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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.
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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
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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
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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
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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
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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
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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.
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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
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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)
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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).
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5.2.2. Study Design
A schematic of the flow of the study is presented in Figure 1.
Figure 1: Schematic of Study Design
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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.
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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.
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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.
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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
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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
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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).
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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
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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.
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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
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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
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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
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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.
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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
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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.
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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
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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.
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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
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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
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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.
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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
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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
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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:
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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.
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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
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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
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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
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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.
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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
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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]
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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.
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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.
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