in the patients who did not experience a HF-event (Group 2). Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 10 of 44 Confidential 5.2.2. Study Design A schematic of the flow of the study is presented in Figure 1. Figure 1: Schematic of Study Design Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 11 of 44 Confidential 5.2.2.1. Type of Study NOTICE-HF was a prospective, multi-centre, field following study. There was no control group. 5.2.2.2. Study Endpoints Purpose I: To assess the appropriate clinical performance by evaluating and documenting: Sensing, impedance and threshold tests per applicable Reference guide All adverse events and all Product Experiences VT/VF detection & conversion if performed at implant or pre-discharge Spontaneous episode conversion Wanded and wireless telemetry Performance was compared with historical data. Purpose II: To assess the clinical relevance of daily median respiratory rate in HF patients by comparing the changes in mean daily median respiratory rate in patients with a protocol-defined HF event (HFE) to those in patients without a protocol-defined HFE. 5.2.3. Ethical Considerations This study was conducted utilizing practices that ensured adherence to Good Clinical Practice (GCP) and protection of the subjects, as required by guidelines, regulations, and directives in operation at the time as indicated in the CIP. A copy of the CIP, proposed Informed Consent forms, and other written subject information was submitted to the Independent Ethics Committee (IEC) for written approval. Copies of the written IEC approval of the CIP and Informed Consent form were received by the Sponsor before recruitment of subjects into the study and shipment of product. The investigator was responsible for submitting and obtaining approval from the IEC for all CIP amendments and changes to the Informed Consent form. The investigator was responsible for notifying the IEC of deviations from the CIP, Serious Adverse Events (SAEs) or Unanticipated Adverse Device Effects (UADEs) occurring at the site, and reports received from the Sponsor (Boston Scientific Corporation [BSC]) in accordance with local procedures and IEC requirements. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 12 of 44 Confidential The investigator was responsible for obtaining annual IEC approval and renewal throughout the duration of the study. Copies of the investigator’s reports and the IEC continuance (or extension) of approval were sent to the Sponsor. 5.2.4. Data Quality Assurance Boston Scientific Corporation was responsible for study monitoring, data management, and statistical analyses for this study. Clinical sites were monitored at regular intervals during the study to ensure that all aspects of the currently approved CIP and CIP amendment(s) were followed. The investigator and study site personnel ensured that designated BSC personnel and Regulatory Authorities had access to source documents as appropriate. Case report forms (CRFs) were designed by the sponsor and were provided to the clinical site personnel for completion. Training on data collection and CRF completion was provided by the sponsor and was adherent to the study specific monitoring plan. The above-mentioned tasks were performed according to relevant quality system Standard Operating Procedures (SOP) within BSC. 5.2.5. Study Subject Population 5.2.5.1. Inclusion/Exclusion Criteria Patients who met all of the inclusion and none of the exclusion criteria were enrolled in the study. It was recommended that devices were implanted in patients based on standard implant guidelines from the European Society of Cardiology (ESC) and Institutional device reimbursement policy as the Sponsor was not responsible for reimbursement. The criteria of inclusion and exclusion are showing in Table 2 and 3. Table 2: Inclusion Criteria General Inclusion Criteria Patients who were willing and capable of providing informed consent, undergoing a device implant, participating in all testing associated with this clinical study; Patients whose age was 18 or above, or of legal age to give informed consent specific to national law Patients indicated for an ICD according to normal clinical practice (for those patients receiving an INCEPTA ICD). o As soon as 20 ICD patients were included in the study for purpose I, only NYHA Class III patients were allowed in the study. NYHA class was documented in the last 3 months. NYHA Class III patients indicated for a CRT-D according to normal clinical practices (for those patients who received an INCEPTA CRT-D). NYHA class was documented in the last 3 months. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 13 of 44 Confidential Subjects were ineligible to participate in the study if they met the following exclusion criteria. Table 3: Exclusion Criteria General Exclusion Criteria 5.2.5.2. Women of childbearing potential who were or might be pregnant at the time of the study (method of assessment upon physician’s discretion) Enrolled in any other concurrent study. Inability or refusal to comply with the follow-up schedule Patients that have received routinely scheduled intravenous inotropic therapy as part of their drug regimen within the past 90 days Patients prescribed to positive airway pressure therapy A life expectancy of less than 1 year, per physician discretion Patient in NYHA Class IV during the last 4 weeks Patient who lived at such a distance from the clinic that travel for follow-up visits would be unusually difficult Sample Size The sample size calculations supported the enrollment of at least 120 patients, refer to section 5.2.8.2. 5.2.6. Treatment and Treatment Allocation Schedule Subjects were implanted with a study device according to standard of care, then followed at pre-discharge, 1 month, 3 months, 6 months, and 9 months. The testing and data requirements are defined in Table 4. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 14 of 44 Confidential Table 4 Data Collection and Testing Summary Reportable Items Timeframe Implant Data Enrollment Implant post NA within 14 days of enrollment Patient Informed Consent form NYHA class LVEF (within 180 days prior to Enrollment) Intrinsic QRS duration Device Evaluation VT/VF conversion Device Parameter Printout Wireless ECG Save All to Disk/USB Demographics and Medical History Physical Assessment HF Medications 24h Holter monitoring Lead Connection Questionnaire Telemetry Questionnaire Basic Questionnaire AE reporting$ Deviation reporting Patient Study Journal Polysomnography (PSG) data collection √ -- Predischarge 1month 3Month 6Month 9Month 30 ± 7 days 90 ± 30 days 180 ± 30 days 270 ± 30 days -- -- -- -- -- Additional Follow-up -- -- -- -- -- -- -- -- -- √* -- -- -- -- -- -- -- √ √+ -- -- -- -- -- -- NA NA NA √ √** √*** √ √ √ # -- -- -- -- √ √ √ √ √ # NA NA √ √ -- -- -- -- -- -- √ √ √ √ √ √* √ -- -- -- -- -- -- -- √ -- -- √* √* √* √* √* √ -- --- √ √ √ √ -- √ -- √* √**** NA √ -- -- -- -- -- -- NA -- √ -- -- -- -- -- -- -- -- √ √ √ √ √* √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ -- -- -- √ √ √ √ √* -- -- -- √* √* √* √* √* √ √*** √ -- -- √ -- √ $ Death, HF event, hospitalization, and patient withdrawal information were collected # Recommended 副 Required 副+ If not available at this point, the intrinsic QRS duration can be determined by the device. 副* if available 副** Must be performed using wanded telemetry 副*** Recommended as per Reference guide, at implant or pre-discharge 副**** In case the patient experienced a HF event as defined in the protocol Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 15 of 44 Confidential 5.2.7. Duration of Follow-up Upon enrollment into the study, patients were followed at, pre-discharge, 1 month, 3 months, 6 months, and 9 months after the implant of their device. 5.2.8. Statistical Analysis 5.2.8.1. Study Hypotheses In this study, a hypothesis was applicable only for purpose II: H0: ∆RR1 = ∆RR2, H1: ∆RR1 ≠ ∆RR2, where ∆RR represented change in mean daily median respiratory rate. The index time was defined as the day of the first HF event with sufficient data in patients having one or more protocol-defined HF events (group 1) and as the day of 6month follow up in patients having no protocol-defined HF event (group 2). Group 1 contained patients with at least one protocol defined HFE. Group 2 contained all patients without a protocol defined HFE who completed the 9 month follow-up visit. The baseline time window was the 5-day period from 60 to 56 days before the index time. The baseline median Respiratory Rate (RR) value was the average of the daily median RR values during this baseline window. The event time window was defined as the 5-day period from 11 to 7 days before the index time. The event median RR value was the average of the daily median RR values during this event window. 5.2.8.2. Sample Size Calculation Available data from a previous study with a small number of HF events23, 24, was used to estimate an expected difference of 2.96 breaths/minute (br/min) in HF patients with an event (♀RR 1, N = 5) with a standard deviation of 1.62 br/min and an expected difference of 0.37 br/min in HF patients without an HF event (♀RR 2, N = 174) with a standard deviation of 1.24br/min. Based on these assumptions, to detect a non-zero difference between groups (※ =0.05) with 90% power, it required valid data sets be available for at least 8 patients with an HF event and at least 8 patients without an HF event. Assuming 20% of missing data (4% missing data in the window of interest, 16% not having sufficient 60-day baseline), at least10 patients with an HF event and at least 10 patients without an HF event were needed. Data from the DECODE study indicated a HF event rate in the class III CRT-D Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 16 of 44 Confidential patients was 0.2 events/patient-year. The number of unique patients having a HF event per patient-year monitored was 0.15. The rate in class III ICD patients was expected to be similar if not higher based on previously published study25. Assuming that 0.15 HF patients would experience at least one HF event per patientyear monitored in class III HF patients, a total of 67 patient-year data was needed for this analysis (or 90 patients with 9 month follow-up data). Based on Boston Scientific historical clinical study data, 83% of the ICD patient population in a clinical study was NYHA class I or II. In order to mitigate the risk that the 20 ICD patients for study purpose I would not have the required HF event rate, 20*83% = 17 additional patients were enrolled. This brought the total number of patients to be followed up for 9 months to 107. Assuming an attrition rate of 12% for patient withdrawal and loss of follow-up, a total of 120 patients with 9 month follow-up was required for this endpoint. 5.2.8.3. Statistical Analysis Methods For purpose I, a subset of data was analyzed as soon as 15 ICD patients and 15 CRTD patients had completed their 1 month follow-up. Descriptive statistics were used for describing the patient cohort and the observed device parameters of interest. In the analysis of purpose II, two average daily median respiratory rates were calculated for every patient: 60 to 56 days before an index time and 11 to 7 days before the same index time. The difference between these two averaged daily median respiratory rates was calculated. The index time was defined as the day of the first heart failure (HF) event with sufficient data in patients having one or more protocoldefined HF events (group 1) and as the day of the 6 months follow- up in patients having no protocol-defined HF event (group 2). Wilcoxon signed-rank test was conducted to test the study hypotheses and compare the difference between group 1 and 2. The following patients contributed to the purpose II analysis: (1) patients who had a HF event with a valid data set, or (2) patients who did not have a HF event but who had completed their 6 month follow-up with a valid data set. A valid data set was defined as a patient that has more than 60% valid daily median respiratory rate during each time window of interest (i.e., 5*60% = 3 daily median respiratory rate values). Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 17 of 44 Confidential 6. Results 6.1. Study Initiation Date The first patient was enrolled on 05 November 2010. 6.2. Study Completion The last study follow up visit was completed on 28 December 2011. The database was closed to all users on 29 February 2012. 6.3. Subject Disposition There were 121 patients enrolled in the study, of which120 were classified as an implant and implanted with a study device. One patient was withdrawn before receiving a study device and classified as an intent and therefore did not count toward the enrollment ceiling. The Intent patient signed the informed consent form, was enrolled in the study to receive a device upgrade from an ICD to a CRT-D, however further review of medical records indicated the patient already had an CRT-D without an LV lead. The patient was subsequently withdrawn from the study and classified as an intent. Figure 2 shows subject disposition, and per study patient classification. The total implant duration for study subjects that were implanted with the study device and followed was 1041 months as shown in Table 5. The mean duration of follow up post-implant was 8.7 ± 1.9 months as shown in Table 5. The reasons for withdrawal are presented in Table 6. The analysis on death will be reported in section 6.7.4. Enrolled 121 Intent 1 Implant 120 Active 108 Attempt 0 Inactive 12 Withdrawal 7 Death 0 Death 5 Figure 2: Subject Disposition in NOTICE HF Study Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 18 of 44 Confidential Table 5: Duration of Follow-up Post-implant Statistic N Mean ± SD Range Total Patient Months Implant Duration(Months) 120 8.7 ± 1.9 0.5 - 10.9 1041 Table 6 : Withdrawal Number of Patients Withdrawn Percent of Total Study Patients Withdrawn (Total Study N=121) Patient refused testing/follow-up 4 3.3% Pt did not meet eligibility criteria 1 0.8% Pt has Respiratory Sensor programmed OFF 1 0.8% Other: After patient signed consent it was discovered that his in-situ ICD was actually a Cognis CRT-D with LV port plugged, so a new INCEPTA CRT-D not implanted for his device upgrade procedure. 1 0.8% Other: Patient had been consented and randomised into a stem cell CTIMP study by another centre and therefore due to good clinical practice had to be withdrawn 1 0.8% Total 8 6.6% Withdrawal Reason 6.4. Subject Demographics Table 7 presents baseline demographic and clinical characteristics for the patients implanted with a device. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 19 of 44 Confidential Table 7: Baseline Demographic and Clinical Characteristics All patients implanted or attempted, N=120 ICD (N=43) CRT (N=77) 43 77 Mean ± SD 62.7 ± 10.6 67.4 ± 10.1 Range 31.0 - 80.0 39.0 - 85.0 Male 36 (84) 64 (83) Female 7 (16) 13 (17) I 3 (7) 0 (0) II 10 (23) 0 (0) III 30 (70) 77 (100) N 33 75 Characteristic Measurement Age at Implant (years) N Gender [N (%)] NYHA Class [N (%)] LVEF (%) QRS Duration (ms) Heart Rate at Rest (bpm) Resting Respiratory Rate (breaths/min) Concomitant Medications* [N (%)] Mean ± SD 30.2 ± 12.5 26.3 ± 7.8 Range 15.0 - 77.0 15.0 - 55.0 39 71 Mean ± SD 115 ± 25 147 ± 33 Range 74 - 180 78 - 222 39 71 N N Mean ± SD 71 ± 17 72 ± 16 Range 42 - 127 34 - 115 N 0.02 0.93 <0.001 0.05 <0.001 0.92 39 65 Mean ± SD 17.4 ± 7.5 17.1 ± 4.4 Range 12.0 - 48.0 0.0 - 28.0 Beta Blocker 38 (88) 68 (88) 0.99 Diuretics 32 (74) 70 (91) 0.02 ACE Inhibitor 30 (70) 57 (74) 0.62 Aldosterone Antagonist 18 (42) 33 (43) 0.92 Angiotensin Receptor Blocker 9 (21) 17 (22) 0.88 Anti-arrhythmic drugs 4 (9) 9 (12) 0.69 Renin Inhibitors Ventricular Arrhythmias* [N (%)] P-value** 0.78 0 (0) 1 (1) 0.45 Other 18 (42) 37 (48) 0.51 Nonsustained VT 12 (28) 8 (10) 0.01 Monomorphic VT (MVT) 4 (9) 8 (10) 0.85 Ventricular Fibrillation (VF) 6 (14) 5 (6) 0.17 Polymorphic VT (PVT) 2 (5) 1 (1) 0.26 Other 2 (5) 6 (8) 0.51 None 20 (47) 51 (66) 0.04 Other Pre-Existing Conditions* [N (%)] Hypertension 22 (51) 53 (69) 0.06 Coronary Artery Disease 18 (42) 38 (49) 0.43 Diabetes 11 (26) 30 (39) 0.14 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 20 of 44 Confidential Characteristic ICD (N=43) CRT (N=77) P-value** Renal Disease 7 (16) 23 (30) 0.10 Palpitation 10 (23) 12 (16) 0.30 5 (12) 12 (16) 0.55 Pulmonary Hypertension 3 (7) 10 (13) 0.31 Asthma 2 (5) 5 (6) 0.68 Hepatic Disease 1 (2) 3 (4) 0.65 Sleep disordered breathing 1 (2) 2 (3) 0.93 Anemia 0 (0) 1 (1) 0.45 None 2 (5) 0 (0) 0.06 29 (67) 46 (60) 0.58 12 (28) 24 (31) 2 (5) 7 (9) Yes 19 (44) 35 (45) No 19 (44) 34 (44) Unknown 5 (12) 8 (10) Measurement COPD (chronic pulmonary disease) Previous hospitalizations in last 6 No months [N (%)] Yes Unknown Prior Myocardial Infarction [N (%)] obstructive 0.98 *Patients may appear in more than one category **P-values for comparing means were calculated with a Student’s t-test; p-values for comparing proportions were calculated with a Chi-squared test. 6.5. CIP Compliance 6.5.1. CIP Deviations Protocol deviations were reported by centers in the electronic data capture system, then reviewed and classified by the Sponsor according to Table 8. Table 9 is a summary of the 184 deviations reported in 73 patients. Table 8: Classification of Deviation Type Circumstance or rationale A Deviation to protect the life or physical well-being of a patient in an unforeseen emergency B Deviation based on medical judgment to prevent harm to a patient in a non-emergency situation Deviation due to a misunderstanding of protocol requirements (training is an issue) C D Deviation due to a situation that is beyond control E Deviation due to an oversight, error or protocol non-compliance Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 21 of 44 Confidential Table 9: Deviations Class Deviations Class Number of Events Percent of Events Type A 0 0% Type B 0 0% Type C 3 2% Type D 39 21% Type E 142 77% Total Incidence 184 100% Total Unique Patients 73 N/A 6.6. Analysis 6.6.1. Device Technical Performance There were 65 product experiences (PEs) reported in the study related to the INCEPTA ICD or CRT-D are shown in Table 10. No Unanticipated Adverse Device Effects (UADEs) were reported during the NOTICE-HF study. The majority of the PEs reported were related to the shock impedance noise display (refer to section 10), problems with the USB, programmer parameter mismatch, Reverse Mode Switches, EGM noise without over sensing, lead connection issues, or customer device feedback. Table 10: Product Experience frequency Model Associated with Product Experience Frequency P162 24 P163 11 F160 9 F162 9 F161 8 F163 4 Total 65 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 22 of 44 Confidential 6.7. Study Endpoint Results 6.7.1. Purpose I The clinical performance was analyzed when a minimum of 15 ICD and 15 CRT-D patients completed followed-up for 1 month. The results of pacing thresholds, sensing amplitudes, lead impedances, VT/VF detection and conversion are reported in this section. A summary of product experiences and adverse events for the full data set are provided in sections 226.6.1 and 6.7.3 respectively. 6.7.1.1. Pacing thresholds (V) Pacing thresholds are presented in Table 11 for Purpose I. Per the protocol thresholds were measured using a pulse width of 0.4 ms. Pacing thresholds at implant, predischarge, and 1 month were within the normal range recommended in the INCEPTA PTM, and are consistent with internal historical data. Table 11: Pacing thresholds (V) – Purpose I Pacing Threshold (V) Device CRT Major Structure Left Ventricle Right Atrium Visit Type N Mean+/- SD Implant 14 1.4 +/- 0.7 Pre-Discharge 14 1.4 +/- 0.8 1Month Follow-up 15 1.1 +/- 0.5 Implant 12 0.8 +/- 0.6 Pre-Discharge 12 0.8 +/- 0.7 1Month Follow-up 11 1.2 +/- 1.3 16 0.6 +/- 0.2 Pre-Discharge 16 0.6 +/- 0.3 1Month Follow-up 16 0.8 +/- 0.2 Implant 5 1.3 +/- 0.9 Pre-Discharge 5 1.3 +/- 1.1 1Month Follow-up 5 1.4 +/- 1.0 16 0.8 +/- 0.3 Pre-Discharge 16 1.0 +/- 1.6 1Month Follow-up 15 0.9 +/- 0.5 Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Pacing thresholds are presented in Table 12 for the entire study cohort. The mean pacing threshold at each follow-up was within normal acceptable ranges. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 23 of 44 Confidential Table 12: Pacing thresholds (V) – All data Pacing Threshold (V) Device CRT Major Structure Left Ventricle Right Atrium Visit Type N Mean +/- SD Implant 78 1.3 +/- 0.8 Pre-Discharge 75 1.5 +/- 1.2 1Month Follow-up 73 1.3 +/- 0.9 3Month Follow-up 74 1.3 +/- 0.9 6Month Follow-up 69 1.2 +/- 0.9 9Month Follow-up 65 1.2 +/- 1.1 Additional Follow-up 32 1.1 +/- 0.5 Implant 56 0.8 +/- 0.7 Pre-Discharge 57 0.8 +/- 0.9 1Month Follow-up 54 1.0 +/- 1.0 3Month Follow-up 53 1.0 +/- 0.9 6Month Follow-up 48 0.9 +/- 0.7 9Month Follow-up 48 0.9 +/- 0.7 Additional Follow-up 14 0.6 +/- 0.4 79 0.7 +/- 0.3 Pre-Discharge 78 0.7 +/- 0.3 1Month Follow-up 75 0.9 +/- 0.5 3Month Follow-up 74 0.9 +/- 0.6 6Month Follow-up 71 0.8 +/- 0.6 9Month Follow-up 67 0.8 +/- 0.3 Additional Follow-up 28 0.7 +/- 0.4 Implant 11 1.0 +/- 0.7 Pre-Discharge 11 0.9 +/- 0.8 1Month Follow-up 11 1.0 +/- 0.7 3Month Follow-up 9 1.0 +/- 0.8 6Month Follow-up 10 1.1 +/- 0.8 9Month Follow-up 9 1.3 +/- 0.8 Additional Follow-up 3 1.3 +/- 1.1 46 0.8 +/- 0.5 Pre-Discharge 45 0.8 +/- 1.1 1Month Follow-up 43 1.4 +/- 1.7 3Month Follow-up 43 1.0 +/- 0.7 6Month Follow-up 43 1.0 +/- 0.6 Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 24 of 44 Confidential Pacing Threshold (V) Major Structure Device 6.7.1.2. Visit Type N Mean +/- SD 9-Month Follow-up 44 1.0 +/- 0.6 Additional Follow-up 21 1.1 +/- 1.5 Sensed Amplitude (mV) Sensing amplitudes are presented in Table 13. Sensing amplitudes at implant, predischarge, and 1 month were within normal range recommended in the INCEPTA PTM, and are consistent with internal historical data. Table 13: Sensing Amplitude (mV) – Purpose I Sensed Amplitudes (mV) Device CRT Major Structure Left Ventricle Right Atrium Visit Type N Mean +/- SD Implant 13 15.6 +/- 6.9 Pre-Discharge 12 18.3 +/- 6.7 1Month Follow-up 12 21.0 +/- 5.1 Implant 12 4.0 +/- 1.9 Pre-Discharge 12 4.3 +/- 1.9 1-Month Follow-up 11 4.2 +/- 1.8 14 18.6 +/- 4.3 Pre-Discharge 14 20.1 +/- 4.9 1-Month Follow-up 12 20.6 +/- 4.9 Implant 5 2.3 +/- 1.0 Pre-Discharge 5 2.7 +/- 1.7 1Month Follow-up 5 2.8 +/- 1.3 16 14.2 +/- 5.2 Pre-Discharge 16 15.9 +/- 5.5 1Month Follow-up 15 16.6 +/- 6.0 Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Sensing amplitudes are presented in Table 14 for the entire study cohort. The mean sensed amplitude at each follow-up was within acceptable ranges. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 25 of 44 Confidential Table 14: Sensing Amplitude (mV) – All Data Sensed Amplitudes (mV) Device CRT Major Structure Left Ventricle Right Atrium Visit Type N Mean +/- SD Implant 74 14.4 +/- 7.3 Pre-Discharge 69 14.9 +/- 7.7 1Month Follow-up 68 17.2 +/- 7.1 3Month Follow-up 68 16.4 +/- 7.3 6Month Follow-up 64 17.4 +/- 6.9 9Month Follow-up 62 17.2 +/- 7.1 Additional Follow-up 32 15.4 +/- 7.9 Implant 55 3.8 +/- 2.0 Pre-Discharge 55 4.1 +/- 2.0 1Month Follow-up 53 4.9 +/- 2.9 3Month Follow-up 51 4.9 +/- 3.0 6-Month Follow-up 46 4.5 +/- 2.3 9Month Follow-up 47 4.7 +/- 2.9 Additional Follow-up 13 4.4 +/- 2.7 74 16.2 +/- 6.6 Pre-Discharge 73 16.7 +/- 6.1 1Month Follow-up 68 17.9 +/- 6.2 3Month Follow-up 67 18.5 +/- 6.0 6Month Follow-up 66 17.9 +/- 6.4 9Month Follow-up 63 18.3 +/- 6.1 Additional Follow-up 28 16.0 +/- 6.8 Implant 11 3.2 +/- 2.2 Pre-Discharge 11 3.9 +/- 2.6 1Month Follow-up 11 3.7 +/- 2.7 3Month Follow-up 9 3.4 +/- 3.0 6Month Follow-up 10 4.1 +/- 3.3 9Month Follow-up 9 3.2 +/- 1.5 Additional Follow-up 3 5.6 +/- 4.9 45 15.8 +/- 5.8 Pre-Discharge 44 16.9 +/- 5.9 1-Month Follow-up 43 17.1 +/- 6.6 3Month Follow-up 43 17.3 +/- 6.6 6Month Follow-up 43 17.1 +/- 6.0 Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 26 of 44 Confidential Sensed Amplitudes (mV) Device 6.7.1.3. Major Structure Visit Type N Mean +/- SD 9-Month Follow-up 44 17.3 +/- 5.6 Additional Follow-up 21 16.2 +/- 7.0 Pacing Impedance (Ohms) Pacing impedances are presented in Table 16 for Purpose I. Pacing impedances at implant, pre-discharge, and 1 month were within the normal range recommended in INCEPTA PTM, and are consistent with internal historical data. Table 15: Pacing impedance (Ohms) – Purpose I Pacing Impedance (Ohms) Device CRT Major Structure Left Ventricle Right Atrium Visit Type N Mean +/- SD Implant 14 828 +/- 213 Pre-Discharge 14 721 +/- 215 1Month Follow-up 15 699 +/- 205 Implant 12 492 +/- 61 Pre-Discharge 12 464 +/- 58 1-Month Follow-up 11 489 +/- 104 16 667 +/- 206 Pre-Discharge 16 605 +/- 168 1-Month Follow-up 16 595 +/- 131 Implant 5 827 +/- 656 Pre-Discharge 5 819 +/- 661 1-Month Follow-up 5 822 +/- 660 16 613 +/- 166 Pre-Discharge 16 587 +/- 168 1Month Follow-up 15 579 +/- 181 Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Pacing impedances are presented in Table 16 for the entire study cohort. The mean pacing impedance at each follow-up was within normal acceptable ranges. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 27 of 44 Confidential Table 16: Pacing impedance (Ohms) – All data Pacing Impedance (Ohms) Device CRT Major Structure Left Ventricle Right Atrium N Mean +/SD Implant 78 879 +/- 296 Pre-Discharge 75 777 +/- 244 1Month Follow-up 73 778 +/- 265 3Month Follow-up 74 791 +/- 253 6-Month Follow-up 69 792 +/- 260 9Month Follow-up 66 779 +/- 253 Additional Follow-up 32 703 +/- 176 Implant 56 538 +/- 132 Pre-Discharge 57 512 +/- 141 1Month Follow-up 54 534 +/- 152 3Month Follow-up 53 539 +/- 168 6Month Follow-up 48 535 +/- 181 9Month Follow-up 48 544 +/- 187 Additional Follow-up 14 497 +/- 56 79 637 +/- 208 Pre-Discharge 78 604 +/- 196 1Month Follow-up 75 590 +/- 209 3Month Follow-up 74 610 +/- 236 6Month Follow-up 71 602 +/- 214 9Month Follow-up 67 589 +/- 183 Additional Follow-up 28 559 +/- 161 Implant 11 670 +/- 443 Pre-Discharge 11 656 +/- 448 1Month Follow-up 11 655 +/- 447 3Month Follow-up 9 684 +/- 494 6Month Follow-up 10 672 +/- 469 9Month Follow-up 9 687 +/- 494 Additional Follow-up 3 1021 +/- 849 46 807 +/- 385 Pre-Discharge 45 686 +/- 284 1Month Follow-up 43 658 +/- 295 3Month Follow-up 43 655 +/- 285 6Month Follow-up 43 638 +/- 277 Visit Type Right Ventricle Implant ICD Right Atrium Right Ventricle Implant Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 28 of 44 Confidential Pacing Impedance (Ohms) Device 6.7.1.4. Major Structure N Mean +/SD 9Month Follow-up 44 635 +/- 274 Additional Follow-up 21 612 +/- 243 Visit Type VT/VF detection & conversion A summary of induced and spontaneous VT/VF episodes are provided in this section. Only the visits at scheduled follow ups which there were induced episodes and conversions are displayed in Table 17, Table 18, Table 19, and Table 20. Induced VT/VF episodes were converted successfully 100% of the time as shown in Table 17 for Purpose I. Table 17: Induced episodes – Purpose I Device CRT ICD Induced Episodes Successfully Converted Induced Episodes Implant 9 9 (100%) Pre-Discharge 1 1 (100%) Implant 9 9 (100%) Visit Type Conversion rates for induced VT/VF episodes for the entire study cohort are presented in Table 18. There were a total of 68 induced episodes with a 100% successful conversion rate at implant and the scheduled follow up visits Table 18: Induced episodes – All Data Device CRT ICD Total Induced Episodes Successfully Converted Induced Episodes Implant 30 30 (100%) Pre-Discharge 4 4 (100%) 1Month Follow-up 1 1 (100%) 3Month Follow-up 6 6 (100%) 9Month Follow-up 1 1 (100%) Implant 22 22 (100%) 1Month Follow-up 1 1 (100%) 3Month Follow-up 3 3 (100%) 68 68(100%) Visit Type Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 29 of 44 Confidential The mean detection time of induced episodes was less than 2.66 seconds for Purpose I, as shown in Table 19. Table 19: Induced episodes detection time – Purpose I Detection Time (seconds) Device CRT ICD Visit Type N Mean ± SD* Implant 9 2.46 ± 0.22 Pre-Discharge 1 2.66 Implant 9 2.31 ± 0.41 * Standard deviation is not applicable and therefore not presented for scenarios in which only one measurement was collected. Induced VT/VF episode detection times are presented in Table 20 for the entire study cohort. The longest mean detection times were observed at implant for patients with either a CRT or an ICD. Table 20: Induced episodes detection time – All Data Detection Time (seconds) Device CRT ICD Visit Type N Mean ± SD* Implant 30 2.46 ± 0.38 Pre-Discharge 4 2.31 ± 0.66 1Month Follow-up 1 2.06 3Month Follow-up 6 2.28 ± 0.28 9Month Follow-up 1 2.30 Implant 22 2.40 ± 0.42 1Month Follow-up 1 2.06 3Month Follow-up 3 2.29 ± 0.06 * Standard deviation is not applicable and therefore not presented for scenarios in which only one measurement was collected. In NOTICE-HF 20% (n=6) of patients had a spontaneous episode, as shown in Table 21 for Purpose I. Spontaneous episodes were converted 100% of the time. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 30 of 44 Confidential Table 21: Spontaneous Episodes – Purpose I Device Total Patients Number (%) of Patients with Spontaneous Episodes Total Number of Spontaneous Episodes Number (%) of Converted Spontaneous Episodes* CRT 15 4 (27%) 20 20 (100%) ICD 15 2 (13%) 3 3 (100%) Total 30 6 (20%) 23 23 (100%) * Episodes could have converted spontaneously or due to device therapy. Table 22 presents the spontaneous episode conversion rates for the entire study cohort. There were 21 (18%) patients who had a spontaneous episode, with a 100% successful conversion rate. Table 22: Spontaneous Episodes – All Data Device Total Patients Number (%) of Patients with Spontaneous Episodes Total Number of Spontaneous Episodes Number (%) of Converted Spontaneous Episodes* CRT 77 13 (17%) 54 54 (100%) ICD 43 8 (19%) 42 42 (100%) Total 120 21 (18%) 96 96 (100%) * Episodes could have converted spontaneously or due to device therapy. 6.7.1.5. Wanded and Wireless Telemetry At the pre-discharge follow-up, following the device evaluation investigators completed a questionnaire on the performance of wanded telemetry. There were no reports of issues with the device interrogation as shown in Table 23 for Purpose I. Table 23: Results for Telemetry – Purpose I Questionnaire Item Issue during device interrogation Number of Yes Responses/Total Responses (%) 0/30 (0.0%) A summary of the 118 responses to the wanded telemetry questionnaire from the entire study cohort are shown in Table 24. There was only one (0.8%) report of an issue during device interrogation. There were no reports of an issue with Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 31 of 44 Confidential communication dropout, delay in the case or duration of the follow-up because of a telemetry issue, or problems with commands. Table 24: Results for Telemetry – All Data Questionnaire Item Issue during device interrogation Number of Yes Responses/Total Responses (%) 1/118 (0.8%) Issue with initiating communication (among those with issues during device interrogation) 1/1 (100%) Communication dropout (among those with issues during device interrogation) 0/1 (0.0%) Delay in the case or duration of the follow-up because of a telemetry issue (among those with issues during device interrogation) 0/1 (0.0%) Problems with commands - either initiating or terminating command (among those with issues during device interrogation) 0/1 (0.0%) Other issues (among those with issues during device interrogation) 1/1 (100%) 6.7.2. Purpose II A comparison of the change in respiratory rate over time was made between patients who experienced a protocol-defined HF event (HFE) (Group1: Patients with a HFE) and patients who did not experience a protocol-defined heart failure event (Group2: Patients without a HFE), as described in Section 5.2.8.3. Only patients with at least 3 valid daily RRT values (60%) out of each 5-day window were evaluated. In Group 1, there were 17 HF events in 13 patients. For patients with multiple HFEs, only the first HFE with sufficient data was used for each patient. Of the 13 patients with a HFE, 8 had sufficient data for the endpoint analysis. One patient was missing data in the specified windows. The HFE occurred too early in the other four patients to establish a sufficient baseline. In Group 2, there were 95 patients that completed the 9 month follow-up. Of the 95 patients, 90 had datasets eligible for inclusion in the endpoint analysis. One patient was missing data in the specified windows, 2 patients missed the 6 month FU (index time for group 2) due to AEs, 1 patient’s disk was missing, and 1 patient did not have valid RRT measurements. As shown in Table 25, there was not a statistically significant change in the respiratory rate (P = 0.361) when calculated using the pre-specified windows, therefore the null hypothesis could not be rejected (H0, see section 5.2.8.1). This was Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 32 of 44 Confidential likely caused by two reasons: first, the increase in the median RR prior to the HFE was smaller than expected and second, other adverse events that occurred during the 60 days prior to the first HFE in group 1 have influenced the baseline median RR, thus delta RR, in this group. Table 25: Changes in Respiratory Rate Change in Respiratory Rate Baseline Window to Event Window (breaths/minute) Group Number of Patients Mean ± SD Median (25th, 75th percentile) Group 1: Patients with a HFE 8 0.26 ± 1.57 -0.30 (-0.47, 0.30) Group 2: Patients without a HFE 90 0.22 ± 1.06 0.00 (-0.40, 0.80) Wilcoxon rank-sum p = 0.361 It is worth noting that, although the Purpose II objective was not met, an increase in the median respiratory rate was observed two to three weeks prior to the protocoldefined HF event. 6.7.3. Summary of Adverse Events Adverse events were classified per ISO 14155 definitions: Adverse Device Effect (ADE) – any untoward and unintended response to a medical device (any device related adverse event) Note: This definition includes any event resulting from insufficiencies or inadequacies in the instructions for use or the deployment of the device, and any event that is a result of user error. Adverse Event (AE) – any untoward medical occurrence in a subject Note: This definition does not imply that there is a relationship between the Adverse Event and the device under investigation. Serious Adverse Device Effect (SADE) – adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event or that might have led to any of these consequences if suitable action had not been taken or intervention had not been made or if circumstances had been less opportune Serious Adverse Event (SAE) – adverse event that: Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 33 of 44 Confidential o led to a death o led to a serious deterioration in the health of the subject that: o resulted in a life threatening illness or injury o resulted in a permanent impairment function of a body structure or body o required in-patient hospitalization or prolongation of existing hospitalization o resulted in a medical or surgical intervention to prevent permanent impairment of a body structure or a body function o led to fatal distress, fatal death or a congenital abnormality or birth defect A total of 216 AEs were collected during the course of the study. There were 69 AEs, 112 SAEs, 19ADEs and 16SADEs reported during the study, as shown in Table 26. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 34 of 44 Confidential Table 26: Adverse Events by ISO 14155 Classification All patients implanted or attempted, N=120 ISO Classification Serious Adverse Event Serious Adverse Adverse Device Adverse Device Event Effect Effect Classification Ev Pts % Ev Pts % Ev Pts % Ev Pts Total % Ev Pts % Cardiovascular 28 23 19.2% 49 33 27.5% 0 0 0.0% 1 1 0.8% 78 49 40.8% Defib Lead 0 0 0.0% 0 0 0.0% 1 1 0.8% 3 2 1.7% 4 3 2.5% LV Lead 0 0 0.0% 0 0 0.0% 11 11 9.2% 3 2 1.7% 14 13 10.8% Noncardiovascular 29 23 19.2% 50 31 25.8% 4 4 3.3% 0 0 0.0% 83 46 38.3% PG 0 0 0.0% 0 0 0.0% 2 2 1.7% 1 1 0.8% 3 3 2.5% Procedure 6 5 4.2% 12 10 8.3% 0 0 0.0% 0 0 0.0% 18 15 12.5% RA Lead 0 0 0.0% 0 0 0.0% 0 0 0.0% 4 4 3.3% 4 4 3.3% RV Lead 0 0 0.0% 0 0 0.0% 0 0 0.0% 4 4 3.3% 4 4 3.3% Other 4 3 2.5% 1 1 0.8% 0 0 0.0% 0 0 0.0% 5 4 3.3% Unknown 2 2 1.7% 0 0 0.0% 0 0 0.0% 0 0 0.0% 2 2 1.7% 0 0 0.0% 0 0 0.0% 1 1 0.8% 0 0 0.0% 1 1 0.8% 69 44 36.7% 112 56 46.7% 19 17 14.2% 16 14 11.7% 216 82 68.3% Unclassified Comment Total - Ev = Number of Events Pts = Number of Patients with Event(s) % = Percent of All Patients with Event(s) 6.7.4. Death Summary There were 5 (4.2%) deaths during the NOTICE-HF study. A summary of the causes of death are presented in Table 27. There was no evidence of a device malfunction related to any of the deaths. Table 27: Patient Deaths All patients implanted or attempted; N=120 Primary Organ Cause Cardiac: Pump Failure Cardiac: Unknown Unknown Total Deaths (N) 3 1 1 5 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 35 of 44 Confidential 7. Bibliography/Publications 7.1. References Cited in the Report 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. American heart association., 2003 heart and stroke statistical update. Dallas. Tex. Aha 2002. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the united states, 1989 to 1998. Circulation. 2001;104:2158-2163 A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The antiarrhythmics versus implantable defibrillators (avid) investigators. N Engl J Med. 1997;337:1576-1583 Moss A, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. New England Journal of Medicine. 1993;335:1933-1940 Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549 Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, Boehmer JP, Higginbotham MB, De Marco T, Foster E, Yong PG. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003;42:1454-1459 Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, McKenna W, Fitzgerald M, Deharo JC, Alonso C, Walker S, Braunschweig F, Bailleul C, Daubert JC. Long-term benefits of biventricular pacing in congestive heart failure: Results from the multisite stimulation in cardiomyopathy (mustic) study. J Am Coll Cardiol. 2002;40:111-118 Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-1853 Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-2150 Wilkoff BL, Hess M, Young J, Abraham WT. Differences in tachyarrhythmia detection and implantable cardioverter defibrillator therapy by primary or secondary prevention indication in cardiac resynchronization therapy patients. J Cardiovasc Electrophysiol. 2004;15:1002-1009 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 36 of 44 Confidential 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda JM, Jr., Magalski A, Zile MR, Smith AL, Smart FW, O'Shaughnessy MA, Jessup ML, Sparks B, Naftel DL, Stevenson LW. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: The compass-hf study. J Am Coll Cardiol. 2008;51:1073-1079 Ewald GA, Roosevelt Gilliam F, Sweeney RJ. Use of remote data collection to track hf patient status: Decompensation detection study (decode). Journal of Cardiac Failure. 2006;12:S81 Fonarow GC, Corday E. Overview of acutely decompensated congestive heart failure (adhf): A report from the adhere registry. Heart Fail Rev. 2004;9:179185 Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure: Symptoms, patterns of onset, and contributing factors. Am J Med. 2003;114:625-630 Respiration rate trend and rapid shallow breathing index trend in patients with chronic and acute heart failure. Journal of Cardiac Failure. 2005;11:S181 Sullivan MJ, Higginbotham MB, Cobb FR. Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation. 1988;77:552-559 Duguet A, Tantucci C, Lozinguez O, Isnard R, Thomas D, Zelter M, Derenne JP, Milic-Emili J, Similowski T. Expiratory flow limitation as a determinant of orthopnea in acute left heart failure. J Am Coll Cardiol. 2000;35:690-700 Dimopoulou I, Tsintzas OK, Alivizatos PA, Tzelepis GE. Pattern of breathing during progressive exercise in chronic heart failure. Int J Cardiol. 2001;81:117-121; discussion 121-112 Clark AL, Volterrani M, Swan JW, Coats AJ. The increased ventilatory response to exercise in chronic heart failure: Relation to pulmonary pathology. Heart. 1997;77:138-146 Burgess KR, Berend N. Increased lung water without hypocapnia does not cause central sleep apnoea in a lamb model. Respirology. 2004;9:60-65 Maurizio L, Page E, Galley D, Ritter P, Serio A, Frattini F, Casset C, Cazeau S, Tavazzi L. Minute ventilation and patient's activity may predict acute heart failure events in crt patients. Heart Rhythm. 2006;3:S250 Da Cunha DNQ, Pedraze A, Kuenzler R, Dalal Y, Brockway M, Zhang Y, Hatlestad J, Hamlin R. Trends in respiration rate as an indicator of worsening heart failure. Journal of Cardiac Failure. 2007;13:S173 B. Merkely JS, J. Mont I Girbau, Y. Zhang, T. Kayser, V. Averina, N. Wold, P. Bloch Thomsen Daily maximum and median respiratory rate are elevated during clinical events when compared to a post-implant baseline in crt-d patients 2009 Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 37 of 44 Confidential 24. 25. . Mont I Girbau BL, B. Merkely, Y. Zhang, T. Kayser, V. Averina, N. Wold, P. Bloch Thomsen Daily maximum and median respiratory rate becomes elevated several weeks before hf hospitalization in patients with implantable devices 2009 Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA, 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W. Cardiac-resynchronization therapy for the prevention of heartfailure events. N Engl J Med. 2009;361:1329-1338 7.2. Publications Based on the Study Not applicable 8. Discussion and Overall Conclusions NOTICE-HF was a field following study to evaluate the clinical performance of the INCEPTA ICDs and CRT-Ds, and the changes in respiratory rate prior to HF events. With regard to product performance, INCEPTA ICD/ CRT-D lead measurements recorded were within recommended acceptable ranges in the Physicians Technical Manual for the INCEPTA and similar to internal historical data. The VT/VF conversion rate was 100% for both induced and spontaneous episodes. Although an increase in the median respiratory rate was not observed between group 1 and group 2 during the pre-specified windows, an increase was observed prior to HFEs. A larger study or a study with different designed windows is warranted to demonstrate the clinical relevance of daily respiratory rate trends in HF patient management. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 38 of 44 Confidential 9. Abbreviated Terms and Definitions 9.1. Abbreviated Terms Table 28: Abbreviation Abbreviation ADE AE CIP CRF CRM CRT-D ECG HFE ICD ISO PSG PTM RMS RRT SADE SAE SVT VF VT Full Word Adverse Device Effect Adverse Event Clinical Investigation Plan Case Report Form Cardiac Rhythm Management Cardiac Resynchronization Therapy Defibrillator Electrocardiogram Heart Failure Event Implantable Cardioverter Defibrillator International Standards Organization Polysomnography Physicians Technical Manual Reverse Mode Switch Respiratory Rate Trend Serious Adverse Device Effect Serious Adverse Event Supra Ventricular Tachyarrhythmia Ventricular Fibrillation Ventricular Tachycardia Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 39 of 44 Confidential 10. Investigators and Administrative Structure 10.1. List of Investigators The list of investigators is provided in Annex 12.1. 10.2. Sponsor(s) or Representative(s) Sponsor: Guidant Europe, a Boston Scientific Company International CRM Clinical Research Department Green Square, Lambroekstraat 5D, 1831 Diegem, Belgium Representative Ljubomir Manola Clinical Project Manager Tel: +32 241 67219 Fax: +32 2 4167202 Email: [email protected] Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 40 of 44 Confidential 12. Annex 12.1. List of Principal Investigators and Sites Table 29: Enrollments by Investigational Center All patients enrolled; N=121 Investigational Center/Primary Investigator Deutsches Herzzentrum Berlin/Stephan Goetze The Heart Hospital/Pier Lambiase St. Bartholomews Hospital/Richard Schilling A.o. Krankenhaus der Elisabethinen Linz/Siegmund Winter Marienhospital Herne, Univ. of Bochum/Hans-Joachim Trappe Krankenhaus Neu Bethlehem/Claudius Hansen Rigshospitalet/Regitse Videbaek Segeberger Kliniken GmbH/Gert Richardt Academisch Ziekenhuis Maastricht (AZM)/An L. Moens Skejby Sygehus/Jens Cosedis-Nielsen Hospital de Gran Canaria Doctor Negrin/Antonio Garcia Quitana Krankenhaus Hietzing/Stefan Fritsch Otto-von-Guericke-Universitaet Magdeburg/Rüdiger C. Braun-Dullaeus Universitätsklinikum Erlangen/Prof. Daniel Gottsegen National Institute of Cardiology Hungary (GOKI)/Csaba Foeldesi Klinikum Frankfurt Höchst/Thomas Massa Universitaetsklinik Eppendorf/Ali Aydin Haukeland University Hospital/Svein Faerestrand Hospital Clinico Universitario de Malaga/Javier Alzueta Medisch Centrum Alkmaar (MCA)/Jacob Ruiter UMC Utrecht/Mathias Meine Danderyds Sjukhus AB/Viveka Frykman Hospital de Santa Cruz/Pedro Adragao Queen Mary Hospital/Raymond Chan St. Bartholomews Hospital/Professor Richard Schilling Tel Aviv Sourasky Medical Center/David Zeltser Total Implants 15 10 10 8 Attempts 0 0 0 0 Intents 0 1 0 0 Total 15 11 10 8 8 0 0 8 7 7 7 5 0 0 0 0 0 0 0 0 7 7 7 5 5 4 0 0 0 0 5 4 4 4 0 0 0 0 4 4 4 3 0 0 0 0 4 3 3 3 2 2 0 0 0 0 0 0 0 0 3 3 2 2 2 2 1 1 1 1 1 120 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 1 1 1 1 1 121 12.1.1. Summary of Qualifications or CVs Curriculum vitae for the study principal investigator(s) may be provided upon written request to the Sponsor. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 43 of 44 Confidential 12.2. List of Monitors A list of monitors may be provided upon written request to the Sponsor. The head of the monitors for the NOTICE-HF study was: Sara Temporin, Sr. Manager Site Management Tel: +39 2 269 83 275 Email: [email protected] 12.3. List of ECs A list of ECs may be provided upon written request to the Sponsor. 12.4. Tabulation of Data Sets 12.4.1. CIP Deviations CIP deviations are summarized in section 6.5.1. Additional detail on CIP deviations may be provided upon written request to the Sponsor. 12.4.2. Adverse Events A summary of adverse events is discussed in section 6.7.3 . Additional detail on adverse events may be provided upon written request to the Sponsor. 12.4.3. Withdrawal and Discontinued Subjects See Section 6.4 for information on discontinued subjects. Boston Scientific NOTICE-HF Final Report CDM00051629/ver AA Page 44 of 44