Cardiac Implantable Electronic Device (CIED) Antibiotic Envelope Infection Prevention Trial
Phase: PHASE4
Conditions: CIED Related Infection
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

World-wide Randomized 
Antibiotic EnveloPe 
Infection PrevenTion Trial 
(WRAP-IT) 
NCT02277990 
 
• Clinical Investigation Plan, version 1.0 29JUL2014 
• Statistical Analysis Plan, version 1.0, 21JUL2015 
o Statistical Analysis Plan Amendment #1, version 1.0, 05JAN2018 
o Statistical Analysis Plan Amendment #2, version 1.0, 10JUL2018 
o Final Statistical Analysis Plan, version 1.0 + Amendments, 31JUL2018 
 
 

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World-wide Randomized 
Antibiotic EnveloPe 
Infection PrevenTion Trial
(WRAP-IT) 
Clinical Investigation Plan
Version 1.0
29JUL2014

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Regional Sponsors and Contacts
Medtronic, Inc.
8200 Coral Sea Street NE
Mounds View, MN U.S.A. 
55112
(+1)-800-328-2518
Medtronic, Bakken 
Research Center B.V.
Endepolsdomein 5
6229 GW Maastricht
The Netherlands
(+31)-43-35-66-566
Medtronic Australasia Pty 
Ltd
97 Waterloo Rd, 
North Ryde 2113
PO Box 945, North Ryde
Australia, 1670
(+61)-2-9857-9000
Medtronic Latin America 
HQ
Medtronic USA, Inc.,
Doral Corporate Center II
3750 NW 87th Avenue, 
Suite 700
Miami, FL U.S.A. 33178
(+1)-305-500-9328
India Medtronic Pvt. Ltd.
1241, Solitaire Corporate 
Park,
Building No 12, 4th Floor,
Andheri-Ghatkopar Link 
Road, Andheri (E), 
Mumbai MH 400093
India
(+91)-22-33074700-1/2/3
Medtronic International Ltd.
1101-06, 11/F, Tower 1,
The Gateway,
Harbour City, Kowloon, 
Hong Kong
Hong Kong SAR, China
(+852)-2919-1300
Medtronic International Ltd.
F-39-7 Crest, 3 Two 
Square, 2 Jalan 19/1,
Petaling Jaya, Selangor
Malaysia 46300
(+60)-379-534-800
Medtronic International 
Ltd.
49 Changi South Avenue 
2
Nasaco Tech Centre
Singapore 486056
(+65)-6436-5000

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TABLE OF CONTENTS
Table of Contents............................................................................................................. 3
Listing of Tables ............................................................................................................... 8
Listing of Abbreviations ................................................................................................... 9
Sponsor Contact Information........................................................................................ 11
Contract Research Organizations, Academic research organizations and Core 
Lab.................................................................................................................. 12
Steering Committee ....................................................................................................... 13
1
Introduction............................................................................................... 14
1.1
Study Purpose .............................................................................................14
1.2
Study Scope ................................................................................................14
2
Background and Justification ............................................................. 15
2.1
CIED Migration Background.........................................................................15
2.2
CIED Infection Background..........................................................................15
2.2.1
The Rate of CIED Infection
15
2.2.2
Risk Factors
16
2.2.3
Microbiology and Pathogenesis
16
2.2.4
Diagnosis
17
2.2.5
Management
17
2.2.6
Financial Cost
18
2.2.7
Mortality
18
2.2.8
TYRXTM Non-Absorbable and Absorbable Antibacterial Envelope
19
2.3
.............................................23
2.4
Study Justification........................................................................................24
3
System Description and Intended Use.............................................. 25
3.1
Medtronic TYRXTM Absorbable Antibacterial Envelope ................................26
3.2
Market-Released Medtronic IPG, ICD, CRT-P or CRT-D Device .................26
3.2.1
IPG
26
3.2.2
CRT-P
27
3.2.3
ICD
27
3.2.4
CRT-D
27
3.2.5
RV Defibrillation Lead Monitoring Features
27
3.3
Market-Released Lead(s).............................................................................28
3.4
Market-Released Medtronic CareLink® Monitor and Medtronic CareLink®
Network .......................................................................................................28
3.5
Market-Released Medtronic CareLink® Programmer....................................29
3.6
Additional system components.....................................................................29
4
Regulatory Compliance ......................................................................... 30
5
Methodology .............................................................................................. 31
5.1
Study design................................................................................................31

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5.2
Study objectives...........................................................................................31
5.2.1
Primary objective
31
5.2.2
Secondary objectives
32
5.2.3
Ancillary objectives
32
5.3
Subject selection criteria ..............................................................................33
5.3.1
Inclusion criteria
33
5.3.2
Exclusion criteria
33
5.4
Randomization.............................................................................................34
5.5
Blinding........................................................................................................34
5.6
Minimization of Bias.....................................................................................34
6
Study Procedures..................................................................................... 36
6.1
Investigator / Investigation site selection......................................................36
6.2
Site initiation ................................................................................................36
6.3
Equipment requirements..............................................................................37
6.4
Data collection .............................................................................................38
6.5
Patient informed consent process................................................................39
6.6
Enrollment/Baseline.....................................................................................41
6.6.1
Eligibility Verification (Inclusion/Exclusion)
42
6.6.2
Relevant Medical History
42
6.6.3
Medications
42
6.7
CIED Procedure...........................................................................................42
6.7.1
Infection Control Strategies
43
6.7.2
CIED replacement, upgrade, revision, or implant
43
6.7.3
Required Programming (ICD and CRT-D devices only)
44
6.7.4
Final System Configuration
45
6.7.5
Final Device Interrogation
45
6.7.6
Assessment for AE/SAEs
45
6.8
Pre-hospitalization Discharge.......................................................................45
6.9
Scheduled follow-up visits............................................................................46
6.10
Unscheduled follow-up visits........................................................................47
6.11
Potential CIED Infection...............................................................................48
6.12
..........................49
6.13
................49
6.14
Device Interrogation.....................................................................................50
6.15
Healthcare Utilization ...................................................................................50
6.16
System Modification.....................................................................................51
6.16.1
System Modifications in Subjects Randomized to the TYRX Envelope Group
51
6.16.2
System Modifications in Subjects Randomized to the Control Group
51
6.17
Subject Exit or Withdrawal ...........................................................................52
6.17.1
Lost To Follow-Up
53
6.17.2
Subject Withdrawal
53
7
Investigational device/software storage, handling and 
traceability.................................................................................................. 54

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8
Study Deviations....................................................................................... 55
9
Adverse events and Device Deficiencies........................................... 56
9.1
Adverse Event and Device Deficiency definitions.........................................56
9.2
Adverse Event and Device Deficiency Assessment .....................................59
9.2.1
Adverse Events
59
9.2.2
Device Deficiencies
59
9.2.3
Processing Updates and Resolution
60
9.3
Adverse Events, Device Deficiency Classification and Reporting.................60
9.4
Product Complaints / Vigilance Reporting ....................................................64
9.5
Subject Death ..............................................................................................65
9.5.1
Death data collection
65
9.5.2
Death classification and reporting
66
9.6
Clinical Events Committee (CEC) review .....................................................66
10
Risk Analysis ............................................................................................. 69
10.1
Potential Risks and Side Effects ..................................................................69
10.2
Potential Benefits.........................................................................................69
10.3
Risk-to-Benefit Analysis ...............................................................................69
11
Planned study closure, early termination of study or study 
suspension................................................................................................... 71
11.1
Planned study closure..................................................................................71
11.2
Early termination or suspension...................................................................71
11.2.1
Study-wide termination or suspension
71
11.2.2
Investigator/site termination or suspension
71
11.3
Procedures for termination or suspension....................................................72
11.3.1
Medtronic-initiated and regulatory authority-initiated
72
11.3.2
Investigator-initiated
72
11.3.3
Ethics committee-initiated
72
12
Statistical methods and data analysis ............................................... 73
12.1
General Considerations ...............................................................................73
12.2
Analysis Cohorts..........................................................................................73
12.3
Interim Analysis and Type 1 Error Control....................................................73
12.4
General Summaries.....................................................................................75
12.4.1
Description of Baseline Variables
75
12.5
Primary Objective: Major CIED Infection Rate through 12-months...............75
12.5.1
Objective
75
12.5.2
Hypothesis
75
12.5.3
Major CIED Infection Definition
75
12.5.4
Sample Size Determination
75
12.5.5
Analysis Methods
78
12.5.6
Determination of subjects for analysis
78
12.5.7
Pre-specified Subgroup analyses
79
12.5.8
Missing data
79
12.6
Secondary Objectives ..................................................................................79

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12.6.1
Secondary Objective #1:  Procedure- or System-related complications 
through 12-months
80
12.6.2
Secondary Objective #2:  Major CIED Infection Rate through Study Duration
83
12.6.3
Secondary Objective #3:  Major and Minor CIED Infection Rate through 12-
months 84
12.7
Ancillary Objectives......................................................................................86
12.7.1
Ancillary Objective #1:  Mortality
86
12.7.2
Ancillary Objective #2:  CIED procedure success rate
86
12.7.3
Ancillary Objective #3:  Summarize adverse events
87
12.7.4
Ancillary Objective #4:  Predictors of CIED infection
87
12.7.5
Ancillary Objective #5: Quality of Life
88
12.7.6
Ancillary Objective #6:  Healthcare System Cost Effectiveness
88
12.8
12.9
13
Data and quality management ............................................................ 95
14
Warranty/Insurance information ...................................................... 97
14.1
Warranty......................................................................................................97
14.2
Insurance (EMEA)........................................................................................97
14.3
Insurance (ASEAN (Singapore and Malaysia)) ............................................97
14.4
Insurance (New Zealand).............................................................................97
14.5
Insurance (Greater China (Hong Kong)) ......................................................97
14.6
Insurance (India)..........................................................................................97
14.7
Insurance (Latin America)............................................................................97
15
Monitoring.................................................................................................. 98
15.1
Monitoring Visits ..........................................................................................98
16
Required records and reports ............................................................. 99
16.1
Investigator records .....................................................................................99
16.2
Investigator reports ....................................................................................100
16.3
Sponsor records ........................................................................................101
16.4
Sponsor reports .........................................................................................101
Appendix A: Infection Definitions................................................................................ 104
Appendix B: Data Collection Elements (electronic Case Report Forms)............. 109
Appendix C: Preliminary Publication Plan................................................................. 110

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Appendix D: Data Monitoring Committee (DMC)..................................................... 112
Appendix E: Study Overview....................................................................................... 114
Appendix F: Patient Informed Consent Templates.................................................. 121
Appendix G: Foreseeable Adverse Event List.......................................................... 122
Appendix H: Participating Investigators and Institutions......................................... 124
Appendix I: Ethics Committee and Competent Authority list.................................. 125
Appendix J: Labeling .................................................................................................... 126
Appendix K: Bibliography............................................................................................. 127
Appendix L: Preclinical Testing................................................................................... 134
Appendix M: Previous Clinical Studies ...................................................................... 135
Appendix N: Committees ............................................................................................. 136
Appendix O: Clinical Investigation Plan signature page (only applicable if not 
covered in the CTA)................................................................................... 137
Appendix P: Model Numbers of the market-released IPGs, CRT-Ps, ICDs and 
CRT-Ds in the respective geographies ................................................... 138

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LISTING OF TABLES
Table 1: Study sponsor contact information...................................................................11
Table 2: CRO, ARO and core lab information................................................................12
Table 3: Steering Committee contact information..........................................................13
Table 4: System component information .......................................................................25
Table 5: Data collection and study procedure requirements at subject visits .................38
Table 6: Programming Requirements............................................................................44
Table 7: Data collection and study procedure requirements at subject visits .................46
Table 8: CIED Infection-Related EQ-5D Assessment Windows.....................................48
Table 9: Adverse Event definitions ................................................................................56
Table 10: Adverse Event classification responsibilities..................................................61
Table 11: Reporting requirements .................................................................................61
Table 12: Subject death classification responsibilities ...................................................66
Table 13:  
..................................................................................67
Table 14: 12-Month Infection Rates for Initial Implants by Device Type and Data Source
......................................................................................................................................76
Table 15: System or Procedure-Related Complications Reported Previous Studies......81
Table 16:  Power to Test Secondary Objective #1 with Sample Size of 6,988 Subjects.82
Table 17: Investigator reports applicable for all geographies per Medtronic requirements
....................................................................................................................................100
Table 18: Investigator reports applicable to India ........................................................100
Table 19: Sponsor reports for Europe, the Middle East, Africa, Latin America, Greater 
China (Hong Kong), New Zealand, India, ASEAN (Singapore and Malaysia) ..............101
Table 20: Sponsor reports for the United States..........................................................102

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LISTING OF ABBREVIATIONS
AE
Adverse Event
ASEAN
Association of Southeast Asian Nations
CDC
Centers for Disease Control and Prevention
CEC
Clinical Events Committee 
CFR
Code of Federal Regulations
CI
Confidence Interval
CIED
Cardiovascular Implantable Electronic Devices
CIP
Clinical Investigation Plan
CoNS
Coagulase-Negative Staphylococci
CRDM
Cardiac Rhythm Disease Management
CRMD
Cardiac Rhythm Management Device
CRO
Clinical Research Organization
CRT
Cardiac Resynchronization Therapy 
CRT-D
Cardiac Resynchronization Therapy Defibrillator
CRT-P
Cardiac Resynchronization Therapy Pacemaker
CTA
Clinical Trial Agreement
DM 
Data Management 
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EC
Ethics Committee
EGM
Electrogram
EMEA
Europe, the Middle East and Africa
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act of 1996
HV
High Voltage
ICD
Implantable Cardioverter-Defibrillator 
ICH
International Conference on Harmonization
IE
Indeterminate Event
IFL
Instructions For Use, Label
IPG
Implantable Pulse Generator
IRB
Institutional Review Board
ITT
Intent to Treat
LIA
Lead Integrity Alert
LNA
Lead Noise Alert
LSE
Lead System Event

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LV
Left Ventricular
LVAD
Left Ventricular Assist Device 
MRSA
Methicillin-resistant Staphylococcus aureus
NIS
Nationwide Inpatient Sample
NLE
Non-Lead System Event
PI
Principal Investigator
PIC
Patient Informed Consent
PHI
Protected Health Information
RA
Right Atrial
RV
Right Ventricular
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
SIC
Short Interval Count
SSI
Surgical Site Infection
SOC 
Standard of Care 

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SPONSOR CONTACT INFORMATION
Medtronic contact information is provided below. This information is subject to change 
during the course of the clinical study. Periodic updates to study contact information will 
be sent to the sites as needed.
Table 1: Study sponsor contact information
Study Sponsors and Contacts 
Worldwide clinical study leader
Daniel Lexcen, Clinical Research Specialist
Direct Phone: (+1-763)-526-9702
Direct Fax: (+1-763)-367-5904
daniel.lexcen@medtronic.com
Europe, the Middle East and Africa (EMEA)
Latin America
India
Greater China
New Zealand
Association of Southeast Nations (ASEAN)
Study Monitors and Contacts 
Worldwide monitoring leader
Monitoring leader EMEA, Greater China, ASEAN, New 
Zealand and India

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Name, title, address and contact number of the sponsor’s medical expert for the 
study:
This information may be subject to change during the course of the clinical study. 
Updates will be sent to the sites as needed.
David Steinhaus, M.D., VPGM CRDM, Heart Failure 
Medtronic, Inc.
Cardiac Rhythm Disease Management
8200 Coral Sea Street N.E., MVC42
Mounds View, MN 55112
United States
Phone: (+1-763)-526-1250
Fax: (+1-651)-367-0671
david.m.steinhaus@medtronic.com
CONTRACT RESEARCH ORGANIZATIONS, ACADEMIC 
RESEARCH ORGANIZATIONS AND CORE LAB
Contract research organization (CRO), Academic Research Organization (ARO), and 
Core Lab information is provided in the table below. Additional CROs, AROs, and Core 
Labs may be added at a later time; contact information may be provided under separate 
cover.
Table 2: CRO, ARO and core lab information
Contact Information
Duties performed
Cognizant Technology Solutions

Developments of study electronic case report forms, edit
checks, and study management reports.

Review of electronic case report forms, management of 
discrepancies, and coding of medications and deviations.
C5 Research (ARO), Cleveland Clinic
 
 

Project Manager to provide a single point of contact  for 
sponsor to communicate with the CEC team, Stats team, and 
CCF physicians

Assist in the education of study personnel and sites and 
development of study tools 

Support the DMC 

Coordinate CEC activities

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STEERING COMMITTEE
Seven steering committee members were chosen for this study and are listed below.  
Additional members may be added at a later date. The steering committee members are 
appointed by the sponsor to assist in development and execution of this clinical study.
Table 3: Steering Committee contact information
Committee Member 
Contact information
Bruce Wilkoff, MD
Steering Committee Chair
 
Professional Position: Director of Cardiac Pacing and Tachyarrhythmia Devices
Charles Kennergren, MD, 
PhD
Professional Position: Senior Consultant, Associate Professor Department of 
Cardiothoracic surgery
Jeanne Poole, MD
 
Professional Position: Professor of Medicine, Section Head of Electrophysiology
Ralph Corey, MD
 
Professional Position: Professor of Medicine and Pathology, Gary Hock Professor 
of Global Health
Suneet Mittal, MD
Professional Position: Director, Electrophysiology Laboratory; The Valley Hospital 
Health System; Ridgewood, NJ and New York, NY
Khaldoun Tarakji, MD, MPH
 
Professional Position: Staff Electrophysiologist Section of Cardiac Pacing and 
Electrophysiology Heart and Vascular Institute Cleveland Clinic
Daniel Mark, MD, MPH
Professional Position: Vice Chief for Academic Affairs
Division of Cardiology, Department of Medicine; Director, Outcomes Group,
Duke Clinical Research Institute

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1
INTRODUCTION
1.1
Study Purpose
Medtronic, Inc. is sponsoring the World-wide Randomized Antibiotic EnveloPe Infection 
PrevenTion Trial (WRAP-IT), a randomized, prospective, multi-center, single blinded, 
post-market, interventional clinical study.  The study has three purposes.  First, the 
WRAP-IT study will serve as a post-approval study for those geographies requiring a 
post-approval study to facilitate collection of complications related to the Cardiovascular 
Implantable Electronic Device (CIED) procedure or system in subjects randomized to 
receive the TYRXTM Absorbable Antibacterial Envelope (henceforth referred to as TYRX 
envelope).  Next, this study will evaluate the ability of the TYRX envelope to reduce 
major CIED infections through 12-months post-procedure following CIED generator 
replacement, upgrade, revision, or the implant of a de novo CRT-D.  Subjects 
undergoing CIED generator replacement, upgrade, revision or the implant of a de novo 
CRT-D system will be randomized to either receive the TYRX envelope or not to receive 
the TYRX envelope.  Randomization will be 1:1 and be stratified by study site and device 
type, high power (ICD and CRT-D) vs. low power devices (IPG and CRT-P).  Finally this 
large device study provides the unique opportunity to prospectively characterize the 
performance of Medtronic’s lead monitoring features in subjects whose CIED system 
includes a transvenous RV defibrillation lead.  These features include the lead integrity 
alert (LIA), lead noise alert (LNA), RV pacing impedance, and high voltage (HV) pacing 
impedance to detect events that affect a RV lead’s pacing, sensing, or defibrillation
circuit lead system events (LSE).  
1.2
Study Scope
The study is expected to be conducted at up to 225 sites worldwide with up to 7,764 
subjects enrolled in order to randomize approximately 6,988 subjects.  Enrollment of 
subjects receiving a replacement low power device (i.e. IPG or CRT-P) will be capped at 
approximately 25% of the total randomized study population (i.e. approximately 1,746 
subjects). Relative to high power device recipients, patients receiving a low power 
device may be at reduced risk of a major CIED infection. Thus, to ensure an adequate 
CIED infection event rate in the control arm, there is a desire to include a higher 
proportion of high power devices in the trial. 
The enrollment period is expected to start in late 2014 and to take approximately 24
months. Subjects will be followed for a minimum of 12 months.  Therefore, the 
anticipated study duration is approximately 36 months and subjects may be followed for 
up to 36 months depending on when they enroll in the study.  
Expected participating geographies include, but are not limited to, the United States 
(US), Europe, the Middle East and Africa (EMEA), Greater China (Hong Kong), New 
Zealand, Latin America, the Association of South East Asian Nations (ASEAN)
(Singapore and Malaysia), and India.
To ensure a widespread distribution of data, minimize site bias in study results and
ensure that sites will be able to adequately manage and follow subjects enrolled in the 
study, the maximum number of randomized subjects allowed at a single site is 100 
subjects.  Sites are encouraged to enroll as many consecutive eligible subjects as 
appropriate. There is no specific minimum number of enrollments required, except where 
stated in the clinical trial agreement between the sponsor and the individual site.

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The WRAP-IT study utilizes a group sequential design and has up to two planned 
analyses of the primary objective.  The first analysis will occur when a minimum of 3,200 
randomized subjects complete the 6-month visit and the final analysis will occur when all 
randomized subjects have the opportunity to complete the 12-month study visit.  The 
study may be considered successful at the first analysis in which the primary objective is 
met. An independent Data Monitoring Committee (DMC) will periodically review the 
accumulating data and review the results of the analysis of the primary objective at each 
pre-specified analysis time point. Should the DMC indicate that the study is successful 
at the interim analysis, the study may continue to enroll and follow subjects to evaluate 
the effect of the TYRX envelope on CIED infections that develop post-12 months as well 
as collect additional follow-up in subjects with a defibrillation system in which to evaluate 
the lead monitoring features.  However, subjects enrolled following review of the interim 
analysis may no longer be randomized upon recommendation of the DMC if the TYRX 
envelope is found to have a clear benefit.
2 BACKGROUND AND JUSTIFICATION
Over the last few decades, there has been a growing evidence of the importance of 
CIEDs in improving both quality of life and survival among patients with heart disease.1, 2
This has resulted in expansion of the indications for CIED implantation which is reflected 
in the most recent guidelines from the American College of Cardiology / American Heart 
Association/Heart Rhythm Society for CIED implantation and its most recent update.3, 4
With expanding indications for these devices and an increasingly aging population, more 
devices are implanted in older patients with more comorbidities.5, 6 In addition, battery 
depletion, evolving CIED indications (e.g., upgrades), and generator or lead advisories 
and recalls may necessitate one or more replacements of the device in a patient’s 
lifetime.7, 8, 9  This growth of implanted CIEDs has led to an increased recognition and 
awareness of post-implant complications.  Migration of the CIED generator from the 
implant site is a complication of CIED therapy that can be associated with increased
morbidity and expense.  Additionally, infections and lead system issues are among the 
most common complications, specifically post replacement.10   CIED migration, CIED 
infections and delayed LSE detection can create a significant resource burden on the 
healthcare system and can be associated with an increased risk of morbidity or 
mortality.11, 12, 13
2.1
CIED Migration Background
Published rates of generator migration have been reported to be 0.1%-1.2% 14, 15
Twiddler’s syndrome is a form of CIED migration in which conscious or unconscious 
manual manipulation of the CIED by the patient leads to device migration.  Importantly, 
recent published series of CIED implantations that utilize modern CIED generators 
indicate generator migration continues to occur at a clinically significant rate (1.2%) 15
2.2
CIED Infection Background
2.2.1
The Rate of CIED Infection
The reported prevalence rate of CIED infection varies widely in the literature and ranges 
from 0.13% to above 12%.16-23 This wide variation stems from the fact that most data 
come from retrospective series or single site registries using different definitions of CIED 
infections. The lack of a clear denominator and the use of different durations for follow 

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up have been major obstacles towards understanding of the true incidence rate of CIED 
infection. The Prospective Evaluation of Pacemaker Lead Endocarditis (PEOPLE) study 
was a multi-center prospective survey of the incidence and risk factors of CIED 
infections after IPG or ICD implantations 6319 patients followed for 12 months.  The 
incidence of CIED infection was 0.56% after de-novo implantation and 0.99% for the 
non-de-novo procedures.24 The REPLACE registry, a prospective, multi-center study 
collecting data about complications after device replacement (IPGs and ICDs), revealed 
that the 6 month infection rate was 1.4% for patients who underwent device replacement 
with no intent to replace leads and 1.1% for patients who underwent device replacement 
with planned lead addition.10 Currently, it is believed that the risk of CIED infection for 
primary device implantation is less than 0.5%, while for device replacement or upgrade 
surgeries, the risk is estimated to be between 1-5%.24, 25  Although the incidence of CIED 
infection remains low, the rate of increase in CIED infection each year is alarming. 
Among Medicare beneficiaries, the rate of cardiac device infections in general increased 
from 0.94 to 2.11 per 1000 patients between 1990 and 1999, representing a 124% 
increase during the study period.26 Similarly the National Hospital Discharge Survey 
showed that between 1996 and 2003, the number of new CIED implants in the US 
increased by 49% (160% for ICDs vs 31% for IPGs). During the same period, the 
number of hospitalizations for CIED infections increased 3.1 fold (2.8 fold for IPGs and 
6.0 fold for ICDs). Similarly, data from the Nationwide Inpatient Sample (NIS) discharge 
records between 1993 and 2008 showed that the incidence of CIED implantation 
increased an average of 4.7% annually, and the overall CIED implantation increased by 
96%.27  During the same time period, the rate of CIED infection was 1.61% representing 
a 210% increase. 
2.2.2
Risk Factors
Several studies have identified risk factors for developing CIED infections. These 
include renal dysfunction,28, 29 heart failure,28 fever within 24 hours prior to implantation,24
diabetes,28 oral anticoagulation use,29 steroid use,30 temporary pacing system at time of 
implant,24 secondary procedures (device replacement or upgrade) as opposed to de-
novo procedure 24,28,29, 31,32, presence of more than one lead, 30,32 ICD implant compared 
to IPG,33 abdominal implant compared to pectoral transvenous system,18, physician 
experience,34  and early intervention for hematoma or lead dislodgement. 22, 35 Some
factors are related to the microbiology of blood stream infection as the risk of CIED 
infection with Staphylococcus bacteremia is higher than the risk with gram-negative 
bacilli.32, 35, 36 Importantly, blood stream infections increase the risk of CIED infection and, 
thus, risk factors for S. aureus blood stream infection, such as end stage renal disease 
requiring dialysis, may be secondarily associated with an increased risk of CIED 
infection.
2.2.3
Microbiology and Pathogenesis
Most infections are monomicrobial but some are polymicrobial.11 Staphylococcal 
species are the major culprit and account for up to 80% of cases in most published 
series (coagulase-positive, e.g., Staphylococcus aureus, or coagulase-negative, e.g. 
Staphylococcus epidermidis). 
Almost half of these staphylococcal species are 
methicillin resistant.11,24,33,36,37,38 Other microorganisms involved include 
Corynebacterium species Propionibacterium acnes, Enterococci, Gram-negative bacilli, 
fungi, anaerobes, Candida species and rarely mycobacteria.11,38 In addition, a significant

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number of patients may have negative cultures despite clear presentation of CIED 
infection. This is often due to poorly obtained cultures or prior antibiotic therapy.11 It is 
believed that most infections within the first 12 months after implant are related to the 
initial implantation procedure or during generator change or upgrade procedures. If the 
generator or electrode erodes through the skin, they are by default infected, but most 
commonly the erosion is a manifestation of an underlying infection. Pocket infection 
might then spread intravascularly along the leads. Less commonly, the leads and the 
device pocket are infected as a result of hematogenous seeding during episodes of 
bacteremia.23,25
2.2.4
Diagnosis
CIED infection can present as a pulse generator pocket infection, or blood stream 
endovascular infection, or both, with or without CIED-related endocarditis. Most patients 
present with pocket infection with inflammatory changes involving the device pocket 
itself. These changes include erythema, warmth, tenderness, drainage, and erosion 
through the skin with exposure of the generator or the leads.11, 38 These local changes 
are sometimes accompanied by systemic signs and symptoms that include fever, chills 
and malaise. Other patients may present with a device pocket that looks intact but with 
a combination of signs and symptoms supported by blood culture findings and 
occasionally imaging data, especially transesophageal echo, that suggest endovascular 
infection involving the CIED.11, 38, 39   Patients are classified as having CIED endocarditis 
if they have positive echocardiographic findings and two or more positive blood cultures 
for typical skin organisms (coagulase-negative staphylococci, Corynebacterium species, 
Propionobacterium species), or one positive blood culture for all other microorganisms.  . 
Positive echocardiographic findings for CIED-related endocarditis are defined as:
1. Presence of an oscillating intracardiac mass on cardiac valve or supporting 
structures (in the path of regurgitant jets) or CIED leads in the absence of an 
alternative anatomic explanation, 
or 
2. Visualization of a cardiac abscess, 
3. New dehiscence of prosthetic valve. 
Recommendations for diagnosis of CIED infections were published in the consensus 
statement in 2010.23  Despite these definitions, the diagnosis of CIED infection often 
represents a challenge to both the electrophysiologist and the infectious disease 
specialist. The challenge begins early after CIED implantation when it is important to 
make the distinction between CIED pocket infection and simple incisional erythema or 
stitch abscess, which usually responds to local measures or sometimes to a short 
course of oral antibiotic.  Pocket hematomas can also occur after new CIED implant and 
are usually treated conservatively. The other challenge is often the indolent course of 
CIED infection (especially when the causative organism is of limited virulence, e.g., 
CoNS, corynebacterium, or propionobacterium) before it manifests. Pocket infection can 
manifest acutely but more often gradually over the course of several months or years 
after original implant or last pulse generator change.11
2.2.5
Management
Although clinical presentation of endovascular and isolated pocket infection are quite
different, the management of both types whether pocket infection or endovascular 

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infection involves complete system removal and antibiotic therapy. However, the type 
and extent of infection might affect the duration of the antibiotic therapy and the decision 
for the timing and strategy of re-implant. 
Determining the presence of an indolent pocket infection, however, can be quite difficult. 
It is not rare to have erythema at the incision site during the first week of healing after 
device implantation. Less frequently, but still common during the first two weeks after 
CIED implantation, are small, superficial stitch abscesses that does not involve the 
pocket. This usually responds to local measures and a short course of oral antibiotics 
directed against staph species.23,25 However, when the diagnosis of CIED infection is 
made, complete removal of all hardware is recommended regardless whether it is a 
device pocket infection or endovascular infection.11,23,37,40  Previously published studies 
have shown that conservative management has an unacceptably high failure rate with 
higher mortality.24,37,38,41  Partial removal of the pulse generator and capping the lead 
should not be performed even in cases of pocket infection, as the relapse rate due to the 
retained wire is high.23    Antimicrobial therapy is adjunctive in patients with CIED 
infections. Since the majority of CIED infections are caused by staphylococcal species 
and half of these are methicillin resistant, vancomycin may be initiated empirically after 
the appropriate cultures are sent. Antibiotic therapy afterwards may be tailored based 
on the culture and sensitivity data. 
2.2.6
Financial Cost
CIED infections result in significant financial burden for patients, hospitals, and third-
party payers, including prolonged hospitalization, prolonged antibacterial treatment, 
management of systemic complications of sepsis, and costs involved in device 
extraction and possible re-implantation. Over the last two decades, the in-hospital 
charges for CIED infection increased by almost 100%.27 Among a large cohort of 
Medicare patients who were admitted for CIED generator implantation, replacement or 
revision, CIED infection increased the cost by 1.4 to 1.8 fold depending on the type of 
CIED. Intensive care hospitalization accounted for more than 40% of the incremental 
costs. Cost ratios with ICD infection appeared to be substantially higher than with IPG
infection.42
2.2.7
Mortality
The high mortality associated with CIED-related endocarditis has been recognized by 
many investigators in the past, even before the recent surge in CIED implantation. This 
mortality could be as high as 31-66%, if the device is not removed, and 18% with 
complete device removal and antibiotic therapy.41,43 More recently, several studies 
looked into the mortality after CIED infection, whether associated with endocarditis or not,
with alarming results. The National Hospital Discharge Survey showed that CIED 
infection increased the risk of in-hospital death more than 2-fold.44  Among 210 patients 
admitted with CIED infection between 1995 and 2006 to one tertiary site, in-hospital 
mortality was 8% and 6 months mortality was 18%.37 At the Cleveland Clinic, the 1-year 
mortality among 412 patients with CIED infections that underwent system removal 
percutaneously between 2002 and 2007 was 17% and was higher among patients with 
endovascular infection compared to the pocket infection group (25% vs 12% 
respectively).11 Over the last two decades, the analysis of the Nationwide Inpatient 
Sample (NIS) showed that the in-patient mortality associated with CIED infection 
averaged 4.39%; however this mortality increased from 2.91% in 1993 to 4.69% in 2008, 

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representing an increase of 1% per decade.27  Sohail et al. studied admission and long 
term mortality in a retrospective cohort of 200,219 Medicare patients admitted for CIED 
generator implantation, replacement, or revision between January 2007 and December 
2007.  Depending on CIED type, infection was associated with significant increases in 
adjusted admission mortality (rate ratios ranged between 4.8% and 7.7%) and long-term 
mortality (rate ratios ranged between 1.6% and 2.1%) among the 5817 patients admitted 
with diagnosis of infection.42  
A retrospective review of all 416 cases of CIED infection at Mayo Clinic between 1991 
and 2008 learned that the 30-day mortality was 5.5% and the 1-year mortality was 
14.6%.45  In addition, a 3-fold protective effect (HR 0.35, 95% CI 0.16 to 0.75) against 1-
year mortality was found among those who underwent immediate device removal as 
compared to those with delayed device removal after failure of antimicrobial therapy or 
no device removal.  International Collaboration on Endocarditis-Prospective Cohort 
Study (ICE-PCS) enrolled 2760 patients with definitive endocarditis from 61 sites in 28 
countries.46  The in-hospital and 1-year mortality of 177 diagnosed with CIED-related
endocarditis was 14.7% and 23.2%, respectively. Device removal during the first index 
hospitalization with CIED-related endocarditis appeared to be associated with improved 
1 year survival (but not in hospital mortality), and the presence of concomitant valve 
infection and health-care related infections were associated with worse survival. 
In a recent study from the Netherlands, Dr. De Bie et al. reviewed the cases of all 
patients who received an ICD or CRT-D over the last decade at one tertiary care 
facility.47  The 3-year incidence of CIED infection among the 2476 patients was 2.6% 
and the 1-year mortality following first CIED infection was 16.9% CIED infection 
appeared to be associated with 1.9 fold (2.4-fold after controlling for possible 
confounders) increased risk of mortality compared to patients who did not experience 
infection. 
In summary, high mortality related to CIED infections has been identified prior to the 
recent growth in CIED implants.  Moreover, studies between 1991 and 2012 reported in-
hospital and 1-year mortality, ranging from 8% to 14.7% and 14.6% to 23.3%, 
respectively.  Immediate device removal appeared to improve survival rates.  Although 
lower survival rates among patients with CIED infections have been challenged in some 
other studies48, both acute and long-term mortality was shown to be strongly associated 
with CIED infections.
2.2.8
TYRXTM Non-Absorbable and Absorbable Antibacterial Envelope 
The TYRX Antibacterial Envelope is designed to hold a CIED to create a stable 
environment when implanted in the body.  The envelope is comprised of a substrate 
mesh coated with an absorbable tyrosine-based polymer that contains the antimicrobial 
agents rifampin and minocycline.
There are two TYRX Antibacterial Envelopes: partially absorbable and fully absorbable 
(henceforth referred to as TYRX Non-Absorbable envelope and TYRX envelope, 
respectively).  For purposes of this study, only the TYRX Absorbable envelope will be 
used. The TYRX envelope was cleared for marketing in the United States on May 20, 
2013, approved by Health Canada on January 15, 2013 and at the time of this protocol 
version CE Mark is pending.  No study site related activities will occur in a geography 
until the TYRX envelope is commercially available, unless pre-market use for clinical 
trials is allowed per local regulations and law.

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The TYRX envelope is made of a knitted Glycoprene II mesh substrate coated with a 
mixture of absorbable tyrosine-based polyarylate polymer containing the ancillary 
medicinal substances minocycline and rifampin, each at the same concentration.  
The envelope anchors the electronic device, and provides a substrate for tissue in-
growth.  After implantation, the TYRX envelope anchors the implanted cardiac device
and the absorbable polyarylate polymer elutes the antibiotics while the polymer is being 
degraded by the patient’s body.  The antibiotics are completely eluted in 7-10 days. 

Rifampin dose per TYRX envelope:  102 µg/cm2 is released over 7 to 10 days.  
Rifampin is a bactericidal antimicrobial which interferes with DNA-dependent RNA 
polymerase activity.  Rifampin has been shown to be effective against Gram-positive 
bacteria including Staphylococcus aureus (including MRSA), Staphylococcus 
epidermidis, and Staphylococcus Lugdunensis, and Gram-negative bacteria, such as 
Haemophilus influenzae. 

Minocycline dose per TYRX envelope: 102 µg/cm2 is released over 7 to 10 days.  
Minocycline is a bacteriostatic antimicrobial which inhibits protein synthesis.  Minocycline 
has been shown to be effective against Gram-positive bacteria, such as Staphylococcus 
aureus and Streptococcus pneumoniae and Gram-negative bacteria, such as 
Escherichia coli, Enterobacter aerogenes, Haemophilus influenzae and Acinetobacter 
baumannii. 
The above antibiotic combination has been shown to reduce infection in an in vivo model 
of bacterial challenge following CIED implantation.  Additionally, multiple randomized 
clinical trials (RCTs) have demonstrated that incorporating the combination of rifampin 
and minocycline into medical devices including central venous catheters, hemodialysis 
catheters, and external ventricular cerebrospinal fluid drainage catheters significantly 
reduces device-associated infections, especially those due to S. aureus and coagulase-
negative staphylococci (CoNS).49-54  A meta-analysis of the 5 RCTs of central venous 
catheters demonstrated the odds ratio for developing a catheter-related bloodstream 
infection is 0.26 [95% CI 0.15-0.47; P<0.0001] for the catheters incorporating 
minocycline and rifampin, compared to those that do not.  This corresponds to a 74% 
reduction in the risk for central venous catheter infections when the catheters 
incorporate minocycline and rifampin. 
In contrast to the TYRX Non-Absorbable envelope, the TYRX envelope’s surgical mesh 
substrate (Glycoprene II) is absorbable. Therefore, there is no residual mesh remaining 
in the tissue pocket to serve as a potential nidus of infection.  The duration of use of the 
TYRX envelope is rate limited by the time it takes for the patient’s body to absorb the 
Glycoprene II mesh, about 9 weeks.  
2.2.8.1
Preclinical Studies of TYRXTM Absorbable Antibacterial Envelope
In in vitro studies, the TYRX envelope demonstrated antimicrobial activity against 
organisms that include methicillin-resistant Staphylococcus aureus (MRSA), methicillin-
sensitive Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus 
Lugdunensis, E. coli, and Acinetobacter baumannii.55  The TYRX envelope has also 
been shown to reduce infection in an in vivo animal model of bacterial challenge 
following surgical implantation of the CIED pulse generator (data provided by TYRX, 

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Inc.).55 Nearly identical results were obtained against a similar set of pathogens with the 
TYRX Non-Absorbable envelope.80
2.2.8.2
Clinical Studies of TYRXTM Non-Absorbable Antibacterial Envelope
The clinical performance of the TYRX Non-Absorbable envelope has been evaluated in 
the completed COMMAND (COoperative Multicenter study Monitoring a CIED 
ANtimicrobial Device) clinical study published in Pacing and Clinical Electrophysiology 
(PACE).56  The COMMAND study was a multi-center registry of patients receiving the 
TYRX Non-Absorbable envelope at 10 U.S. academic, community and Veterans Affairs 
medical sites.  The primary endpoints were successful CIED implantation and CIED 
infection.  All patients were enrolled according to an IRB-reviewed protocol.  All primary 
clinical end-point events were adjudicated by an independent Clinical Events Committee 
(CEC), and no investigator or member of the CEC was a paid consultant to, or had a 
financial interest in, TYRX, Inc. A total of 642 consecutive CIED recipients undergoing 
an initial implantation or revision/replacement procedures utilizing the TYRX Non-
Absorbable envelope at 10 U.S. medical sites (2 academic, 7 community, 1 Veterans 
Affairs) between June 2008 and June 2009 were enrolled. Of the 642 procedures, 17 
following an explanation of a CIED secondary to a prior CIED infection and 1 utilizing the 
TYRX Non-Absorbable envelope for an off-label indication were excluded. Analyses 
were performed on the remaining 624 patients. The 624 eligible procedures (patient age 
70+/-13 years, 32% women, 22% Black and Hispanic, 39% diabetes, 27% renal 
insufficiency, 35% oral anticoagulant use) utilized pacemakers (35%), ICDs (29%), and 
CRT-Ds (36%). Importantly, more than two-thirds (68%) of cases in the COMMAND 
study were revision/replacement procedures.  Nearly half of the patients (49%) had at 
least 3 pre-defined risk factors for CIED infection.  CIED implantation was successful in 
621 procedures (99.5% [95%CI 98.7-99.9]).  There were 3 major infections (0.48% 
[95%CI 0.17-1.40]) after 1.9+/-2.4 months follow-up.  The infections followed one ICD 
revision and two CRT-D replacements.  The infection rate for initial procedures was 0% 
[95% CI 0.01-1.82] and for revision/replacement procedures was 0.71% [95% CI 0.26-
2.06]. Additionally, IPG procedures had an infection rate of 0% [95%CI 0.01-1.66] and 
the combined infection rate of, ICD/CRT-D procedures was 0.74 [95% CI 0.27-2.16%].  
There were two adverse events attributed to the antibacterial envelope; one 
unsuccessful CIED implantation and one threatened erosion. Both were treated without 
complication. There were 11 deaths (4 noted after publication of the study results). 
None were attributed to the anti-bacterial envelope or the CIED procedure. In the cohort 
at highest risk for CIED infection, the ICD/CRT revision/replacement procedures (n=286; 
1.9 +/- 2.2 months follow-up), there were 70% fewer CIED infections compared to a
historical cohort of ICD/CRT replacement procedures that did not utilize the antibacterial 
envelope, (n=533; 2.7+/-2.8 months follow-up) published by Gould et al. (1.05% vs. 
3.56%).57
Presently, two large post-marketing, prospective cohort studies of the TYRX Non-
Absorbable envelope in CIED replacement procedures have completed enrollment.
These two studies evaluated rates of infection and mechanical complication between 
patients receiving the TYRX Non-Absorbable envelope and those who did not using a 
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These studies are the Citadel (upgrade/replacement dual and single chamber ICDs –
ClinicalTrials.gov NCT01043861) and Centurion (upgrade/replacement CRT-Ds and 
CRT-Ps – ClinicalTrials.gov NCT01043861) studies. The studies began in January 2009 
and over 50 Principal Investigators from academic, community and Veterans Affairs
hospitals participated as clinical research sites. A planned 3-month interim analysis 
demonstrated efficacy by reducing major infections relative to implants without the TYRX 
Non-Absorbable envelope with no significant increase in the rate of mechanical 
complication. As a result of this, enrollment was limited to 464 subjects for Citadel 
(originally planned for 2,300 subjects) and 673 subjects for Centurion (originally planned 
for 2,000 prospective patients and 2,000 case-matched, non-TYRX Non-Absorbable 
envelope patients).
The 3-month interim analysis of the first 1,000 subjects (combined analysis of 402 
Citadel and 598 Centurion subjects) completing 3 months of follow up showed an 
incidence of 0.10 % major infections in the TYRX Non-Absorbable envelope group vs. 
1.88 % for the  historical published control group (p < 0.001) using a one-sided z-static 
test with significance cutoff of 0.01. The rate of CIED malfunction requiring pocket 
revision (0.20 %) was significantly lower with TYRX Non-Absorbable envelope, 
compared to the pre-specified historical published control group without TYRX Non-
Absorbable envelope (1.5 %; p = 0.003).
At 3-months, 533-subjects in the CRT cohort (Centurion) had case matched controls.  
The TYRX non-absorbable cohort showed no major infections (0.00 %), which was 
significantly lower than the rate among the 533- case-matched control subjects who did 
not received the TYRX Non-Absorbable envelope (1.13 %; p = 0.006).  The rate of 
overall mechanical complications was 3.8 % for the CRT/ TYRX Non-Absorbable 
envelope subjects (prospective cohort) compared with 4.1 % for the retrospective case-
matched control cohort that did not receive the TYRX Non-Absorbable envelope (p = 
0.75).
A second pre-specified analysis was implemented for this 1,000 patient cohort of 
subjects completing 6 months of follow up (combined cohort from Centurion and Citadel).
During the first 6 months after implantation, there were 2 major CIED infections (0.2 %) 
among those patients receiving the TYRX Non-Absorbable envelope antibacterial 
envelope. The major infections in the TYRX Non-Absorbable envelope combined group 
occurred in 1 ICD (Citadel) subject and 1 CRT (Centurion) Patient. Despite longer 
follow-up, the incidence of major infection among the combined Centurion/Citadel cohort 
(TYRX Non-Absorbable envelope subjects) was significantly lower (p < 0.001) than the 
historical published control group (ICD/CRT cohorts) at 45 days and 3 months 
(1.88 %).,57,58
A 6-month pre-specified analysis of 533 Centurion-only subjects (CRT Ds and CRT Ps) 
identified 1 major infection for the TYRX Non-Absorbable envelope subject population 
(0.2 %) compared to 6 major infections among the case-matched control group (1.1 %; p 
= 0.029). There was a rate of 5.1 % mechanical complications among the TYRX Non-
Absorbable envelope subjects and 4.9 for the retrospective case-matched control 
subjects. There was a 6-month mortality rate of 3.4 % for TYRX Non-Absorbable 
envelope subjects vs. 1.3 % (p = 0.001) for the retrospective case-matched control 
subjects. As a reference, the reported 6-month mortality rate in a cohort of de novo
CRT-D device recipients from the MIRACLE ICD trial was 7.6%.79  Therefore, it is 
possible that this difference in mortality rates was due to ascertainment bias created 

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because the control group was derived from case-matched and non-prospective medical 
chart reviews.
2.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 

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2.4
Study Justification
Previous case control and single arm studies suggest that the TYRX envelope may be 
effective at preventing CIED infection.73  However, definitive evidence in the form of a 
randomized clinical trial regarding the effectiveness of the TYRX envelope to prevent 
CIED infections is lacking.  Thus, the WRAP-IT study is warranted.  Specifically, the 
WRAP-IT study will evaluate the utility of the TYRX envelope for preventing CIED 
infections in a large randomized single blinded study conducted in a group of subjects at 
high risk for CIED infection.  In addition, the large size of the WRAP-IT study provides a 
mechanism to address the CE mark post approval requirements of the TYRX envelope 
as well as enables the first prospective assessment of the performance of Medtronic’s 
lead monitoring feature set.  

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3 SYSTEM DESCRIPTION AND INTENDED USE
The study will be conducted using the components described in the table below. 
Instructions for use of the devices used in this study are provided in Appendix J and the
Investigator’s Brochure (TYRXTM Absorbable Antibacterial Envelope, henceforth referred 
to as TYRX envelope) or their respective manuals (other system components).
Subjects meeting one or more of the following criteria may be enrolled: 1) an 
ACC/AHA/HRS or ESC guideline-recommended need for a de novo CRT-D and subject 
has a geography approved indication for a CRT-D, 2) an existing IPG, CRT-P, ICD, or 
CRT-D undergoing generator replacement or generator upgrade with or without the 
addition of new leads, or 3) an existing IPG, CRT-P, ICD, or CRT-D undergoing a CIED 
system revision (pocket or lead) procedure. Subjects who enroll in the study and 
proceed with a device procedure must be implanted with a Medtronic single, dual, or 
triple chamber pacemaker or defibrillator that has received appropriate license or 
regulatory approval and is commercially available by Medtronic in the geography in 
which the implant will take place. Any market-released, commercially available lead(s) 
can be used in this study. 
Additional study components which may be utilized in this study for subjects include 
Medtronic CareLink® Monitor and CareLink® Network, and Medtronic programmers. 
These components are described in the following sections.
Table 4: System component information
Model Number
Component (Manufacturer)
Market-released
System Components
CMRM6122 or
CMRM6133
Medtronic TYRXTM Absorbable Antibacterial 
Envelope
Market Released*
Refer to 
Appendix P
New or previously implanted market released 
Medtronic IPG models which may include: 
Adapta, Advisa, Ensura, Relia, Revo, Sensia, 
Versa or any subsequently market-released 
Medtronic IPG
Market-released models may vary by 
geography
Refer to 
Appendix P
New or previously implanted market released
Medtronic CRT-P models which may include: 
Consulta, Syncra, Viva XT or any 
subsequently market-released Medtronic 
CRT-P
Market-released models may vary by 
geography
Refer to 
Appendix P
New or previously implanted market released
Medtronic ICD models featuring 
SmartShock™ Technology, which may 
include: Evera S, Evera XT, Protecta, Protecta 
XT, or any subsequently market-released 
Medtronic ICD
Market-released models may vary by 
geography 
Refer to 
Appendix P
New or previously implanted market released
Medtronic CRT- D models featuring 
SmartShock™ Technology, which may 
include: Brava, Brava Quad, Protecta, 
Protecta XT, Viva S, Viva S Quad, Viva XT, 
and Viva XT Quad, or any subsequently 
market-released Medtronic CRT-D
Market-released models may vary by 
geography

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--
Any new or previously implanted market-
released transvenous right ventricular (RV) 
lead
Market Released
--
Any new or previously implanted market-
released transvenous right atrial (RA) lead
(if applicable)
Market Released
--
Any new or previously implanted market-
released transvenous left ventricular (LV) lead 
(if applicable)
Market Released
Accessory Components
2090 series
Medtronic CareLink® Programmer
Market Released
2490C
Medtronic CareLink® Monitor
(where applicable)
Market Released
--
Medtronic CareLink® Network
Market Released
2067 or 2067L
Medtronic Programming Head (where 
applicable)
Market Released
DR 220
NorthEast Monitoring Holter Monitor
Market Released
* Will be market released prior to study start in the respective geographies.
3.1
Medtronic TYRXTM Absorbable Antibacterial Envelope
The Medtronic TYRXTM Absorbable Antibacterial Envelope is an absorbable sterile 
prosthesis designed to hold a pacemaker pulse generator or defibrillator to create a 
stable environment when implanted in the body.  The TYRX envelope is constructed 
from multifilament knitted mesh (polymer made of glycolide, caprolactone, and 
trimethylene carbonate) that is coated with an absorbable polyarylate polymer. The 
purpose of the absorbable coating is to act as a carrier for the antimicrobial agents. 
Animal data demonstrates that the absorbable antibacterial envelope absorbs in 
approximately 9 weeks. The TYRX envelope is made of an absorbable polymer coating 
containing the antimicrobial agents rifampin and minocycline in concentrations of 102 
µg/cm2 for both the medium size (IPG) and large size (ICD) envelopes. The TYRX
envelope releases the antimicrobial agents for a minimum of 7 days to reduce the risk of 
infection of the implanted CIED following surgery. No study site-related activities will 
occur in a respective geography until the TRYX envelope is commercially available, 
unless pre-market use for clinical trials is allowed per local regulations and law.
3.2
Market-Released Medtronic IPG, ICD, CRT-P or CRT-D Device
3.2.1
IPG 
Subjects who enroll in the study must be scheduled for a generator replacement with a 
Medtronic IPG or, in the case of a revision, must have an existing Medtronic IPG 
implanted. The Medtronic IPG must have received appropriate license or regulatory 
approval and is commercially available by Medtronic in the geography in which the 
implant will take place. Examples from the Medtronic family of devices include but are 
not limited to the Adapta, Advisa, Ensura, Relia, Revo, Sensia, or Versa. Other devices 
may become available during the course of the clinical study and may be used if the 
aforementioned criteria are met. The device must not have been previously implanted in 
another patient.

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3.2.2
CRT-P
Subjects who enroll in the study must be scheduled for a generator replacement or 
upgrade with a Medtronic CRT-P or, in the case of a revision, must have an existing 
Medtronic CRT-P implanted. The Medtronic CRT-P must have received appropriate 
license or regulatory approval and is commercially available by Medtronic in the 
geography in which the implant will take place. Examples from the Medtronic family of 
devices include but are not limited to the Consulta, Syncra, or Viva XT. Other devices 
may become available during the course of the clinical study and may be used if the 
aforementioned criteria are met. The device must not have been previously implanted in 
another patient.
3.2.3
ICD
Subjects who enroll in the study must be scheduled for a generator replacement or 
upgrade with a Medtronic ICD or, in the case of a revision, must have an existing 
Medtronic ICD implanted. The Medtronic ICD must have received appropriate license or 
regulatory approval and is commercially available by Medtronic in the geography in 
which the implant will take place. Only Medtronic ICDs with SmartShock™ Technology, 
which includes the RV Lead Noise Discrimination and RV Lead Integrity Alert algorithms,
are permitted. The Medtronic family of SmartShock™Technology ICDs include Evera S, 
Evera XT, Protecta, and Protecta XT. Other devices may become available during the 
course of the clinical study and may be used if the aforementioned criteria are met. The 
device must not have been previously implanted in another patient.
.
3.2.4
CRT-D
Subjects who enroll in the study must be scheduled for a de novo Medtronic CRT-D 
implant, a generator replacement or upgrade with a Medtronic CRT-D, or, in the case of 
a revision, must have an existing Medtronic CRT-D implanted. The Medtronic CRT-D 
must have received appropriate license or regulatory approval and is commercially 
available by Medtronic in the geography in which the implant will take place. Only 
Medtronic CRT-Ds with SmartShock™ Technology, which includes the RV Lead Noise 
Discrimination and RV Lead Integrity Alert algorithms, are permitted. The Medtronic 
family of SmartShock™Technology CRT-Ds include Brava, Brava Quad, Protecta, 
Protecta XT, Viva S, Viva S Quad, Viva XT, and Viva XT Quad. Other devices may 
become available during the course of the clinical study and may be used if the 
aforementioned criteria are met. The device must not have been previously implanted in 
another patient.
3.2.5
RV Defibrillation Lead Monitoring Features
ICD and CRT-D devices utilized in the WRAP-IT study include four features designed to 
monitor lead integrity:
1. The RV lead noise discrimination (RV LND) feature analyzes the far-field EGM signal 
at each near-field sensed event to differentiate sinus rhythm on the far-field EGM 
(RV lead noise on near-field) from true VT/VF.  If sinus rhythm is identified when 
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Noise alert is triggered both as a tone to warn the subject and as a CareAlert 
notification to warn the clinician.  The RV LND feature is nominally programmed ON.  
2. The RV lead integrity alert (RV LIA) feature monitors RV pacing lead impedance for 
abrupt impedance changes, the frequency of rapid non-sustained VT episodes, and 
the frequency of very short ventricular intervals counted on the Sensing Integrity 
Counter.  If two of these three criteria are satisfied, an RV LIA alert is triggered as an 
audible tone to warn the subject and as a CareAlert to warn the clinician.  The RV 
LIA feature is nominally programmed ON.
3. The RV pacing impedance (P/S impedance) alert both sounds an audible alert and 
sends a CareAlert if the P/S impedance is lower than the lower programmable 
threshold (nominally 200Ω) or higher than the upper programmable threshold 
(nominally 3000Ω).  
4. The HV defibrillation impedance (HV impedance) alert both sounds an audible alert 
and sends a CareAlert if the HV impedance on the RV coil or SVC coil is lower than 
the lower programmable threshold (nominally 20Ω) or is greater than the upper 
programmable threshold (nominally 200Ω).  
An RV lead alert produced by any four of these lead monitoring features may indicate an 
RV lead system event (LSE).  Additionally, other sources of lead noise or impedance 
change such as the presence of electromagnetic interference (EMI), T-wave 
oversensing, or R-wave double counting may also trigger one of the lead monitoring 
features.
3.3
Market-Released Lead(s)
Any market-released, commercially available transvenous lead(s) may be used in this 
study. Any RV, RA and LV lead may be used, if applicable and compatible with the 
device. Any lead under recall, even if not in the country of implant, should not be 
implanted in study subjects; however, active leads previously implanted under recall may 
be connected to the study device, if previously implanted.
3.4
Market-Released Medtronic CareLink® Monitor and Medtronic CareLink®
Network
The Medtronic CareLink® Monitor and the Medtronic CareLink® Network are indicated for 
use in the transfer of patient data from some Medtronic implantable cardiac devices 
based on physician instructions and as described in the product manual. These 
products are not a substitute for appropriate medical attention in the event of an 
emergency and should only be used as directed by a physician.  
The Medtronic CareLink® Network enables subjects to remotely transfer data from their 
device to the clinic. Subjects may be requested to use the Medtronic CareLink® Monitor 
to send their device data to the clinic. Study site personnel can access the data by 
logging onto the CareLink® website via the internet.
The use of the Medtronic CareLink® Home Monitor is not required for this study and it 
may not be available in all participating geographies. However, if the subject uses 
CareLink® to transmit their device data, the data may be used in the analysis of the study 
objectives, where allowed by local law.

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3.5
Market-Released Medtronic CareLink® Programmer
Medtronic’s market-released Model 2090 CareLink® programmer (or future models, 
which become market released in the geographies where this study takes place) must 
be available at each site to support study visits. Programmers will be used to gather 
lead electrical data, interrogate devices, program devices, and save device data.
3.6
Additional system components
A subset of subjects in this study may be required to use the market-released model DR 
220 Holter Monitor (NorthEast Monitoring, Inc., Maynard MA).  The DR220 Holter 
monitor system communicates with Medtronic implanted devices via telemetry.

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4 REGULATORY COMPLIANCE
The WRAP-IT study is a single-blinded, randomized, prospective, multi-center, single 
blinded post-market, interventional clinical study. This study is required to be in 
compliance with the Clinical Investigation Plan (CIP), Clinical Trial Agreement (CTA) and 
local laws/regulations within the respective geographies in which the study is being 
conducted.
The WRAP-IT clinical study is designed to reflect the Good Clinical Practice (GCP)
principles and other international clinical requirements outlined below. These include the 
protection of the rights, safety and well-being of human subjects, controls to ensure the 
scientific conduct and credibility of the clinical study, and the definition of responsibilities 
of the sponsor and investigators.
The study will be conducted according to federal, national and local laws, regulations, 
standards, and requirements of the countries/geographies where the study is being 
conducted. The study will also be conducted in accordance with the Declaration of 
Helsinki (2013). The principles of the Declaration of Helsinki have been implemented 
through the Patient Informed Consent (PIC) process, Ethics Board/IRB/MEC (all 
henceforth referred to as an “Ethics Committee”) approval, study training, clinical trial 
registration, preclinical testing, risk-benefit assessment, and publication policy.

In EMEA, local laws and regulations will be followed.

In the US, the study will be conducted in compliance with 21 CFR Parts 11, 50,
and 56.

In Greater China (Hong Kong), applicable local regulations will be followed.

In New Zealand, local laws and regulations will be followed.

In ASEAN (Singapore and Malaysia), local laws and regulations will be followed.

In India, applicable India laws and regulations will be followed.

In Latin America, local laws will be complied with.
For additional countries added at a later time, local laws and regulations will be followed.  
Geography-specific requirements will be documented under a separate cover. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 
Food and Drug Administration Amendments Act (FDAA) and Declaration of Helsinki on 
http://clinicaltrials.gov (PL 110-85, Section 810 (a)).
Approval of the CIP is required from the following groups prior to any study procedures 
at a study site: 

Medtronic 

Principal Investigators (by signing the CTA or the CIP signature page)

Geography-specific regulatory authorities (if regulatory approval is required) 

An independent Ethics Committee.
Similarly, approval of subsequent revisions to the CIP is required at each study site from 
the above mentioned groups prior to implementation of the revised CIP at that site.
Each site’s Ethics Committee will also be required to approve any subject recruitment
materials prior to use in the study, if applicable.

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5 METHODOLOGY
5.1
Study design
The WRAP-IT study is a randomized, prospective, multi-center, single blinded, post-
market, interventional clinical study.  The study has three purposes.  First, the WRAP-IT 
study will serve as a post-approval study for those geographies requiring a post-approval 
study to facilitate collection of complications related to the Cardiovascular Implantable 
Electronic Device (CIED) implant procedure or system in subjects randomized to receive 
the TYRXTM Absorbable Antibacterial Envelope (TYRX envelope).  Next, this study will 
evaluate the ability of the TYRX envelope to reduce major CIED infections through 12-
months post-procedure following CIED generator replacement, upgrade, revision, or the 
implant of a de novo CRT-D system.  Subjects undergoing CIED generator replacement, 
upgrade, or revision, or the implant of a de novo CRT-D system with a new CIED will be 
randomized to either receive the TYRX envelope or not to receive the TYRX envelope.  
Randomization will be 1:1 and be stratified by study site and device type high power
(ICD and CRT-D) vs. low power devices (IPG and CRT-P).
Finally this large device study provides the unique opportunity to prospectively 
characterize the performance of Medtronic’s lead monitoring features in subjects whose 
CIED system includes a transvenous RV defibrillation lead.
5.2
Study objectives
5.2.1
Primary objective
The primary study objective is to compare the rate of major CIED infections through 12-
months post-procedure between the TYRX envelope group and the control group (no 
TYRX envelope).
CIED infections are defined as:  (1) superficial cellulitis in the region of the CIED pocket 
with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or 
organ/space (generator pocket) surgical site infection (SSI) that meet the Centers for 
Disease Control and Prevention (CDC) criteria, independent of time from surgery (3) 
persistent bacteremia or (4) endocarditis. 24,38,43,46,74-76   See Appendix A for specific 
details.
Major CIED infections are defined as CIED infections resulting in one or more of the 
following:
CIED system removal
Any invasive procedure (e.g. pocket opened) without system removal
Treatment with antibiotic therapy if the subject is not a candidate for system 
removal and infection recurrence after completion of antibiotic therapy or evidence 
of deep infection with wound dehiscence, erosion, or purulent drainage.
Death
Note: All other CIED infections including superficial incisional SSIs that meet the CDC 
criteria, independent of the time from surgery, are defined as minor CIED infections 
unless they meet the major CIED infection criteria.

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5.2.2
Secondary objectives

Secondary Objective #1:
Confirm that the TYRX envelope does not increase the CIED procedure-related or 
system-related complication rate through 12-months post-procedure.

Secondary Objective #2:
Compare the major CIED infection rate during the entire follow-up between the TYRX 
envelope group and the control group.

Secondary Objective #3:
Compare the rate of major and minor CIED infections through 12-months post-procedure 
between the TYRX envelope group and the control group.
5.2.3
Ancillary objectives

Compare all-cause mortality rates between the TYRX envelope group and the 
control group

Evaluate the CIED procedure success rate in the TYRX envelope group and the 
control group

Control: device and leads all implanted  

Treatment: TYRX envelope, device, and leads all implanted

Summarize the adverse events

Identify the predictors of CIED infection

Summarize quality of life

Evaluate the cost effectiveness of the TYRX envelope
 
 
 
 

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5.3
Subject selection criteria
Subjects will be screened to ensure they meet all of the inclusion and none of the 
exclusion criteria.  
Subjects are considered enrolled in the study upon signing the PIC.  Informed consent 
must be obtained prior to performing any of the study-related procedures.  The complete 
informed consent process will include giving the subject adequate information about the 
study and ensuring that there is a sufficient amount of time to comprehend the 
information in the PIC and have all questions answered before making a decision to 
participate in the study and audio-video record the consent process when applicable per 
local laws and regulations.
5.3.1
Inclusion criteria
Patients must meet the following inclusion criteria to be eligible to participate in the study:

Patient is willing to sign and date the study PIC form

Patient is at least 18 years of age and meets age requirements per local law

Patient is planned to undergo at least one of the following:
a. Patient has existing CIED and is undergoing IPG (including CRT-P), ICD 
or CRT-D replacement or upgrade with a new Medtronic generator 
i.
Subjects planned to have leads added, or extracted and added for 
upgrades can be enrolled
OR
b. Patient will undergo a de novo Medtronic CRT-D system implant per 
approved indications
OR
c.
Patient has existing study eligible Medtronic CIED in which the pocket 
was not accessed within the last 365 days, and is undergoing pocket or 
lead revision

Willing to provide the contact information for the physician who provides follow-
up for his/her CIED.

Willing and able to comply with scheduled follow-up and study related activities.
5.3.2
Exclusion criteria
Patients must not meet any of the following exclusion criteria to be eligible to participate 
in the study:

Known allergy to minocycline or rifampin or their derivatives, or any other known 
contraindications to implantation of the TYRX envelope. 

Current therapy with chronic oral immunosuppressive agents or ≥ 20mg/day of
Prednisone or equivalent.

Hemodialysis or peritoneal dialysis.

Prior Cardiac transplantation or existing Ventricular Assist Device (VAD).

Require long-term vascular access for any reason.

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
Prior history of a CIED infection, other prosthetic device infection, or 
endovascular infection, including endocarditis, in the past 12 months.

Physical, clinical, or laboratory signs or symptoms consistent with an active 
infection (including but not limited to pneumonia, urinary tract, cellulitis, or 
bacteremia)

Systemic lupus erythematous, because minocycline has been reported to 
aggravate this condition

Female patient who is pregnant, or of childbearing potential and not on a reliable 
form of birth control. Women of childbearing potential are required to have a 
negative pregnancy test within 7 days prior to device procedure

Participation in another study that may confound the results of this study. Co-
enrollment in concurrent trials is only allowed when documented pre-approval is 
obtained from the Medtronic study manager.
5.4
Randomization
Enrolled subjects are eligible for randomization after completion of the baseline 
assessment if all inclusion and none of the exclusion criteria are met.  Subjects will be 
randomized in a 1:1 fashion to receive the TYRX envelope during their CIED procedure
(treatment group) or not to receive the TYRX envelope during their CIED 
implant/revision procedure (control group).  
Subjects will be randomized using an electronic randomization system according to the 
randomization schedule generated by a Medtronic statistician or designee.  The 
randomization schedule will be stratified by study site and device type (high power or low 
power devices) to ensure that within each study site and device type randomization is 
1:1.  Since randomization must occur prior to the CIED procedure, it is recommended 
that randomization occur as close as possible, but prior to the procedure to minimize 
study attrition following randomization but prior to the CIED procedure.
Once subjects are assigned to a study group (TYRX envelope or control), they are 
considered randomized and will be included in the analysis using their randomized 
assignment regardless of which therapy was actually received.  All randomized subjects 
should be encouraged to comply with the WRAP-IT study procedures until study closure.
5.5
Blinding
Due to the nature of the CIED procedure, it is not possible to blind the implanting 
investigator or study site staff.  However, efforts should be employed to blind the study 
subject to their randomized treatment throughout the duration of the study.  In particular, 
efforts to keep the subject blinded to their randomized treatment in the procedure room 
will be necessary in the setting of conscious sedation.
All randomized subjects will be unblinded at the end of the study.
5.6
Minimization of Bias
Selection of subjects, treatment of subjects, and evaluation of study data are potential 
sources of bias. Methods incorporated in the study design to minimize potential bias 
include (but are not limited to):

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
Subjects will be evaluated at baseline to confirm eligibility for enrollment with 
defined inclusion/exclusion criteria prior to randomization.

Subjects will be randomly assigned to their treatment assignment.

Subjects will be blinded to their randomized treatment assignment.

Subject demographics, medical history, and CIED procedure information will be 
collected at baseline and at CIED procedure to allow collection of possible 
differences that may affect the study’s primary endpoint.

To ensure widespread distribution of data between sites, the maximum number 
of randomized subjects per site is no more than 100.

Data collection requirements and study procedures will be standardized across 
all sites and geographies.

All study site personnel and Medtronic personnel will be trained on their 
respective aspects of the study using standardized training materials.  All study 
clinicians will be trained on and required to follow the CIP.

Regular monitoring visits will be conducted for adherence to the CIP and to 
verify source data.

An independent clinical events committee (CEC) will regularly review and 
adjudicate all reported adverse events.  The CEC will not be informed of the 
treatment group when adjudicating adverse events.  However, the CEC may be 
able to infer the treatment group in cases where an adverse event is potentially 
related to the TYRX envelope.

A statistical analysis plan will be developed prior to analyzing the study’s 
primary or secondary objectives.
In summary, potential sources of bias that may be encountered in this clinical study have 
been considered and minimized by careful study design.

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6 STUDY PROCEDURES
Prior to performing study related procedures, all sites must have Ethics Committee and 
associated regulatory authority approval if applicable (e.g., Competent Authority 
approval) as well as documentation from Medtronic of site readiness.
Medtronic representatives may provide support as required for the study under 
supervision of the Principal Investigator, including:

Study training relevant and pertinent to the involvement of personnel conducting 
study activities and investigator responsibilities

Technical support at all visits under the supervision of a study investigator, but no 
data entry, shall be performed by Medtronic personnel or their representatives at 
sites
6.1
Investigator / Investigation site selection
All clinical investigators managing the subject’s cardiac rhythm disease must be qualified 
practitioners and experienced in the diagnosis and treatment of subjects with cardiac 
rhythm disease.  All implanting physicians must be experienced and/or trained in the 
handling of CIEDs.
The role of the principal investigator is to implement and manage the day-to-day conduct 
of the clinical study as well as ensure data integrity and the rights, safety and well-being 
of the subjects involved in the clinical study.
The principal investigator shall:

Be qualified by education, training, and experience to assume responsibility for 
the proper conduct of the clinical study.

Be experienced in the field of application and training in the use of CIEDs.
The principal investigator shall be able to demonstrate that the proposed investigational 
site:

Has the required number of eligible subjects needed within the recruitment 
period.

Has one or more qualified investigators, a qualified study team and adequate 
facilities for the foreseen duration of the clinical study.

Has required infrastructure and personnel to ensure audio-visual recording of 
the informed consent procedure, where required as per local requirements.
Site personnel training and delegation will be completed prior to participation in this 
clinical study.
6.2
Site initiation
During the initiation process (prior to subject enrollment), Medtronic will train site 
personnel on the Clinical Investigation Plan, relevant standards and regulations, if 
needed, informed consent, and on data collection and reporting tools. If new members 
join the study site team, they will receive training on the applicable clinical study 
requirements relevant to their role before contributing to the clinical study.

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A CTA shall be entered into effect by Medtronic, the participating investigation site 
and/or the principal clinical investigator at each investigation site as per the local legal 
requirements, and returned, fully executed, to Medtronic prior to the commencement of 
any study activities.  Financial aspects of conducting and reporting a study will be 
specified in the agreement. By signing and dating the agreement the investigator 
indicates approval of the CIP 
Prior to performing study related activities, all sites must have Ethics Committee 
approval, as applicable for that geography.
All local and regional regulatory requirements will be fulfilled prior to site initiation and 
enrollment of subjects into the study. Each study site must have written documentation 
of site and investigator readiness before beginning any study-related activities. 
Requirements for initiation vary by geography, and may include, but are not limited to:

Written documentation of Ethics Committee approval of the current version of the 
CIP and PIC (approved versions must be retrievable from the Ethics Committee 
approval letter or submission letter) and voting list, as required by local law, 

Regulatory authority approval or notification (as required per local law)

Executed CTA on file with sponsor

Current Curriculum Vitae (CV) of investigators 

Documentation of delegated tasks

Documentation of study site personnel training
Additional requirements imposed by the Ethics Committee and regulatory authority shall 
be followed, if appropriate. Medtronic will provide each study site with documentation of 
study site/investigator readiness; this letter must be received prior to subject enrollment.
6.3
Equipment requirements
The following equipment must be available at each site to support study activities:

Access to a clinical lab to test and obtain the results of bacterial cultures 
collected from any suspected infection.

Access to equipment to collect a chest X-ray image of the CIED system in the 
instance of a suspected LSE.

Site has the access to high speed internet to submit data through an internet 
based interface.
Calibration and maintenance of equipment listed above will be done by the site
according to hospital practice (documented proof of said activities should be available 
upon request by Medtronic).

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6.4
Data collection
Data collection requirements are summarized in
Table 5.
Clinical data will be collected at baseline, procedure/pre-hospital discharge, and every 6-
months following CIED procedure until study closure.  Data will be collected using 
electronic case report forms (eCRFs) using an electronic data management system for 
clinical studies.  In addition to eCRF data, non-eCRF data will be collected which 
includes: device interrogation files, CareLink® transmission files, and Holter files.  Data 
will be stored in a secure, password-protected database, which will be backed up nightly.  
Data will be reviewed using programmed and manual data checks.  Data queries will be 
made available to study sites for resolution.  Study management reports will be 
generated by Medtronic to monitor data quality and study progress.  At the end of the 
study, the data will be frozen and retained indefinitely by Medtronic.
Table 5: Data collection and study procedure requirements at subject visits
Study Procedure
Baseline
Procedure
Pre-
Hospital 
Discharge
Biannual 
Follow-up 
Visits
Unschedul
ed Visit
Study Exit
Patient Informed Consent
X
Inclusion/Exclusion Assessment 
X
Subject Demographics
X
Record Medications1
X
X
X
X
X
X
Medical History 
X
System and Procedure 
Information
X
Confirm Programming 
Requirements (subjects with ICD 
or CRT-D only)
X
X
X
Evaluate Subject for Signs and 
Symptoms of CIED Infection
X
X
X
X
Evaluate Subject and Device for 
LSEs 
X
X
X
X
Final Device Interrogation / 
CareLink® Transmission
X
X
X
X
X

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Study Procedure
Baseline
Procedure
Pre-
Hospital 
Discharge
Biannual 
Follow-up 
Visits
Unschedul
ed Visit
Study Exit
EQ-5D
X
X 
(12 month 
visit only)
X (Only if 
exited prior 
to 12 month 
visit)
Collect or Confirm Contact 
Information of CIED follow-up 
Physician2
X
X
X
Exit Subject
X
CIED Infection
As they occur
CIED Infection-Related Health 
Care Utilization
As they occur
CIED Infection–Related EQ-5D
Within 2 weeks following a diagnosis of CIED infection, and subsequently 1, 3, 
and 6 months post infection diagnosis
Lead System Event (ICD and 
CRT-D Subjects only)
As they occur
Holter for Suspected LSE if 
required (ICD and CRT-D 
Subjects only)
As they occur
Adverse Events (AEs)
As they occur
Device Deficiencies
As they occur
System Modifications
As they occur
Study Deviations
As they occur
Device Disposition for TYRX 
envelope 
As it occurs in geographies where required
Death
As it occurs
1 Record any anti-platelet agents, anticoagulants, antibiotics, corticosteroids, insulin or oral 
diabetic agents.  
2 The CIED follow-up physician could also be the referring cardiologist or other physician
overseeing care of the patient following procedure.
All records and other information about subjects participating in this study will be treated 
as confidential. Data will be transferred and processed by Medtronic or a third party 
designated by Medtronic in a key-coded form unless it is impossible to make it 
anonymous, for instance, where the patient’s name cannot be removed from the data 
carrier (such as x-rays). Participating subjects will not be identified by name in any 
published reports about the study.
6.5
Patient informed consent process
Patient informed consent (PIC) is defined as a legally effective documented confirmation 
of a subject’s (or their legally authorized representative or guardian) voluntary
agreement to participate in a particular clinical study after information has been given to 
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to participate. This process includes obtaining a PIC and a/an Authorization to Use and 
Disclose Personal Health Information/Research Authorization/other privacy language as 
required by law that has been approved by the study site’s Ethics Committee and signed 
and dated by the subject (or their legally authorized representative or guardian).  A 
subject may only consent after information has been given to the subject on all aspects 
of the clinical study that are relevant to the subject’s decision to participate.  Informed 
consent may be given by the legally authorized representative only if a subject is unable 
to make the decision to participate in a clinical study and in accordance with local law. In 
such cases, the subject shall also be informed about the clinical study within his/her 
ability to understand.
Prior to enrolling subjects, each site’s Ethics Committee will be required to approve the 
PIC and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law. Any changes to a previously 
approved PIC throughout the course of the study must be reviewed and approved by 
Medtronic and the Ethics Committee reviewing the application before being used to 
consent a prospective study subject. The document(s) must be controlled (i.e. versioned 
and dated) to ensure it is clear which version(s) were approved by Medtronic and the 
Ethics Committee. All important new information should be provided in written form to 
new and existing subjects throughout the study. If relevant, all affected subjects must be 
asked to confirm their continuing informed consent in writing.
Prior to initiation of any study-specific procedures, patient informed consent must be 
obtained from the subject (or their legally authorized representative or guardian). 
Likewise, privacy or health information protection regulation may require subjects to sign 
additional forms to authorize sites to submit subject information to the study sponsor.  
The process of obtaining patient informed consent shall:

Ensure that the principal investigator or an authorized designee conducts the PIC 
process.

Include all aspects of the clinical study that are relevant to the subject's decision 
to participate throughout the clinical study.

Avoid any coercion or undue improper influence on, or inducement of the subject 
to participate.

Not waive or appear to waive the subject’s legal rights.

Ensure the PIC and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/HIPAA/other privacy language as required by 
law are given to the subject (or their legally authorized representative or 
guardian) in a non-technical language the subject is able to read and understand.

Provide ample time and opportunity for the subject to read and understand the 
PIC to inquire about details of the study, and to consider participation. All 
questions about the study should be answered to the satisfaction of the subject.

Include a personally dated signature of the subject (or legally authorized 
representative or guardian if applicable) acknowledging that their participation in 
the study is voluntary.

Include a personally dated signature by the principal investigator or authorized 
designee responsible for conducting the PIC process, as required by local law.

Include any other locally required signatories, such as witnesses, as indicated by 
country-specific legislations.

In addition to the requirement of obtaining written informed consent, audio-visual 
recording of the informed consent process of each trial subjects, including the 

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procedure of providing information to the subject and his/her understanding on 
such consent is required to be done while adhering to the principles of 
confidentiality, where required by local regulations or Ethics Committee 
requirements. Such audio-visual recording and related documentation would be 
preserved.

Provide the subject with a copy of the PIC, the Authorization to Use and Disclose 
Personal Health Information/Research Authorization/HIPAA/other privacy 
language and any other written information, signed and dated if required by local 
law.

Ensure the subject (or their legally authorized representative or guardian) are 
notified of any significant new findings about the study that become available
during the course of the study which are pertinent to the safety and well-being of 
the subject, as this could impact a subject’s willingness to participate in the study. 
If the patient informed consent is obtained the same day the subject begins participating 
in study-related procedures, it must be documented that consent was obtained prior to 
participation in any study-related procedures. It is best practice for the PIC process to 
be documented in the subject’s case history, regardless of circumstance.
In the event the subject cannot read and/or write, witnessed (impartial third party) patient
informed consent will be allowed, provided detailed documentation of the process is 
recorded in the subject’s case history and the witness signs and dates the PIC. The 
patient informed consent shall be obtained through a supervised oral process. An 
independent witness must be present throughout the process. The PIC and any other 
information must be read aloud and explained to the prospective subject or his/her 
legally authorized representative. The witness signs and personally dates the PIC
attesting that the information was accurately explained and that informed consent was 
freely given. The subject should “make his mark” (sign or otherwise physically mark the 
document so as to indicate consent) on the PIC as well. The PIC should document the 
method used for communication with the prospective subject and the specific means by 
which the prospective subject communicated agreement to participate in the study.
The original of the signed and dated PIC must be filed in the hospital/clinical chart or 
with the subject’s study documents. 
The PIC and Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law must be available for monitoring 
and auditing.  Any designated Medtronic personnel who support the procedure must be 
able to review the subject’s signed and dated PIC and verify its completeness prior to 
proceeding with the procedure.  In the event the designated Medtronic personnel identify 
PIC as being incomplete, the procedure will not be allowed to occur until the consent of 
the subject can be adequately and appropriately obtained. 
Refer to Appendix F: Patient Informed Consent Templates for the sample PIC(s).
6.6
Enrollment/Baseline
When a patient (or legally authorized representative or guardian if applicable) and the 
principal investigator or authorized designee (if applicable) signs and dates the PIC, the 
patient is considered a subject enrolled in the study.  The date the subject signed the 
PIC and data protection authorization must be documented in the subject’s medical 

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records. Enrollment can be a stand-alone visit or can occur on the same day as the 
baseline visit.  Medtronic should be notified (via Enrollment Notification eCRF) as soon 
as possible to aid in enrollment tracking. Once consent is obtained, report adverse 
events, device deficiencies, study deviations, system modifications, and subject exits or 
deaths as they occur.
The baseline visit can be a stand-alone visit or can be performed on the same day as, 
but prior to the procedure.  Women of childbearing potential should practice birth control 
30 days prior to CIED generator replacement, upgrade, revision, or de novo CRT-D 
implant and are required to have a negative pregnancy test within 7 days prior to device 
procedure.
The following information is required to be collected at the baseline visit:

Patient Informed Consent Date (Enrollment Date)

Eligibility Verification (Inclusion/Exclusion Assessment)

Patient Demographics

Medications

Relevant Medical History

Collect contact information of the CIED follow-up physician and/or referring 
cardiologist or any other referring physician in the patient chart.

EQ-5D
6.6.1
Eligibility Verification (Inclusion/Exclusion)
Confirm subjects meet all inclusion criteria and none of the exclusion criteria.  It is not a 
study deviation if eligibility violations are discovered after signing the informed consent 
but prior to randomization or attempting a CIED procedure.  However, subjects with 
eligibility violations discovered prior to randomization should be exited prior to 
randomization.  Eligibility violations discovered after randomization require a study 
deviation, but these subjects should continue to be followed per intention-to-treat 
principles.  
6.6.2
Relevant Medical History
The subject’s relevant medical history including cardiovascular medical history, 
indicators of severity of disease state (e.g. NYHA classification), and CIED device 
history (e.g. number of previous systems, leads) will be collected.
6.6.3
Medications
Record the use of any anti-platelet, anticoagulant, antibiotics, corticosteroids, insulin, or 
oral diabetic agents at baseline.
6.7
CIED Procedure
Prior to procedure, but as close as reasonably possible to the CIED procedure, randomly 
assign the subject to either the TYRXTM Absorbable Antibacterial Envelope group or 
control group using the electronic randomization system. The randomization schedule 
automatically gets populated on the eCRF.  All randomized subjects must be implanted 

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with a Medtronic CIED shown in Table 4, as the ancillary objectives will require data 
collection from the device via a device interrogation.  If a non-Medtronic CIED is 
implanted, the subject should remain in the study per intention-to-treat principles, but a 
study deviation is required.  Non-Medtronic leads are allowed.
6.7.1
Infection Control Strategies
Standard strategies to minimize the risk of infection utilized during the CIED procedure 
include recommendations to:

Ensure that the subject does not have any clinical signs of infection prior to the 
CIED implant including absence of fever for 48 hours prior to the procedure.

Administer prophylactic parenteral antibiotics immediately prior to the CIED 
implant per guidelines.23

Pre-operative antiseptic preparation of the surgical site. 

Avoid shaving the operative site: clip if necessary.

Maintain proper sterile technique throughout the replacement or upgrade 
procedure. 

Compulsive attention to the maintenance of sterile technique throughout the 
replacement or upgrade procedure. 

Utilize separate tables for instruments and gowns/gloves.

Mechanically wash the pocket. Note: avoid using iodine and providone as 
indicated in the TYRX Envelope Instructions for Use.

Prevent or minimize hematoma formation by meticulous cautery of bleeding sites. 

Management of perioperative anticoagulation should be individualized. If 
Warfarin is continued, INR at time of procedure should be less than 3.0 and less 
than 3.5 for patients with mechanical valves.81

Resume any necessary systemic anticoagulation post procedure with caution to 
avoid pocket hematoma formation. Low molecular heparin immediately post 
procedure should be avoided. 

At the time of this protocol version there are no data to support the administration 
of postoperative antibiotic therapy, and it is not recommended because of the risk 
of drug adverse events, selection of drug resistant organisms, and cost. 23
6.7.2
CIED replacement, upgrade, revision, or implant

Perform any site specific standard of care pre-operative laboratory assessments 
if not already completed during the screening period.

Perform the CIED replacement, upgrade, revision or implant of de novo CRT-D 
system following site standard of care procedures ensuring that the infection 
control strategies outlined above are considered.   

For subjects randomized to the TYRX envelope group, implant the TYRX
envelope following its instructions for use. Note: removal of part of the TYRX 
envelope for resizing may decrease the amount of antibiotic on the TYRX 
envelope.

Do not use the TYRX envelope for those subjects randomized to the control 
group.

Complete procedure eCRF

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A CIED procedure attempt occurs when the device pocket is opened or venous 
access was gained (i.e. skin was cut).  All procedure attempts should be recorded on 
a procedure eCRF.  If the device remains in the body following the procedure
attempt, any future revisions to the system once the CIED remains in the body 
following pocket closure require a system modification eCRF to be completed. (For 
example, an additional LV lead implant attempt several days after an implant attempt
where the CIED remains in the body, but the LV lead could not be placed require an 
implant eCRF for the CIED implant and a system modification eCRF for the 
additional LV lead implant attempt).
Subjects undergoing a procedure attempt where the CIED does not remain in the 
body following the procedure completion may undergo another CIED procedure
attempt on the same or separate date per the site’s standard medical practice.  Each 
CIED procedure attempt should be recorded on a new procedure eCRF.  However, 
subjects with a procedure attempt who never have a CIED chronically placed in the 
body should continue with study follow-up per intention-to-treat principles.
6.7.3
Required Programming (ICD and CRT-D devices only)
 
 
 
 
 
 
 
 
 
 
 

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EGM vectors for VR
EGM1: RVtip-RVring
EGM2: Can-RVcoil
EGM3: RVtip-RVcoil
LECG: Can-SVC (Note: SVC 
electrode must be present for 
this configuration) 
EGM1: RVtip-RVring
EGM2: Can-RVcoil
EGM3: RVtip-RVcoil
LECG: Can-SVC (Note: SVC 
electrode must be present for this 
configuration)
6.7.4
Final System Configuration
Record the final system configuration.  This will include the serial number and location of 
the implanted CIED device and active leads.
6.7.5
Final Device Interrogation 
At the end of the procedure, perform a device interrogation and save on a USB flash 
drive or other removable electronic media.  Device interrogation data must be sent to 
Medtronic, with a copy being maintained at the site in the subject’s file.  Device data 
should be sent to Medtronic using the secure, electronic Clinical Transfer utility.  A 
deviation is required if a device interrogation is missed.
6.7.6
Assessment for AE/SAEs
Document any reportable AE/SAEs including AEs related to CIED infections or lead 
system events (refer to section 9 Adverse Events and Device Deficiencies).
6.8
Pre-hospitalization Discharge
The following actions are required prior to hospital discharge:

Evaluate subject for signs and symptoms of CIED infection.  If CIED infection 
suspected see section 6.11.

Educate subject on signs and symptoms of CIED infection and remind subject to 
contact their device follow-up clinic if they have signs or symptoms of CIED 
infection

Record the use of any anti-platelet, anticoagulant, antibiotics, corticosteroids, 
insulin, or oral diabetic agents

Perform a device interrogation and save on a USB flash drive or other removable 
electronic media.  Device interrogation data must be sent to Medtronic, with a 
copy being maintained at the site in the subject’s file.  Device data should be sent 
to Medtronic using the secure, electronic Clinical Transfer utility.  A deviation is 
required if a device interrogation is missed.

Verify contact information of CIED follow-up physician

Document any reportable AEs 
Subjects with ICD or CRT-D only:  
o
 

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o
 
 
6.9
Scheduled follow-up visits
After receiving notice of a successful procedure (or unsuccessful procedure if a future 
CIED procedure attempt is not planned), Medtronic will provide the target dates and 
windows for each visit to the implanting site. Should a subject miss a visit or the visit falls
outside the pre-specified window, a study deviation must be reported and the original 
follow-up schedule maintained for subsequent visits.
Data analyses include follow-up visits, regardless of whether the visit occurs within the 
window.  Therefore, a late visit is preferred over a missed visit but must be accompanied 
by a deviation. Follow-up visit windows are listed in Table 7 and are based on days post-
CIED procedure.
Table 7: Data collection and study procedure requirements at subject visits
Study Follow-up
Visit
Window
(Calculated days post-CIED procedure)
Window Start
(days post-
procedure)1
Target
(days post-
procedure)
Window End
(days post-
procedure)
6-Month
168
183
198
12-Month
365
3652
395
18-Month
521
549
577
24-Month
702
730
758
30-Month
887
915
943
36-Month
1070
1098
1126
1Days post-randomization if subject never had a CIED procedure attempt.
2The target date and window start date intended to be equal for primary objective analysis 
purposes.
It is recommended that scheduled follow-up visits occur in the clinic where device 
interrogations can occur; however, remote visits via telephone are an acceptable 
alternative in cases where the patient utilizes the CareLink® Network and when a clinic 
visit is not possible.  If the follow-up visit is conducted via telephone and CareLink®, 
review the subject’s CareLink® transmission and review the subject’s medical records 
(hospitalizations, emergency department visits) and assess for adverse events, including 
any system related events and CIED infections prior to making phone call.
The following information is required to be collected at the follow-up visit:

Assess subject for CIED infection
o
If CIED infection is suspected refer to section 6.11

Document any reportable AEs (refer to section 9 Adverse Events and Device 
Deficiencies)

Record current use of any anti-platelet, anticoagulant, antibiotics, corticosteroids, 
insulin, or oral diabetic agents at the time of the visit

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
Verify contact information of CIED follow-up physician

For follow-up visits occurring in the clinic, perform a device interrogation and 
save on a USB flash drive or other removable electronic media.  Device 
interrogation data must be sent to Medtronic, with a copy being maintained at the 
site in the subject’s file.  Device data should be sent to Medtronic using the 
secure, electronic Clinical Transfer utility.  A deviation is required if a device 
interrogation is missed.

If the follow-up visit occurs via telephone, ensure the subject has completed a 
CareLink transmission prior to the telephone follow-up.  Deviations are required 
for telephone follow-up visits not associated with a CareLink transmission.

Schedule the next follow-up visit

EQ-5D (12-month visit only)
Subjects with a ICD or CRT-D only:  
o
Assess subject and review device diagnostics for LSEs (lead failures, lead 
dislodgements, lead perforation, or header connector issues).  If a LSE is 
suspected refer to section 6.12.
o
Review all device alerts.  If LIA, LNA, or impedance out of range alerts are 
present update the device alert log eCRF.  Report any reprogramming or 
system modifications associated with the device alert.
o
Confirm required programming in Table 6
6.10 Unscheduled follow-up visits
An unscheduled visit is defined as any non-standard of care visit to the study site for 
reasons related to the implanted CIED system including suspected CIED infection and 
any device alerts.  The following procedures are required at each unscheduled visit:

Assess subject for potential CIED infection.  If a CIED infection is suspected see 
section 6.11.

Record current use of any anti-platelet, anticoagulant, antibiotics, corticosteroids, 
insulin, or oral diabetic agents at the time of the visit

Document any reportable AEs (refer to section 9 Adverse Events and Device 
Deficiencies)

Perform a device interrogation and save on a USB flash drive or other removable 
electronic media.  Device interrogation data must be sent to Medtronic, with a 
copy being maintained at the site in the subject’s file.  Device data should be sent 
to Medtronic using the secure, electronic Clinical Transfer utility.  A deviation is 
required if a device interrogation is missed.
Subjects with an ICD or CRT-D only:  

Assess subject and review device diagnostics for LSEs (lead failures, lead 
dislodgements, lead perforation, or header connector issues).  If a LSE is 
suspected see section 6.12.

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
Review all device alerts.  If LIA, LNA, or impedance out of range alerts are 
present, update the device alert log eCRF.  Report any reprogramming or 
system modifications associated with the device alert.
6.11 Potential CIED Infection
Infection related information should be reported for each suspected CIED infection.  The 
actions should be taken:

Collect source documents including any physician notes, admission/discharge 
summaries, microbiology reports, echocardiograms, invasive procedure reports, 
and antibiotic administration records)

Complete infection eCRF

Verify that an AE for the potential CIED infection was reported on an AE eCRF

Complete a system modification eCRF if CIED system revised

Obtain healthcare utilization information for all hospitalizations, emergency 
department visits, urgent visits, and clinic visits associated with the CIED 
infection diagnosis.

Complete UB-04 collection where UB-04 forms and data are available

Perform a device interrogation and save on a USB flash drive or other removable 
electronic media.  Device interrogation data must be sent to Medtronic, with a 
copy being maintained at the site in the subject’s file.  Device data should be sent 
to Medtronic using the secure, electronic Clinical Transfer utility.  A deviation is 
required if a device interrogation is missed.

Administer the EQ-5D quality of life assessment within two weeks of the infection 
diagnosis and again at approximately 1-month, 3-months, and 6-months post-
infection diagnosis.  See Table 8 for CIED related infection assessment windows.  
EQ-5D questionnaires may be administered remotely via telephone.  If any of the 
infection related EQ-5D assessments coincide with the 12 month follow-up, only 
one EQ-5D assessment (either infection or 12 month) is required.

If possible, it is strongly recommended that a photo of the infection site/pocket be 
obtained.
Table 8: CIED Infection-Related EQ-5D Assessment Windows
CIED Infection EQ-5D 
Assessment
Window
(Calculated days post-CIED infection diagnosis)
Window Start
(days post-
diagnosis)1
Target
(days post-
diagnosis)
Window End
(days post-
diagnosis)
At Diagnosis
0
NA
14
1-month
23
30
37
3-month
75
90
105
6-month
168
183
198

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6.12
 
 
 
 
 
 
 
 
6.13
 
 
 
 
 
 
 
 
 
 
 
 

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6.14 Device Interrogation 
For scheduled follow up and unscheduled follow up visits occurring at the study site, a 
final device interrogation file (.pdd) must be obtained and saved in a digital format (e.g., 
floppy, USB). Alternatively, if the follow-up visit occurs remotely over the phone, a 
CareLink® transmission must be submitted. Store the original file at the site and send a 
copy to Medtronic. It is recommended that data are not cleared during any interrogation.
6.15 Healthcare Utilization
Health Care Utilization information related to CIED infections will be collected for each 
suspected CIED infection.  All hospitalizations, emergency department visits, urgent 
care, or unscheduled follow-up visits associated with the suspected CIED infection, 
regardless of location of care, are considered reportable HCUs for this study.  
HCU information will be included in the review of suspected CIED infection by the CEC.  
Supporting source documentation such as hospital admission/discharge reports or 
procedure notes may be requested if needed for study or endpoint evaluation.  
Additionally, UB04 codes where available will be collected with all healthcare utilizations 
related to CIED infections.

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6.16 System Modification
A system modification will be reported in the event the device and/or leads require 
invasive modification (e.g., generator or lead explant, generator or lead replacement, 
lead repositioning, CIED system explant due to infection).  This includes instances 
where additional lead implant attempts are made following a procedure where the CIED 
remains in the device pocket following the initial CIED procedure. In the event of a 
system modification, the follow-up schedule for the subject will remain unchanged and 
will continue to be followed until the end of the study. For a system modification the 
following activities are required:

Perform an initial device interrogation prior to the system modification and save 
on a USB flash drive or other removable electronic media.  

Complete a system modification eCRF

If the system modification is related to a CIED infection, ensure that an AE, HCU 
and infection eCRF are completed

Perform a final device interrogation following the system modification if the 
subject’s device remains in the body or was replaced with a new system and 
save on a USB flash drive or other removable electronic media.  

Submit copies of the initial and final (if done) device interrogations to Medtronic, 
with copies being maintained at the site in the subject’s file.  Device data should 
be sent to Medtronic using the secure, electronic Clinical Transfer utility.  
If the device is taken out of service (e.g, explanted or capped) and a replacement will not 
be implanted or the replacement is not a study approved device, the subject will still be 
followed at the normally scheduled follow-up visits through the end of the study.
All explanted product (device, leads, etc.) should be returned to the respective 
manufacturer for analysis when permissible by local laws and regulations. 
In the event that a subject has a re-attempt after a previous unsuccessful system 
modification, the subsequent attempt(s) must be reported via eCRF as separate system 
modifications.
6.16.1 System Modifications in Subjects Randomized to the TYRX Envelope 
Group
Subjects randomized to the TYRX envelope group must receive a new TYRX envelope 
as part of all system modifications where the device pocket is opened and the CIED is 
removed or replaced. 
6.16.2 System Modifications in Subjects Randomized to the Control Group
Subjects randomized to the control group must not receive a TYRX envelope as part of a 
system modification. 

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6.17 Subject Exit or Withdrawal
A study exit eCRF is required for all subjects except in the case of death.  Prior to exiting 
a subject from the study, it is recommended to follow the subject until all ongoing system 
and/or procedure related AEs (including CIED infections) are resolved or unresolved 
with no further actions planned.  Following exit, subjects will continue to receive standard 
medical care.  Upon exiting from the study, no further study data will be collected or 
study visits will occur for the subject.  Exited subjects will not be replaced with newly 
enrolled subjects.
Subjects are urged to remain in the study as long as possible but may be exited from the 
study for any of the following situations:

Study closure

Subject lost to follow-up (refer to section 6.17.1 for more information)

Subject did not meet inclusion/exclusion criteria

Subject was not randomized

Subject did not provide consent or data use protection authorization

Subject chooses to withdraw (refer to section 6.17.2 for more information) 

Investigator deems withdrawal necessary (e.g., medically justified, 
inclusion/exclusion criteria not met) 
For study exit visits for reasons other than subject lost to follow-up the following 
information is required:   

Assess subject for CIED infection.

Assess subject for potential CIED infection.  If a CIED infection is suspected see
section 6.11.

Document any reportable AEs (refer to section 9 Adverse Events and Device 
Deficiencies).

Record current use of any anti-platelet, anticoagulant, antibiotics, corticosteroids, 
insulin, or oral diabetic agents at the time of the visit.

For study exit visits occurring in the clinic, perform a device interrogation and 
save on a USB flash drive or other removable electronic media.  Device 
interrogation data must be sent to Medtronic, with a copy being maintained at the 
site in the subject’s file.  Device data should be sent to Medtronic using the 
secure, electronic Clinical Transfer utility.  A deviation is required if a device 
interrogation is missed.

If the study exit visit occurs via telephone, ensure the subject has completed a 
CareLink transmission prior to the telephone follow-up.  Deviations are required 
for telephone study exit visits not associated with a CareLink transmission.

Administer the EQ-5D if the subject exit occurs prior to completing the 12 month 
follow-up visit.

Document the reason for subject exit or withdrawal.
Subjects with a ICD or CRT-D only:  

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
Assess subject and review device diagnostics for LSEs (lead failures, lead 
dislodgements, lead perforation, or header connector issues).  If a LSE is 
suspected refer to section 6.12.

Review all device alerts.  If LIA, LNA, or impedance out of range alerts are 
present update the device alert log eCRF.  Report any reprogramming or system 
modifications associated with the device alert.
6.17.1 Lost To Follow-Up
In the case that the subject is determined to be lost to follow-up, a minimum of two 
attempts to contact the subject must be recorded on the eCRF.  The recommended 
method of contact is one letter and one phone record or two letters. In addition, follow 
the regulations set forth by the governing Ethics Committee.
6.17.2 Subject Withdrawal
A subject will be exited from the study in the event that he or she is unable to participate, 
expresses a desire to withdraw, or is unwilling to continue participation in the study. In 
addition, a subject may be exited from the study if an investigator feels it is necessary to
withdraw the subject from the study due to a medical condition, if the inclusion/exclusion 
criteria are not met or other reason. In such cases, the subject will be notified and 
provided an explanation regarding the reasons for the study exit.
The subject should be informed that their future care or treatment will not be affected in 
any way as a result of choosing to not participate in this study.  Furthermore, alternative 
treatments and medical consequences of exiting the study should be discussed with the 
subject. Any significant new findings related to the study that may develop, which may 
relate to the subject’s willingness to continue participation, should be communicated to 
the subject.

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7 INVESTIGATIONAL DEVICE/SOFTWARE STORAGE, 
HANDLING AND TRACEABILITY
All products used in this study will be market released in the geographies they are used,
Device Traceability may be required per local laws and regulations. TYRX™ Absorbable 
Antibacterial Envelope (if applicable), device and lead information of implanted system 
will be collected at implant (e.g., model number). 
If there are additional local requirements related to implanted information beyond what is 
collected by Medtronic on the electronic Case Report Form, this is the Investigator’s 
responsibility and should be recorded in the subject’s medical records, but will not be 
collected by Medtronic (e.g., national registration card number, identification code linked 
to names and contact information, log of all subjects enrolled in the clinical study, lot or 
batch number).
Commercially available product supply will be managed in a manner consistent with 
other market-released products. 

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8 STUDY DEVIATIONS
A study deviation is defined as an event within a study that did not occur according to 
the Clinical Investigation Plan or the Clinical Trial Agreement.
Prior approval by Medtronic is expected in situations where the investigator anticipates, 
contemplates, or makes a conscious decision to deviate. Prior approval is not required 
when a deviation is necessary to protect the safety, rights or well-being of a subject in an 
emergency or in unforeseen situations beyond the investigator’s control (e.g. subject 
failure to attend scheduled follow-up visits, inadvertent loss of data due to computer 
malfunction, inability to perform required procedures due to subject illness).
For medically justifiable conditions which preempt a subject’s ability to complete a study-
required procedure, it may be permitted to report only one deviation which will apply to 
all visits going forward. This may also apply for other unforeseen situations (e.g. the 
subject permanently refuses to complete a study required procedure and the data will 
not contribute to the primary end point analysis). However, prior approval from 
Medtronic is required for such situations.
All study deviations must be reported on the eCRF to Medtronic regardless of whether 
medically justifiable, pre-approved by Medtronic, an inadvertent occurrence, or taken to 
protect the subject in an emergency. In the occurrence of a corrupted device 
interrogation file, Medtronic may request a deviation to document that a readable 
interrogation file is unavailable.
In the event the deviation involves a failure to obtain a subject’s consent, or is made to 
protect the life or physical well-being of a subject in an emergency, the deviation must be 
reported to the Ethics Committee as well as Medtronic within five (5) working days, or 
according to local requirements. Reporting of all other study deviations should comply 
with Ethics Committee policies, local laws and/or regulatory agency requirements must 
be reported to Medtronic as soon as possible upon the site becoming aware of the 
deviation. . Refer to Table 17 for deviation reporting requirements for all geographies
and timeframes for reporting to Medtronic and/or regulatory bodies. 
Medtronic is responsible for analyzing deviations, assessing their significance, and 
identifying any additional corrective and/or preventive actions (e.g. amend the Clinical 
Investigation Plan, conduct additional training, and terminate the clinical study).
Repetitive or serious investigator compliance issues may result in initiation of a 
corrective action plan with the investigator and site, and in some cases, necessitate 
suspending enrollment until the problem is resolved or ultimately terminating the 
investigator's participation in the study. Medtronic will provide site-specific reports to 
investigators summarizing information on deviations that occurred at the investigational 
site on a periodic basis.

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9 ADVERSE EVENTS AND DEVICE DEFICIENCIES
Timely, accurate, and complete reporting and analysis of safety information for clinical 
studies are crucial for the protection of subjects. Reporting and analysis of safety data 
are mandated by regulatory authorities worldwide. Medtronic has established 
procedures in conformity with worldwide regulatory requirements to ensure appropriate 
reporting of safety information. This study is conducted in accordance with these 
procedures and regulations.
Since the safety reporting requirements and classification systems vary for each 
regulatory agency, requirements from all geographies are taken into account for the 
collection and reporting of safety information.
For the WRAP-IT study AEs will be collected for all adverse events that are potentially 
CIED system related (including TYRX envelope related), procedure related, CIED 
infection related, and all serious adverse events regardless of their relationship to the 
CIED system or procedure.
9.1
Adverse Event and Device Deficiency definitions
Where the definition indicates “device,” it refers to any device used in the study. This 
might be the device under investigation, or any market released component of the 
system. For the purposes of this study, all adverse events will be classified according to 
ISO 14155:2011.
Table 9: Adverse Event definitions
General
Adverse Event (AE)
(Adapted from ISO 14155:2011, 3.2)
Any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory findings) 
in subjects,  whether or not related to the medical device
Note 1: This definition includes events related to the device under 
investigation or the comparator.
Note 2: This definition includes events related to the procedures 
involved.
Adverse Device Effect (ADE)
(ISO 14155:2011, 3.1)
Adverse event related to the use of a medical device
Note 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
medical device.
Note 2: This definition includes any event resulting from an error 
use or from intentional misuse of the medical device
Device Deficiency (DD)
(ISO 141155:2011, 3.15)
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and 
inadequate labeling 
Relatedness

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CIED system related
(includes all implantable components 
and features, associated introduction 
tools, operational and download 
software and programmers necessary 
for conducting study-related procedures 
as defined in the Clinical Investigation 
Plan)
Device-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the device 
RA lead-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the RA lead 
RV lead-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the RV lead 
LV lead-related: An adverse event that results from the presence 
or performance (intended or otherwise) of the LV lead 
Implant tool-related: An adverse event that results from the 
presence or performance (intended or otherwise) of the implant 
tool
Programmer-related: An adverse event that results from the 
presence or performance (intended or otherwise) of the 
programmer
TYRX™ Absorbable Antibacterial Envelope-related: An adverse 
event that results from the presence or performance of the 
TYRX™ Absorbable Antibacterial Envelope
CIED procedure related
An adverse event that occurs due to any procedure related to the 
implantation or surgical modification of the system including the 
TYRX envelope (if applicable)
CIED infection related
A adverse event resulting from the  procedure or surgical 
modification that results in a CIED infection, which includes:

CIED pocket infections

Persistent bacteremia

CIED endocarditis
Seriousness
Serious Adverse Event (SAE)
(ISO 14155:2011, 3.37)
Adverse event that:
a) led to death,
b) led to serious deterioration in the health of the subject, that 
either resulted in
1) a life-threatening illness or injury, or
2) a permanent impairment of a body structure or a body 
function, or
3) in-patient or prolonged hospitalization, or
4) medical or surgical intervention to prevent life-
threatening illness or injury or permanent impairment to a 
body structure or a body function,
c) led to foetal distress, foetal death or a congenital abnormality 
or birth defect
Note: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in 
health, is not considered a serious adverse event.
Serious Adverse Device Effect (SADE) 
(ISO 14155:2011, 3.36)
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
Unanticipated Serious Adverse Device 
Effect (USADE)
(ISO 14155:2011, 3.42)
Serious adverse device effect which by its nature, incidence, 
severity or outcome has not been identified in the current version 
of the risk analysis report
Note: Anticipated serious adverse device effect (ASADE) is an 
effect which by its nature, incidence, severity or outcome has 
been identified in the risk analysis report.

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Complication
An adverse event that includes the following is considered a 
complication: 

Results in death, 

Involves any termination of significant device 
function, or 

Requires an invasive intervention 
Non-invasive (21 CFR 812): when applied to a diagnostic device 
or procedure, means one that does not by design or intention: 

Penetrate or pierce the skin or mucous membranes of 
the body, the ocular cavity, or the urethra, or 
o
Penetrate: to pass, extend, pierce, or diffuse 
into or through something; to enter by 
overcoming resistance; to gain entrance to 
o
Pierce: to force a way into or through something 

Enter the ear beyond the external auditory canal, the 
nose beyond the nares, the mouth beyond the pharynx, 
the anal canal beyond the rectum, or the vagina beyond 
the cervical os 
Note (FDA): Blood sampling that involves simple venipuncture is 
considered noninvasive, and the use of surplus samples of body 
fluids or tissues that are left over from samples taken for non-
investigational purposes is also considered noninvasive.
Observation
Any Adverse Event that is not a complication.
Note 1: Only system or procedure related AEs will be classified as 
complication or observation
Major CIED infection
A CIED infection resulting in one or more of the following:

CIED system removal

Any invasive procedure (e.g. pocket opened) without 
system removal

Treatment with antibiotic therapy if the subject is not a 
candidate for system removal and infection recurrence 
after completion of antibiotic therapy or evidence of deep 
infection with wound dehiscence, erosion, or purulent 
drainage.

Death
Minor CIED infection
All other CIED infections including superficial incisional SSIs that 
meet the CDC criteria, independent of the time from surgery, are 
defined as minor CIED infections unless they meet the major 
CIED infection criteria
Other

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Unavoidable Adverse Event
An Adverse Event inherent to a surgical procedure that is 
expected to occur in all subjects for a projected duration according 
to the Investigator’s opinion, including, but not limited to: 
Event Description
Timeframe 
(hours) from 
the Surgical 
Procedure
Anesthesia related nausea / vomiting 
24
Low-grade fever (<100°F or 37.8°C)
48
Pocket site / Incisional pain
72
Mild to moderate bruising / ecchymosis
168
Sleep problems (insomnia)
72
Back pain related to laying on table
72
Shoulder pain/discomfort/stiffness related to 
shoulder immobilization during procedure
72
9.2
Adverse Event and Device Deficiency Assessment
9.2.1
Adverse Events
Adverse event definitions are provided in Table 9.  To ensure that all AEs that are 
potentially relevant to the WRAP-IT study are collected, all adverse events that are 
potentially CIED system related (including TYRX envelope related), procedure related, 
CIED infection related, and all serious adverse events regardless of their relationship to 
the CIED system or procedure will be collected and reported to Medtronic during the 
study, starting from the time the subject signs the PIC.  Reporting of these events to 
Medtronic will occur on the AE eCRF.  
Each AE must be recorded on a separate AE eCRF and include a description of the 
event, the diagnosis, the date of event onset, the date the site became aware of the 
event, the relatedness and seriousness of the event, diagnostic tests and procedures 
performed, actions taken as a result of the event, and the outcome of the event. Serious 
AEs that are not related to the CIED system or procedure may collect only the necessary 
information required for regulatory reporting. Documented pre-existing conditions are 
not considered AEs unless the nature or severity of the condition has worsened. In all 
geographies, Unavoidable Adverse Events, listed in Table 9 need not be reported unless 
the adverse event worsens or is present outside the stated timeframe post-CIED 
procedure.
For AEs that require immediate reporting (see Table 11), initial reporting may be done by 
phone, fax (refer to Table 1 for sponsor contact information), or on the eCRF completing 
as much information as possible. The AE eCRF must be completed as soon as possible. 
9.2.2
Device Deficiencies
Device deficiency information will be collected throughout the study and reported to 
Medtronic. Note that device deficiencies that result in an adverse device effect (ADE) to 
the subject should be captured as an Adverse Event only.
Device deficiencies that did not lead to an AE but could have led to a Serious Adverse 
Device Effect (SADE) (i.e., if suitable action had not been taken, if intervention had not 

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been made, or if the circumstances had been less fortunate) require immediate reporting 
(see Table 11).
9.2.3
Processing Updates and Resolution
For any changes in status of a previously reported adverse event (i.e. change in actions 
taken, change in outcome, change in relatedness), updated information must be 
reported by updating the AE eCRF. All adverse events must be followed until the 
adverse event has been resolved, is unresolved with no further actions planned, the 
subject exits the study or until study closure, whichever occurs first. 
In the event that a subject is exited from the study prior to study closure, all efforts 
should be made to continue following the subject until all unresolved procedure or 
system related adverse events, as classified by the investigator, are resolved or they are 
unresolved with no further actions planned. 
At the time of study exit, all adverse events with an outcome of “Unresolved, further 
actions or treatment planned” must be reviewed and the original AE updated. At a 
minimum, if there are no changes to the description, relatedness, test and procedures or 
actions taken, the outcome must be updated to reflect “Unresolved at time of study exit.”
9.3
Adverse Events, Device Deficiency Classification and Reporting
All reportable adverse events and device deficiencies will be reviewed by a Medtronic 
representative. AEs will be classified according to the definitions provided. 
Upon receipt of adverse events at Medtronic, a Medtronic representative will review the 
adverse event/device deficiency for completeness and accuracy and when necessary 
will request clarification and/or additional information from the Investigator. Medtronic will 
utilize MedDRA, the Medical Dictionary for Regulatory Activities, to assign a MedDRA 
term for each adverse event based on the information provided by the investigator. 
Regulatory reporting of all safety events, which may include SAEs and device 
deficiencies that could have led to an SADE, will be completed according to local 
regulatory requirements. Refer to Table 11 for a list of required investigator and 
Medtronic reporting requirements and timeframes. It is the responsibility of the 
investigator to abide by any additional AE reporting requirements stipulated by the Ethics 
Committee responsible for oversight of the study.
Appendix G contains the Foreseeable Adverse Event List (FAL), which is a list of 
adverse events related to the system or procedure that have been observed in previous 
studies and may be experienced by subjects. This list may help to assess if an adverse 
event is unexpected in nature.  For emergency contact regarding a USADE, SAE and/or 
SADE, contact a clinical study representative immediately (refer to the study contact list 
provided in the site’s study documents binder/investigator site file or refer to the contact 
information provided on the title page).
Adverse Events and Deaths will be classified according to the standard definitions as 
outlined below: 

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Table 10: Adverse Event classification responsibilities
What is classified? Who classifies? Classification Parameters
Relatedness
Investigator
CIED system-related (Device related, RA lead, RV lead, 
LV lead, Implant tool, Programmer, TYRXTM Absorbable 
Antibacterial Envelope related), CIED procedure related,  
CIED infection related
Sponsor
CIED system related (Device related, RA lead, RV lead, 
LV lead, Implant tool, Programmer, TYRXTM Absorbable 
Antibacterial Envelope related), CIED procedure related, 
CIED infection related
Severity
Investigator
SAE,  
Sponsor
SAE, USADE, Complication or Observation (for all 
system, TYRXTM Absorbable Antibacterial Envelope, or 
procedure related adverse events),
Diagnosis
Investigator
Based on presenting signs and symptoms and other 
supporting data
Sponsor
MedDRA term assigned based on the data provided by 
Investigator
Death Classification Investigator
Sudden Cardiac, Non-sudden Cardiac, Non-Cardiac, 
Unknown
An independent Clinical Events Committee (CEC) will review and adjudicate at a 
minimum, all events classified by the investigator or Medtronic as procedure or system 
related to determine relatedness and complication/observation classification. 
Additionally, the CEC will provide an adjudication of the death classification for all 
reported deaths.  
Table 11: Reporting requirements
Serious Adverse Events (SAEs)
Investigator submit to:
Medtronic
EMEA: Immediately after the investigator first learns of the event or of new information in 
relation with an already reported event. (ISO 14155 and local law)
All other geographies: Submit in a timely manner after the investigator first learns of the event.
India: All serious adverse events shall be reported to the sponsor. (Indian GCP section 
3.3.4.3). It is recommended to report all serious adverse events to the sponsor within 24h. For 
reported deaths the investigator shall supply any additional information e.g. autopsy report 
and terminal medical reports. (Indian GCP section 3.3.4.5)
All other geographies: Report to the sponsor, without unjustified delay, all serious adverse 
events.
Ethics 
Committee, 
All geographies: Submit to Ethics Committee per local reporting requirement.
Regulatory 
authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Sponsor submit to:
Regulatory 
authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.

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Serious Adverse Device Effects (SADEs), including Unanticipated Serious Adverse Device Effect 
(USADE):
Investigator submit to:
Medtronic
EMEA: Immediately after the investigator first learns of the event or of new information in 
relation with an already reported event. (ISO 14155 and local law)
India: All serious adverse device effects shall be reported to the sponsor. (Indian GCP section 
3.3.4.3). It is recommended to report all serious adverse events to the sponsor within 24h.
All other geographies: Submit in a timely manner after the investigator first learns of the 
event.
Regulatory 
Authority
All geographies: As per local reporting requirement.
Ethics 
Committee
All geographies: Submit per local Ethics Committee requirement.
Sponsor submit to:
Regulatory 
authorities
Singapore: All events should be reported immediately and not later than 10 calendar days for 
events that have led to the death, or a serious deterioration in the state of health, of a patient, 
a user of the medical device or any other person. (GN-05-R2 section 4)
New Zealand: Sponsor is required to report all fatal or life-threatening suspected unexpected 
serious adverse reactions occurring in New Zealand trial participants where the treatment is 
known.  Reports must be sent to Medsafe within 7 days of the sponsor receiving an 
investigator’s report of a USADE. Adverse reactions occurring in a clinical trial participants 
are considered to be unexpected if they are not outlined in the protocol and investigator’s 
brochure, and are not defined study end-points (e.g. death or hospitalization). (Guideline on 
the Regulation of Therapeutic Products in New Zealand – Part 11- Edition 1.2 section 5.4.2
All other geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.
Adverse Device Effects
Investigator submit to:
Medtronic
EMEA: Immediately after the investigator first learns of the effect. (ISO 14155 and local law)
All other geographies: Submit in a timely manner after the investigator first learns of the 
effect.
Regulatory 
authority
All geographies: As per local reporting requirement.
Ethics 
Committee
All geographies: Reporting timeframe as per local Ethics Committee requirement.
Sponsor submit to:
Regulatory 
authorities
Singapore: All adverse device effects that represents a serious threat to public
Health should be reported immediately and not later than 48 hours. (GN-05-R2:Guidance on 
the Reporting of Adverse Events for Medical Devices section 4)
All events that occur outside of Singapore but where the medical devices have also been 
supplied in Singapore do not require reporting unless:

the registration or license conditions of those medical devices require so, or

a notice requesting for adverse event information has been issued by the Authority.
(GN-05-R2 section 2)
All other geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.

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All other reportable Adverse Events
Investigator submit to:
Medtronic
All geographies: Submit in a timely manner after the investigator first learns of the event.
Regulatory
Authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.
Sponsor submit to:
Regulatory
authorities
New Zealand: Sponsor is required to hold reports of all (worldwide) USADEs. These reports 
should not be routinely sent to Medsafe, but must be held in an accessible form and made 
available to Medsafe on request. (Guideline on the Regulation of Therapeutic Products in 
New Zealand – Part 11- Edition 1.2 section 5.4.3)
All other geographies: Submit to regulatory authority per local reporting requirement.
Device Deficiencies with SADE potential
Investigator submit to:
Medtronic
EMEA: Immediately after the investigator first learns of the deficiency or of new information in 
relation with an already reported deficiency.
All other geographies: Submit or report as required per local reporting requirements.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.
Regulatory 
authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Sponsor submit to:
Regulatory 
authorities
Singapore: All events should be reported immediately and not later than 30 calendar days for 
events where a recurrence of which might lead to the death, or a serious deterioration in the 
state of health, of a patient, a user of the medical device or any other person. (GN-05-R2
section 4)
All geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.
All other Device Deficiencies
Investigator submit to:
Medtronic
All geographies: Submit in a timely manner after the investigator first learns of the event.
Regulatory 
Authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to Ethics Committee per local reporting requirement.
New information that may adversely affect safety of the subjects or the conduct of the study
Investigator submit to:
Medtronic
India: Investigator shall promptly report to sponsor and monitor new information that may
adversely affect safety of the subject or the conduct of the study. (Indian GCP section 3.3.4.4).
All other geographies: Submit in a timely manner after the investigator first learns of the 
event.
Ethics 
Committee
India: Investigator shall promptly report new information that may adversely affect safety of
the subject or the conduct of the study. (Indian GCP section 3.3.4.4).
All other geographies: Submit to Ethics Committee per local reporting requirement.

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Sponsor submit to:
Regulatory
authorities
All geographies: Submit to regulatory authority per local reporting requirement.
Ethics 
Committee
All geographies: Submit to regulatory authority per local reporting requirement.
9.4
Product Complaints / Vigilance Reporting
All devices used in this study will be market released at study start. Therefore, product 
complaint reporting and vigilance reporting are applicable and AEs related to any
market-released device during the study must be reported.  The reporting of product 
complaints should be done in addition to the Adverse Event reporting requirements.  
Refer to local regulations for reporting requirements.  In case the adverse event is 
related to a non-Medtronic market released device used during the study, post-market 
surveillance is also applicable and the investigator is responsible for immediate reporting 
of the product complaint via the regular channels for market-released products.
Product Complaint: Any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a medical device that has been placed on the market.
Abuse: Abnormal use (definition acc. #4.1 of Meddev 2.12-1 rev6)
Misuse: Use error (definition acc. #4.20 of Meddev 2.12-1 rev6)
It is the responsibility of the investigator and the clinical study team to report all product 
complaint(s) associated with a medical device distributed by Medtronic, regardless 
whether they are related to intended use, misuse or abuse of the product.  Reporting 
must be done immediately and via the regular channels for market-released products.  
The reporting of product complaints by the clinical team must be done according to the 
local Standard Operating Procedures. Medtronic will notify the regulatory authorities 
(e.g. Competent Authority) as applicable for the following incidents immediately upon 
learning of them:

Any malfunction or deterioration in the characteristics and/or performance of a 
device, as well as any inadequacy in the labeling or instructions for use which led 
or might have led to the death or serious deterioration in the state of health of a 
patient, user, or other person.

Any technical or medical reason resulting in withdrawal of a device from the 
market by the manufacturer.
A serious deterioration in the state of heath includes:

Life-threatening illness or injury.

Permanent impairment of a body function or permanent damage to a body 
structure.

A condition necessitating medical or surgical intervention to prevent permanent
impairment of a body function or permanent damage to a body structure.

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9.5
Subject Death
9.5.1
Death data collection
All subject deaths must be reported by the investigator to Medtronic on a Subject Death 
form immediately or in a timely manner per geography requirements after the 
investigator first learns of the death.  The SAE leading to death should also be reported 
on an Adverse Event Form.  There should only be one AE form with an outcome of 
death.
In the event of a subject’s death, the implanted system should be explanted and 
returned to Medtronic (or per other manufacturer’s procedure) for analysis whenever 
possible. Local laws and procedures must be followed where applicable.
System Interrogation Data Recommendations:

After the subject has died but prior to explant, it is strongly recommended that the 
system be interrogated and a full summary interrogation (Interrogate All) 
performed when possible.  Save a copy of the device interrogation on a USB 
flash drive or other removable electronic media.  Device data should be sent to 
Medtronic using the secure, electronic Clinical Transfer utility.  

Make the interrogation file before any programming to prevent overwriting 
information in the device’s memory and/or distinguishing between events 
detected during versus before the explant procedure.

Recommend obtaining the exact date and time of death as lower temperatures 
after death can cause ERI and other “event flags” to be stored in the device 
memory.
For ICD systems, the VT and VF detection capabilities must be disabled to avoid 
inadvertent shocks. If any system component is returned to Medtronic, internal return 
product reporting systems may be used to gather additional information about the 
returned device/component.
A copy of the death certificate, if available and allowed by state/local law, should be sent 
to the Medtronic clinical study team. When a death occurs in a hospital, a copy of the 
death summary report and all relevant hospital records when obtainable should be sent 
to the Medtronic clinical study team, if available. If an autopsy is conducted, the autopsy 
report should also be sent to the Medtronic clinical study team if available and allowed 
by state/local law. When the death occurs at a remote site, it is the investigative site’s 
responsibility to attempt retrieval of information about the death. Additionally, device 
disposition information should be updated. In summary, the following data will be 
collected:

Date of death

Detailed description of death

Cause of death 

Relatedness to system and/or procedure

Device interrogation (if available)

Device disposition information

Death summary/hospital records (if available and allowed by state/local law)

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
Autopsy report (if available and allowed by state/local law)

Death certificate (if available and/or allowed by state/local law)
9.5.2
Death classification and reporting
Sufficient information will be required in order to properly classify the subject’s death. 
The Investigator shall classify each subject death per the following definitions:
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the 
heart.
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt 
loss of consciousness within one hour of the onset of acute symptoms; preexisting heart 
disease may have been known to be present, but the time and mode of death are 
unexpected. If time of onset cannot be determined, SCD will alternatively be defined as 
any unexpected cardiac death occurring out of the hospital or in the emergency room as 
dead on arrival.
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, 
including all cardiac deaths of hospitalized subjects on inotropic support.
Non-cardiac Death: A death not classified as a cardiac death.
Unknown Cardiac Classification: Unknown death classification is intended for use only 
when there is insufficient or inadequate information to classify the death
Table 12: Subject death classification responsibilities
What is classified? Who classifies? Classification Parameters
Death Classification Investigator
Sudden Cardiac, Non-sudden Cardiac, Non-cardiac, 
Unknown
The Clinical Events Committee (CEC) will review deaths and provide a final adjudication 
of the classification of death.
Regulatory reporting of Subject Deaths will be completed according to local regulatory 
requirements.
9.6
Clinical Events Committee (CEC) review
At regular intervals, an independent CEC will review and adjudicate all CIED system 
related (including TYRX envelope related), CIED procedure related, and all CIED 
infection related adverse events as classified by the investigator or Medtronic. In addition 
the CEC will review and adjudicate the classification of all deaths as well as the serious 
AEs leading to death. 
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that 
are not participating investigators for the study, including a CEC chairperson. The 
details of the CEC procedures, including how potential events for adjudication are 
identified, will be provided in a separate CEC Charter. CEC adjudications will be used for 
data analysis.
The CEC members will not be made aware of subjects’ randomization assignment 
and/or other data or procedures that may influence their decision whenever possible.
However, in certain instances (e.g. events related to the TYRX envelope), the CEC 
members may become aware of the subjects treatment assignment.

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Medtronic personnel may assist in facilitating CEC meetings but will be non-voting 
members.
For adverse events and deaths reviewed by the CEC, Medtronic will provide the CEC
with the Investigator’s description and classification and supportive documentation 
(when available).  The CEC will review applicable definitions, and determine final 
classifications for all adjudication parameters. For adverse events related to the CIED 
system, CIED procedure, classification includes relatedness and complication or 
observation. Additionally, the CEC will provide an adjudication of the cardiac 
classifications for all reported deaths. The CEC will also review each CIED infection and 
determine, if each CIED infection meets the primary endpoint definition.
 
 
 
 
 
 
 
 
 
 
 
 

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.

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10 RISK ANALYSIS
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life 
of a product, from the business analysis phase through development, market release, 
and post-market surveillance.
All devices used in the WRAP-IT study will be commercially released and used in
accordance with their approved labeling. The safety and clinical performance of these 
devices have been demonstrated through previous pre-clinical testing and previous 
clinical studies.  
Subjects who are pregnant may be at increased risk (e.g., radiation exposure, and other 
unforeseen risk to the fetus), and are excluded from participation in the study. If a 
subject becomes pregnant during the study, she must notify the physician immediately. 
The subject will remain in the study for intention to treat analysis, but the investigator will 
avoid any procedures that may be determined harmful. 
The risks must be continuously monitored, assessed and documented by the 
investigator.
A summary of the risk analysis and risk assessment will be listed in the Investigator 
Brochure.
10.1 Potential Risks and Side Effects
The potential risks and side effects associated with the study can be found in the IFL
(refer to Appendix J) and the foreseeable adverse event list (Appendix G) which are
consistent with
market-released IPG/CRT-P, ICD/CRT-D systems
and TYRXTM
Absorbable Antibacterial Envelopes (henceforth referred to as TYRX envelopes). 
Additional risks for participating in this study may include the following:

In the event that a LSE is suspected and a Holter is required, the electrodes used 
with the Holter recorder might cause mild skin discomfort or irritation or some 
skin discomfort following electrode removal. 
10.2 Potential Benefits
The potential benefits of having the TYRX envelope include holding the CIED generator 
securely in the pocket providing a stable environment and reducing the risk of CIED 
infection. In addition, subjects enrolled in the study may have additional contact with 
their physicians or other medical care staff beyond their normal standard of care visits, 
which may provide benefit from a patient care perspective. The information gained from 
this study could result in the improved management of other methods to reducing CIED 
infections. Additionally, information collected from this study may assist in the design of 
new product(s)/therapy(ies) and/or instructions for use.
10.3 Risk-to-Benefit Analysis
The potential risks associated with the commercially available IPG/CRT-P, ICD/CRT-D 
and TYRX envelope implant were identified and have been successfully mitigated.  Any 
potential risks associated with this study are further minimized by selecting qualified 
investigators and training study personnel on the Clinical Investigation Plan.  Medtronic 

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has also attempted to minimize risk to subjects implementing a Data Monitoring 
Committee to review safety issues as part of the study. In addition, investigators will be 
actively involved in the implantation and follow-up of the subjects.  Risks will be 
minimized by careful assessment of each subject prior to, during, and after implant.  
Medtronic has further minimized the possibility of risks by product testing applicable to 
all commercially available devices prior to their use in this clinical study, implementing 
quality control measures into production processes, providing guidelines for subject 
selection and evaluation, and providing adequate instructions and labeling.  After 
implantation, subjects in this clinical study will be followed at regular intervals to monitor 
the condition of the implanted system and the battery. At each CIP-required follow-up, in 
all subjects, the investigator must interrogate the IPG/CRT-P, ICD/CRT-D device to 
verify appropriate IPG/CRT-P, ICD/CRT-D function and to assess any adverse events.
Taking the risk mitigation and risk minimization into account, the potential benefits 
outweigh the potential risks for patients participating in this study.

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11 PLANNED STUDY CLOSURE, EARLY TERMINATION OF 
STUDY OR STUDY SUSPENSION
11.1 Planned study closure
Study Closure is a process initiated by distribution of a study closure letter. Study 
closure is defined as closure of a clinical study that occurs when Medtronic and/or 
regulatory requirements have been satisfied per the Clinical Investigation Plan and/or by 
a decision by Medtronic or regulatory authority, whichever occurs first. The study 
closure process is complete upon distribution of the Final Report or after final payments, 
whichever occurs last. Ongoing Ethics Committee oversight is required until the overall 
study closure process is complete. Upon study closure, patients should be managed and 
followed per physician discretion
11.2 Early termination or suspension
Early Termination of the Study is the closure of a clinical study that occurs prior to 
meeting defined endpoints. This is possible for the whole study or a single site. Study 
Suspension is a temporary postponement of study activities related to enrollment and 
distribution of the product. This is possible for the whole study or a single site.
11.2.1 Study-wide termination or suspension
Possible reasons for considering study suspension or termination of the study include 
but are not limited to:

Adverse events associated with the system or product under investigation which 
might endanger the safety or welfare of the subject

Observed/suspected performance different from the product’s design intent

Decision by Medtronic or regulatory body (where the study is operating under 
regulatory body authority)

Recommendation of early termination by the Data Monitoring Committee (DMC) 
based on interim analyses.

Technical issues during the manufacturing process
11.2.2 Investigator/site termination or suspension
Possible reasons for clinical investigator or site termination or suspension include but 
are not limited to:

Failure to obtain initial Ethics Committee approval or annual renewal of the study

Persistent non-compliance to the clinical study (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)

Lack of enrollment

Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. 
failure to submit data in a timely manner, failure to follow-up on data queries and 
monitoring findings in a timely manner, etc.)

Ethics Committee suspension of the site

Fraud or fraudulent misconduct is discovered (as defined by local law and 
regulations)

Investigator request (e.g. no longer able to support the study) 

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11.3 Procedures for termination or suspension
11.3.1 Medtronic-initiated and regulatory authority-initiated

Medtronic will promptly inform the clinical investigators of the (early) termination 
or suspension and the reasons and inform the regulatory authority(ies) where 
required.

In the case of study termination or suspension for reasons other than a 
temporary Ethics Committee/Head of Medical Institution approval lapse, the 
investigator will promptly inform the Ethics Committee.

In the case of study termination, the investigator must inform the subjects and 
may inform the personal physician of the subjects to ensure appropriate care and 
follow-up is provided.

In the case of a study suspension, subject enrollment must stop until the 
suspension is lifted by Medtronic.

In the case of a study suspension, enrolled subjects should continue to be 
followed out of consideration of their safety, rights and welfare.
11.3.2 Investigator-initiated

The investigator will inform Medtronic and provide a detailed written explanation 
of the termination or suspension.

The investigator will promptly inform the institution (where required per regulatory 
requirements).

The investigator will promptly inform the Ethics Committee.

The investigator will promptly inform the subjects and/or the personal physician 
of the subjects to ensure appropriate care and follow-up is provided.

In the case of a study suspension, subjects enrolled should continue to be 
followed out of consideration of their safety, rights and welfare.
11.3.3 Ethics committee-initiated

The investigator will inform Medtronic and provide a detailed written explanation 
of the termination or suspension within 5 business days.

Subject enrollment must stop until the suspension is lifted.

Subjects already enrolled should continue to be followed in accordance with 
Ethics Committee/ policy or its determination that an overriding safety concern or 
ethical issue is involved.

The investigator will inform his/her institution (where required per local 
requirements).

The investigator will promptly inform the subjects, or legally-authorized designees 
or guardians and/or the personal physician of the subjects, with the rationale for 
the study termination or suspension.

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12 STATISTICAL METHODS AND DATA ANALYSIS
12.1 General Considerations
Medtronic employees or their designated representatives will perform all statistical 
analysis.  The lead study statistician will be blinded to all interim analyses in which the 
treatment groups are compared.  An Intention-to-Treat (ITT) analysis will be performed 
and will serve as the primary analysis for all objectives in this study unless otherwise 
specified.  The ITT analysis cohort will include all randomized subjects regardless of 
treatment received.
Additionally, a separate Statistical Analysis Plan (SAP) will be developed to further 
describe statistical methods, pre-specified data handling rules, and pre-specified 
analyses that will be included in the final study report and primary study publication(s). 
However, additional exploratory analyses of the data may be conducted as deemed 
appropriate.
The SAP for this study will also include information regarding:

Procedures for reporting any deviation(s) from the original statistical plan with 
justification

Procedures that take into account all the data with justification (also described 
below)

The treatment of missing, unused, unauthentic or spurious data, including drop-
outs and withdrawals with justification (also described below)
The study will be considered successful if the primary objective is met.
12.2 Analysis Cohorts
Intention-to-Treat (ITT):  The ITT analysis cohort will include all randomized subjects in 
the groups to which they are randomized regardless of treatment received and will serve 
as the primary analysis cohort for each objective unless otherwise specified.
As Treated (AT):  The AT cohort includes subjects in the ITT cohort but analyzes 
subjects using the treatment they actually received.  For subjects with a TYRX envelope
this means the TYRX envelope remained in the pocket following pocket closure.
modified As Treated (mAT):  The mAT cohort includes all subjects and follow-up time in 
the AT cohort that were successfully implanted with a CIED system (including the TYRX
envelope if subject had a successfully placed TYRX envelope) up until the point where a 
CIED modification (i.e. pocket revision) was required.  Thus, subjects with a system 
modification for reasons other than device infection will be considered censored at the 
time of the system modification.
12.3 Interim Analysis and Type 1 Error Control
The study has up to two planned analyses of the primary objective.  The study may be 
considered successful at the first analysis in which the primary objective is met.  

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The first analysis will occur when approximately 50% of the total follow-up within 12-
months of randomization occurs; based on enrollment projections described below this is 
defined as the point where 3200 randomized subjects complete the 6-month post-
procedure visit.  The purpose of this first analysis is two-fold:
(1) To assess whether the study’s primary objective has been met.  If the DMC 
indicates that the study has met its objective, the study may continue to enroll 
and follow subjects to study the effect of the TYRX envelope on long-term CIED 
infections as well as accumulate LSEs.  However, subjects enrolling following 
review of the interim analysis may no longer be randomized upon 
recommendation of the DMC if the TYRX envelope is found to have a clear 
benefit. 
(2) To assess whether the study may end earlier than planned for futility.
The timing of the interim analysis was selected so that sufficient data is collected to 
contribute to the interim analysis before decisions that impact the study are made.  The 
Hwang-Shih-DeCani alpha spending function with a gamma parameter of negative 4 (-4) 
is used to control the overall alpha level at 5% (two-sided; 2.5% one-sided in the 
direction favorable to the TYRX envelope).  This function spends the alpha at a level 
analogous to the O’Brien-Fleming boundary.  The boundary condition at the interim 
analysis will be based on the information fraction at the interim analysis and computed 
by dividing the accrued number of major CIED infections observed at the interim 
analysis by the total number of major CIED infections anticipated at the final analysis.  
Assuming the information fraction at the interim analysis is 50%, the boundary condition 
at the interim analysis is 0.003 (2.75 on the Z-scale or 0.006 on the two-sided p-value 
scale) and is purposely low to allow early claims of study success only when the TYRX 
envelope is highly effective.  At the final analysis, the boundary condition is 0.0238 (1.98 
on the Z-scale or 0.0476 on the two-sided p-value scale) when the information fraction is 
50% at the interim analysis.  Since the analytical methods for the secondary objectives 
also utilize survival analysis methods, the same alpha spending function will be used to 
compute the success boundaries for the secondary objectives.
If the primary objective of the study is met, the secondary objectives will be tested using 
the Holm procedure to protect the overall type I error rate of the study and allow 
statistically valid claims of significance.  Specifically, at analysis k (k=1,2), the ordered 
hypotheses H(1k), H(2k), H(3k) corresponding to the ordered p-values p(), p(	), p() of the 
secondary objectives will be tested based off the sequentially rejective algorithm. The 
hypothesis H(1k) is rejected if p() ≤ 3
⁄ .  Futher, H(jk) is rejected at the jth step if 
p() ≤ (3 − + 1)
⁄
. Otherwise, H(jk),…H(3k) are retained and the algorithm terminates.
To help assess whether the study may end earlier than planned for futility, stochastic 
curtailment methods will be used to calculate the futility index for the primary objective.  
The futility index (1-P1, where P1 is the predictive power observed at the interim analysis)
is based on predictive power as computed using equation 10.6 in Jennison and Turnball 
(2000) and is defined as the probability the study will not meet its primary objective at 
the final analysis 82 time point based on data accrued at the time of the interim analysis.  
Although non-binding, a futility index greater than 0.9 at the interim analysis provides 
strong evidence that the study will not achieve its primary objective if the study were to 
continue to its full sample size and follow-up.

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12.4
General Summaries
12.4.1 Description of Baseline Variables
Standard baseline and relevant medical history will be collected on the eCRFs for all 
enrolled subjects.  Baseline and medical history variables to be summarized include, but 
are not limited to:  age, sex, race, device type (CRT-D, ICD, CRT-P, and IPG), number 
of previous CIED devices, NYHA class, arrhythmia history, and baseline medication use.
For continuous variables, mean, standard deviation, median, and range will be reported.  
For categorical variables, frequency and percentage will be reported.  Summaries of 
baseline information will be summarized for all randomized subjects.  The TYRX 
envelope and control groups will be compared using T-tests for continuous variables and 
the Chi-square test for categorical variables to quantify any imbalance in treatment 
groups.
12.5 Primary Objective: Major CIED Infection Rate through 12-months
12.5.1 Objective
The primary study objective is to compare the rate of major CIED infections through 12-
months post-procedure between the TYRX envelope group and the control group (no 
TYRX envelope).
12.5.2 Hypothesis
The primary study objective will be tested with the following hypothesis:
Ho: T(t) = c(t) for all t ≤ 12 months (365 days), versus
Ha: T(t) c(t) for some t ≤ 12 months (365 days)
where T(t) is the hazard function for major CIED infection in the TYRX envelope group 
and c(t) is the hazard function for major CIED infection in the control group.
12.5.3 Major CIED Infection Definition
Major CIED infection is defined in section 5.2.1.
12.5.4 Sample Size Determination
Background
The reported prevalence rate of CIED infection varies widely in the literature and is 
dependent on the nature of data collection (retrospective vs prospective, single center vs 
multi-center), CIED infection definition, and population studied.  The REPLACE study 
prospectively evaluated CIED infection requiring system removal or intravenous 
antibiotics in 1744 subjects undergoing a device replacement or upgrade. The infection 
rate at 6-months post-procedure for subjects receiving a device replacement was 1.4% 
and 1.1% for those subjects undergoing a device upgrade.10  
Analysis of 103,020 device implant claims from Medicare evaluated for Medtronic by 
Truven Analytics suggested that subsequent invasive procedures related to device 
infection occurred at a rate of 4.0% for CRT-D, 3.9% for ICDs, and 2.6% for pacemakers 
through 12-months.  The 12-month CIED infection rate associated with replacement 
devices was 4.1% for CRT-D, 5.4% for ICDs, and 3.4% for pacemakers with 12-month 

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infection rates associated with initial device implants ranging from 4.0% in CRT-Ds to 2.2% 
in pacemakers.  However, examination of CIED infections reported in Medtronic studies, 
suggests that the Medicare claims data may overestimate the CIED infection rate that 
may be observed in clinical trials for initial implants by at least 50% (Table 14).  
Table 14: 12-Month Infection Rates for Initial Implants by Device Type and Data Source
Data Source
Device
Medicare Claims 
Data
12-Month CIED 
Infection Rate
Medtronic Studies (12-
month CIED Infection Rate 
(95% CI))
CRT-D
4.1%
2.0% (1.2% - 3.4%)1
ICD
3.0%
1.5% (0.3% - 6.7%)2
Pacemaker
2.2%
1.2% (0.8% - 1.7%)3
1Based on 753 subjects with an attempted CRT-D implant in the REVERSE and 
BLOCK-HF studies. 
2Based on 246 subjects from the Model 6947, 6948, and 6949 RV defibrillation lead 
studies
3Based on 2799 subjects from the 3830, 4074, 5076, Advisa MRI, EnRhythm, EnRhythm 
MRI, and SAVEPACe studies.
Based on the assumption that the Medicare claims data may overestimate the actual 
CIED infection rate that may be observed in a clinical trial, it is hypothesized that the 12-
month infection rate for initial CRT-D implants, replacement (or upgrade) CRT-D 
implants, and replacement (or upgrade) ICD implants is 2.4% and is 0.6% for 
replacement pacemaker implants.  Since low power replacement procedures (i.e. 
pacemaker and CRT-P replacement procedures) will be capped at 25% of the total 
sample size, an overall 12-month CIED infection rate for the control group is assumed to 
be 2% for sample size calculation purposes.
Retrospective evidence from the COMMAND study demonstrated that in 624 subjects 
consecutively implanted with the TYRX envelope the CIED infection rate was 0.48% and 
raged from 0% during initial implant procedures and 1.05% during ICD/CRT-D 
replacement/revision procedures. 56  Additionally, recently published data from Mittal, et. 
al showed that the CIED infection rate was 1.1% in 275 subjects that received the TYRX
envelope compared to 3.6% in 275 propensity matched control subjects over a 6-month 
period across both low power and high power devices. 73  Finally, early evidence from 
the CITADEL/CENTURION  studies suggests that CIED infection rate among a cohort of 
1000 ICD/CRT-D subjects receiving the TYRX envelope is 0.2% at 6-months post-
replacement/upgrade; a 9-fold decrease compared to published controls at 6-months.  
Based on this experience, it is assumed that the TYRX envelope will reduce the risk of 
CIED infection by 50% through 12-months post-procedure.
Sample Size Calculation
The sample size is derived based on the following assumptions:
1.One-to-one randomization to the TYRX envelope or control group
2.Power to test the primary objective is at least 90%
3.One interim analysis and final analysis
4.The interim analysis will occur when approximately 50% of the statistical 
information has been accrued
5.One-sided alpha level of 2.5%

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6.Hwang-Shih-DeCani alpha spending function with a gamma parameter of negative 
4 (-4) which approximates O’Brien-Fleming boundaries
7.Assumed control CIED infection rate of 2% at 12-months
a. 2.4% for high power (CRT-D/ICD) devices
b. 0.6% for low power (pacemaker/CRT-P) devices
c.
Low power devices are capped at 25% of the required sample size
8.TYRX envelope assumed to reduce the control infection rate by 50%
9.Non-binding futility assessment based on stochastic curtailment at the interim 
analysis
10. 15% annualized attrition rate that is independent of treatment group and infection 
status
The method of Lakatos (1988) as implemented in the POWER procedure of SAS v9.2, 
indicated 6,988 randomized subjects (3,494 randomized to each group) are required to 
test the primary objective based on the assumptions described above.  Thus, up to 
7,764 subjects may be enrolled to allow for up to a 10% discontinuation rate between 
enrollment (i.e. subject consent) and randomization.77  
A simulation study was performed to confirm the sample size calculation.  In addition to 
the sample size assumptions described above, the simulation assumed that 50% of 
CIED infections occur within the first month of device procedure.  Simulations were 
performed when the CIED infection risk reduction associated with the TYRX envelope
ranged from 0% (null case) to 60%.  Figure 1 confirms the sample size calculation and 
demonstrates that the type I error rate is well controlled.

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Figure 1:  Empirical Power to Test the Primary Objective (n=6,988)  
12.5.5 Analysis Methods
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the primary endpoint.  The primary method to be used to test the 
primary objective will be the Cox proportional hazard model.  The Cox model will be 
stratified by device type (low power versus high power) and include treatment as an 
independent variable.  Days of follow-up for each subject will be set to the minimum of 
days from procedure (or randomization if the subject was randomized but no procedure 
attempt) to:  (1) onset date of a subject’s first CIED infection meeting the primary 
endpoint, (2) study exit date (if exited), (3) date of death (if death occurs), (4) date of 12-
month visit (if completed), (5) date of last follow-up, or (6) 365 days post-procedure.  
Subjects not meeting the primary endpoint during the follow-up period will be considered 
censored.  Based on this statistical test, it will be claimed that the TYRX envelope
reduces major CIED infection if the hazard ratio estimate is less than one and the 
resulting p-value from the Wald test falls below the specified type I error boundary as 
determined by the Hwang-Shih-DeCani alpha spending function.   
12.5.6 Determination of subjects for analysis
All randomized subjects will be included in the primary analysis regardless of the 
treatment they actually receive or their study compliance (i.e. Intention-to-Treat principle).  
Sensitivity analyses may be conducted by evaluating the performance of the TYRX
envelope the AT or mAT cohorts as described above.

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12.5.7 Pre-specified Subgroup analyses
The primary objective will be evaluated separately within high power (CRT-D, ICD) 
devices and low power (pacemaker, CRT-P) devices to assess the performance of the 
TYRX envelope within each of these device types.   Due to the large number of high 
power devices in this study (n=5,242), combined with the higher assumed CIED infection 
rate, the study has 89% power to test the primary objective within subjects implanted 
with a CRT-D or ICD.  Figure 2 displays the power of the study to evaluate the primary 
objective among subjects implanted with high power devices as evaluated in the 
simulation study described above.   Cox regression models will be used to evaluate the 
homogeneity of the treatment effect across device type by including an interaction term 
for device type and treatment.
Figure 2:  Empirical Power to Test the Primary Objective in Subjects Receiving CRT-D 
or ICD Devices (n=5,242)
12.5.8 Missing data
The primary analysis cohort will include all follow-up from all randomized subjects 
through the 12-month visit or 365 days post-randomization, whichever occurs first.  
However, missing data could arise if a randomized subject exits the study or dies prior to 
the 12-month visit without experiencing a CIED infection meeting the primary endpoint.  
Thus, if missing data becomes an issue, sensitivity analyses will be conducted to assess 
the sensitivity of the primary results to the missing data.
12.6 Secondary Objectives
The following secondary objectives will be evaluated to gain additional information about 
the performance of the TYRX envelope.  The type I error is controlled for the secondary 
objectives as described in section 12.3.

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Provided the primary objective is met, then the secondary objectives will be assessed 
using the Holm multiple comparisons procedure as described in section 12.3.
12.6.1 Secondary Objective #1:  Procedure- or System-related complications 
through 12-months
12.6.1.1 Objective
Confirm that the TYRX envelope does not increase the CIED procedure-related or 
system-related complication rate through 12-months post-procedure.  
12.6.1.2 Hypothesis
The first secondary objective will be tested with the following non-inferiority hypothesis:
Ho: T(t)/c(t) ≥ 1.33 for t ≤ 12 months (365 days), versus
Ha: T(t)/c(t) < 1.33 for t ≤ 12 months (365 days)
where T(t) is the hazard function for CIED system or procedure related complications in 
the TYRX envelope group and c(t) is the hazard function for CIED system related 
complications in the control group.  Rejecting the null hypothesis would indicate that the 
TYRX envelope does not increase the CIED system or procedure related complication 
rate by more than 33% on a relative scale or 4.4% on a linear scale when the underlying 
CIED system or procedure complication freedom rate at 12-months is 85%. 
12.6.1.3 CIED system or procedure related complications
A CIED system related complication is defined as an adverse event that meets the 
complication definition as defined in Table 9 and is considered as related to one of the 
implanted CIED system components (i.e. device, RV lead, RA lead, LV lead, other lead,
or the TYRX envelope).
A CIED procedure related complication is defined as an adverse event that meets the 
complication definition as defined in Table 9 and is considered related to the CIED
procedure (i.e. replacement/upgrade/new implant/revision) or a system modification
including the TYRX envelope (if applicable).
12.6.1.4 Power to test the objective
Background
Table 15 displays the procedure- or system-related complication rates from several 
Medtronic and non-Medtronic sponsored studies.  These data indicate that complications 
related to the implanted system (i.e. device and leads) or procedure range from 4.0% to 
24.7% depending on complication definition, devices studied, and study population.  
Based on these data it appears reasonable based on the mix of devices and population 
under investigation in the WRAP-IT study that the underlying system or procedure 
complication free rate could range from 80% to 90% at 12-months post-procedure.

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Table 15: System or Procedure-Related Complications Reported Previous Studies
Study
Devices 
Studied
Population
Time 
Frame
Complication Rate (95% 
CI)
Gould et. al 20081
ICD (n=451)
Replacements
12-months
9.1% (NR)
REPLACE2
IPG (n=515)
ICD (n=327)
CRT-D (n=175)
CRT-P (n=14)
Replacements
6-months
4.0% (2.9%-5.4%)
REPLACE
IPG (n=329)
ICD (n=320)
CRT-D (n=49)
CRT-P (n=15)
Upgrades
6-months
15.3% (12.7% - 18.1%)
BLOCK-HF
CRT-D (n=230)
New Implants
12-months
22.9% (18.0% - 29.0%)
BLOCK-HF
CRT-P (n=531)
New Implants
12-months
17.7% (14.7% - 21.3%)
REVERSE
CRT-D (n=523)
New Implants
12-months
17.0% (14.0% - 20.5%)
REVERSE
CRT-P (n=104)
New Implants
12-months
24.7% (17.5% - 34.4%)
4074 Study
IPG (n=132)
New Implants
6-months
13.9% (9.0% - 21.1%)
EnRhythm MRI3
IPG (n=469)
New Implants
12-months
11.3% (8.8% - 14.6%)
Advisa MRI3
IPG (n=269)
New Implants
6-months
9.2% (6.3% - 13.4%)
1Gould et. al.  2008. Heart Rhythm 5: 1675-1681.  Major complication defined as post-operative death, nonfatal 
MI, cardiogenic shock, or event requiring reoperation.
2Poole et. al. 2010. Circulation 122:1553-1561.  Major complications defined as an event defined in Table 1 of 
the manuscript.  In general major complications required invasive intervention.
3Does not include system complications related to the RA lead only.
Power Calculation
Since the primary objective of the study dictates the sample size for the study, the power 
to test this secondary objective under several scenarios was determined based on the 
method of Lakatos 77 as implemented in PASS 2008.  The following assumptions were 
made in the power calculation:
1. Sample size of 6,988 subjects randomized 1:1 to the TYRX envelope or control 
group
2. One interim analysis and final analysis
3. The interim analysis will occur when approximately 50% of the follow-up is accrued
4. One-sided alpha level of 2.5%
5. Hwang-Shih-DeCani alpha spending function with a gamma parameter of negative 4 
(-4) which approximates O’Brien-Fleming boundaries and means the final test will be 
conducted at a one-sided alpha-level of 0.0238 which is analogous to a two-sided 
alpha level of 0.0476.
6. 15% annualized attrition rate that is independent of treatment group and system 
related complication
7. 12-month system or procedure related complication rate in the control group could 
range from 10% to 20%
8. The TYRX envelope has no effect on the system or procedure related complication 
rate
9. Non-inferiority margin of 33% on a relative scale or 4.4% on a linear scale when the 
underlying CIED system complication freedom rate at 12-months is 85%

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Table 16 indicates that the statistical power to test the non-inferiority hypothesis 
associated with secondary objective #1 is greater than 94% based on the assumptions 
above across a range of plausible control group event rates.
Table 16:  Power to Test Secondary Objective #1 with Sample Size of 6,988 Subjects
12-month system-
related Complication 
Free Rate
Control Group 
Hazard Rate
Non-inferiority 
Margin (Relative 
Scale)
Non-inferiority Margin 
(Linear Scale)1
Power
90%
0.1054
1.33
3.1%
94.9%
88%
0.1278
3.6%
97.6%
86%
0.1508
4.2%
98.9%
85%
0.1625
4.4%
99.3%
84%
0.1744
4.7%
99.5%
82%
0.1985
5.2%
99.8%
80%
0.2231
5.7%
99.9%
1The non-inferiority margin on the linear scale is defined as the difference in the survival curves for the event rate at 12-
months post-randomization between the control group and the TYRXTM Absorbable Antibacterial Envelope group.
12.6.1.5 Analysis Methods
All potential adverse events potentially related to the implanted system (i.e. device, leads) 
the TYRX envelope, or the CIED replacement/upgrade/implant or system modification 
procedure will be reported on the eCRFs as they occur.  The CEC will adjudicate each 
reported adverse event for its relationship to the CIED system and CIED procedure.  
Additionally, the CEC will classify each CIED system related or procedure related 
adverse event as a complication or observation.  Days of follow-up for each subject will 
be set to the minimum of days from procedure (or randomization if a subject was 
randomized but not implanted) to:  (1) onset date of a subject’s first CIED system related 
or procedure related complication (including the TYRX envelope where applicable), (2) 
study exit date (if exited), (3) date of death (if death occurs), (4) date of 12-month visit (if 
completed), (5) date of last follow-up, or (6) 365 days post-procedure.  Subjects not 
having a CIED system related or procedure related complication during the follow-up 
period will be considered censored.
The effect of the TYRX envelope on the rate of CIED system or procedure related 
complications will be tested using a Cox proportional hazards regression model stratified 
by device type (low power versus high power) containing an indicator term for treatment 
group.  The observed hazard ratio from the Cox model will be compared to the non-
inferiority margin of 1.33.  The null hypothesis will be rejected in favor of the alternative 
and the TYRX envelope will be considered non-inferior to the control group if the p-value 
computed from the non-inferiority test is less than the type I error boundary as 
determined by the Hwang-Shih-DeCani alpha spending function and Holm adjustment 
for multiple comparisons.  
12.6.1.6 Determination of subjects for analysis
Since non-inferiority tests based on intention-to-treat principles may be anti-conservative, 
the results of the non-inferiority test will be reported for both the ITT and AT cohorts as 
recently suggested.78  However, statistical inference for this objective will be based on 
the AT cohort.  All randomized subjects and all follow-up from randomized subjects is 
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up from all subjects will be included, but the analysis will be based on the treatment the 
subject actually received.
12.6.1.7 Pre-specified Subgroup analyses
The TYRX envelope to control group hazard ratio along with its 95% confidence interval 
will be displayed separately within high power (CRT-D, ICD) devices and low power (IPG, 
CRT-P) devices to assess the performance of the TYRX envelope within each of these 
device types. 
12.6.1.8 Missing Data
The analysis cohorts will include all follow-up from all randomized subjects through the 
12-month visit or 365 days post-randomization, whichever occurs first.  However, 
missing data could arise if a randomized subject exits the study or dies prior to the 12-
month visit without experiencing a CIED system or procedure related complication.  
Thus, if missing data becomes an issue, sensitivity analyses will be conducted to assess 
the sensitivity of the results to the missing data.
12.6.2 Secondary Objective #2:  Major CIED Infection Rate through Study 
Duration
12.6.2.1 Objective
Compare the major CIED infection rate during the entire follow-up between the TYRX
envelope group and the control group.  
12.6.2.2 Hypothesis
The second secondary objective will be tested with the following hypothesis:
Ho: T(t) = c(t) for all t ≤ T, versus
Ha: T(t) c(t) for some t ≤ T
where T(t) is the hazard function for major CIED infection in the TYRX envelope group 
and c(t) is the hazard function for major CIED infection in the control group during the 
entire follow-up period. 
12.6.2.3 Major CIED Infection Definition
Major CIED infection is defined in section 5.2.1.
12.6.2.4 Analysis Methods
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  The primary method to be used to 
test this objective will be the Cox proportional hazard model.  The Cox model will be 
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independent variable.  Days of follow-up for each subject will be set to the minimum of 
days from procedure (or randomization if a subject was randomized but not implanted) to:  
(1) onset date of a subject’s first CIED infection meeting the primary endpoint, (2) study 
exit date (if exited), (3) date of death (if death occurs), or, (5) date of last follow-up.  
Subjects not having a major CIED infection during the follow-up period will be 
considered censored at their last follow-up day.  Based on this statistical test, it will be 
claimed that the TYRX envelope reduces major CIED infection during the entire study 
period if the hazard ratio estimate is less than one and the resulting p-value from the 
Wald test falls below the specified type I error boundary as determined by the Hwang-
Shih-DeCani alpha spending function and Holm adjustment for multiple comparisons.
12.6.2.5 Determination of subjects for analysis
All randomized subjects will be included in the primary analysis regardless of the 
treatment they actually receive or their study compliance (i.e. Intention-to-Treat principle).  
Sensitivity analyses may be conducted by evaluating the performance of the TYRX
envelope in the AT or mAT cohorts as described above. 78
12.6.2.6 Pre-specified Subgroup analyses
The TYRX envelope to control group hazard ratio along with its 95% confidence interval 
will be displayed separately within high power (CRT-D, ICD) devices and low power (IPG, 
CRT-P) devices to assess the performance of the TYRX envelope within each of these 
device types.  Cox regression models will be used to evaluate the homogeneity of the 
treatment effect across device type.
12.6.2.7 Missing Data
The primary analysis cohort for this objective will include all follow-up from all 
randomized subjects through the end of the study or visit cutoff for the interim analysis
(i.e. Intention-to-Treat principle).  However, missing data could arise if a randomized 
subject exits the study or dies prior to the end of the study (or visit cutoff) without 
experiencing a major CIED infection.  Thus, if missing data becomes an issue, sensitivity 
analyses will be conducted to assess the sensitivity of the results to the missing data.
12.6.3 Secondary Objective #3:  Major and Minor CIED Infection Rate through 
12-months 
12.6.3.1 Objective
Compare the rate of major and minor CIED infections through 12-months post-procedure
between the TYRX envelope group and the control group.  
12.6.3.2 Hypothesis
The third secondary objective will be tested with the following hypothesis:

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Ho: T(t) = c(t) for all t ≤ 12 months (365 days), versus
Ha: T(t) c(t) for some t ≤ 12 months (365 days)
where T(t) is the hazard function for major and minor CIED infection in the TYRX 
envelope group and c(t) is the hazard function for major and minor CIED infection in the 
control group. 
12.6.3.3 Major and Minor CIED Infection Definition
Major and minor CIED infections are defined in section 5.2.1.  
12.6.3.4 Analysis Methods
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  Those infections related to the 
CIED that do not meet the major CIED infection will be considered minor CIED infections.  
The primary method to be used to test the primary objective will be the Cox proportional 
hazard model.  The Cox model will be stratified by device type (low power versus high 
power) and include treatment as an independent variable.  Days of follow-up for each 
subject will be set to the minimum of days from procedure (or randomization if a subject 
is randomized but not implanted) to:  (1) onset date of a subject’s first major or minor 
CIED infection, (2) study exit date (if exited), (3) date of death (if death occurs), (5) date 
of last follow-up, or (6) 365 days post-procedure.  Subjects not having a major or minor 
CIED infection during the follow-up period will be considered censored.  Based on this 
statistical test, it will be claimed that the  TYRX envelope reduces major or minor CIED 
infection if the hazard ratio estimate is less than one and the resulting p-value from the 
Wald test falls below the specified type I error boundary as determined by the Hwang-
Shih-DeCani alpha spending function and Holm adjustment for multiple comparisons.
12.6.3.5 Determination of subjects for analysis
All randomized subjects will be included in the analysis of this secondary objective 
regardless of the treatment they actually receive or their study compliance (i.e. Intention-
to-Treat principle).  Sensitivity analyses may be conducted by evaluating the 
performance of the TYRX envelope in the AT or mAT cohorts as described above.
12.6.3.6 Pre-specified Subgroup analyses
The TYRX envelope to control group hazard ratio along with its 95% confidence interval 
will be displayed separately within high power (CRT-D, ICD) devices and low power (IPG, 
CRT-P) devices to assess the performance of the TYRX envelope within each of these 
device types.  Cox regression models will be used to evaluate the homogeneity of the 
treatment effect across device type.
12.6.3.7 Missing Data
The primary analysis cohort for this objective will include all follow-up from all 
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whichever occurs first.  However, missing data could arise if a randomized subject exits 
the study or dies prior to the 12-month visit without experiencing a major or minor CIED 
infection.  Thus, if missing data becomes an issue, sensitivity analyses will be conducted 
to assess the sensitivity of the primary results to the missing data.
12.7 Ancillary Objectives
The following ancillary objectives are intended to gain additional information about the 
performance of the TYRX envelope.  The type I error rate is not controlled for the 
ancillary objectives.
12.7.1 Ancillary Objective #1:  Mortality
Objective
To compare all-cause mortality rates between the TYRX envelop group and the control 
group.
Endpoint
Death for any cause
Hypothesis
This ancillary objective will be tested with the following hypothesis:
Ho: T(t) = c(t) for all t ≤ T, versus
Ha: T(t) c(t) for some t ≤ T
where T(t) is the hazard function for death for any cause in the TYRX envelope group 
and c(t) is the hazard function for death any cause in the control group during the entire 
follow-up period.
Analysis Methods
The primary method to be used to evaluate the hypothesis above will be the Cox 
proportional hazard model.  The Cox model will be stratified by device type (low power 
versus high power) and include treatment as an independent variable.  Days of follow-up 
for each subject will be set to the minimum of days from procedure (or randomization if a 
subject was randomized but not implanted) to the (1) date of death or (2) last date 
subject was known to be alive.  Subjects alive at their last follow-up day will be 
censored..  A p-value less than 0.05 will be considered statistically significant.
Determination of Subjects for Analysis
All randomized subjects will be included in the primary analysis regardless of the 
treatment they actually receive or their study compliance (i.e. Intention-to-Treat principle).
12.7.2 Ancillary Objective #2:  CIED procedure success rate
Objective
Evaluate the CIED procedure success rate in the TYRX envelope group and the control 
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Analysis Methods
Information related to the CIED procedure (i.e. initial implant or index 
replacement/upgrade or index system revision) will be collected on the procedure eCRF.  
A procedure attempt is defined as any CIED procedure where the device pocket is 
opened or venous access was gained (i.e. skin was cut).  A successful procedure is 
defined as an implant attempt where the device is successfully connected to the 
system’s leads and the CIED system remains in the body and the device pocket is 
closed. Additionally, for those subjects randomized to the TYRX envelope group, the 
TYRX envelope must also remain in the device pocket following pocket closure to qualify 
as a successful CIED procedure.  The CIED procedure success rate will be defined as 
the number of subjects with a successful CIED procedure divided by the number of 
subjects with a CIED procedure attempt.  Fisher’s exact test will be used to compare the 
procedure success rate between the TYRX envelope group and the control group.
Determination of Data for Analysis
Data from all randomized subjects with a CIED procedure attempt will be included in the 
analysis.
12.7.3 Ancillary Objective #3:  Summarize adverse events
Objective
To summarize adverse events by treatment group
Analysis Methods
Subjects will be queried for AEs at all scheduled and unscheduled visits.  All AEs 
potentially related to the CIED system, CIED implant or system modification procedure, 
and all SAEs regardless of their relationship to the CIED system  or CIED procedure 
(including the TYRX envelope if applicable) will be collected.  Medtronic safety 
specialists will ensure that at a minimum all AEs that are potentially related to the CIED 
system (including the TYRX envelope), or CIED procedure, or death are classified by the 
CEC.  Summary tables will be compiled categorizing the AEs with respect to procedure 
relatedness, CIED relatedness (including CIED component), and TYRX envelope
relatedness.  For events classified by the CEC, the CEC classification will be used in the 
analysis.  In cases where only the investigator classifies the event, the investigator’s 
classification will be used.  In addition, the number of events and number of subjects 
with events by MedDRA term will be displayed.  Additionally, the nominal p-value from 
the log-rank test will be used to identify AEs occurring on or after a CIED procedure
attempt by MedDRA preferred term that may differ between treatment groups.  This test 
does not protect the type I error, but may help identify specific AEs that differ between 
randomized treatment group for further evaluation.
Determination of Data for Analysis
All adverse events collected during the study will be included in this analysis.
12.7.4 Ancillary Objective #4:  Predictors of CIED infection
Objective
To identify predictors of major CIED infection

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Analysis Methods
Subject demographics and medical history including previous device history will be 
collected at baseline.  CIED procedure related variables such as antibiotic prophylaxis, 
surgical site preparation, procedure duration, device type, and number of leads will be 
collected for each CIED procedure.  Additionally, device characteristics such as 
impedance, optivol fluid status, and heart rate variability will be collected via device 
interrogations at each follow-up visit.  Cox regression modeling will be employed using 
subjects in the control group to develop a major CIED infection model using a candidate 
set of predictors.  The number of degrees of freedom available and hence the number of 
candidate predictors available for modelling will be determined by the number of major 
CIED infections in the control group.
Determination of Data for Analysis
All subjects randomized to the control group with a CIED procedure attempt who do not 
receive the TYRX envelope at CIED procedure.
12.7.5 Ancillary Objective #5: Quality of Life
Objective
Summarize quality of life.
Analysis Methods
Subjects will be asked to complete the EQ-5D questionnaires at baseline and at the 12-
month visit (or study exit if the subject exits the study for reasons other than lost to 
follow-up prior to completing the 12-month visit).  Additionally, subjects with a CIED 
infection will be asked to complete the EQ-5D within two weeks following their CIED 
infection diagnosis and at 1-month, 3-months, and 6-months post-CIED infection 
diagnosis.  Descriptive statistics will be used to summarize the change in EQ-5D scores
from baseline to the 12-month visit by randomized treatment group.  Additionally, the 
changes in EQ-5D between CIED infection and post-CIED infection will be computed 
using summary statistics for all subjects with a major CIED infection as classified by the 
CEC.
Determination of Data for Analysis
Completed EQ-5D questionnaires from all randomized subjects will be used to describe 
the changes in EQ-5D score from baseline.  All completed EQ-5D questionnaires 
following an adjudicated CIED infection will be used to summarize the change in EQ-5D 
score from baseline following CIED infection.
12.7.6 Ancillary Objective #6:  Healthcare System Cost Effectiveness
Objective
To assess the cost-effectiveness of the TYRX envelope.
Analysis Methods
Health care utilizations (HCUs) related to suspected CIED infection will be collected on 
the eCRFs.  HCUs related to CIED infection include all hospitalizations, emergency 
department visits, urgent care, or unscheduled follow-up visits associated with the 

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suspected CIED infection regardless of location of care.  Summary statistics will be used 
to quantify HCU related to CIED infection by treatment group.  
Additionally, the cost incurred from each major CIED infection will be based on the 
actions taken to address each major CIED infection.  The total cost of major CIED 
infections observed in the study will be compared to the total cost incurred by adding the 
TYRX envelope to the CIED procedure.  Economic models will be employed to quantify 
the cost savings and/or cost-effectiveness of the TYRX envelope.  The decision-analytic 
framework of any potential economic model will be detailed in the health economics 
analysis plan.  
Note: While cost-effectiveness is an important objective of the WRAP-IT study, cost-
effectiveness data will be analyzed separately from those included in the WRAP-IT study 
report and primary manuscript.
12.8
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
12.8.1
 
  

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12.8.2
 
 
 
 
 
 
 
 
 
 
12.8.3
.

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12.8.4
  
 
 
 
 
 
 
 

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13 DATA AND QUALITY MANAGEMENT
Data will be collected using an electronic data management system for clinical studies.  
eCRF data will be stored in a secure, password-protected database which will be backed 
up nightly.  Data will be reviewed using programmed and manual data checks.  Data 
queries will be made available to sites for resolution.  Study management reports may 
be generated to monitor data quality and study progress.  At the end of the study, the 
data will be frozen and will be retained indefinitely by Medtronic.
All records and other information about subjects participating in this study will be treated 
as confidential. Data will be transferred to and processed by Medtronic or a third party 
designated by Medtronic but solely in a key-coded form, unless it’s impossible to make it 
anonymous, for instance, where the patient’s name cannot be removed from the data 
carrier, such as X-rays.   In the case that de-identifying is impossible or involves a 
disproportionate effort, files containing personal data of patients shall only be made 
accessible to authorized persons (secured role-based access).
Procedures in the CIP require source documentation.  Source documentation will be 
maintained at the site. Source documents, which may include, but are not limited to,
worksheets, patient medical records, lab results, ECGs, programmer printouts, and 
interrogation files, must be created and maintained by the investigational site team. In 
some cases, the data reported in the eCRFs may be considered source, as long as 
there is evidence of the visit in the subject’s record.  The electronic case report form 
(eCRF) may serve as the primary source for the following data points:

Enrollment Notification
o
Site assigned patient reference

Baseline
o
Administrative Information
o
Cardiac Disease Classification

Adverse Event eCRF
o
Date study center became aware of event
o
Relatedness of adverse event

Device Deficiency eCRF
o
Date study center became aware of event

Subject Death
o
Date study center became aware of death
o
Relatedness of death
o
System Explant Information

System Modification
o
Justification for explanted product not being returned to Medtronic.

Deviations

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o
Reason for deviation
The data reported on the eCRFs shall be derived from source documents and be 
consistent with these source documents, and any discrepancies shall be explained in 
writing. When copies or print-outs of the source documents are made, the 
investigational site study team must sign and date any copies or printouts of original 
source documents with a statement that this is complete and true reproduction of the 
original source document. 
Device data from CareLink® transmissions will be uploaded to secure servers and made 
accessible to the study team.  Device interrogation files collected via electronic media at 
office visits will be sent to Medtronic.  Upon receipt via transmission or electronic media, 
device data will be maintained within secure databases and retrieved for analysis and 
reporting.

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14 WARRANTY/INSURANCE INFORMATION
14.1 Warranty
There is no warranty associated with the TYRXTM Absorbable Antibacterial Envelope.
14.2 Insurance (EMEA)
Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic, Inc., 
which as the parent company of such entity maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply 
with applicable local law and custom concerning specific insurance coverage. If required, 
a Clinical Trial insurance statement/certificate will be provided to the Ethics Committee.
14.3 Insurance (ASEAN (Singapore and Malaysia))
Medtronic International Ltd. is a wholly owned subsidiary of Medtronic, Inc., which as the 
parent company of such entity maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage. If required, a 
Clinical Trial insurance statement/certificate will be provided to the Ethics Committee.
14.4 Insurance (New Zealand)
Medtronic Australasia Pty Ltd is a wholly owned subsidiary of Medtronic, Inc., which as 
the parent company of such entity maintains appropriate clinical study liability insurance 
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage.  If required, a 
Clinical Study insurance statement/certificate will be provided to the Ethics Committee.
14.5 Insurance (Greater China (Hong Kong))
Medtronic International Ltd. is a wholly owned subsidiary of Medtronic, Inc., which as the 
parent company of such entity maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage. If required, a 
Clinical Trial insurance statement/certificate will be provided to the Ethics Committee.
14.6 Insurance (India)
India Medtronic Pvt. Ltd. is a wholly owned subsidiary of Medtronic, Inc., which as the 
parent company of such entity maintains appropriate clinical study liability insurance
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage.  If required, a 
Clinical Study insurance statement/certificate will be provided to the Ethics Committee.
14.7 Insurance (Latin America)
Medtronic Latin America HQ is a wholly owned subsidiary of Medtronic, Inc., which as 
the parent company of such entity maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with 
applicable local law and custom concerning specific insurance coverage. If required, a 
Clinical Trial insurance statement/certificate will be provided to the Ethics Committee.

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15 MONITORING
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  
Trained Medtronic personnel or delegates appointed by Medtronic may perform study 
monitoring at the study site in order to ensure that the study is conducted in accordance 
with the CIP, the Clinical Trial Agreement, and applicable regulatory and local 
requirements. Medtronic, or delegates, must therefore be allowed access to the subjects’ 
case histories (clinic and hospital records, and other source data/documentation) upon 
request as per the PIC, Research Authorization (where applicable) and Clinical Trial 
Agreement. The principal investigator should also be available during monitoring visits.  
The sponsor or a regulatory authority may audit or inspect the study site to evaluate the 
conduct of the study. The clinical investigator(s)/institution(s) shall allow study related 
monitoring, audits, Ethics Committee review, and regulatory inspection (s) by providing 
direct access to source data/documents.  If study site’s documents are electronic, these 
must be made available in their original form (or print outs signed and dated with the 
statement that this is complete and true reproduction of the original source document) if 
requested by the sponsor and/or regulatory authority.  Study sites should inform 
Medtronic upon notification of an audit by a regulatory body immediately.
A list of acceptable source documents, are described in section 13, Data Quality and 
Management.  
15.1 Monitoring Visits
Frequency of monitoring visits may be based upon subject enrollment, duration of the 
study, study compliance, number of adverse events, number of deviations, findings from 
previous monitoring visits and any suspected inconsistency in data that requires 
investigation.
Monitoring visits may be conducted periodically to assess site study progress, the 
investigator’s adherence to the CIP, regulatory compliance, including but not limited to 
Ethics Committee approval and review of the study, maintenance of records and reports, 
and review of source documents against subject eCRFs. Monitors review site regulatory 
and study compliance by identifying findings of non-compliance and communicating 
those findings along with recommendations for preventative/corrective actions to site 
personnel.  Monitors may work with study personnel to determine appropriate corrective 
action recommendations and to identify trends within the study or at a particular site. 

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16 REQUIRED RECORDS AND REPORTS
16.1 Investigator records
The investigator is responsible for the preparation and retention of the records including, 
but not limited to the records cited below. All of the below records, with the exception of 
case history records and case report forms, should be kept in the Investigator Site File 
(i.e., the study binder provided to the investigator) or Subject Study Binder. eCRFs must 
be maintained and signed electronically within the electronic data capture system during 
the study. The following records are subject to inspection and must be retained for a 
period of two years (or longer as local law or hospital administration requires) after 
product approval or the date on which the clinical study is terminated. Measures will be 
taken to avoid loss or premature destruction.
All correspondence between the Ethics Committee, sponsor, monitor, regulatory 
authority and/or the investigator that pertains to the clinical study, including 
required reports. 
Subject’s case history records, including: 
Signed and dated PIC form, in accordance with local requirements
Observations of adverse events/adverse device effects/device deficiencies
Medical history
Baseline, CIED procedure and follow-up data (if applicable)
Documentation of the dates and rationale for any deviation from the protocol
Electronically signed and dated eCRFs and blank set of eCRFs where required by 
local law
List of investigation sites
All approved versions of the CIP and PIC
All approved versions of the Investigator Brochure, 
Signed and dated Clinical Trial Agreement
Current curriculum vitae of investigators 
Documentation of delegated tasks. 
Ethics Committee approval documentation: written information that the investigator 
or other study staff, when member of the Ethics Committee, did not participate in 
the approval process. 
Approval documentation must include the Ethics 
Committee composition, where required per local law.  
Regulatory authority notification, correspondence and approval, where required per 
local law.
Study training records for site staff. 
Insurance certificates (EMEA, New Zealand, Latin America, India, ASEAN
(Singapore and Malaysia) and Greater China (Hong Kong) only). 
Any other records that local regulatory agencies require to be maintained
Final Study Report including the statistical analysis. 

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16.2 Investigator reports
The investigator is responsible for the preparation (review and signature) and 
submission to the sponsor of all case report forms, adverse events and adverse device 
effects (reported per the country-specific collection requirements), device deficiencies, 
deaths, and any deviations from the Clinical Investigation Plan.  If any action is taken by 
an Ethics Committee with respect to this clinical study, copies of all pertinent 
documentation must be forwarded to Medtronic in a timely manner. Reports are subject 
to inspection and to the retention requirements as described above for investigator 
records. 
Investigator reporting requirements for safety data are listed in Section 9 Adverse Events 
and Device Deficiencies. 
Table 17: Investigator reports applicable for all geographies per Medtronic 
requirements
Report 
Submit to
Description/Constraints
Withdrawal of Ethics 
Committee approval
Sponsor and 
Relevant 
Authorities
The investigator must report a withdrawal of approval by 
the reviewing Ethics Committee of the investigator’s part of 
the investigation within 5 working days or local law.
Study Deviations 
Sponsor and
Ethics Committee
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation.
Notice of deviations from the CIP to protect the life or 
physical well-being of a subject in an emergency shall be 
given as soon as possible, but no later than 5 working days 
after the emergency occurred.  Except in such emergency, 
prior approval is required for changes in the plan or 
deviations. 
Failure to obtain 
informed consent
Sponsor and
Ethics Committee
Informed consent shall be obtained in writing and 
documented before a subject is enrolled into the clinical 
study.
Final Report
Ethics Committee
and 
Relevant 
Authorities
This report must be submitted within 3 months of study 
completion or termination, or per local requirements.
Table 18: Investigator reports applicable to India
Report 
Submit to
Description/Constraints
Agreed termination
or suspension
Subjects, Ethics
Committee and
regulatory
authorities
In case the investigator and sponsor agree to prematurely
terminate or suspend the study for any reason, the
investigator / institution should promptly inform the study
subjects, the Ethics Committee as well as the Regulatory
Authorities. The investigators should also ensure
appropriate therapy and follow-up for the subjects. (India
GCP section 3.3.8)
Not agreed
termination or
suspension
All concerned
parties
If the investigator or the sponsor or the Ethics Committee
decide to terminate or suspend the study without prior
agreement of all parties concerned then the party initiating
the suspension / termination should promptly inform all the
concerned parties about such suspension / termination and
suspension along with a detailed written explanation for
such termination / suspension. (India GCP section 3.3.8)

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16.3 Sponsor records
Medtronic shall maintain the following accurate, complete, and current records that 
includes, but is not limited to:

All correspondence which pertains to the clinical study

Executed CTAs

Current curriculum vitae of investigators  

Documentation of delegated tasks

Electronically signed and dated eCRFs

All approved PIC templates, and other information provided to the subjects and 
advertisements, including translations

Copies of all Ethics Committee approval letters and relevant Ethics Committee
correspondence and Ethics Committee voting list/roster/letter of assurance

Names of the institutions in which the clinical study will be conducted

Regulatory authorities correspondence, notification and approval as required by 
national legislation

Insurance certificates (EMEA, New Zealand, Latin America, ASEAN (Singapore
and Malaysia) and Greater China (Hong Kong) only)

Names/contact addresses of monitors

Monitoring reports (site qualification visit reports, interim monitoring visit reports 
and close-out visit reports) 

Statistical analyses and underlying supporting data

Final report of the clinical study

The Clinical Investigation Plan, Patient Informed Consent, Investigator’s
Brochure/ and revisions

Study training records for site personnel and Medtronic personnel involved in the 
study

Any other records that local regulatory agencies require to be maintained. 
16.4 Sponsor reports
Medtronic shall prepare and submit the following complete, accurate, and timely reports 
listed in the tables below (by geography).  In addition to the reports listed below, 
Medtronic shall, upon request of reviewing Ethics Committee or regulatory agency, 
provide accurate, complete and current information about any aspect of the clinical 
study. Medtronic reporting requirements for safety data are listed in Table 11 of Section 
9 (Adverse Events and Device Deficiencies). 
Table 19: Sponsor reports for Europe, the Middle East, Africa, Latin America, Greater
China (Hong Kong), New Zealand, India, ASEAN (Singapore and Malaysia)
Report 
Submit to
Description/Constraints
Premature 
termination or 
suspension of the 
clinical study
Investigators,
Ethics 
Committee,
Relevant
authorities
Provide prompt notification of termination or suspension 
and reason(s) per local law,. 

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Report 
Submit to
Description/Constraints
Withdrawal of  Ethics 
Committee approval
Investigators,
Ethics Committee 
and relevant 
authorities
Investigators and other Ethics Committees will be notified 
only if required by local laws or by the Ethics Committee.
Withdrawal of CA 
approval
Investigators,
Ethics 
Committee, and
relevant 
authorities
Investigators, Ethics Committees and relevant authorities 
will be notified only if required by local laws or by the Ethics 
Committee.
Progress Reports
Ethics Committee
and regulatory 
authorities
This will be submitted to the Ethics Committee and 
regulatory authorities only if required by local law
Final report
Investigators, 
Ethics 
Committee, and
Regulatory 
authorities upon 
request

The investigator shall have the opportunity to review 
and comment on the final report.

If a clinical investigator does not agree with the final 
report, his/her comments shall be communicated to the 
other investigator(s).

The coordinating investigator shall sign the report. If no 
coordinating investigator is appointed, then the 
signature of the principal Investigator in each site
should be obtained.
Study deviation 
Investigators
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and 
the final report of the clinical study.  Site-specific study 
deviations will be submitted to investigators periodically.  
Table 20: Sponsor reports for the United States
Report 
Submit to
Description/Constraints
Withdrawal of Ethics 
Committee approval
Investigators, I
Ethics 
Committee,
and
relevant 
authorities
Notification within five working days.  
Recall and device 
disposition
Investigators,
Head of 
Institution,
Ethics 
Committee, and
relevant 
authorities
Notification within 30 working days and will include the 
reasons for any request that an investigator return, repair, 
or otherwise dispose of any devices.  (21 CFR 
812.150(b)(6))
Final report
Investigators,
Ethics 
Committee, 
Regulatory 
authorities upon 
request
A final report will be submitted to the, investigators, and 
Ethics Committee s within six months after completion or 
termination of this study.  
Study deviation 
Investigators
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and 
the final report of the clinical study. 
Site specific study deviations will be submitted to 
investigators periodically.  

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Report 
Submit to
Description/Constraints
Other
IRB, 
Accurate, complete, and current information about any 
aspect of the clinical study. 
Medtronic records and reports will be maintained in a password-protected document 
management system, and paper documents (where applicable) will be stored in stored in 
secured file cabinets at Medtronic during the course of this study. After closure of the 
study, Medtronic will archive records and reports indefinitely.

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APPENDIX A: INFECTION DEFINITIONS
CIED pocket infection
Infection with positive cultures is defined as clinical signs 
and symptoms of local infection at the generator pocket site  
(including  erythema, warmth, fluctuation, wound dehiscence, 
erosion, tenderness, or purulent drainage) in addition to 
microbiological confirmation based on positive cultures on 
intraoperative samples from purulent discharge, the pocket 
tissue, explanted CIED, lead tip, or blood. 38
Infection with negative cultures is defined as clinical signs 
and symptoms of local infection at the generator pocket site 
(including erythema, warmth, fluctuation, wound dehiscence, 
erosion, tenderness, or purulent drainage) without 
microbiological confirmation, if the subject received any 
antibiotic therapy or if there is no other explanation of the 
localized signs and symptoms. 38
Persistent Bacteremia
Persistent bacteremia is defined as two or more positive blood 
cultures for typical skin organisms (coagulase-negative 
staphylococci, Corynebacterium species, Propionobacterium
species), or one positive blood culture for all other 
microorganisms, with or without endocarditis, when no other 
source is identified to explain the bacteremia and resolution of 
blood stream infection after device explantation. 38
Cases of bacteremia originating from a source other than the 
CIED that resolve without any evidence of CIED involvement 
and/or the need for CIED removal should not be considered 
as CIED infection.

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CIED endocarditis
CIED endocarditis is defined as two or more positive blood 
cultures for typical skin organisms (coagulase-negative 
staphylococci, Corynebacterium species, Propionobacterium
species), or one positive blood culture for all other 
microorganisms, with positive echocardiographic findings for 
CIED endocarditis, defined as presence of an oscillating 
intracardiac mass on cardiac valve or supporting structures, in 
the absence of an alternative anatomic explanation, or 
visualization of a cardiac abscess, or new dehiscence of 
prosthetic valve.24,38
Vegetation is defined as an oscillating intracardiac mass on 
the, cardiac valve leaflets, or endocardial surface confirmed 
by imaging in more than 1 echocardiographic plane, in the 
absence of an alternative explanation. 38,43,46,74
Intracardiac abscess is defined as a thickened area or mass 
with a heterogeneous echogenic or echolucent appearance 
by echocardiography or as the presence of pus by direct 
visualization at the time of surgery.46
Subcategories of infections:

Health care-associated CIED infection 

Community acquired CIED infection
Superficial incisional 
surgical site 
infection75,76
Superficial incisional surgical site infection (SSI) must meet 
the following criteria:
Infection occurs within 30 days after any National Healthcare 
Safety Network (NHSN) operative procedure (where day 1 = 
the procedure date), including other operative procedures not 
included in the NHSN categories.
AND
Involves only skin and subcutaneous tissue of the incision.
AND
Patient has at least one of the following:

Purulent drainage from the superficial incision.

Organisms isolated from an aseptically-obtained 
culture of fluid or tissue from the superficial incision.

Superficial incision that is deliberately opened by a 
surgeon, attending physician** or other designee and 
is culture positive or not cultured.
AND
Patient has at least one of the following signs or 
symptoms: pain or tenderness; localized swelling; 
redness; or heat. A culture negative finding does not 
meet this criterion.

Diagnosis of a superficial incisional SSI by the 
surgeon or attending physician* or other designee.

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Deep incisional surgical 
site infection75,76
Deep incisional SSI must meet the following criteria:
Infection occurs within 30 or 90 days after the NHSN 
operative procedure (where day 1 = the procedure date) 
according to the list in Table X.
AND
Involves deep soft tissues of the incision (e.g., fascial and 
muscle layers)
AND
Patient has at least one of the following:

Purulent drainage from the deep incision.

A deep incision that spontaneously dehisces or is 
deliberately opened by a surgeon, attending 
physician** or other designee and is culture-positive or 
not cultured.
AND
Patient has at least one of the following signs or 
symptoms: fever (>38°C); localized pain or 
tenderness. A culture-negative finding does not meet 
this criterion.

An abscess or other evidence of infection involving the 
deep incision that is detected on direct examination, 
during invasive procedure, or by histopathologic 
examination or imaging test.
Organ/space surgical 
site infection75,76
Organ/Space SSI must meet the following criteria:
Infection occurs within 30 or 90 days after the NHSN 
operative procedure (where day 1 = the procedure date) 
according to the list in Table X.
AND
Infection involves any part of the body, excluding the skin 
incision, fascia, or muscle layers, that is opened or 
manipulated during the operative procedure.
AND

Patient has at least one of the following:

Purulent drainage from a drain that is placed into the 
organ/space

Organisms isolated from an aseptically-obtained 
culture of fluid or tissue in the organ/space

An abscess or other evidence of infection involving the 
organ/space that is detected on direct examination, 
during invasive procedure, or by histopathologic 
examination or imaging test
AND
Meets at least one criterion for a specific organ/space 
infection site listed in Table Y.

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* Surgeon(s), infectious disease, other physician on the case, emergency physician or 
physician’s designee (nurse practitioner or physician’s assistant).
Table X: Surveillance Period for Deep Incisional or Organ/Space SSI Following Selected 
NHSN Operative Procedure Categories. Day 1 = the date of the procedure.75
30-day surveillance
Code
Operative Procedure
Code
Operative Procedure
AAA
Abdominal aortic aneurysm repair
LAM
Laminectomy
AMP
Limb amputation
LTP
Liver transplant
APPY Appendix surgery
NECK
Neck surgery
AVSD Shunt for dialysis
NEPH
Kidney surgery
BILI
Bile duct, liver or pancreatic surgery
OVRY
Ovarian surgery
CEA
Carotid endarterectomy
PRST
Prostate surgery
CHOL Gallbladder surgery
REC
Rectal surgery
COLO Colon surgery
SB
Small bowel surgery
CSEC Cesarean section
SPLE
Spleen surgery
GAST Gastric surgery
THOR
Thoracic surgery
HTP
Heart transplant
THYR
Thyroid and/or parathyroid surgery
HYST Abdominal hysterectomy
VHYS
Vaginal hysterectomy
KTP
Kidney transplant
XLAP
Exploratory Laparotomy
OTH
Other operative procedures not 
included in the NHSN categories
90-day surveillance
Code
Operative Procedure
BRST
Breast surgery
CARD
Cardiac surgery
CBGB
Coronary artery bypass graft with both chest and donor site incisions
CBGC
Coronary artery bypass graft with chest incision only
CRAN
Craniotomy
FUSN
Spinal fusion
FX
Open reduction of fracture
HER
Herniorrhaphy
HPRO
Hip prosthesis
KPRO
Knee prosthesis
PACE
Pacemaker surgery
PVBY
Peripheral vascular bypass surgery
RFUSN Refusion of spine
VSHN
Ventricular shunt
Note: Superficial incisional SSIs are only followed for a 30-day period for all procedure 
types.
Table Y: Specific Sites of an Organ/Space SSI.75

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Code
Site
Code
Site
BONE Osteomyelitis
LUNG
Other infections of the respiratory 
tract
BRST Breast abscess or mastitis
MED
Mediastinitis
CARD Myocarditis or pericarditis
MEN
Meningitis or ventriculitis
DISC
Disc space
ORAL
Oral cavity (mouth, tongue, or gums)
EAR
Ear, mastoid
OREP
Other infections of the male or 
female reproductive tract
EMET Endometritis
OUTI
Other infections of the urinary tract
ENDO Endocarditis
PJI
Periprosthetic Joint Infection
EYE
Eye, other than conjunctivitis
SA
Spinal abscess without meningitis
GIT
GI tract
SINU
Sinusitis
HEP
Hepatitis
UR
Upper respiratory tract
IAB
Intraabdominal, not specified
VASC
Arterial or venous infection
IC
Intracranial, brain abscess or dura
VCUF
Vaginal cuff
JNT
Joint or bursa

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APPENDIX B: DATA COLLECTION ELEMENTS
(ELECTRONIC CASE REPORT FORMS)
Electronic Case Report Forms (eCRFS) for the WRAP-IT study will be provided under 
separate cover.  Final eCRFs will be provided to sites via the electronic data 
management system after the site has fulfilled all requirements for database access.

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APPENDIX C: PRELIMINARY PUBLICATION PLAN
Publications from the WRAP-IT study will be handled according to Cardiac Rhythm 
Disease Management Standard Operating Procedures and as indicated in the Clinical 
Trial Agreement.
Publication Committee
The WRAP-IT Steering Committee members will serve as members of the Publication 
Committee, in addition to Medtronic representative(s).     This committee will manage 
study publications with the goal of publishing findings from the data.  The Publication 
Committee will develop the final Publication Plan as a separate document.  
The Publication Committee’s role is to: 
1) manage elements addressed in the publication plan as outlined in this appendix, 
2) develop the final Publication Plan under separate cover, 
3) execute the Publication Plan, 
4) oversee the publication of primary, secondary and ancillary study results, 
5) review and prioritize publication proposals, 
6) provide input on publication content, and 
7) determine authorship. 
In addition, the committee will apply and reinforce the authorship guidelines set forth in 
the Publication Plan.  Membership in the Publication Committee does not guarantee 
authorship.  The committee will meet as needed.
Management of Primary, Secondary and Ancillary Publications
The Publication Committee reviews, prioritizes, and manages all publications including 
primary, secondary and ancillary publications.  Primary and secondary publications are 
those that address analyses of any or all primary objectives or secondary objectives, 
respectively, as specified in the Clinical Investigation Plan. 
An ancillary publication is any publication that does not address the study objectives 
identified in the Clinical Investigation Plan.  They include publications proposed and 
developed by other Medtronic departments or entities, clinicians participating in this 
clinical study, and clinicians not participating in this clinical study.  The committee will 
work with Medtronic to ensure that requests do not present conflicts with other 
proposals, are not duplicative, and to determine which ancillary publication proposals, if 
any, will be supported.  
The committee may decide that no publications, including abstracts, will be published 
prior to the end of the study or with individual site data.  Requests for publications on 
study objectives utilizing subset data (e.g., regional) will be evaluated for scientific 
validity and the ability of Medtronic to provide resources.  
Criteria for Determining Authorship
Publications will adhere to authorship criteria defined by the International Committee of 
Medical Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to 
biomedical journals, www.icmje.org).  Individual authorship criteria defined by the target 
journal or conference will be followed when it differs from ICMJE criteria.

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Authors, including Medtronic personnel, must at a minimum meet all of the conditions 
below:

Substantial contribution to conception and design, or acquisition of data, or 
analysis and interpretation of data

Drafting the article or revising it critically for important intellectual content

Final approval of the version to be published
Decisions regarding authorship and contributor-ship will be made by the committee. The 
selected authors will be responsible for drafting the publication. All selected authors 
must fulfill the authorship conditions stated above to be listed as authors, and all 
contributors who fulfill the conditions must be listed as authors.
All investigators not listed as co-authors will be acknowledged as the “Medtronic WRAP-
IT Clinical Study Investigators” and will be individually listed according to the guidelines 
of the applicable scientific journal when possible and affiliation. Any other contributors 
will be acknowledged by name with their specific contribution indicated.
Transparency
Transparency of study results will be maintained by the following means:

a final report, describing the results of all objectives and analysis, will be 
distributed to all investigators, Ethics Committees and Competent Authorities of 
participating countries when required by local law

registering and posting the study results on ClinicalTrials.gov based on the 
posting rules stipulated 

submitting for publication the primary study results after the study ends 

disclosing conflicts of interest (e.g., financial) of the co-authors of publications 
according to the policies set forth by the corresponding journals and conferences 

making an individual sites study data accessible to the corresponding investigator 
after the completion of the study, if requested

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APPENDIX D: DATA MONITORING COMMITTEE (DMC)
Point 
Examples
DMC will be used
Ongoing oversight for this study will be provided by an independent 
Data Monitoring Committee (DMC). It is anticipated that the DMC 
will meet periodically during the study to review the accumulating 
data.
Who will be 
involved
The DMC will have one statistician, at least one physician 
specializing in electrophysiology and at least one specializing in 
infections. A chairperson from among those members will be 
identified.  None of the DMC members will be participating 
investigators in the WRAP-IT study.   
Sponsor clinical staff, except for the sponsor statistician(s) and/or
statistical programmer(s) (or designates) preparing the closed DMC 
report will remain blinded to any aggregate study results separated 
by treatment group during the course of the study.  The DMC charter 
will outline the procedures for maintaining the confidentiality of 
unblinded aggregate study data. 
Responsibility of 
the DMC
The DMC will be responsible for assessing the safety and efficacy of 
the interventions during the study, assessing the scientific 
soundness with respect to study conduct, accruing data, and 
external developments, and for monitoring the overall conduct of the 
clinical study.  To enhance the integrity of the study, the DMC may 
also formulate recommendations related to the selection, 
recruitment, and retention of subjects, their management, 
improvement of adherence to protocol-specified regimens and 
procedures for data management and quality control.
The DMC is retained to assess the safety of the interventions during 
the study on an ongoing basis and evaluate the unblinded study 
results at the predefined interim analysis.  The DMC is also retained 
to monitor the overall conduct of the study.  
The DMC will periodically review safety data and the conduct of the 
trial, review results of the interim analyses, and provide 
recommendations to the Steering Committee and study sponsor 
regarding continuation of the study and modifications in design and 
conduct.

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Point 
Examples
Recommendations The DMC will be advisory to the sponsor.  The DMC may provide 
recommendations for early termination of the study or early release
of unblinded study results based on the interim analysis.  Review 
and consensus by the entire committee is required to recommend 
that the study should be stopped or unblinded results disseminated.  
The DMC may also make recommendations related to the selection, 
management and retention of subjects, improvement of adherence 
to protocol-specified regimens, and procedures for data 
management and quality control.
The DMC may monitor the CIED infection rates in the study on an 
ongoing basis, and if necessary, they may recommend randomizing 
more subjects in order to ensure enough CIED infections occur to 
adequately assess the primary study objective.  The DMC may also 
recommend early study termination if an adequate CIED infection 
rate cannot be achieved in the control group.
Decision 
Boundaries (if 
there are pre-
determined 
stopping rules)
Statistical decision boundaries for the study are outlined in the 
statistical methods section of this document.  These are to be used 
only as guidelines by the DMC when deciding whether the study 
objectives have been met.
The DMC may provide recommendations to unblind and disseminate
the study results early based on the interim analysis.  In order to 
recommend early dissemination of the study results, the primary 
objective must meet the predetermined decision boundary.  At the 
interim analysis, the DMC assessment will balance the evidence on 
the primary study objective as well as evidence relating to the 
secondary study objectives. In addition, other considerations for 
early dissemination of study results may include, but are not limited 
to, the magnitude of effect, secondary objectives, data quality, and 
consistency of results across subgroups.  In the event that a 
decision is made to unblind the study following the interim analysis, 
the DMC may recommend that the study continue to enroll and 
follow subjects to evaluate the effect of the TYRX envelope on CIED 
infections that develop post-12-months as well as collect additional 
follow-up in subjects with a defibrillation system in which to evaluate 
the lead monitoring features.  However, the DMC may recommend 
that subjects no longer be randomized in the TYRX envelope is 
found to have a clear benefit.

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APPENDIX E: STUDY OVERVIEW
Title
World-wide Randomized Antibiotic EnveloPe Infection PrevenTion Trial.
Short title
WRAP-IT
Purpose
Medtronic, Inc. is sponsoring the World-wide Randomized Antibiotic EnveloPe Infection 
PrevenTion Trial (WRAP-IT), a randomized, prospective, multi-center, single blinded, 
post-market, interventional clinical study.  The study has three purposes.  First, the 
WRAP-IT study will serve as a post-approval study for those geographies requiring a 
post-approval study to facilitate collection of complications related to the Cardiovascular 
Implantable Electronic Device (CIED) procedure or system in subjects randomized to 
receive the TYRXTM Absorbable Antibacterial Envelope (henceforth referred to as TYRX 
envelope).  Next, this study will evaluate the ability of the TYRX envelope to reduce 
major CIED infections through 12-months post-procedure following CIED generator 
replacement, upgrade, revision, or de novo CRT-D implant.  Subjects undergoing CIED
generator replacement, upgrade, revision or the implant of a de novo CRT-D system will 
be randomized to either receive the TYRX envelope or not to receive the TYRX 
envelope.  Randomization will be 1:1 and be stratified by study site and device type high 
power (ICD and CRT-D) vs. low power devices (IPG and CRT-P).  Finally this large 
device study provides the unique opportunity to prospectively characterize the 
performance of Medtronic’s lead monitoring features in subjects whose CIED system 
includes a transvenous RV defibrillation lead.  These features include the lead integrity 
alert (LIA), lead noise alert (LNA), RV pacing impedance, and high voltage (HV) pacing 
impedance to detect events that affect a RV lead’s pacing, sensing, or defibrillation 
circuit lead system events (LSE).  
Design
The study is expected to be conducted at up to 225 sites worldwide with up to 7,764 
subjects enrolled in order to randomize approximately 6,988 subjects.  Enrollment of 
subjects receiving a replacement low power device (i.e. IPG or CRT-P) will be capped at 
approximately 25% of the total randomized study population (i.e. approximately 1,746 
subjects).  Relative to high power device recipients, patients receiving a low power 
device may be at reduced risk of a major CIED infection. Thus, to ensure an adequate 
CIED infection event rate in the control arm, there is a desire to include a higher 
proportion of high power devices in the trial. 
The enrollment period is expected to start in late 2014 and to take approximately 24
months. Subjects will be followed for a minimum of 12 months.  The anticipated study 
duration is approximately 36 months and subjects may be followed for up to 36 months
depending on when they enroll in the study.
Expected participating geographies include, but are not limited to, the United States 
(US), Europe, the Middle East and Africa (EMEA), Greater China (Hong Kong), New 
Zealand, Latin America, the Association of South East Asian Nations (ASEAN) 
(Singapore and Malaysia), and India.

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To ensure a widespread distribution of data, minimize site bias in study results and 
ensure that sites will be able to adequately manage and follow subjects enrolled in the 
study, the maximum number of randomized subjects allowed at a single site is 100 
subjects.  Sites are encouraged to enroll as many consecutive eligible subjects as 
appropriate. There is no specific minimum number of enrollments required, except where 
stated in the clinical trial agreement between the sponsor and the individual site.
Medical device
The Medtronic TYRX envelope is an absorbable sterile prosthesis designed to hold a 
pacemaker pulse generator or defibrillator to create a stable environment when 
implanted in the body.  The TYRX envelope is constructed from multifilament knitted 
mesh (polymer made of glycolide, caprolactone, and trimethylene carbonate) that is 
coated with an absorbable polyarylate polymer. The purpose of the absorbable coating 
is to act as a carrier for the antimicrobial agents. The absorbable antibacterial envelope 
absorbable polymer coating contains antimicrobial agents in concentrations of 8.0 mg 
rifampin and 5.1 mg minocycline (Medium size, IPG), and 11.9 mg rifampin and 7.6 mg 
minocycline (Large size, ICD). The TYRX envelope releases the antimicrobial agents 
rifampin and minocycline for a minimum of 7 days to reduce the risk of infection of the 
implanted CIED following surgery. The TYRX envelope will be used in combination with 
market-released Medtronic CIED generator replacement, upgrade, revision or implant of 
a de novo CRT-D system with any commercially released RV, RA (if applicable), and LV 
(if applicable) leads.
Objectives and endpoints
Primary objective
The primary study objective is to compare the rate of major CIED infections 
through 12-months post-procedure between the TYRX envelope group and the 
control group (no TYRX envelope).
Secondary objectives

Confirm that the TYRX envelope does not increase the CIED procedure-
related or system-related complication rate through 12-months post-
procedure.

Compare the major CIED infection rate during the entire follow-up between 
the TYRX envelope group and the control group.

Compare the rate of major and minor CIED infections through 12-months 
post-procedure between the TYRX envelope group and the control group.
Ancillary objectives

Compare all-cause mortality rates between the TYRX envelope group and 
the control group

Evaluate the CIED procedure success rate in the TYRX envelope group and 
the control group

Control: device and leads all implanted  

Treatment: TYRX envelope, device, and leads all implanted

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
Summarize the adverse events

Identify the predictors of CIED infection

Summarize quality of life

Evaluate the cost effectiveness of the TYRX envelope
 
 
 
 
 
 
 
 
Primary endpoint
Major CIED infections are defined as CIED infections resulting in one or more of the 
following:
CIED system removal
Any invasive procedure (e.g. pocket opened) without system removal
Treatment with antibiotic therapy if the subject is not a candidate for system 
removal and infection recurrence after completion of antibiotic therapy or evidence 
of deep infection with wound dehiscence, erosion, or purulent drainage.
Death
Note: All other CIED infections including superficial incisional SSIs that meet the CDC 
criteria, independent of the time from surgery, are defined as minor CIED infections 
unless they meet the major CIED infection criteria.
Subject population
Subjects meeting one or more of the following criteria may be enrolled: 1) an 
ACC/AHA/HRS or ESC guideline-recommended need for a de novo CRT-D and subject 
has a geography approved indication for a CRT-D, 2) an existing IPG, CRT-P, ICD, or 
CRT-D undergoing generator replacement or generator upgrade with or without the 
addition of new leads, or 3) an existing IPG, CRT-P, ICD, or CRT-D undergoing a CIED 
system revision procedure (6,988 randomized subjects (3,494 randomized to each 
group)).  Subjects who enroll in the study and proceed with a device procedure must be 
implanted with a Medtronic single, dual, or triple chamber pacemaker or defibrillator that 
has received appropriate license or regulatory approval and is commercially available by
Medtronic in the geography in which the procedure will take place.  Any market-
released, commercially available transvenous lead(s) can be used in this study.  The 

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total study duration is expected to be approximately 36 months, including 24 months for 
subject recruitment and 12 months for subject follow-up.
Treatment
Subjects undergoing CIED generator replacement, upgrade, or revision or the implant of 
a de novo CRT-D system with a new Medtronic CIED will be randomized to either 
receive the TYRX envelope or not to receive the TYRX envelope.  Randomization will be 
1:1 and be stratified by study site and device type (high power (ICD and CRT-D) vs. low 
power devices (IPG and CRT-P)).
Due to the nature of the CIED procedure, it is not possible to blind the implanting 
investigator or study site staff.  However, efforts should be employed to blind the study 
subject to their randomized treatment throughout the duration of the study.  In particular, 
efforts to keep the subject blinded to their randomized treatment in the procedure room 
will be necessary in the setting of conscious sedation.  All randomized subjects will be 
unblinded at the end of the study.
Inclusion criteria
Patients must meet the following inclusion criteria to be eligible to participate in the study:

Patient is willing to sign and date the study Patient Informed Consent (PIC) Form 

Patient is at least 18 years of age and meets age requirements per local law

Patient is planned to undergo at least one of the following:
a. Patient has existing CIED and is undergoing IPG (including CRT-P), ICD 
or CRT-D replacement or upgrade with a new Medtronic generator 
i.
Subjects planned to have leads added, or extracted and added for 
upgrades can be enrolled
OR
b. Patient will undergo a de novo Medtronic CRT-D system implant per 
approved indications
OR
c.
Patient has existing study eligible Medtronic CIED in which the pocket 
was not accessed within the last 365 days, and is undergoing pocket or 
lead revision

Willing to provide the contact information for the physician who provides follow-
up for his/her CIED.

Willing and able to comply with scheduled follow-up and study related activities.
Exclusion criteria
Patients must not meet any of the following exclusion criteria to be eligible to participate 
in the study:

Known allergy to minocycline or rifampin or their derivatives, or any other known 
contraindications to implantation of the TYRX envelope. 

Current therapy with chronic oral immunosuppressive agents or ≥ 20mg/day of 
Prednisone or equivalent.

Hemodialysis or peritoneal dialysis.

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
Prior Cardiac transplantation or existing Ventricular Assist Device (VAD).

Require long-term vascular access for any reason.

Prior history of a CIED infection, other prosthetic device infection, or 
endovascular infection, including endocarditis, in the past 12 months.

Physical, clinical, or laboratory signs or symptoms consistent with an active 
infection (including but not limited to pneumonia, urinary tract, cellulitis, or 
bacteremia)

Systemic lupus erythematous, because minocycline has been reported to 
aggravate this condition

Female patient who is pregnant, or of childbearing potential and not on a reliable 
form of birth control. Women of childbearing potential are required to have a 
negative pregnancy test within 7 days prior to device procedure

Participation in another study that may confound the results of this study. Co-
enrollment in concurrent trials is only allowed when documented pre-approval is 
obtained from the Medtronic study manager.
Clinical Procedures
Study Procedure
Baseline
Procedure
Pre-
Hospital 
Discharge
Biannual 
Follow-up 
Visits
Unschedul
ed Visit
Study Exit
Patient Informed Consent
X
Inclusion/Exclusion Assessment 
X
Subject Demographics
X
Record Medications1
X
X
X
X
X
X
Medical History 
X
System and Procedure 
Information
X
Confirm Programming 
Requirements (subjects with 
ICD or CRT-D only)
X
X
X
Evaluate Subject for Signs and 
Symptoms of CIED Infection
X
X
X
X
Evaluate Subject and Device for 
LSEs 
X
X
X
X
Final Device Interrogation / 
CareLink® Transmission
X
X
X
X
X

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Study Procedure
Baseline
Procedure
Pre-
Hospital 
Discharge
Biannual 
Follow-up 
Visits
Unschedul
ed Visit
Study Exit
EQ-5D
X
X 
(12 month 
visit only)
X (Only if 
exited prior 
to 12 month 
visit)
Collect or Confirm Contact 
Information of CIED follow-up 
Physician2
X
X
X
Exit Subject
X
CIED Infection
As they occur
CIED Infection-Related Health 
Care Utilization
As they occur
CIED Infection–Related EQ-5D
Within 2 weeks following a diagnosis of CIED infection, and subsequently 1, 3, 
and 6 months post infection diagnosis
Lead System Event (ICD and 
CRT-D Subjects only)
As they occur
Holter for Suspected LSE if 
required (ICD and CRT-D 
Subjects only)
As they occur
Adverse Events (AEs)
As they occur
Device Deficiencies
As they occur
System Modifications
As they occur
Study Deviations
As they occur
Device Disposition for TYRX 
envelope 
As it occurs in geographies where required
Death
As it occurs
1 Record any anti-platelet agents, anticoagulants, antibiotics, corticosteroids, insulin or oral 
diabetic agents.  
2 The CIED follow-up physician could also be the referring cardiologist or other physician
overseeing care of the patient following procedure.
Subjects are considered enrolled in the study upon signing the PIC.  Enrolled subjects 
are eligible for randomization after completion of the baseline assessment and if all 
inclusion and none of the exclusion criteria are met.  Randomized subjects may be 
followed for up to 36 months depending on when they enroll in the study.  After Baseline 
and Procedure, subjects will return for biannual follow-ups up until their study exit.    

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Study Follow-up
Visit
Window
(Calculated days post-CIED procedure)
Window Start
(days post-
procedure)1
Target
(days post-
procedure)
Window End
(days post-
procedure)
6-Month
168
183
198
12-Month
365
3652
395
18-Month
521
549
577
24-Month
702
730
758
30-Month
887
915
943
36-Month
1070
1098
1126
1Days post-randomization if subject never had a CIED procedure 
attempt.
2The target date and window start date intended to be equal for primary 
objective analysis purposes.

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APPENDIX F: PATIENT INFORMED CONSENT 
TEMPLATES
Geography-specific Patient Informed Consent (PIC) templates will be provided under 
separate cover.

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APPENDIX G: FORESEEABLE ADVERSE EVENT LIST
The information provided in this section pertains to foreseeable adverse events that may 
be observed in WRAP-IT subjects and may assist in identifying those events for a given 
device or therapy that are unexpected in nature.  The foreseeable adverse events 
information may be used in combination with device labeling, current event reporting 
information, and other published data to assess for an unexpected occurrence.
The implantation of the CIED system and the TYRXTM Absorbable Antibacterial 
Envelope (henceforth referred to as TYRX envelope) involves surgery. Therefore, 
standard adverse events associated with a surgical procedure may be experienced, 
such as anesthesia complications, injury, infections, bleeding, exacerbation of pre-
existing conditions, healing complications, etc. However, the focus of this section is to 
specifically address those events that are foreseeable due to the implantation, use, 
performance, and/or presence of the system under investigation. 
Potential risks associated with the implantation of the CIED system and the TYRX 
envelope as well as risk minimization are discussed within section 10.  Treatment 
required for procedure- and/or system-related adverse events that are experienced may 
include medication, device reprogramming, device modification (e.g. repositioning, 
surgical abandonment, surgical removal), or other surgical and medical remedies. 
The list of foreseeable TYRX envelope-related adverse events and adverse device 
effects is composed based on the Instructions For Use, Label submitted to the notified 
body, the Combined 6 Month Analysis of Centurion and Citadel Clinical Studies and the 
Clinical Evaluation Report for the TYRXTM Non-Absorbable Antibacterial Envelope and 
TYRXTM Absorbable Antibacterial Envelope.  The foreseeable TYRX envelope-related
adverse events include, but are not limited to, the following:
Foreseeable TYRX envelope-related Adverse Events and Adverse Device Effects
Generator or lead malfunction 
Generator dislodgement or migration
Lead dislodgement or migration
Lead fracture
Skin erosion
Wound dehiscence
Bleeding 
Infection 
Seroma
Adhesions 
Hematoma
Inflammation
Extrusion 
Fistula formation 
Unresolved infection that may require 
removal of prosthesis
Rifampin allergic reaction
Rifampin side effects
Minocycline allergic reaction
Minocycline side effects
Allergic reaction to resorbable suture-
like components
TYRX envelope may complicate 
generator removal and replacement
Additional stress on the hepatic and 
renal systems
The adverse events associated with the use of transvenous leads, pacing and 
defibrillation systems include, but are not limited to, the following:

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Foreseeable CIED-related Adverse Events and Adverse Device Effects
Acceleration of tachyarrhythmias
Air embolism
Angina pectoris
Anxiety
Atrial arrhythmia
Bleeding/hemorrhage
Cardiac (heart wall or vein wall)
rupture
Cardiac dissection
Cardiac perforation
Cardiac tamponade
Cardiac vein dissection
Cardiac vein perforation
Cerebrovascular accident
Coronary sinus dissection
Coronary sinus perforation
Deep vein thrombosis
Depression
Device battery issue
Device connection issue
Device electrical impedance  issue
Device lead damage
Device lead fracture
Device migration
Device protrusion/extrusion
Device rejection
Dysplasia
Electrical conduction disorders
Electromagnetic interference
Elevated pacing threshold
Emotional distress
Endocarditis
Erosion
Exit block
Failure to capture
Far-field R-wave sensing
Fibrotic tissue growth
Fluid accumulation
Heart block
Heart failure worsening
Hemothorax
Impedance increased
Implant delivery tool problem
Implant site bruising
Implant site cellulitis
Implant site discharge
Implant site erythema
Implant site fibrosis
Implant site hematoma
Implant site infection
Implant site necrosis
Implant site pain
Implant site seroma
Implant site swelling
Inappropriate device signal
detection
Inappropriate device therapy
Inappropriate extra-cardiac
device stimulation
Incision site hematoma
Infection
Keloid scar
Lead abrasion and discontinuity
Lead conductor failure
Lead connector failure
Lead dislodgement
Lead insulation failure
Loss of capture
Myocardial damage
Myocardial infarction
Myocardial irritability
Myopotential sensing
Nerve damage
Oversensing
Pacemaker syndrome
Pericardial effusion
Pericardial hemorrhage
Pericardial rub
Pericarditis
Phrenic nerve stimulation
Pneumothorax
Pocket erosion
Pulmonary/pleural effusion
Sepsis
Septic shock
Subcutaneous emphysema
Syncope
Thromboembolism
Thrombosis
Tissue necrosis
Transient ischemic attack
Twiddler's syndrome
Undersensing
Valve damage
Vasovagal reaction
Venous occlusion
Venous stenosis
Ventricular arrhythmia

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APPENDIX H: PARTICIPATING INVESTIGATORS AND
INSTITUTIONS
At the time of WRAP-IT Clinical Investigation Plan (CIP) Version 1.0 completion, site
confirmation was not finalized. A complete list of participating investigators and 
institutions (including names, titles, address(es), and telephone numbers) where study 
activities will be conducted will be distributed under a separate cover when available. 
Approval of the WRAP-IT CIP will be documented by signing the Clinical Trial 
Agreement or the CIP signature page.

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APPENDIX I: ETHICS COMMITTEE
At the time of WRAP-IT Clinical Investigation Plan Version 1.0 completion, site
confirmation was not finalized. Therefore, a complete list of participating Ethics 
Committee and the Chairperson(s) will be distributed under a separate cover when 
available upon request.

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APPENDIX J: LABELING
Labeling and package for all products used in this study will follow the local regulatory 
requirements.  Labeling for all system components market released at study start in the 
respective geographies (including labeling for the TYRXTM Absorbable Antibacterial 
Envelope) can be found with each package insert and/or will be available on 
http://manuals.medtronic.com.

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APPENDIX K: BIBLIOGRAPHY
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Epstein AE, Dimarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes 
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NM, Creager MA, Demets D, Ettinger SM, Guyton RA, Hochman JS, Kushner FG, 
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Bloom H, Heeke B, Leon A, Mera F, Delurgio D, Beshai J, Langberg J. Renal 
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MJ, van Erven L. Risk factors and time delay associated with cardiac device 
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Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, 
Steckelberg JM, Stoner SM, Baddour LM. Risk factor analysis of permanent 
pacemaker infection. Clin Infect Dis. 2007;45:166-173
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Borleffs CJ, Thijssen J, de Bie MK, van Rees JB, van Welsenes GH, van Erven L, 
Bax JJ, Cannegieter SC, Schalij MJ. Recurrent implantable cardioverter-
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Krahn AD, Morillo CA, Connolly SJ, Healey JS. Device-related infection among 
patients with pacemakers and implantable defibrillators: Incidence, risk factors, 
and consequences. J Cardiovasc Electrophysiol. 2010;21:786-790
33.
Uslan DZ, Sohail MR, St Sauver JL, Friedman PA, Hayes DL, Stoner SM, Wilson 
WR, Steckelberg JM, Baddour LM. Permanent pacemaker and implantable 
cardioverter defibrillator infection: A population-based study. Arch Intern Med. 
2007;167:669-675
34.
Al-Khatib SM, Lucas FL, Jollis JG, Malenka DJ, Wennberg DE. The relation 
between patients' outcomes and the volume of cardioverter-defibrillator 
implantation procedures performed by physicians treating medicare beneficiaries. 
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35.
Chamis AL, Peterson GE, Cabell CH, Corey GR, Sorrentino RA, Greenfield RA, 
Ryan T, Reller LB, Fowler VG, Jr. Staphylococcus aureus bacteremia in patients 
with permanent pacemakers or implantable cardioverter-defibrillators. Circulation. 
2001;104:1029-1033
36.
Uslan DZ, Sohail MR, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, 
Baddour LM. Frequency of permanent pacemaker or implantable cardioverter-
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Klug D, Lacroix D, Savoye C, Goullard L, Grandmougin D, Hennequin JL, Kacet 
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Le KY, Sohail MR, Friedman PA, Uslan DZ, Cha SS, Hayes DL, Wilson WR, 
Steckelberg JM, Baddour LM. Impact of timing of device removal on mortality in 
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de Bie MK, van Rees JB, Thijssen J, Borleffs CJ, Trines SA, Cannegieter SC, 
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49.
Raad I, Darouiche R, Dupuis J, Abi-Said D, Gabrielli A, Hachem R, Wall M, 
Harris R, Jones J, Buzaid A, Robertson C, Shenaq S, Curling P, Burke T, 
Ericsson C. Central venous catheters coated with minocycline and rifampin for 
the prevention of catheter-related colonization and bloodstream infections: A 
randomized, double-blind trial. Ann Intern Med. 1997;127:267-274
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Marik PE, Abraham G, Careau P, Varon J, Fromm RE, Jr. The ex vivo 
antimicrobial activity and colonization rate of two antimicrobial-bonded central 
venous catheters. Crit Care Med. 1999;27:1128-1131
51.
Chatzinikolaou I, Finkel K, Hanna H, Boktour M, Foringer J, Ho T, Raad I. 
Antibiotic-coated hemodialysis catheters for the prevention of vascular catheter-
related infections: A prospective, randomized study. The American Journal of 
Medicine. 2003;115:352-357
52.
Hanna H, Benjamin R, Chatzinikolaou I, Alakech B, Richardson D, Mansfield P, 
Dvorak T, Munsell MF, Darouiche R, Kantarjian H, Raad I. Long-term silicone 
central venous catheters impregnated with minocycline and rifampin decrease 
rates of catheter-related bloodstream infection in cancer patients: A prospective 
randomized clinical trial. J Clin Oncol. 2004;22:3163-3171
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Leon C, Ruiz-Santana S, Rello J, de la Torre MV, Valles J, Alvarez-Lerma F, 
Sierra R, Saavedra P, Alvarez-Salgado F. Benefits of minocycline and rifampin-
impregnated central venous catheters. A prospective, randomized, double-blind, 
controlled, multicenter trial. Intensive Care Med. 2004;30:1891-1899
54.
Zabramski JM, Whiting D, Darouiche RO, Horner TG, Olson J, Robertson C, 
Hamilton AJ. Efficacy of antimicrobial-impregnated external ventricular drain 

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catheters: A prospective, randomized, controlled trial. J Neurosurg. 2003;98:725-
730
55.
TYRX Sponsored Studies: M10-1191, TR-2011-040, TP-20111-055, TR-2012-
001, Wuxi Apptec Study No. 132830, Wuxi Apptec Study No. 131902, TR2011-
047, TR2011-043, TR-2011-044, TR-2011-056
56.
Bloom HL, Constantin L, Dan D, De Lurgio DB, El-Chami M, Ganz LI, Gleed KJ, 
Hackett FK, Kanuru NK, Lerner DJ, Rasekh A, Simons GR, Sogade FO, Sohail 
MR. Implantation success and infection in cardiovascular implantable electronic 
device procedures utilizing an antibacterial envelope. Pacing Clin Electrophysiol. 
2011;34:133-142
57.
Gould PA, Krahn AD. Complications associated with implantable cardioverter-
defibrillator replacement in response to device advisories. JAMA. 2006;295:1907-
1911
58.
Birnie, D. H., Healey, J. S., Wells, G. A., Verma, A., Tang, A. S., Krahn, A. D., et 
al. (2013, May 9). Pacemaker or Defibrillator Surgery without Interruption of 
Anticoagulation. The New England Journal of Medicine, 2084-2093.
Durack, D. T., Lukes , A. S., & Bright, D. K. (1994). New criteria for diagnosis o 
finfective endocarditis: Utilization of specific echocardiographic findings. Duke 
Endocarditis Service. Am J Med, 96(3), 200–209.
Klug, D., Lacroix, D., Savoye, C., Goullard, L., Grandmougin, D., Hennequin, J. L., et al. 
(1997). Systemic infection related to endocarditis on pacemaker leads: Clinical 
presentation and management. Circulation, 95(8), 2098-2107.
Krahn, A. D., Lee, D. S., Birnie, D., Healey, J. S., Crystal, E., Dorian, P., et al. (2011, 
February 15). Predictors of Short-Term Complications After Implantable 
Cardioverter-Defibrillator Replacement Results from the Ontario ICD Database. 
Circ Arrhythm Electrophysiol, 4, 136-142.
Mangram, A. J., Horan, T. C., Pearson, M. L., Leah , S. C., & Jarvis, W. R. (1999). 
Guideline for Prevention of Surgical Site Infection, 1999. Infection Control and 
Hospital Epedemiology, 20(4), 250-278.
Young, J. B., Abraham, W. T., Smith, A. L., Leon, A., & Lieberman, R. (2003, May). 
Combined Cardiac Resynchronization and Implantable Cardioversion 
Defibrillation in Advanced Chronic Heart Failure. JAMA, 289(20), 2685-2694.
63. 
Gunderson BD, Swerdlow CD, Wilcox JM, Hayman JE, Ousdigian KT, 
Ellenbogen KA. Causes of ventricular oversensing in implantable cardioverter-
defibrillators: implications for diagnosis of lead fracture. Heart Rhythm 
2010;7:626–33.
64. 
Swerdlow CD, Gunderson BD, Ousdigian KT, Abeyratne A, Stadler RW,Gillberg 
JM, Patel AS, Ellenbogen KA. Downloadable algorithm to reduce inappropriate 
shocks caused by fractures of implantable cardioverterdefibrillator leads. 
Circulation. 2008;118:2122–2129.
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Swerdlow CD, Gunderson BD, Ousdigian KT, Abeyratne A, Sachanandani H, 
Ellenbogen KA. Downloadable software algorithm reduces inappropriate shocks 
caused by implantable cardioverter-defibrillator lead fractures: a prospective 
study. Circulation. 2010;122:1449–1455.
66. 
Gunderson BD, Patel AS, Bounds CA, Shepard RK, Wood MA, Ellenbogen KA. 
An algorithm to predict implantable cardioverter-defibrillator lead failure. J Am 
Coll Cardiol. 2004;44:1898–1902.

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67.
Gunderson BD, Gillberg JM, Wood MA, et al. Development and testing of an 
algorithm to detect implantable cardioverter-defibrillator lead failure. Heart 
Rhythm 2006;3:155–162.
68. 
Koneru JN, Gunderson BD, Sachanandani H, Wohl BN, Kendall KT, Swerdlow 
CD, Ellenbogen KA. Diagnosis of High Voltage Conductor Fractures in Sprint 
Fidelis Leads. Heart Rhythm. 2013;10:813-818.
69.
Ellenbogen KA, Gunderson BD, Stromberg KD, Swerdlow CD. Performance of 
Lead Integrity Alert to Assist in the Clinical Diagnosis of Implantable Cardioverter 
Defibrillator Lead Failures: Analysis of Different Implantable Cardioverter 
Defibrillator Leads. Circ Arrhythm Electrophysiol. 2013;6:1169-77.  
70. 
Goldstein M, Badri M, Kocovic D, Kowey PR. Electrical failure of a St Jude 
Durata lead due to a presumed insulation defect only diagnosed by a maximum 
output shock. Pacing Clin Electrophysiol. 2013;36:1068–1071.
71.
Lakshmanadoss U, Lahoda D, Deshmukh P. Riata lead failure with normal 
electrical lead parameters and normal fluoroscopic appearance. J Interv Card 
Electrophysiol 2013; 36:87–89.
72.
Hauser RG, Abdelhadi R, McGriff D, Retel LK. Deaths caused by the failure of 
Riata and Riata ST implantable cardioverter–defibrillator leads. Heart Rhythm 
2012; 9:1227–1235.
73.
Mittal, S., Shaw, R. E., Palekar, R., Arshad, A., Mustat, D., et al. (2014). Cardiac 
implantable electronic device infections: Incidence, risk factors, and the effect of 
the AigisRx antibacterial envelope. Heart Rhythm, 11, 595-601.
74.
Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for 
the diagnosis of infective endocarditis. Clin Infect Dis. Apr 2000; 30(4): 633-638.
75. 
Surgical Site Infection (SSI) Event- Centers for Disease Control and Prevention. 
2014.  http://www.cdc.gov/nhsn/pdfs/pscmanual/9pscssicurrent.pdf
76. 
Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for 
prevention of surgical site infection, 1999. Hospital Infection Control Practices 
Advisory Committee. Infect Control Hosp Epidemiol 1999; 20:250–278.
77.
Lakatos, E. (1988), "Sample Sizes Based on the Log-Rank Statistician Complex 
Clinical Trials," Biometrics, 44, 229-241
78.
Head, SJ et. al. 2012.  Non-inferiority study design: lessons to be learned from 
cardiovascular trials.  EHJ: 33(11) 1318-1384.
79.
Birnie, D. H., Healey, J. S., Wells, G. A., Verma, A., Tang, A. S., Krahn, A. D., et 
al. (2013, May 9). Pacemaker or Defibrillator Surgery without Interruption of 
Anticoagulation. The New England Journal of Medicine, 2084-2093.
Durack, D. T., Lukes , A. S., & Bright, D. K. (1994). New criteria for diagnosis o 
finfective endocarditis: Utilization of specific echocardiographic findings. Duke 
Endocarditis Service. Am J Med, 96(3), 200–209.
Klug, D., Lacroix, D., Savoye, C., Goullard, L., Grandmougin, D., Hennequin, J. L., et al. 
(1997). Systemic infection related to endocarditis on pacemaker leads: Clinical 
presentation and management. Circulation, 95(8), 2098-2107.
Krahn, A. D., Lee, D. S., Birnie, D., Healey, J. S., Crystal, E., Dorian, P., et al. (2011, 
February 15). Predictors of Short-Term Complications After Implantable 
Cardioverter-Defibrillator Replacement Results from the Ontario ICD Database. 
Circ Arrhythm Electrophysiol, 4, 136-142.
Mangram, A. J., Horan, T. C., Pearson, M. L., Leah , S. C., & Jarvis, W. R. (1999). 
Guideline for Prevention of Surgical Site Infection, 1999. Infection Control and 
Hospital Epedemiology, 20(4), 250-278.

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Young, J. B., Abraham, W. T., Smith, A. L., Leon, A., & Lieberman, R. (2003, May). 
Combined Cardiac Resynchronization and Implantable Cardioversion 
Defibrillation in Advanced Chronic Heart Failure. JAMA, 289(20), 2685-2694.

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APPENDIX L: PRECLINICAL TESTING
A summary and results of preclinical testing with the TYRXTM Absorbable Antibacterial 
Envelope is provided in the Investigator’s Brochure.

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APPENDIX M: PREVIOUS CLINICAL STUDIES
A summary of and results from previous clinical studies related to the WRAP-IT study or 
devices with similar features is provided in the Investigator’s Brochure. 

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APPENDIX N: COMMITTEES
Steering Committee
A Steering Committee (SC) will serve to oversee and guide the conduct of the study as 
well as develop publications and presentations. The SC is independent from Medtronic, 
Inc. and will be blinded to the study data while the study is ongoing.
The Steering Committee will serve as a publication committee and will be primarily 
responsible for the creation, review, and submission of publications and presentations 
related to the study. A publication plan will be developed in conjunction with the Sponsor 
prior to the start of the trial. This publication plan may need to be adjusted, as 
appropriate, based on the progress of the study.
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be independent of Medtronic, Inc. and the 
Executive Steering Committee. The committee will not include any investigators involved 
with the study. The Executive Steering Committee Chair and Medtronic, Inc. will 
collaborate to appoint the DMC. The DMC will evaluate the safety results as well as 
conduct an interim analysis during the course of the study. The membership and 
responsibilities of the DMC will be defined in a separate document entitled the Data 
Monitoring Committee Charter.
Clinical Event Committee
A Clinical Events Committee (CEC) will provide an independent and blinded assessment 
of the study endpoints as defined in the CEC Charter, based on standardized 
classifications and definitions.  The members of this committee will not directly 
participate in the conduct of the study and will be blinded to treatment allocation 
throughout the conduct of the study. 

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APPENDIX O: CLINICAL INVESTIGATION PLAN 
SIGNATURE PAGE (ONLY APPLICABLE IF NOT 
COVERED IN THE CTA)
WRAP-IT
The WRAP-IT is a randomized, prospective, multi-center, single blinded, post-market,
interventional clinical study.  The study has three purposes.  First, the WRAP-IT study 
will serve as a post-approval study for those geographies requiring a post-approval study 
to facilitate collection of complications related to the Cardiovascular Implantable 
Electronic Device (CIED)  procedure or system in subjects randomized to receive the 
TYRXTM Absorbable Antibacterial Envelope (henceforth referred to as TYRX envelope).  
Next, this study will evaluate the ability of the TYRX envelope to reduce major CIED 
infections through 12-months post-procedure following CIED generator replacement, 
upgrade, revision, or de novo CRT-D implant.  Finally this large device study provides 
the unique opportunity to prospectively characterize the performance of Medtronic’s lead 
monitoring features in subjects whose CIED system includes a transvenous RV 
defibrillation lead.  
Clinical Investigation Plan Version 1.0 – 29 JUL 2014
I/we acknowledge that I/we have read, understood and agreed to abide by all conditions, 
instructions and restrictions contained in the above mentioned Clinical Investigation Plan. 
I/we agree to carry out all of its items in accordance with applicable regulations and in 
full compliance with the guidelines.
Hospital 
Title, First and last Name  
Signature 
Date (dd/MMM/yyyy)

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APPENDIX P: MODEL NUMBERS OF THE MARKET-RELEASED IPGs, CRT-Ps, ICDs
AND CRT-Ds IN THE RESPECTIVE GEOGRAPHIES
Device
Model
Respective Geography Model Numbers
United 
States
ANZ
Latin 
America
Brazil
Western 
Europe
CEE
Middle 
East
South 
Africa
Hong 
Kong
India
Malaysia
Singapore
IPG
Adapta
ADDR03
ADDR06
ADDRL1
ADDRS1
ADDRS1P
ADSR01P
ADSR03
ADSR06
ADDR01
ADSR01
ADVDD01
ADDR03
ADDR06
ADDRL1
ADDRS1
ADSR01P
ADSR03
ADSR06
ADDR01
ADSR01
ADVDD01
ADDR03
ADDRL1
ADDRS1
ADDRS1P
ADSR06
ADD01
ADDR01
ADSR01
ADVDD01
ADDR03
ADDR06
ADDRS1
ADSR03
ADSR06
ADDR01
ADSR01
ADDR01P
ADDR03
ADDR06
ADDRL1
ADDRS1
ADSR03
ADSR06
ADD01
ADDR01
ADSR01
ADVDD01
ADDRL1
ADDRS1
ADSR06
ADDR01
ADSR01
ADDR03
ADDRL1
ADSR03
ADD01
ADDR01
ADSR01
ADVDD01
ADDR03
ADDRL1
ADSR03
ADSR06
ADDR01
ADSR01
ADVDD01
ADDR03
ADDRL1
ADDRS1
ADSR03
ADSR06
ADDR01
ADSR01
ADDRL1
ADD01
ADDR01
ADSR01
ADVDD01
ADDRL1
ADDR01
ADDR03
ADDRL1
ADSR06
ADDR01
ADSR01
ADVDD01
Advisa
A2DR01
A4DR01
A3DR01
A5DR01
A2DR01
A3SR01
A3DR01
A5DR01
A3DR01
A3SR01
A5DR01
A3DR01
A3DR01
A5DR01
A3DR01
A3DR01
A5DR01
A3DR01
A3DR01
A5DR01
A3DR01
A5DR01
Ensura
EN1DR01
EN1DR01
EN1DR01
EN1DR01
EN1SR01
EN1DR01
EN1DR01
EN1DR01
EN1DR01
EN1DR01
EN1DR01
EN1DR01
Relia
REDR01
RESR01
EDR01
RES01
RESR01
REVDD01
RED01
REDR01
RES01
RESR01
REVDD01
RED01
REDR01
RES01
RESR01
REVDD01
REDR01
RES01
RESR01
REVDD01
REDR01
RESR01
RED01
REDR01
RES01
RESR01
RED01
REDR01
RES01
RESR01
REVDD01
RED01
REDR01
RES01
RESR01
RED01
REDR01
RES01
RESR01
REVDD01
Revo
RVDR01
RVDR01

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Sensia
SEDR01
SESR01
SEDRL1
SEDR01
SESR01
SEDRL1
SED01
SEDR01
SES01
SESR01
SEDR01
SESR01
SEDRL1
SED01
SEDR01
SES01
SESR01
SEDRL1
SED01
SEDR01, 
SES01
SESR01
SEDRL1
SED01
SEDR01
SES01
SESR01
SED01
SEDR01
SES01
SESR01
SEDRL1
SED01
SEDR01 
SES01
SESR01
SEDRL1
SED01
SEDR01 
SES01
SESR01
SEDRL1
SED01
SEDR01
SES01
SESR01
SEDRL1
SED01
SEDR01
SES01
SESR01
Versa
VEDR01
VEDR01
VEDR01
VEDR01
VEDR01
VEDR01
CRT-D
Brava
DTBC2D1
DTBC2D4
DTBC2D1
DTBC2D4
DTBC2D1
DTBC2D4
DTBC2D1
DTBC2D4
DTBC2D1
DTBC2D4
Brava Quad
DTBC2Q1
DTBC2QQ
DTBC2QQ
DTBC2Q1
DTBC2QQ
DTBC2QQ
DTBC2Q1 
DTBC2QQ
Protecta
D334TRG
D334TRM
D364TRG
D364TRM
D364TRG
D364TRG
D364TRM
D364TRG
D364TRM
D364TRG
D364TRM
D364TRM
D364TRM
D364TRG
D364TRM
D364TRG
D364TRM
Protecta XT
D314TRG
D314TRM
D354TRG
D354TRM
D314TRG
D314TRM
D354TRG
D354TRM
D314TRG
D354TRG
D354TRM
D354TRG
D354TRM
D354TRG
D354TRM
D354TRG
D354TRM
D354TRG
D354TRM
D354TRG
D354TRM
D354TRG
D354TRM
D354TRM
D354TRG
D354TRM
Viva S
DTBB1D1
DTBB1D4
DTBB2D1
DTBB2D4
DTBB2D1
DTBB2D4
DTBB2D1
DTBB2D4
DTBB2D1
DTBB2D4
DTBB2D4
DTBB2D4
Viva S Quad
DTBB2QQ
DTBB2QQ
DTBB2QQ
DTBB2QQ
Viva XT
DTBA1D1
DTBA2D1
DTBA2D1
DTBA2D4
DTBA1D1
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
DTBA2D1
DTBA2D4
Viva XT Quad
DTBA2Q1
DTBA2QQ
DTBA2QQ
DTBA2Q1
DTBA2QQ
DTBA2Q1
DTBA2QQ
DTBA2Q1
DTBA2QQ
DTBA2QQ
DTBA2QQ
DTBA2QQ
DTBA2QQ
DTBA2QQ
CRT-P
Consulta
C4TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
C3TR01
Syncra
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
C2TR01
Viva XT
C5TR01
C5TR01
C5TR01

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ICD
Evera S
DDBC3D1
DDBC3D4
DVBC3D1
DVBC3D4
DDBC3D1
DDBC3D4
DDMC3D4
DVBC3D1
DVBC3D4
DVMC3D4
DDBC3D1
DDBC3D4
DDMC3D4
DVBC3D1
DVBC3D4
DVMC3D4
DVBC3D1
DDBC3D1
DDBC3D4
DDMC3D4
DVBC3D1
DVBC3D4
DVMC3D4
DDBC3D1
DDBC3D4
DDMC3D4
DVBC3D1
DVBC3D4
DDBC3D1
DDBC3D4
DVBC3D4
Evera XT
DTBB1D1
DTBB1D4
DVBB1D1
DVBB1D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DVMB2D4
DDBB2D1
DTBB1D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DVMB2D4
DDBB2D1
DTBB2D4
DVBB2D1
DVBB2D4
DVMB2D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DVMB2D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DVMB2D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DDBB2D1
DDMB2D4
DTBB2D4
DVBB2D1
DVBB2D4
DDBB2D1
DTBB2D4
DVBB2D4
Protecta
D334DRG
D334DRM
D334VRG
D334VRM
D364DRG
D364DRM
D364VRG
D364VRM
D364VRG
D364DRG
D364DRM
D364VRG
D364VRM
D364DRG
D364DRM
D364VRG
D364VRM
D364DRG
D364DRM
D364VRG
D364VRM
D364DRG
D364DRM
D364DRG
D364DRM
D364VRG
D364VRM
D364DRM
D364VRG
D364VRM
D364DRM
D364VRG
D364VRM
Protecta XT
D314DRG
D314DRM
D314VRG
D314VRM
D354DRG
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1 
 
 
 
 
 
 
 
 
 
 
 
World-wide Randomized 
Antibiotic EnveloPe 
Infection PrevenTion Trial  
(WRAP-IT)  
 
Statistical Analysis Plan 
 
 
 
 
Version 1.0  
July 21, 2015 
 
 
 
 
 
 
Pei Li, Sr Statistician 
Kurt Stromberg, Sr Principal Statistician

2 
 
TABLE OF CONTENTS 
1 
PURPOSE ................................................................................................................................ 4 
2 
RATIONALE FOR STUDY DESIGN ....................................................................................... 4 
3 
DESCRIPTION OF ANALYSIS ............................................................................................... 5 
3.1 General Summaries .......................................................................................................... 5 
3.1.1 Description of Baseline Variables ........................................................................... 5 
3.1.2 Special Considerations ........................................................................................... 5 
3.1.2.1 
Pooling ................................................................................................................... 5 
3.1.2.2 
Missing Data ........................................................................................................... 5 
3.1.2.3 
Visit Windows ......................................................................................................... 5 
3.1.2.4 
Database Freeze .................................................................................................... 5 
3.1.2.5 
Randomization Date ............................................................................................... 5 
3.1.2.6 
Interim Analysis Type I Error Control ..................................................................... 6 
3.1.3 Early Study Success ............................................................................................... 7 
3.1.4 Reports for which this Statistical Analysis Plan applies ......................................... 7 
3.1.5 Analysis Cohort ...................................................................................................... 7 
3.2 Primary Objective .............................................................................................................. 8 
3.2.1 Hypothesis .............................................................................................................. 8 
3.2.2 Endpoint Definition ................................................................................................. 8 
3.2.3 Performance Requirements .................................................................................... 8 
3.2.4 Rationale for Performance Criteria ......................................................................... 8 
3.2.5 Analysis Methods ................................................................................................... 8 
3.2.6 Sample Size.......................................................................................................... 10 
3.2.7 Determination of Subjects’ Data for Analysis ....................................................... 12 
3.2.8 Missing Data ......................................................................................................... 12 
3.2.9 Subgroup analysis ................................................................................................ 13 
3.3 Secondary Objectives ..................................................................................................... 13 
3.3.1 Secondary Objective #1 ....................................................................................... 14 
3.3.1.1 
Hypothesis ............................................................................................................ 14 
3.3.1.2 
Endpoint ............................................................................................................... 14 
3.3.1.3 
Analysis Methods ................................................................................................. 14 
3.3.1.4 
Power to test the objective ................................................................................... 15 
3.3.1.5 
Determination of Subjects’ Data for Analysis ....................................................... 17 
3.3.1.6 
Missing Data ......................................................................................................... 17 
3.3.1.7 
Subgroup Analyses .............................................................................................. 17 
3.3.2 Secondary Objective #2 ....................................................................................... 17 
3.3.2.1 
Hypothesis ............................................................................................................ 18 
3.3.2.2 
Endpoint Definition ............................................................................................... 18 
3.3.2.3 
Analysis Methods ................................................................................................. 18 
3.3.2.4 
Determination of Subjects’ Data for Analysis ....................................................... 18 
3.3.2.5 
Missing Data ......................................................................................................... 19 
3.3.2.6 
Subgroup Analyses .............................................................................................. 19 
3.3.3 Secondary Objective #3 ....................................................................................... 19 
3.3.3.1 
Hypothesis ............................................................................................................ 19 
3.3.3.2 
Endpoint Definition ............................................................................................... 20 
3.3.3.3 
Analysis Methods ................................................................................................. 20 
3.3.3.4 
Determination of Subjects’ Data for Analysis ....................................................... 20 
3.3.3.5 
Missing Data ......................................................................................................... 20 
3.3.3.6 
Subgroup Analyses .............................................................................................. 21 

3 
 
3.4 Ancillary Objectives ......................................................................................................... 21 
3.4.1 Ancillary Objective #1:  Mortality .......................................................................... 21 
3.4.1.1 
Endpoint ............................................................................................................... 21 
3.4.1.2 
Hypothesis ............................................................................................................ 21 
3.4.1.3 
Analysis Methods ................................................................................................. 21 
3.4.1.4 
Determination of Subjects for Analysis ................................................................ 22 
3.4.2 Ancillary Objective #2:  CIED procedure success rate ......................................... 22 
3.4.2.1 
Analysis Methods ................................................................................................. 22 
3.4.2.2 
Determination of Data for Analysis ....................................................................... 23 
3.4.3 Ancillary Objective #3:  Summarize adverse events ............................................ 23 
3.4.3.1 
Analysis Methods ................................................................................................. 23 
3.4.3.2 
Determination of Data for Analysis ....................................................................... 23 
3.4.4 Ancillary Objective #4:  Predictors of CIED infection............................................ 23 
3.4.4.1 
Analysis Methods ................................................................................................. 24 
3.4.4.2 
Determination of Data for Analysis ....................................................................... 24 
3.4.5 Ancillary Objective #5: Quality of Life ................................................................... 24 
3.4.5.1 
Analysis Methods ................................................................................................. 24 
3.4.5.2 
Determination of Data for Analysis ....................................................................... 25 
3.4.6 Ancillary Objective #6:  Healthcare System Cost Effectiveness .......................... 25 
3.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
APPENDIX ............................................................................................................................. 33 
4.1 Sample Size Simulation Program ................................................................................... 33 
4.2 Information Fraction Simulation Program........................................................................ 44 
 

4 
 
1 
PURPOSE 
This Statistical Analysis Plan (SAP) has been designed to document, before data are analyzed, 
the rationale for the study design of the WRAP=IT study, and the planned analyses that will be 
included in study reports. This SAP does not limit the analysis in reports, and additional analysis 
of the study data beyond this plan is expected. 
2 
RATIONALE FOR STUDY DESIGN 
The World=wide Randomized Antibiotic EnveloPe Infection PrevenTion Trial (WRAP=IT) is a 
randomized, prospective, multi=center, single blinded, post=market, interventional clinical study.  
The study has three purposes.  First, the WRAP=IT study will serve as a post=approval study for 
those geographies requiring a post=approval study to facilitate collection of complications related 
to the Cardiovascular Implantable Electronic Device (CIED) procedure or system in subjects 
randomized to receive the TYRXTM Absorbable Antibacterial Envelope (henceforth referred to as 
TYRX envelope).  Next, this study will evaluate the ability of the TYRX envelope to reduce major 
CIED infections through 12=months post=procedure following CIED generator replacement, 
upgrade, or revision, or the implant of a de novo CRT=D.  Subjects undergoing CIED generator 
replacement, upgrade, or revision or the implant of a de novo CRT=D system will be randomized 
to either receive the TYRX envelope or not to receive the TYRX envelope.  Randomization will be 
1:1 and be stratified by study site and device type, high power (ICD and CRT=D) vs. low power 
devices (IPG and CRT=P).  Finally this large device study provides the unique opportunity to 
prospectively characterize the performance of Medtronic’s lead monitoring features in subjects 
whose CIED system includes a transvenous RV defibrillation lead.  These features include the 
lead integrity alert (LIA), lead noise alert (LNA), RV pacing impedance, and high voltage (HV) 
pacing impedance to detect events that affect a RV lead’s pacing, sensing, or defibrillation circuit 
lead system events (LSE).   
 
The study is expected to be conducted at up to 225 sites worldwide with up to 7,764 subjects 
enrolled in order to randomize approximately 6,988 subjects.  Enrollment of subjects receiving a 
replacement low power device (i.e. IPG or CRT=P) will be capped at approximately 25% of the 
total randomized study population (i.e. approximately 1,746 subjects).  Relative to high power 
device recipients, patients receiving a low power device may be at reduced risk of a major CIED 
infection. Thus, to ensure an adequate CIED infection event rate in the control arm, there is a 
desire to include a higher proportion of high power devices in the trial.  
The WRAP=IT study utilizes a group sequential design and has up to two planned analyses of the 
primary objective.  The first analysis will occur when a minimum of 3,200 randomized subjects 
complete the 6=month visit and the final analysis will occur when all randomized subjects have the 
opportunity to complete the 12=month study visit.  The study may be considered successful at the 
first analysis in which the primary objective is met.  An independent Data Monitoring Committee 
(DMC) will periodically review the accumulating data and review the results of the analysis of the 
primary objective at each pre=specified analysis time point.  Should the DMC indicate that the 
study is successful at the interim analysis, the study may continue to enroll and follow subjects to 
evaluate the effect of the TYRX envelope on CIED infections that develop post=12 months as well 
as collect additional follow=up in subjects with a defibrillation system in which to evaluate the lead 
monitoring features.  However, subjects enrolled following review of the interim analysis may no 
longer be randomized upon recommendation of the DMC if the TYRX envelope is found to have a 
clear benefit.   
 
The WRAP=IT Study Clinical Investigational Plan Version 1.0 was used to develop the SAP. 
 

5 
 
3 
DESCRIPTION OF ANALYSIS 
3.1 General Summaries 
3.1.1 Description of Baseline Variables 
Standard baseline and relevant medical history will be collected on the eCRFs for all enrolled 
subjects.  Baseline and medical history variables to be summarized include, but are not limited to:  
age, sex, race, device type (CRT=D, ICD, CRT=P, and IPG), number of previous CIED devices, 
NYHA class, arrhythmia history, and baseline medication use. 
 
For continuous variables, mean, standard deviation, median, and range will be reported.  For 
categorical variables, frequency and percentage will be reported.  Baseline information will be 
summarized for all randomized subjects.  The TYRX envelope and control groups will be 
compared using T=tests for continuous variables and the Chi=square test for categorical variables 
to quantify any imbalance in treatment groups. 
 
3.1.2 Special Considerations 
3.1.2.1 
Pooling 
The study may be conducted at up to 225 sites worldwide.  Data from all centers that participate 
in this protocol will be combined for analysis. Expected participating geographies include, but are 
not limited to, the United States (US), Europe, the Middle East and Africa (EMEA), Greater China 
(Hong Kong), New Zealand, Latin America, the Association of South East Asian Nations (ASEAN) 
(Singapore and Malaysia), and India. However, since the majority of study centers will come from 
the US and the primary endpoint is likely to be rare, the primary objective results for US and 
outside the US (OUS) geographies will be presented and poolability analysis will be done. If a 
differential treatment effect (P<0.05) is observed, we will investigate the cause of the differential 
treatment effect (e.g. by comparing baseline characteristics, procedure information and the 
medical practice etc).  
 
3.1.2.2 
Missing Data 
If applicable, treatment of missing data is addressed within each objective. 
 
3.1.2.3 
Visit Windows 
As the visit windows are meant as a guideline for centers, data from CRFs dated outside of the 
prescribed visit windows in the CIP will be used in all analyses.       
3.1.2.4 
Database Freeze 
The visit cut=off date for the database freeze for the interim analysis will be the first date when  a 
minimum of 3200 randomized subjects complete the 6=month visit.  The visit cut=off date for the 
database freeze for the final analysis will be the date when all randomized subjects have had the 
opportunity to complete the 12=month study visit.      
 
3.1.2.5 
Randomization Date 
There may be instances where the date and timestamp for the randomization process in 
the electronic database where randomization is performed may be after the date of the 
CIED procedure.  This occurs when randomization is performed outside of the database 
(e.g. cases where Oracle Clinical is not accessible by the site) and the randomization 

6 
 
routine in the electronic database is executed to document the randomization process on a 
later date.   For such cases, the randomization date will come from the randomization or 
implant procedure eCRF, which ever came first. 
 
3.1.2.6 
Interim Analysis Type I Error Control 
The study has up to two planned analyses of the primary objective.  The study may be considered 
successful at the first analysis in which the primary objective is met.   
 
The first analysis will occur when approximately 50% of the total follow=up within 12=months of 
randomization occurs; based on enrollment projections described below this is defined as the 
point where 3200 randomized subjects complete the 6=month post=procedure visit.  The purpose 
of this first analysis is two=fold: 
 
1. To assess whether the study’s primary objective has been met.  If the DMC indicates that 
the study has met its objective, the study may continue to enroll and follow subjects to 
study the effect of the TYRX envelope on long=term CIED infections as well as 
accumulate LSEs.  However, subjects enrolling following review of the interim analysis 
may no longer be randomized upon recommendation of the DMC if the TYRX envelope is 
found to have a clear benefit.  
  
2. To assess whether the study may end earlier than planned for futility. 
 
The timing of the interim analysis was selected so that sufficient data is collected to contribute to 
the interim analysis before decisions that impact the study are made.  The Hwang=Shih=DeCani 
alpha spending function with a gamma parameter of negative 4 (=4) is used to control the overall 
alpha level at 5% (two=sided; 2.5% one=sided in the direction favorable to the TYRX envelope).  
This function spends the alpha at a level analogous to the O’Brien=Fleming boundary.  The 
boundary condition at the interim analysis will be based on the information fraction at the interim 
analysis and computed by dividing the accrued number of major CIED infections observed at the 
interim analysis by the total number of major CIED infections anticipated at the final analysis.   
 
To obtain the information fraction, a simulation will be performed to estimate the anticipated 
number of events pooled across both treatment groups which are expected to happen after the 
interim analysis.  The event=free survival function is assumed to be piecewise exponential with 
two intervals (interval cutoff to be determined at interim analysis based on observed data).  The 
hazard parameter in each interval will be estimated by data observed at interim analysis.  Then 
complete follow=up data will be simulated to estimate of number of events by end of study. 
Sample R code for performing this simulation is found in section 4.2. 
 
Assuming the information fraction at the interim analysis is 50%, the boundary condition at the 
interim analysis is 0.003 (2.75 on the Z=scale or 0.006 on the two=sided p=value scale) and is 
purposely low to allow early claims of study success only when the TYRX envelope is highly 
effective.  At the final analysis, the boundary condition is 0.0238 (1.98 on the Z=scale or 0.0476 
on the two=sided p=value scale) when the information fraction is 50% at the interim analysis.  
Since the analytical methods for the secondary objectives also utilize survival analysis methods, 
the same alpha spending function will be used to compute the success boundaries for the 
secondary objectives. 
 
If the primary objective of the study is met, the secondary objectives will be tested using the Holm 
procedure to protect the overall type I error rate of the study and allow statistically valid claims of 
significance.  Specifically, at analysis k (k=1,2), the ordered hypotheses H(1k), H(2k), H(3k) 
corresponding to the ordered p=values p(), p(), p(	) of the secondary objectives will be 
tested based off the sequentially rejective algorithm.  The hypothesis H(1k) is rejected if p() ≤

7 
 
 3
⁄ .  Futher, H(jk) is rejected at the jth step if p() ≤ (3 − + 1)
⁄
. Otherwise, H(jk),L H(3k) are 
retained and the algorithm terminates. 
 
To help assess whether the study may end earlier than planned for futility, stochastic curtailment 
methods will be used to calculate the futility index for the primary objective.  The futility index (1=
P1, where P1 is the predictive power observed at the interim analysis) is based on predictive 
power as computed as: 
 
 = Φ   −
 −
 
 
where Z1 is the test statistic at the interim analysis, I1 is the information fraction at the interim 
analysis, I2 is the information fraction at the final analysis (will be considered 1 at the interim 
analysis), and zα is the critical value at the final analysis based on the alpha spending function.  
Although non=binding, a futility index greater than 0.9 at the interim analysis provides strong 
evidence that the study will not achieve its primary objective if the study were to continue to its full 
sample size and follow=up. 
3.1.3 Early Study Success 
Should the DMC indicate that the study is successful at the interim analysis, the study may 
continue to enroll and follow subjects to evaluate the effect of the TYRX envelope on CIED 
infections that develop post 12 months as well as collect additional follow=up in subjects with a 
defibrillation system in which to evaluate the lead monitoring features.  If the study were to 
continue to enroll, it is anticipated that all subjects enrolled after the interim analysis would 
receive the TYRX envelope.  Thus, for the final report, only those subjects randomized prior to 
the decision to end randomized allocation of the TYRX envelope would be included in the 
analysis of the primary and secondary objectives as well as ancillary objective #1.   
3.1.4 Reports for which this Statistical Analysis Plan applies 
This SAP applies to the interim analysis report and final report.  However, the interim analysis 
report will likely evaluate the primary and secondary objectives as well as ancillary objective #1.  
This SAP also applies to the main study manuscript, though not everything specified here will be 
included in the manuscript.  
3.1.5 Analysis Cohort 
 
Intention=to=Treat (ITT):  The ITT analysis cohort will include all randomized subjects in the 
groups to which they are randomized regardless of treatment received and will serve as 
the primary analysis cohort for each objective unless otherwise specified.  The ITT cohort 
will likely be the only cohort evaluated at the time of the interim analysis. 
 
As Treated (AT):  The AT cohort includes subjects in the ITT cohort but analyzes subjects 
using the treatment they actually received at the time of their initial procedure.  For 
subjects with a TYRX envelope this means the TYRX envelope remained in the pocket 
following pocket closure. 
 
modified As Treated (mAT):  The mAT cohort includes all subjects and follow=up time in the 
AT cohort that were successfully implanted with a CIED system (including the TYRX 
envelope if subject had a successfully placed TYRX envelope) up until the point where a 
CIED modification (i.e. system modification) occurred.  Thus, subjects with a system 
modification for reasons other than device infection will be considered censored at the time 
of the system modification. 
 

8 
 
3.2 Primary Objective 
The primary study objective is to compare the rate of major CIED infections through 12=
months post=procedure between the TYRX envelope group and the control group (no 
TYRX envelope). 
 
3.2.1  Hypothesis 
The primary study objective will be tested with the following hypothesis: 
 
Ho: λT(t) = λc(t) for all t ≤ 12 months (365 days), versus 
Ha: λT(t) ≠ λc(t) for some t ≤ 12 months (365 days) 
 
where λT(t) is the hazard function for major CIED infection in the TYRX envelope group and 
λc(t) is the hazard function for major CIED infection in the control group. 
3.2.2 Endpoint Definition 
CIED infections are defined as: (1) superficial cellulitis in the region of the CIED pocket 
with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space 
(generator pocket) surgical site infection (SSI) that meet the Centers for Disease Control 
and Prevention (CDC) criteria, independent of time from surgery (3) persistent bacteremia 
or (4) endocarditis.  
 
Major CIED infections are defined as CIED infections resulting in one or more of the 
following: 
• CIED system removal 
• Any invasive procedure (e.g. pocket opened) without system removal 
• Treatment with antibiotic therapy if the subject is not a candidate for system removal 
and infection recurrence after completion of antibiotic therapy or evidence of deep 
infection with wound dehiscence, erosion, or purulent drainage. 
• Death 
 
3.2.3 Performance Requirements 
If the hazard ratio : λT(t) /λc(t) is significantly different from 1 (and less than 1), the major 
infection rate will be considered lower in the TYRX group.  
3.2.4 Rationale for Performance Criteria 
This study will evaluate the ability of the TYRX envelope to reduce major CIED infections 
through 12=months post=procedure following CIED generator replacement, upgrade, or 
revision, or the implant of a de novo CRT=D system.  The hazard ratio is significantly 
different if the nominal p=value is less than the specified type I error boundary as 
determined by the Hwang=Shih=DeCani alpha spending function described above. 
 
3.2.5 Analysis Methods 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the primary endpoint.  The primary method to be used to test the primary 
objective will be the Cox proportional hazard model.  The Cox model will be stratified by 
device type (low power versus high power) the subject is to receive as documented on the 
randomization eCRF and include treatment as an independent variable.  This stratified Cox 
model assumes that the baseline hazard may be different for each device type, but that the 

9 
 
underlying treatment effect is constant across device type.  Days of follow=up for each 
subject will be set to the minimum of days from last procedure attempt (or randomization if 
the subject was randomized but no procedure attempt) to: (1) onset date of a subject’s first 
CIED infection meeting the primary endpoint, (2) study exit date (if exited), (3) date of 
death (if death occurs), (4) date of last follow=up, or (5) 365 days post=procedure.  
However, if a subject has a major CIED infection during an unsuccessful procedure 
attempt; days of follow=up will be set to zero.    Subjects not meeting the primary endpoint 
during the follow=up period will be considered censored at the end of their follow=up period 
as derived above.  Based on this statistical test, it will be claimed that the TYRX envelope 
reduces major CIED infection if the hazard ratio estimate is less than one and the resulting 
p=value from the Wald test falls below the specified type I error boundary as determined by 
the Hwang=Shih=DeCani alpha spending function.  Kaplan=Meier plots of freedom from 
major CIED infection will be presented by treatment group and by treatment group within 
each device type. 
 
The following sample syntax in SAS will be used to evaluate the primary objective: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     strata device; 
     *different baseline h0 but same HR across device** 
run;  
 
Sample R=code to fit the stratified Cox model is also displayed below: 
 
coxph(Surv(survData$survDays,survData$survStatus)~survData$trt + 
strata(survDat$device)) 
 
 
If the primary objective is met at either the interim or final analysis time point, the following 
two assumptions will be tested: 
 
 
1. Heterogeneity of the hazard ratio across device type: 
The following sample syntax in SAS will be used to evaluate the homogeneity of 
treatment effect across device types for primary objective.  If the interaction effect 
is significant at 0.05 level the treatment effect will not be assumed constant across 
device type and separate analyses will be performed for each device type. 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt device trt*device; 
run;  
 
2. Proportional hazards between treatment groups: 
The proportional hazards assumption for the treatment effect will be examined 
graphically by examining plots of the complementary log=log CIED infection free 
time versus log time.  Additionally, an interaction between event time and 
treatment group will be added to the model.  If this interaction term is significant at 
the 0.05 level then this may provide evidence that the proportional hazards 
assumption is violated.  Should the proportional hazards assumption be violated, 
inference regarding the effect of the TYRX envelope may be made at several 
different time points (e.g. 1=month, 6=months, and 12=months post=procedure).  
The following SAS code implements the test of the proportional hazards 
assumption: 

10 
 
 
*** PLOT THE COMPLEMENTARY LOG LOG; 
 proc lifetest data=<data> plot=(s, lls) noprint; 
   
      time time*censor(0); 
  
      strata trt; 
  
      group device; 
 run;  
 
*** TEST THE TIME VERSUS TREATMENT EFFECT; 
proc phreg data=<data>; 
 
CLASS trt device; 
 
model eventtime*event(0)=trt trtTime; 
 
trtTime = trt*log(eventtime); 
 
strata device; 
run; 
 
 
3.2.6 Sample Size 
 
Background 
The reported prevalence rate of CIED infection varies widely in the literature and is 
dependent on the nature of data collection (retrospective vs prospective, single center vs 
multi=center), CIED infection definition, and population studied.  The REPLACE study 
prospectively evaluated CIED infection requiring system removal or intravenous antibiotics 
in 1744 subjects undergoing a device replacement or upgrade.  The infection rate at 6=
months post=procedure for subjects receiving a device replacement was 1.4% and 1.1% for 
those subjects undergoing a device upgrade.  
 
Analysis of 103,020 device implant claims from Medicare evaluated for Medtronic by 
Truven Analytics suggested that subsequent invasive procedures related to device 
infection occurred at a rate of 4.0% for CRT=D, 3.9% for ICDs, and 2.6% for pacemakers 
through 12=months.  The 12=month CIED infection rate associated with replacement 
devices was 4.1% for CRT=D, 5.4% for ICDs, and 3.4% for pacemakers with 12=month 
infection rates associated with initial device implants ranging from 4.0% in CRT=Ds to 2.2% 
in pacemakers.  However, examination of CIED infections reported in Medtronic studies, 
suggests that the Medicare claims data may overestimate the CIED infection rate that may 
be observed in clinical trials for initial implants by at least 50% (Table 1).   
 
Table 1: 12-Month Infection Rates for Initial Implants by Device Type and Data Source 
 
Data Source
Device
Medicare Claims 
Data 
12-Month CIED 
Infection Rate 
Medtronic Studies (12-
month CIED Infection Rate 
(95% CI)) 
CRT=D 
4.1% 
2.0% (1.2% = 3.4%)1
ICD 
3.0% 
1.5% (0.3% = 6.7%)2
Pacemaker 
2.2% 
1.2% (0.8% = 1.7%)3
1Based on 753 subjects with an attempted CRT=D implant in the REVERSE and 
BLOCK=HF studies.  
2Based on 246 subjects from the Model 6947, 6948, and 6949 RV defibrillation lead 
studies 
3Based on 2799 subjects from the 3830, 4074, 5076, Advisa MRI, EnRhythm, 
EnRhythm MRI, and SAVEPACe studies.
 

11 
 
Based on the assumption that the Medicare claims data may overestimate the actual CIED 
infection rate that may be observed in a clinical trial, it is hypothesized that the 12=month 
infection rate for initial CRT=D implants, replacement (or upgrade) CRT=D implants, and 
replacement (or upgrade) ICD implants is 2.4% and is 0.6% for replacement pacemaker 
implants.  Since low power replacement procedures (i.e. pacemaker and CRT=P 
replacement procedures) will be capped at 25% of the total sample size, an overall 12=
month CIED infection rate for the control group is assumed to be 2% for sample size 
calculation purposes. 
 
Retrospective evidence from the COMMAND study demonstrated that in 624 subjects 
consecutively implanted with the TYRX envelope the CIED infection rate was 0.48% and 
ranged from 0% during initial implant procedures to 1.05% during ICD/CRT=D 
replacement/revision procedures.  Additionally, recently published data from Mittal, et. al 
showed that the CIED infection rate was 1.1% in 275 subjects that received the TYRX 
envelope compared to 3.6% in 275 propensity matched control subjects over a 6=month 
period across both low power and high power devices.  Finally, early evidence from the 
CITADEL/CENTURION studies suggests that CIED infection rate among a cohort of 1000 
ICD/CRT=D subjects receiving the TYRX envelope is 0.2% at 6=months post=
replacement/upgrade; a 9=fold decrease compared to published controls at 6=months.  
Based on this experience, it is assumed that the TYRX envelope will reduce the risk of 
CIED infection by 50% through 12=months post=procedure. 
 
Sample Size Calculation 
The sample size is derived based on the following assumptions: 
1. One=to=one randomization to the TYRX envelope or control group 
2. Power to test the primary objective is at least 90% 
3. One interim analysis and final analysis 
4. The interim analysis will occur when approximately 50% of the statistical information 
has been accrued 
5. One=sided alpha level of 2.5% 
6. Hwang=Shih=DeCani alpha spending function with a gamma parameter of negative 4 
(=4) which approximates O’Brien=Fleming boundaries 
7. Assumed control CIED infection rate of 2% at 12=months 
a. 2.4% for high power (CRT=D/ICD) devices 
b. 0.6% for low power (pacemaker/CRT=P) devices 
c. Low power devices are capped at 25% of the required sample size 
8. TYRX envelope assumed to reduce the control infection rate by 50% 
9. Non=binding futility assessment based on stochastic curtailment at the interim 
analysis 
10. 15% annualized attrition rate that is independent of treatment group and infection 
status 
 
The method of Lakatos (1988) as implemented in the POWER procedure of SAS v9.2, 
indicated 6,988 randomized subjects (3,494 randomized to each group) are required to test 
the primary objective based on the assumptions described above.  Thus, up to 7,764 
subjects may be enrolled to allow for up to a 10% discontinuation rate between enrollment 
(i.e. subject consent) and randomization.   
 
A simulation study was performed to confirm the sample size calculation.  In addition to the 
sample size assumptions described above, the simulation assumed that 50% of CIED 
infections occur within the first month of device procedure.  Simulations were performed 
when the CIED infection risk reduction associated with the TYRX envelope ranged from 
0% (null case) to 60%.  Figure 1 confirms the sample size calculation and demonstrates 
that the type I error rate is well controlled.  The program used to conduct the simulation 
analysis is found in section 4.1. 
 

12 
 
Figure 1:  Empirical Power to Test the Primary Objective (n=6,988)   
 
 
3.2.7 Determination of Subjects’ Data for Analysis 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention=to=Treat principle).  Sensitivity 
analyses may be conducted by evaluating the performance of the TYRX envelope the AT 
or mAT cohorts as described above. 
 
If the primary objective is not met for the ITT cohort, the analysis will be conducted for the 
AT/mAT cohorts.  
3.2.8 Missing Data 
The primary analysis cohort will include all follow=up from all randomized subjects through 
the 12=month visit or 365 days post=randomization, whichever occurs first. Since the 
primary statistical methods involve survival methods all follow=up from all randomized 
subjects will be included.  However, missing data could arise if a randomized subject exits 
the study or dies prior to the 12=month visit without experiencing a CIED infection meeting 
the primary endpoint.  The log=rank test will be used to compare the study attrition rate for 
any reason (study exit or death) between randomized treatment groups to evaluate the 
pattern of data missingness by treatment group.  
 
Additionally, as many cardiology journals are now requesting sensitivity analyses that 
include competing risk for death, a competing risks model will be used to test the effect of 
the TYRX envelope in the presence of competing risk of death unrelated to CIED infection 

13 
 
should the study meet its primary objective.  Sample R code for implementing the stratified 
competing risks model is as follows as recently described by Zhou et. al1 is provided below: 
 
R syntax below will be used to evaluate treatment effect on CIED infection with 
consideration of competing risk of death unrelated to CIED infection: 
 
Library(crrSC) 
Crrs(time, status, cov,strata,failcode=2,cencode=0)   
 
# Status: 0 censor, 1 death unrelated to CIED infection, 2 CIED infection 
# Cov: 0 control, 1 envelope 
# Strata: low=1 high=2 
 
3.2.9 Subgroup analysis 
Subgroup analysis will be performed for subjects within high power (CRT=D, ICD) devices 
and patients with low power (pacemaker, CRT=P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
low to high power ) and patients without device upgrade will be analyzed separately.  
Additional subgroup analyses may also be performed on a post hoc basis. 
 
The following sample syntax in SAS will be used for the subgroup analysis: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     by device; 
run;  
 
Additionally, an interaction between the treatment group and subgroup will be added to the 
model to test for homogeneity of the treatment effect across subgroups.  If this interaction 
term is significant at the 0.05 level the treatment effect will be considered heterogeneous 
between subgroups. 
 
proc phreg data=<data>; 
    CLASS trt subGroup; 
    model eventtime*event(0)=trt subgroup trt*subGroup; 
    run; 
 
3.3 Secondary Objectives 
The following secondary objectives will be evaluated to gain additional information about 
the safety and efficacy of the TYRX envelope in the study population.  Provided the 
primary objective of the study is met with a statistically significant p=value, then the 
secondary objectives will be assessed.  The Holm procedure will be used to control the 
family=wise type I error rate as described in section 3.1.2.6 in order to make statistically 
valid claims of significance. 
                                                     
1 B. Zhou, A. Latouche, V. Rocha, J. Fine.  2011.  Competing risks regression for stratified data.  Biometrics 67: 
661=670. 

14 
 
3.3.1 Secondary Objective #1 
 
Confirm that the TYRX envelope does not increase the CIED procedure=related or system=
related complication rate through 12=months post=procedure.   
3.3.1.1 
Hypothesis 
 
The first secondary objective will be tested with the following non=inferiority hypothesis: 
 
Ho: λT(t)/λc(t) ≥ 1.33 for t ≤ 12 months (365 days), versus 
Ha: λT(t)/λc(t) < 1.33 for t ≤ 12 months (365 days) 
 
where λT(t) is the hazard function for CIED system= or procedure=related complications in 
the TYRX envelope group and λc(t) is the hazard function for CIED system=related 
complications in the control group.  Rejecting the null hypothesis would indicate that the 
TYRX envelope does not increase the CIED system= or procedure=related complication 
rate by more than 33% on a relative scale or 4.4% on a linear scale when the underlying 
CIED system or procedure complication freedom rate at 12=months is 85%.  
 
3.3.1.2 
Endpoint 
 
A CIED system=related complication is defined as an adverse event that meets the 
complication definition as determined by the CEC and is considered by the CEC to be 
related to one of the implanted CIED system components (i.e. device, RV lead, RA lead, 
LV lead, other lead, or the TYRX envelope). 
 
A CIED procedure=related complication is defined as an adverse event that meets the 
complication definition as determined by the CEC and is considered by the CEC to be 
related to the CIED procedure (i.e. replacement/upgrade/new implant/revision) or a system 
modification including the TYRX envelope (if applicable). 
 
3.3.1.3 
Analysis Methods 
 
All potential adverse events potentially related to the implanted system (i.e. device, leads), 
the TYRX envelope, or the CIED replacement/upgrade/implant or system modification 
procedure will be reported on the eCRFs as they occur.  The CEC will adjudicate each 
reported adverse event for its relationship to the CIED system and CIED procedure.  
Additionally, the CEC will classify each CIED system=related or procedure=related adverse 
event as a complication or observation.  Days of follow=up for each subject will be set to 
the minimum of days from last procedure attempt (or randomization if a subject was 
randomized but not implanted) to:  (1) onset date of a subject’s first CIED system related or 
procedure related complication (including the TYRX envelope where applicable), (2) study 
exit date (if exited), (3) date of death (if death occurs), , 4) date of last follow=up, or (5) 365 
days post=procedure.  Subjects with a procedure= and/or system=related complication 
occurring prior to their last CIED procedure attempt will their event date set to day zero.  
Subjects not having a CIED system=related or procedure=related complication during the 
follow=up period will be considered censored on the day as derived above. 
 
The effect of the TYRX envelope on the rate of CIED system= or procedure=related 
complications will be tested using a Cox proportional hazards regression model stratified 
by device type (low power versus high power) containing an indicator term for treatment 
group.  The observed hazard ratio from the Cox model will be compared to the non=

15 
 
inferiority margin of 1.33.  The null hypothesis will be rejected in favor of the alternative and 
the TYRX envelope will be considered non=inferior to the control group if the p=value 
computed from the non=inferiority test is less than the type I error boundary as determined 
by the Hwang=Shih=DeCani alpha spending function and Holm adjustment for multiple 
comparisons.  Kaplan=Meier plots of freedom from system= or procedure=related 
complications will be presented by treatment group and by treatment group within each 
device type. 
 
 
The following sample syntax in SAS will be used to evaluate the second objective #1: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     estimate trt 1/testvalue=0.285 lower;  **ln(1.33)=0.285** 
     strata device; 
run;  
 
If secondary objective #1 is met at either the interim or final analysis time point, the 
following two assumptions will be tested in an analogous fashion as described for the 
primary objective: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 
3.3.1.4 
Power to test the objective 
 
Background 
Table 2 displays the procedure= or system=related complication rates from several 
Medtronic and non=Medtronic sponsored studies.  These data indicate that complications 
related to the implanted system (i.e. device and leads) or procedure range from 4.0% to 
24.7% depending on complication definition, devices studied, and study population.  Based 
on these data it appears reasonable based on the mix of devices and population under 
investigation in the WRAP=IT study that the underlying system or procedure complication 
free rate could range from 80% to 90% at 12=months post=procedure. 
 

16 
 
Table 2: System or Procedure-Related Complications Reported Previous Studies 
Study 
Devices 
Studied 
Population 
Time 
Frame 
Complication Rate (95% 
CI) 
Gould et. al 20081 
ICD (n=451) 
Replacements 
12=months 
9.1% (NR) 
REPLACE2 
IPG (n=515) 
ICD (n=327) 
CRT=D (n=175) 
CRT=P (n=14) 
Replacements 
6=months 
4.0% (2.9%=5.4%) 
REPLACE 
IPG (n=329) 
ICD (n=320) 
CRT=D (n=49) 
CRT=P (n=15) 
Upgrades 
6=months 
15.3% (12.7% = 18.1%) 
BLOCK=HF 
CRT=D (n=230) 
New Implants 
12=months 
22.9% (18.0% = 29.0%) 
BLOCK=HF 
CRT=P (n=531) 
New Implants 
12=months 
17.7% (14.7% = 21.3%) 
REVERSE 
CRT=D (n=523) 
New Implants 
12=months 
17.0% (14.0% = 20.5%) 
REVERSE 
CRT=P (n=104) 
New Implants 
12=months 
24.7% (17.5% = 34.4%) 
4074 Study 
IPG (n=132) 
New Implants 
6=months 
13.9% (9.0% = 21.1%) 
EnRhythm MRI3
IPG (n=469) 
New Implants 
12=months 
11.3% (8.8% = 14.6%) 
Advisa MRI3
IPG (n=269) 
New Implants 
6=months 
9.2% (6.3% = 13.4%) 
1Gould et. al.  2008. Heart Rhythm 5: 1675=1681.  Major complication defined as post=operative death, nonfatal 
MI, cardiogenic shock, or event requiring reoperation. 
2Poole et. al. 2010. Circulation 122:1553=1561.  Major complications defined as an event defined in Table 1 of 
the manuscript.  In general major complications required invasive intervention. 
3Does not include system complications related to the RA lead only. 
 
Power Calculation 
Since the primary objective of the study dictates the sample size for the study, the power to 
test this secondary objective under several scenarios was determined based on the 
method of Lakatos as implemented in PASS 2008.  The following assumptions were made 
in the power calculation: 
1. Sample size of 6,988 subjects randomized 1:1 to the TYRX envelope or control 
group 
2. One interim analysis and final analysis 
3. The interim analysis will occur when approximately 50% of the follow=up is accrued 
4. One=sided alpha level of 2.5% 
5. Hwang=Shih=DeCani alpha spending function with a gamma parameter of negative 4 
(=4) which approximates O’Brien=Fleming boundaries and means the final test will 
be conducted at a one=sided alpha=level of 0.0238 which is analogous to a two=
sided alpha level of 0.0476. 
6. 15% annualized attrition rate that is independent of treatment group and system=
related complication 
7. 12=month system= or procedure=related complication rate in the control group could 
range from 10% to 20% 
8. The TYRX envelope has no effect on the system= or procedure=related complication 
rate 
9. Non=inferiority margin of 33% on a relative scale or 4.4% on a linear scale when the 
underlying CIED system complication freedom rate at 12=months is 85% 
Table 3 indicates that the statistical power to test the non=inferiority hypothesis associated 
with secondary objective #1 is greater than 94% based on the assumptions above across a 
range of plausible control group event rates. 

17 
 
 
Table 3:  Power to Test Secondary Objective #1 with Sample Size of 6,988 Subjects 
12-month system-
related Complication 
Free Rate 
Control Group 
Hazard Rate 
Non-inferiority 
Margin (Relative 
Scale) 
Non-inferiority Margin 
(Linear Scale)1 
Power 
90% 
0.1054 
1.33 
3.1% 
94.9% 
88% 
0.1278 
3.6% 
97.6% 
86% 
0.1508 
4.2% 
98.9% 
85% 
0.1625 
4.4% 
99.3% 
84% 
0.1744 
4.7% 
99.5% 
82% 
0.1985 
5.2% 
99.8% 
80% 
0.2231 
5.7% 
99.9% 
1The non=inferiority margin on the linear scale is defined as the difference in the survival curves for the event rate at 12=
months post=randomization between the control group and the TYRXTM Absorbable Antibacterial Envelope group. 
 
3.3.1.5 
Determination of Subjects’ Data for Analysis 
Since non=inferiority tests based on intention=to=treat principles may be anti=conservative, 
the results of the non=inferiority test will be reported for both the ITT and AT cohorts as 
recently suggested2.  However, statistical inference for this objective will be based on the 
AT cohort.  All randomized subjects and all follow=up from randomized subjects is included 
in the ITT cohort regardless of treatment received.  For the AT cohort, all follow=up from all 
subjects will be included, but the analysis will be based on the treatment the subject 
actually received at the time of their original CIED procedure. 
3.3.1.6 
Missing Data 
 
The analysis cohorts will include all follow=up from all randomized subjects through the 12=
month visit or 365 days post=randomization, whichever occurs first.  Since the statistical 
methods involve survival methods all follow=up from all randomized subjects will be 
included.  However, missing data could arise if a randomized subject exits the study or dies 
prior to the 12=month visit without experiencing a CIED system= or procedure=related 
complication.  As described in section 3.2.8 the log=rank test will be used to compare the 
study attrition rate for any reason between randomized treatment groups to evaluate the 
pattern of data missingness. 
 
3.3.1.7 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high power (CRT=D, ICD) devices 
and patients with low power (pacemaker, CRT=P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
lower to high power) and patients without device upgrade will be analyzed separately using 
the methods described in section 3.2.9. 
3.3.2          Secondary Objective #2 
 
Compare the major CIED infection rate during the entire follow=up between the TYRX 
envelope group and the control group. 
 
                                                     
2 Head, SJ et al.  2012.  Non=inferiority study designs:  lessons to be learned from cardiovascular trials.  European 
Heart Journal 33(11): 1318=1325. 

18 
 
3.3.2.1 
Hypothesis 
The second secondary objective will be tested with the following hypothesis: 
 
Ho: λT(t) = λc(t) for all t ≤ T, versus 
Ha: λT(t) ≠ λc(t) for some t ≤ T 
 
where λT(t) is the hazard function for major CIED infection in the TYRX envelope group 
and λc(t) is the hazard function for major CIED infection in the control group during the 
entire follow=up period.  
 
 
3.3.2.2 
Endpoint Definition 
 
Major CIED infection is defined in section 3.2.2. 
3.3.2.3 
Analysis Methods 
 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  The primary method to be used to 
test this objective will be the Cox proportional hazard model.  The Cox model will be 
stratified by device type (low power versus high power) and include treatment as an 
independent variable.  Days of follow=up for each subject will be set to the minimum of 
days from last procedure attempt (or randomization if a subject was randomized but not 
implanted) to: (1) onset date of a subject’s first CIED infection meeting the primary 
endpoint, (2) study exit date (if exited), (3) date of death (if death occurs), or, (5) date of 
last follow=up.  Subjects who meet the endpoint prior to their last CIED procedure attempt 
will be considered to have met the endpoint on day zero.  Subjects not having a major 
CIED infection during the follow=up period will be considered censored at their last follow=
up day.  Based on this statistical test, it will be claimed that the TYRX envelope reduces 
major CIED infection during the entire study period if the hazard ratio estimate is less than 
one and the resulting p=value from the Wald test falls below the specified type I error 
boundary as determined by the Hwang=Shih=DeCani alpha spending function and Holm 
adjustment for multiple comparisons.  Kaplan=Meier plots of freedom from major CIED 
infection will be presented by treatment group and by treatment group within each device 
type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5.  
 
If secondary objective #2 is met at either the interim or final analysis time point, the 
following two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 
 
 
 
3.3.2.4 
Determination of Subjects’ Data for Analysis 
 

19 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention=to=Treat principle).   
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT/mAT 
cohorts. 
 
3.3.2.5 
Missing Data 
The primary analysis cohort for this objective will include all follow=up from all randomized 
subjects through the end of the study or visit cutoff for the interim analysis (i.e. Intention=to=
Treat principle).  Since the statistical methods involve survival methods all follow=up from 
all randomized subjects will be included.  However, missing data could arise if a 
randomized subject exits the study or dies prior to the end of the study (or visit cutoff) 
without experiencing a major CIED infection.  The log=rank test will be used to compare the 
study attrition rate for any reason (study exit or death) between randomized treatment 
groups to evaluate the pattern of data missingness by treatment group.   
 
Additionally, a competing risks model will be used to test the effect of the TYRX envelope 
in the presence of the competing risk of death unrelated to CIED infection should this 
objective be met as described in section 3.2.8. 
 
3.3.2.6 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high power (CRT=D, ICD) devices 
and patients with low power (pacemaker, CRT=P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
low to high power) and subjects without device upgrade will be analyzed separately using 
the methods described in section 3.2.9. 
 
3.3.3          Secondary Objective #3 
 
Compare the rate of major and minor CIED infections through 12=months post=procedure 
between the TYRX envelope group and the control group.   
 
3.3.3.1 
Hypothesis 
The third secondary objective will be tested with the following hypothesis: 
 
Ho: λT(t) = λc(t) for all t ≤ 12 months (365 days), versus 
Ha: λT(t) ≠ λc(t) for some t ≤ 12 months (365 days) 
 
where λT(t) is the hazard function for major and minor CIED infection in the TYRX envelope 
group and λc(t) is the hazard function for major and minor CIED infection in the control 
group.  
 

20 
 
3.3.3.2 
Endpoint Definition 
 
CIED infections, including major CIED infections are defined in section 3.2.2.  Minor CIED 
infections are CIED infections that are not classified as major CIED infections. 
3.3.3.3 
Analysis Methods 
 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  Those infections related to the CIED 
that do not meet the major CIED infection will be considered minor CIED infections.  The 
primary method to be used to test this objective will be the Cox proportional hazard model.  
The Cox model will be stratified by device type (low power versus high power) and include 
treatment as an independent variable.  Days of follow=up for each subject will be set to the 
minimum of days from last procedure attempt (or randomization if a subject is randomized 
but not implanted) to:  (1) onset date of a subject’s first major or minor CIED infection, (2) 
study exit date (if exited), (3) date of death (if death occurs), (4) date of last follow=up, or 
(5) 365 days post=procedure.  Subjects who meet the endpoint prior to their last CIED 
procedure attempt will be considered to have met the endpoint on day zero.  Subjects not 
having a major or minor CIED infection during the follow=up period will be considered 
censored on the day as derived above.  Based on this statistical test, it will be claimed that 
the TYRX envelope reduces major or minor CIED infection if the hazard ratio estimate is 
less than one and the resulting p=value from the Wald test falls below the specified type I 
error boundary as determined by the Hwang=Shih=DeCani alpha spending function and 
Holm adjustment for multiple comparisons.  Kaplan=Meier plots of freedom from major or 
minor CIED infection will be presented by treatment group and by treatment group within 
each device type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5. 
 
If secondary objective #3 is met at either the interim or final analysis time point, the 
following two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 
3.3.3.4 
Determination of Subjects’ Data for Analysis 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention=to=Treat principle).   
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT/mAT 
cohorts. 
3.3.3.5 
Missing Data 
The primary analysis cohort for this objective will include all follow=up from all randomized 
subjects through the 12=month visit or 365 days post=randomization, whichever occurs first.  
Since the statistical methods involve survival methods all follow=up from all randomized 
subjects will be included.  However, missing data could arise if a randomized subject exits 
the study or dies prior to the 12=month visit without experiencing a major or minor CIED 
infection.  The log=rank test will be used to compare the study attrition rate for any reason 

21 
 
(study exit or death) between randomized treatment groups to evaluate the pattern of data 
missingness by treatment group.   
 
Additionally, a competing risks model will be used to test the effect of the TYRX envelope 
in the presence of the competing risk of death unrelated to CIED infection should this 
objective be met as described in section 3.2.8. 
 
3.3.3.6 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high=power (CRT=D, ICD) devices 
and subjects with low=power (pacemaker, CRT=P) devices to assess the performance of 
the TYRX envelope within each of these device types.  In addition, subgroups of subjects 
with device upgrade (e.g. single chamber to dual chamber, or dual chamber to triple 
chamber, or low to high power) and subjects without device upgrade will be analyzed 
separately using the methods described in section 3.2.9. 
 
3.4 
Ancillary Objectives 
The following ancillary objectives are intended to gain additional information about the 
performance of the TYRX envelope.  The type I error rate is not controlled for the ancillary 
objectives.  Not all ancillary objectives may be evaluated if the study’s primary objective is 
not met. 
3.4.1 Ancillary Objective #1:  Mortality 
 
To compare all=cause mortality rates between the TYRX envelop group and the control 
group. 
3.4.1.1 
Endpoint  
 
Death for any cause 
 
3.4.1.2 
Hypothesis 
 
This ancillary objective will be tested with the following hypothesis: 
 
Ho: λT(t) = λc(t) for all t ≤ T, versus 
Ha: λT(t) ≠ λc(t) for some t ≤ T 
 
where λT(t) is the hazard function for death for any cause in the TYRX envelope group and 
λc(t) is the hazard function for death any cause in the control group during the entire follow=
up period. 
 
3.4.1.3 
Analysis Methods 
The primary method to be used to evaluate the hypothesis above will be the Cox 
proportional hazard model.  The Cox model will be stratified by device type (low power 
versus high power) and include treatment as an independent variable.  Days of follow=up 
for each subject will be set to the minimum of days from last procedure attempt (or 
randomization if a subject was randomized but not implanted) to the (1) date of death or (2) 
last study contact date.  Subjects alive at their last follow=up day will be censored on their 
last day as derived above.  A p=value less than 0.05 will be considered statistically 

22 
 
significant.  Kaplan=Meier plots of subject survival will be presented by treatment group and 
by treatment group within each device type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5 
  
If ancillary objective #1 is met at either the interim or final analysis time point, the following 
two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
3.4.1.4 
Determination of Subjects for Analysis 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention=to=Treat principle). 
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT 
cohort. 
 
3.4.2 Ancillary Objective #2:  CIED procedure success rate 
 
Evaluate the CIED procedure success rate in the TYRX envelope group and the control 
group  
 
3.4.2.1 
Analysis Methods 
Information related to the CIED procedure (i.e. initial implant or index replacement/upgrade 
or index system revision) will be collected on the procedure eCRF.  A procedure attempt is 
defined as any CIED procedure where the device pocket is opened or venous access was 
gained (i.e. skin was cut).  A successful procedure is defined as an implant attempt where 
the device is successfully connected to the system’s leads and the CIED system remains 
in the body and the device pocket is closed.  Additionally, for those subjects randomized to 
the TYRX envelope group, the TYRX envelope must also remain in the device pocket 
following pocket closure to qualify as a successful CIED procedure.   
 
Specifically, for all subjects with a procedure attempt a CIED procedure can only be 
considered successful if the question on the procedure CRF “Was a generator in the 
pocket following the procedure?” is answered as “Yes”.  Additionally, for those subjects 
randomized to the TYRX envelope group, the question “Was the TYRX envelope in the 
device pocket following the implant procedure?” must also be answered as “Yes”.  Note 
that for purposes of determining procedure success, subjects with a CRT device where the 
LV lead cannot be placed adequately may still be considered a success if the generator 
remains in the pocket.  In these cases, a system modification form would be required if 
another LV lead implant attempt is made during a separate procedure. 
 
The CIED procedure success rate will be defined on a per subject basis as the number of 
subjects with their last CIED procedure considered successful divided by the number of 
subjects with at least one CIED procedure attempt.  Fisher’s exact test will be used to 
compare the procedure success rate between the TYRX envelope group and the control 
group. 
 
 

23 
 
The following sample syntax in SAS will be used to evaluate the ancillary objective #2: 
 
proc freq; 
     tables trt*success /exact cmh; 
     weight count; 
run; 
 
Fisher’s exact test will also be used to compare the percentage of subjects with more than 
one procedure attempt (i.e. more than one CIED procedure CRF) by randomized treatment 
group.  For each randomized treatment group the denominator will be the number of 
subjects with a successful procedure and the numerator will be the number of subjects with 
a successful procedure requiring more than one procedure to obtain the successful 
procedure. 
  
3.4.2.2 
Determination of Data for Analysis 
Data from all randomized subjects with a CIED procedure attempt will be included in the 
analysis.  The primary analysis cohort will be the ITT population with the additional 
requirement that the subject must have a CIED procedure attempt.   
 
3.4.3 Ancillary Objective #3:  Summarize adverse events 
To summarize adverse events by treatment group 
 
3.4.3.1 
Analysis Methods 
Subjects will be queried for AEs at all scheduled and unscheduled visits.  All AEs 
potentially related to the CIED system, CIED implant or system modification procedure, 
and all SAEs regardless of their relationship to the CIED system or CIED procedure 
(including the TYRX envelope if applicable) will be collected.  Medtronic safety specialists 
will ensure that at a minimum all AEs that are potentially related to the CIED system 
(including the TYRX envelope), or CIED procedure, or death are classified by the CEC.  
Summary tables will be compiled categorizing the AEs with respect to procedure 
relatedness, CIED relatedness (including CIED component), and TYRX envelope 
relatedness.  For events classified by the CEC, the CEC classification will be used in the 
analysis.  In cases where only the investigator classifies the event, the investigator’s 
classification will be used.  In addition, the number of events and number of subjects with 
events by MedDRA term will be displayed.  Additionally, the nominal p=value from the log=
rank test will be used to identify system= or procedure=related AEs occurring on or after a 
CIED procedure attempt by MedDRA preferred term that may differ between treatment 
groups.  This test does not protect the type I error, but may help identify specific AEs that 
differ between randomized treatment group for further evaluation.  These tests will only be 
performed for preferred terms that occur in more than five subjects. 
 
3.4.3.2 
Determination of Data for Analysis 
All adverse events collected during the study will be included in this analysis. 
 
3.4.4 Ancillary Objective #4:  Predictors of CIED infection 
To identify predictors of major CIED infection 
 

24 
 
3.4.4.1 
Analysis Methods 
Subject demographics and medical history including previous device history will be 
collected at baseline.  CIED procedure=related variables such as antibiotic prophylaxis, 
surgical site preparation, procedure duration, device type, and number of leads will be 
collected for each CIED procedure.  Additionally, device characteristics such as 
impedance, optivol fluid status, and heart rate variability etc. will be collected via device 
interrogations at each follow=up visit.  Cox regression models will be employed using 
subjects in the control group to identify factors that may be associated with major CIED 
infection.  Additionally, multivariable Cox models may be used to develop a risk model for 
major CIED infection.  For any such multivariable Cox model, the number of degrees of 
freedom available and hence the number of candidate predictors available (and their 
functional form) for modelling will be determined by the number of major CIED infections in 
the control group.  This analysis will be exploratory in nature. 
 
3.4.4.2 
Determination of Data for Analysis 
All subjects randomized to the control group with a CIED procedure attempt who do not 
receive the TYRX envelope during their CIED procedure. 
 
3.4.5 Ancillary Objective #5: Quality of Life 
 
Summarize quality of life. 
3.4.5.1 
Analysis Methods 
Subjects will be asked to complete the EQ=5D questionnaires at baseline and at the 12=
month visit (or study exit if the subject exits the study for reasons other than lost to follow=
up prior to completing the 12=month visit).  Additionally, subjects with a CIED infection will 
be asked to complete the EQ=5D within two weeks following their CIED infection diagnosis 
and at 1=month, 3=months, and 6=months post=CIED infection diagnosis.   
The EQ=5D summary health score is calculated based on five “dimension” questions: 
mobility, self=care, usual activities, pain/discomfort, anxiety/depression.  For subjects 
completing the EQ=5D=3L questionnaire (primarily OUS subjects) each dimension has 
three options, which are in general: 1=no problem, 2=some problem, 3=extreme problem.  
For subjects completing the EQ=5D=5L questionnaire (primarily US subjects) each 
dimension has five options which are in general: 1=no problem, 2=slight problem, 
3=moderate problem, 4=severe problem, 5=unable to perform.   
 
For purposes of the final study report, EQ=5D summary scores will be standardized to the 
EQ=5D=3L summary health score using EQ=5D=5L to EQ=5D=3L crosswalk value set current 
at the time the final report is prepared, unless EQ=5D=5L value sets become available from 
EuroQoL during the WRAP=IT study for geographies using the EQ=5D=5L.   
Each subject’s summary health score will be standardized to the same country value set 
(e.g. US) regardless of the subject’s origin using the appropriate EQ=5D=3L value set. 
 
Medtronic’s healthcare economics group may request additional summaries of the EQ=5D 
data following study completion for conducting cost effectiveness analyses described in the 
healthcare economics analysis plan. 
 
Descriptive statistics will be used to summarize the change in EQ=5D scores from baseline 
to the 12=month visit by infection status.  Additionally, the changes in EQ=5D between 
CIED infection and post=CIED infection will be computed using summary statistics for all 
subjects with a major CIED infection as classified by the CEC. More detailed analysis 
methods will be described in the health economics Statistical Analysis Plan.  

25 
 
 
Bar charts will be used to present results from the EQ=5D descriptive system as a health 
profile.  Summary health score will be presented in tables similar to shown below: 
 
EQ=5D 
 
Baseline
12-months
Change
 
 
N 
 
Mean 
± Std. 
Median 
Range 
N 
 
Mean ± 
Std. 
Median 
Range 
N 
 
Mean ± 
Std. 
95%  CI  
EQ-5D 
Health 
Score  
Infection
 
 
 
 
 
 
 
 
 
 
 
 
No Infection
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D 
Visual 
Analog 
Scale 
Infection
 
 
 
 
 
 
 
 
 
 
 
No Infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.5.2 
Determination of Data for Analysis 
Completed EQ=5D questionnaires from all randomized subjects will be used to describe the 
changes in EQ=5D score from baseline.  All completed EQ=5D questionnaires following an 
adjudicated CIED infection will be used to summarize the change in EQ=5D score from 
baseline following CIED infection. 
 
3.4.6 Ancillary Objective #6:  Healthcare System Cost Effectiveness 
Objective 
To assess the cost=effectiveness of the TYRX envelope. 
 
Analysis Methods 
Health care utilizations (HCUs) related to suspected CIED infection will be collected on the 
eCRFs.  HCUs related to CIED infection include all hospitalizations, emergency 
department visits, urgent care, or unscheduled follow=up visits associated with the 
suspected CIED infection regardless of location of care.   
 
For each major CIED infection as classified by the CEC, the following information will be 
compiled and provided to Medtronic’s healthcare economics group: 
• 
Subject identifier, randomized treatment group, and treatment actually received 
• 
For each inpatient hospitalization the hospitalization admission date, discharge 
date, total hours in ICU, and total hours in cardiac ward 
• 
For each outpatient visit the type of outpatient visit, provider type, and visit date 
• 
Date and type of any long=term health care facility stay 
• 
Start date, stop date, frequency per week, and frequency per day for each session 
of home health care 
• 
Medications used to treat the CIED infection as recorded on the AE eCRF 
associated with the major CIED infection 
 
 
Additionally, the following health care utilization information related to major CIED 
infections will be summarized and compared between randomized treatment groups using 
proportional odds models: 

26 
 
• 
Total days hospitalized for major CIED infection 
• 
Total ICU hours (1 day = 24 hours) for major CIED infection 
• 
Total hours (1 day = 24 hours) in cardiac ward for major CIED infection 
• 
Days in long=term health=care facility for major CIED infection 
 
 
Proc logistic data=<data> order=<order>; 
Class trt (param=ref ref=’0’); 
     model nDays(ascending) = trt logFupDays; 
run; 
*** trt=1 for ENVELOPE and trt=0 for NO ENVELOPE; 
 
The following health care utilization information related to major CIED infections will be 
summarized and compared between randomized treatment groups using negative binomial 
regression models: 
• 
Total number of outpatient visits for major CIED infection 
• 
 
• 
Number of home health care visits for major CIED infection 
 
Each negative binomial regression model will include the number of days (or hours) of 
subject follow=up as the offset, randomized treatment group as the independent variable, 
and parameter of interest as the dependent variable.  Subjects without a major CIED 
infection will be considered to have 0 days (or hours) of the parameter of interest.  The 
following sample SAS code implements the negative binomial regression model described 
above: 
 
 proc genmod data=<data> 
     model nEvent = trt / dist=nb link=log offset=logFUPdays; 
run; 
*** trt=1 for ENVELOPE and trt=0 for NO ENVELOPE; 
 
 
Additionally, the cost incurred from each major CIED infection will be based on the actions 
taken to address each major CIED infection.  The total cost of major CIED infections 
observed in the study will be compared to the total cost incurred by adding the TYRX 
envelope to the CIED procedure.  Economic models will be employed to quantify the cost 
savings and/or cost-effectiveness of the TYRX envelope.  The decision=analytic framework 
of any potential economic model will be detailed in the health economics analysis plan.  
Medtronic’s healthcare economics group will be primarily responsible for the cost 
effectiveness analysis but will likely request study data from the WRAP=IT study’s statistical 
staff for their work. 
 
 
3.5 
 
 
 
 
 
 
   
 
  
 
   
 
  
 

27 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
3.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 

28 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

29 
 
 
3.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

30 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

31 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4 
APPENDIX 
4.1 Sample Size Simulation Program 
 
 
 
 
  
                                                               
 
                                                                                   
 
  
                                                                
 
                
                                               
  
                  
 
  
                                       
 
                                      
 
  
                                                                               
 
  
                                            
 
                                                                       
 
     
       
        
       
                         
 
     
       
 
                  
   
   
                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
  
                          
 
 
 
 
 
   
  
 
  
 
  
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 34 of 46  
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Medtronic Confidential 
 
 
 
  
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
                                  
 
   
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
  
 
  
 
   
  
 
  
 
   
  
 
  
 
    
 
    
 
    
 
      
 
     
    
 
      
 
    } 
  } 
   
   

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 35 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
  
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
  
 
  
 
  
 
  
 
   
   
 
 
 
 
 
 
 
 
 
 
 
   
  
 
  
 
  
 
    
 
      
 
     
    
 
      
 
     
   
  
 
 
 
 
 
 
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 36 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
       
 
    
 
 
 
 
 
 
 
                            
 
   
   
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
  
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
  
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 37 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
   
  
 
  
 
  
 
   
  
 
  
 
  
 
  
 
   
  
 
  
 
  
 
  
 
   
   
  
 
  
 
  
 
   
  
 
  
 
  
 
   
  
 
  
 
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
   

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 38 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
   
   
  
 
  
 
 
   
 
 
 
 
 
               
 
  
  
 
           
       
  
 
 
 
 
 
 
 
   
    
  
 
  
 
  
 
  
 
  
 
  
 
  
 
     
  
 
  
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 39 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
  
 
  
 
  
 
  
 
 
   
  
 
  
 
   
   
  
 
  
 
       
 
       
 
       
 
       
 
       
 
   
 
 
 
 
 
 
 
 
 
 
 
                    
 
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 40 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
   
   
  
 
  
 
     
    
 
    
 
     
     
    
 
    
 
                                        
 
                                        
 
                                        
 
                                        
 
     
    
 
    
 
                               
 
                               
 
                               
  
     
     
    
 
    
 
 
     
     
    
 
    
 
     
    
 
    
 
     
    
 
    
 
    
 
     
    
 
    
 
    
 
    
 
    
 
    
 
    
 
    
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 41 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
    
 
    
 
      
 
        
 
       
     
    
 
    
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
        
     
    
 
      
 
      
 
      
 
      
 
      
 
         
 
         
 
       
      
 
        
 
        
 
       
      
 
      
 
      
 
      
 
      
 
      
 
     
        
     
  
 
   
  
 
  
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 42 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
  
 
   
  
 
  
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
       
 
     
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
               
 
               
 
 
 
               
 
               
 
 
 
               
 
               
 
 
 
               
 
               
 
 
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 43 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
               
 
               
 
 
 
               
 
               
 
 
 
               
 
               
 
 
 
 
 
 
 
               
 
               
 
               
 
   
 
 
 
 
              
 
              
 
              
 
 
  
 
  
 
 
 
 
 
 
 
 
               
 
               
 
               
 
 
 
 
 
 
              
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 44 of 46  
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Medtronic Confidential 
 
 
 
              
 
              
 
 
  
 
  
 
 
 
 
 
 
 
   
 
                                    
 
                                    
 
                                    
 
                                    
 
 
 
 
                           
 
                           
 
                           
  
 
 
 
 
       
  
 
 
 
 
4.2 Information Fraction Simulation Program 
The following R program can be used to calculate the information fraction via simulation at the interim analysis 
 
  
 
  
 
 
  
 
  
 
 
 

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 45 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
    
 
 
       
 
 
     
 
 
  
 
 
      
  
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
     
 
    
 
 
       
 
 
   
 
 
     
 
 
 
 
   
 
 
  
 
   
 
 
   
 
  

 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Page 46 of 46  
12JAN2012 
Medtronic Confidential 
 
 
 
 
 
   
 
   
 
 
 
   
 
   
 
 
 
 
 
 
   
 
 
 
 
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Amendment 1 to the WRAP-IT Statistical Analysis Plan, Version 1.0
Page 3 of 11
5 January 2018
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Confidential
Amendment 1 to the WRAP-IT Statistical Analysis Plan
Clinical Investigation Plan Title World-wide Randomized Antibiotic EnveloPe
Infection PrevenTion Trial (WRAP-IT)
Sponsor/Local Sponsor
Medtronic, Inc
8200 Coral Sea St NE
Mounds View, MN USA 55112
1-800-328-2518
Medtronic, Bakken Research Center B.V.
Endepolsdomein 5
6229 GW Maastricht
The Netherlands
(+31)-43-35-66-566
Medtronic Australasia Pty Ltd
97 Waterloo Rd, 
North Ryde 2113
PO Box 945, North Ryde
Australia, 1670
(+61)-2-9857-9000
Medtronic Latin America HQ
Medtronic USA, Inc.,
Doral Corporate Center II
3750 NW 87th Avenue, Suite 700
Miami, FL U.S.A. 33178
(+1)-305-500-9328
India Medtronic Pvt. Ltd.
1241, Solitaire Corporate Park,
Building No 12, 4th Floor,
Andheri-Ghatkopar Link Road, Andheri (E), Mumbai 
MH 400093  India
(+91)-22-33074700-1/2/3
Medtronic International Ltd.
1101-06, 11/F, Tower 1,
The Gateway,
Harbour City, Kowloon, Hong Kong
Hong Kong SAR, China
(+852)-2919-1300

Amendment 1 to the WRAP-IT Statistical Analysis Plan, Version 1.0
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Medtronic International Ltd.
F-39-7 Crest, 3 Two Square, 2 Jalan 19/1,
Petaling Jaya, Selangor
Malaysia 46300
(+60)-379-534-800
Medtronic International Ltd.
49 Changi South Avenue 2
Nasaco Tech Centre
Singapore 486056
(+65)-6436-5000
Document Version
Version 1.0
Document Reference Number
NA
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of Medtronic. Any
distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it may
not be further disclosed by them.

Amendment 1 to the WRAP-IT Statistical Analysis Plan, Version 1.0
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5 January 2018
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Confidential
Table of Contents
1.
Version History .............................................................................................................. 6
2.
Introduction................................................................................................................... 6
2.1.
Purpose............................................................................................................................6
3.
Specific Changes............................................................................................................ 6
3.1.
Definition of the As-Treated Cohort....................................................................................6
3.1.1.
Original Text from WRAP-IT SAP version 1.0 ..........................................................6
3.1.2.
Rationale for Change.............................................................................................6
3.1.3.
Amended Text ......................................................................................................6
3.2.
Definition of Analysis Cohort for Ancillary Objective #2 (CIED Procedure Success) ................7
3.2.1.
Original Text from WRAP-IT SAP version 1.0 ..........................................................7
3.2.2.
Rationale for Change.............................................................................................7
3.2.3.
Amended Text ......................................................................................................8
3.3.
Analysis Methods for Ancillary Objective #6:  (Healthcare System Cost Effectiveness)...........8
3.3.1.
Original Text from WRAP-IT SAP version 1.0 ..........................................................8
3.3.2.
Rationale for Change...........................................................................................10
3.3.3.
Amended Text ....................................................................................................10

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1.
Version History
Version
Summary of Changes
Author(s)/Title
1.0

Initial Release
Kurt Stromberg,
Senior Principal Statistician
2.
Introduction
2.1.
Purpose
The purpose of the amendment to version 1.0 of the WRAP-IT Statistical Analysis Plan (SAP) is to 
document any modifications to the WRAP-IT SAP that were made following the interim analysis, but prior 
to breaking the blind for the final analysis.  The primary purpose of this amendment is to further clarify 
specific sections in the WRAP-IT SAP.  The remainder of WRAP-IT SAP version 1.0 was unchanged.
3.
Specific Changes
3.1.
Definition of the As-Treated Cohort
3.1.1.
Original Text from WRAP-IT SAP version 1.0
As Treated (AT):  The AT cohort includes subjects in the ITT cohort but analyzes subjects using the 
treatment they actually received at the time of their initial procedure.  For subjects with a TYRX envelope 
this means the TYRX envelope remained in the pocket following pocket closure.
3.1.2.
Rationale for Change
The original text in version 1.0 of the WRAP-IT SAP was unclear as to whether subjects without a 
procedure attempt or with no successful procedure attempts would be included in the AT cohort.  
Additionally, the original text did not indicate whether the analysis of the AT cohort would stratify by the 
device type (high power or low power) as randomized or by the device type as actually implanted.
3.1.3.
Amended Text
As Treated (AT):  The AT cohort includes subjects in the ITT cohort but will be defined using the 
treatment actually received at the time of their final index procedure.  Randomized subjects without a 
procedure attempt and randomized subjects without a device remaining in the pocket at their final index 
procedurewill be excluded from the AT cohort.  Thus the number of subjects in the AT cohort will be less 
than the number of subjects in the ITT cohort.   Furthermore, subjects with a device and with a TYRX 
envelope remaining in the device pocket following their procedure will be considered members of the 
TYRX group in the AT cohort regardless of randomization assignment.  Similarly, subjects with a device, 

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Page 7 of 11
5 January 2018
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Confidential
but without a TYRX envelope in their device pocket following procedure will be considered members of 
the control group in the AT cohort regardless of randomization assignment.     
For analyses stratified by device class (high power or low power) the analyses will stratify by the device 
class received at the index procedure implant unless the device class is unknown (e.g., device not 
manufactured by Medtronic) in which case the device class as randomized will be used.
3.2.
Definition of Analysis Cohort for Ancillary Objective #2 (CIED 
Procedure Success)
3.2.1.
Original Text from WRAP-IT SAP version 1.0
Information related to the CIED procedure (i.e. initial implant or index replacement/upgrade or index 
system revision) will be collected on the procedure eCRF.  A procedure attempt is defined as any CIED 
procedure where the device pocket is opened or venous access was gained (i.e. skin was cut).  A 
successful procedure is defined as an implant attempt where the device is successfully connected to the 
system’s leads and the CIED system remains in the body and the device pocket is closed.  Additionally, 
for those subjects randomized to the TYRX envelope group, the TYRX envelope must also remain in the 
device pocket following pocket closure to qualify as a successful CIED procedure.
Specifically, for all subjects with a procedure attempt, a CIED procedure can only be considered 
successful if the question on the procedure CRF “Was a generator in the pocket following the procedure?” 
is answered as “Yes”.  Additionally, for those subjects randomized to the TYRX envelope group, the 
question “Was the TYRX envelope in the device pocket following the implant procedure?” must also be 
answered as “Yes”.  Note that for purposes of determining procedure success, subjects with a CRT device 
where the LV lead cannot be placed adequately may still be considered a success if the generator 
remains in the pocket.  In these cases, a system modification form would be required if another LV lead 
implant attempt is made during a separate procedure.
The CIED procedure success rate will be defined on a per subject basis as the number of subjects with 
their last CIED procedure considered successful divided by the number of subjects with at least one CIED 
procedure attempt.  Fisher’s exact test will be used to compare the procedure success rate between the 
TYRX envelope group and the control group. Data from all randomized subjects with a CIED procedure 
attempt will be included in the analysis.  The primary analysis cohort will be the ITT population with the 
additional requirement that the subject must have a CIED procedure attempt.
Determination of Subjects for Analysis
Data from all randomized subjects with a CIED procedure attempt will be included in the analysis.  The 
primary analysis cohort will be the ITT population with the additional requirement that the subject must 
have a CIED procedure attempt.
3.2.2.
Rationale for Change
The DMC informed Medtronic on 25 February 2017 that Medtronic may want to consider revising the 
analysis cohort for the analysis of the procedure success rate (ancillary objective #2), as several subjects 
randomized to the TYRX envelope group never had a TYRX envelope implant attempt.  Reasons for not 
having a TYRX envelope implant attempt included “TYRX envelope inventory issues” and “study site 
error”.  

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Page 8 of 11
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Confidential
3.2.3.
Amended Text
Information related to the CIED procedure (i.e., initial implant or index replacement/upgrade or index 
system revision) will be collected on the procedure eCRF.  A procedure attempt is defined as any CIED 
procedure where the device pocket is opened or venous access was gained (i.e., skin was cut).  A 
successful procedure is defined as an implant attempt where the device is successfully connected to the 
system’s leads and the CIED system remains in the body and the device pocket is closed.  Additionally, 
for those subjects randomized to the TYRX envelope group, the TYRX envelope must also remain in the 
device pocket following pocket closure to qualify as a successful CIED procedure.
Specifically, for all subjects with a procedure attempt, a CIED procedure can only be considered 
successful if the question on the procedure CRF “Was a generator in the pocket following the procedure?” 
is answered as “Yes”.  Additionally, for those subjects randomized to the TYRX envelope group and with 
an attempted implant of the TYRX envelope, the question “Was the TYRX envelope in the device pocket 
following the implant procedure?” must also be answered as “Yes”.  Note that for purposes of 
determining procedure success, subjects with a CRT device where the LV lead cannot be placed 
adequately may still be considered a success if the generator remains in the pocket.  In these cases, a 
system modification form would be required if another LV lead implant attempt is made during a separate 
procedure.
The CIED procedure success rate will be defined on a per subject basis as the number of subjects with 
their last CIED procedure considered successful divided by the number of subjects with at least one CIED 
procedure attempt.  Fisher’s exact test will be used to compare the procedure success rate between the 
TYRX envelope group and the control group.
Determination of Subjects for Analysis
The primary analysis cohort will be the ITT population with the following additional requirements:
1.
A subject must have a CIED procedure attempt (e.g., skin cut)
2.
Subjects randomized to the TYRX group must have had an attempt to implant the TYRX 
envelope.  Specifically, subjects who crossed over to the control group without an attempted 
TYRX envelope implant were excluded from this analysis.  For example, this includes subjects 
who were crossed over due to TYRX inventory issues or site error.  
3.
Subjects randomized to the control group that crossed over to the TYRX envelope group during 
their implant attempt will be conservatively excluded from the analysis cohort for this objective 
since it is not possible to accurately determine the number of control group subjects with an 
attempted crossover to the TYRX envelope group where the TYRX envelope was not 
successfully implanted.
3.3.
Analysis Methods for Ancillary Objective #6:  (Healthcare System Cost 
Effectiveness)
3.3.1.
Original Text from WRAP-IT SAP version 1.0
Analysis Methods
Health care utilizations (HCUs) related to suspected CIED infection will be collected on the eCRFs.  HCUs 
related to CIED infection include all hospitalizations, emergency department visits, urgent care, or 
unscheduled follow-up visits associated with the suspected CIED infection regardless of location of care.

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For each major CIED infection as classified by the CEC, the following information will be compiled and 
provided to Medtronic’s healthcare economics group:

Subject identifier, randomized treatment group, and treatment actually received

For each inpatient hospitalization the hospitalization admission date, discharge date, total 
hours in ICU, and total hours in cardiac ward

For each outpatient visit the type of outpatient visit, provider type, and visit date

Date and type of any long-term health care facility stay

Start date, stop date, frequency per week, and frequency per day for each session of 
home health care

Medications used to treat the CIED infection as recorded on the AE eCRF associated with 
the major CIED infection
Additionally, the following health care utilization information related to major CIED infections will be 
summarized and compared between randomized treatment groups using proportional odds models:

Total days hospitalized for major CIED infection

Total ICU hours (1 day = 24 hours) for major CIED infection

Total hours (1 day = 24 hours) in cardiac ward for major CIED infection

Days in long-term health-care facility for major CIED infection
Proc logistic data=<data> order=<order>;
Class trt (param=ref ref=’0’);
     model nDays(ascending) = trt logFupDays;
run;
      *** trt=1 for ENVELOPE and trt=0 for NO ENVELOPE;
The following health care utilization information related to major CIED infections will be summarized and 
compared between randomized treatment groups using negative binomial regression models:

Total number of outpatient visits for major CIED infection

Number of home health care visits for major CIED infection
Each negative binomial regression model will include the number of days (or hours) of subject follow-up 
as the offset, randomized treatment group as the independent variable, and parameter of interest as the 
dependent variable.  Subjects without a major CIED infection will be considered to have 0 days (or hours) 
of the parameter of interest.  The following sample SAS code implements the negative binomial 
regression model described above:
proc genmod data=<data>
     model nEvent = trt / dist=nb link=log offset=logFUPdays;
run;
     *** trt=1 for ENVELOPE and trt=0 for NO ENVELOPE;
Additionally, the cost incurred from each major CIED infection will be based on the actions taken to 
address each major CIED infection.  The total cost of major CIED infections observed in the study will be 
compared to the total cost incurred by adding the TYRX envelope to the CIED procedure.  Economic 
models will be employed to quantify the cost savings and/or cost-effectiveness of the TYRX envelope.  
The decision-analytic framework of any potential economic model will be detailed in the health economics 

Amendment 1 to the WRAP-IT Statistical Analysis Plan, Version 1.0
Page 10 of 11
5 January 2018
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Confidential
analysis plan.  Medtronic’s healthcare economics group will be primarily responsible for the cost 
effectiveness analysis but will likely request study data from the WRAP-IT study’s statistical staff for their 
work.
3.3.2.
Rationale for Change
There were two reasons for modifying the original text in version 1.0 of the WRAP-IT SAP.  
First, the blinded study statistician noticed that the distribution of healthcare utilization parameters had 
many more zeros (i.e., subjects with value of zero for healthcare utilization parameter) than could be 
accommodated by a negative binomial distribution.  Specifically, the distribution of these variables was 
highly zero inflated.  Thus, it was necessary to change from the originally specified negative binomial 
model to a negative binomial hurdle model to account for the zero inflation.  
Secondly, the healthcare cost effectiveness analyses are being specified in the healthcare economics 
analysis plan.  Moreover, since many of the healthcare cost effectiveness analyses will likely occur 
following distribution of the WRAP-IT final clinical study report, it was necessary to identify which 
healthcare utilization analyses would appear in the final report.
3.3.3.
Amended Text
Analysis Methods
Health care utilizations (HCUs) related to suspected CIED infection will be collected on the eCRFs.  HCUs 
related to CIED infection include all hospitalizations, emergency department visits, urgent care, or 
unscheduled follow-up visits associated with the suspected CIED infection regardless of location of care.
For each major CIED infection as classified by the CEC, the following information will be compiled and 
provided to Medtronic’s healthcare economics group:

Subject identifier, randomized treatment group, and treatment actually received

For each inpatient hospitalization the hospitalization admission date, discharge date, total hours 
in ICU, and total hours in cardiac ward

For each outpatient visit the type of outpatient visit, provider type, and visit date

Date and type of any long-term health care facility stay

Start date, stop date, frequency per week, and frequency per day for each session of home 
health care

Medications used to treat the CIED infection as recorded on the AE eCRF associated with the 
major CIED infection
Medtronic’s healthcare economics group (or their designees) will use this information to evaluate the 
cost-effectiveness of the TYRX envelope and develop subsequent ancillary study publications.  The 
methodology for the cost-effectiveness models is detailed in the WRAP-IT health economics analysis plan.
For purposes of the final report, the following healthcare utilization parameters will be summarized by 
randomized treatment group for subjects with a major CIED infection within 12-months, major CIED 
infection during the entire follow-up period, any major or minor CIED infection within 12-months, and any 
major or minor CIED infection during the entire follow-up period:

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
Total days hospitalized for hospitalizations exceeding 24 hours

Days in intensive care unit (24 hours = 1 day and fractional days rounded up)

Days in cardiac ward (24 hours = 1 day and fractional days rounded up)

Total days hospitalized for hospitalization less than 24 hours

Number of emergency department visits

Number of urgent clinic visits

Number of clinic visits
For each healthcare utilization parameter, the rate of healthcare contacts per year (e.g., hospitalized days 
per year, number of emergency department visits) in each randomized treatment group will computed by
dividing the total number of contacts by the cumulative total duration of the follow-up in years across all 
subjects in the treatment group.
Additionally, the distribution of healthcare utilization related to major CIED infection within 12-months (or 
during the entire follow-up period) and related to major or minor CIED infection within 12-months (or 
during the follow-up period) will be compared between randomized treatment groups using negative 
binomial hurdle models for the following healthcare utilization parameters:

Total days hospitalized for hospitalizations exceeding 24 hours

Total outpatient visits where outpatient visits were defined as the sum of all hospitalizations less 
than 24 hours, emergency department visits, urgent clinic visits, and clinic visits.
Each negative binomial hurdle model will include the number of healthcare utilizations as the response, 
randomized treatment group as the independent predictor for both the zero distribution and negative 
binomial components of the model, and natural log of follow-up months as the offset.  Under this 
parameterization, each hurdle model provides two estimates of the effect of the TYRX envelope on 
healthcare utilization:  specifically (1) a measure of the change in the log odds of having at least one 
utilization in the TYRX group relative to the control group, and (2) a measure of the change in the 
intensity of healthcare utilization in the TYRX group relative to the control group.  Exponentiated, the 
model estimates (1) and (2) can be interpreted as an odds ratio and conditional relative risk respectively.
The R package pscl will be used to fit each negative binomial hurdle model using the syntax below:
hurd.out <- hurdle(hcuParameter ~ trtgrp | trtgrp
                       offset=logMonths,
                       link="logit",
                       dist="negbin")
where “hcuParameter” represents the count of the number health care utilization contacts for a subject, 
“trtgrp” is the randomized treatment group (parameterized as 1 = TYRX group, 0 = Control group), and 
“logMonts” is the natural log of the follow-up months.  A link of “logit” requests that the logit link function 
be used for the zero component of the hurdle model, and a distribution of “negbin” requests that the 
negative binomial distribution be used to model the positive integer component of the hurdle model.

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Amendment 2 to the WRAP-IT Statistical Analysis Plan
Clinical Investigation Plan Title World-wide Randomized Antibiotic EnveloPe
Infection PrevenTion Trial (WRAP-IT)
Sponsor/Local Sponsor
Medtronic, Inc
8200 Coral Sea St NE
Mounds View, MN USA 55112
1-800-328-2518
Medtronic, Bakken Research Center B.V.
Endepolsdomein 5
6229 GW Maastricht
The Netherlands
(+31)-43-35-66-566
Medtronic Australasia Pty Ltd
97 Waterloo Rd, 
North Ryde 2113
PO Box 945, North Ryde
Australia, 1670
(+61)-2-9857-9000
Medtronic Latin America HQ
Medtronic USA, Inc.,
Doral Corporate Center II
3750 NW 87th Avenue, Suite 700
Miami, FL U.S.A. 33178
(+1)-305-500-9328
India Medtronic Pvt. Ltd.
1241, Solitaire Corporate Park,
Building No 12, 4th Floor,
Andheri-Ghatkopar Link Road, Andheri (E), Mumbai 
MH 400093  India
(+91)-22-33074700-1/2/3
Medtronic International Ltd.
1101-06, 11/F, Tower 1,
The Gateway,
Harbour City, Kowloon, Hong Kong
Hong Kong SAR, China
(+852)-2919-1300

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Medtronic International Ltd.
F-39-7 Crest, 3 Two Square, 2 Jalan 19/1,
Petaling Jaya, Selangor
Malaysia 46300
(+60)-379-534-800
Medtronic International Ltd.
49 Changi South Avenue 2
Nasaco Tech Centre
Singapore 486056
(+65)-6436-5000
Document Version
Version 1.0
Document Reference Number
NA
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of Medtronic. Any
distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it may
not be further disclosed by them.

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Table of Contents
1.
Version History .............................................................................................................. 6
2.
Introduction................................................................................................................... 6
2.1.
Purpose............................................................................................................................6
3.
Specific Changes............................................................................................................ 6
3.1.
Definition of the Intent-To-Treat Cohort .............................................................................6
3.1.1.
Original Text from WRAP-IT SAP version 1.0 Amendment 1.....................................6
3.1.2.
Rationale for Change.............................................................................................6
3.1.3.
Amended Text ......................................................................................................6
3.2.
Determination of Subjects’ Data for Analysis of Primary Objective #1...................................7
3.2.1.
Original Text from WRAP-IT SAP version 1.0 Amendment 1.....................................7
3.2.2.
Rationale for Change.............................................................................................7
3.2.3.
Amended Text ......................................................................................................7

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1.
Version History
Version
Summary of Changes
Author(s)/Title
1.0

Initial Release
Alex Dedrick, Sr. Statistician
2.
Introduction
2.1.
Purpose
The purpose of this additional amendment to version 1.0 of the WRAP-IT Statistical Analysis Plan (SAP) is 
to document any modifications to the WRAP-IT SAP that were made following the interim analysis, but 
prior to breaking the blind for the final analysis.  The primary purpose of this amendment is to further 
clarify specific sections in the WRAP-IT SAP.  The remainder of WRAP-IT SAP version 1.0 and its 
amendment were unchanged.
3.
Specific Changes
3.1.
Definition of the Intent-To-Treat Cohort
3.1.1.
Original Text from WRAP-IT SAP version 1.0 Amendment 1
Intention-to-Treat (ITT): The ITT analysis cohort will include all randomized subjects in the
groups to which they are randomized regardless of treatment received and will serve as
the primary analysis cohort for each objective unless otherwise specified. The ITT cohort will likely be the 
only cohort evaluated at the time of the interim analysis.
3.1.2.
Rationale for Change
The original text in version 1.0 of the WRAP-IT SAP indicates subjects with complications post enrollment
would be included for analysis. Subjects with complications after enrollment are defined as having an 
ongoing infection at procedure, receiving a heart transplant or a VAD, or receiving dialysis initiated after 
enrollment, but prior to procedure. These subjects are at a higher risk for infection and will be analyzed 
separately. A sensitivity analysis will be included to show differences between the ITT population and the 
cohort defined by these subjects.
3.1.3.
Amended Text
Intention-to-Treat (ITT): The ITT analysis cohort will include all randomized subjects in the
groups to which they are randomized regardless of treatment received and will serve as
the primary analysis cohort for each objective unless otherwise specified. The ITT cohort will likely be the 
only cohort evaluated at the time of the interim analysis.

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modified Intent-to-Treat: The mITT cohort will exclude all enrolled subjects from the ITT cohort who, 
after enrollment become a higher risk for infection. This excludes subjects who meet any of the following 
criteria:

Have an ongoing infection post-enrollment, but during procedure,

Receive a heart transplant post-enrollment but prior to procedure,

Receive a VAD (defined as LVAD, RVAD, or BiVAD) post-enrollment but prior to procedure,

Initiate dialysis after enrollment but prior to procedure.
The mITT cohort will be used in a sensitivity analysis on the primary objective to show the effects of 
including subjects with a higher risk of infection and excluding them.
3.2.
Determination of Subjects’ Data for Analysis of Primary Objective #1
3.2.1.
Original Text from WRAP-IT SAP version 1.0 Amendment 1
All randomized subjects will be included in the primary analysis regardless of the treatment they actually 
receive or their study compliance (i.e. Intention-to-Treat principle). Sensitivity analyses may be conducted 
by evaluating the performance of the TYRX envelope the AT or mAT cohorts as described above.
If the primary objective is not met for the ITT cohort, the analysis will be conducted for the AT/mAT 
cohorts.
3.2.2.
Rationale for Change
The initial text did not take into consideration subjects who accumulate exclusion criteria after 
enrollment. An additional cohort is necessary to exclude subjects who are considered a higher risk for 
infection, and would have been excluded from the trial.
3.2.3.
Amended Text
All randomized subjects will be included in the primary analysis regardless of the treatment they actually 
receive or their study compliance (i.e. Intention-to-Treat principle). Sensitivity analyses may be conducted 
by evaluating the performance of the TYRX envelope in the mITT, AT, or mAT cohorts as described 
above.
Sensitivity analyses will be performed for the mITT, AT, and mAT cohorts as necessary.

1 
 
 
 
 
 
 
 
 
 
 
 
World-wide Randomized 
Antibiotic EnveloPe 
Infection PrevenTion Trial  
(WRAP-IT)  
 
Statistical Analysis Plan 
 
 
 
 
Version 1.0 + Amendments 
Initial Version: July 21, 2015 
Final Version: July 31, 2018 
 
 
 
 
 
Pei Li, Sr Statistician 
Kurt Stromberg, Sr Principal Statistician

2 
 
TABLE OF CONTENTS 
1 
PURPOSE ................................................................................................................................ 4 
2 
RATIONALE FOR STUDY DESIGN ....................................................................................... 4 
3 
DESCRIPTION OF ANALYSIS ............................................................................................... 5 
3.1 General Summaries .......................................................................................................... 5 
3.1.1 Description of Baseline Variables ........................................................................... 5 
3.1.2 Special Considerations ........................................................................................... 5 
3.1.2.1 
Pooling ................................................................................................................... 5 
3.1.2.2 
Missing Data ........................................................................................................... 5 
3.1.2.3 
Visit Windows ......................................................................................................... 5 
3.1.2.4 
Database Freeze .................................................................................................... 5 
3.1.2.5 
Randomization Date ............................................................................................... 5 
3.1.2.6 
Interim Analysis Type I Error Control ..................................................................... 6 
3.1.3 Early Study Success ............................................................................................... 7 
3.1.4 Reports for which this Statistical Analysis Plan applies ......................................... 7 
3.1.5 Analysis Cohort ...................................................................................................... 7 
3.2 Primary Objective .............................................................................................................. 8 
3.2.1 Hypothesis .............................................................................................................. 8 
3.2.2 Endpoint Definition ................................................................................................. 8 
3.2.3 Performance Requirements .................................................................................... 9 
3.2.4 Rationale for Performance Criteria ......................................................................... 9 
3.2.5 Analysis Methods ................................................................................................... 9 
3.2.6 Sample Size.......................................................................................................... 10 
3.2.7 Determination of Subjects’ Data for Analysis ....................................................... 13 
3.2.8 Missing Data ......................................................................................................... 13 
3.2.9 Subgroup analysis ................................................................................................ 13 
3.3 Secondary Objectives ..................................................................................................... 14 
3.3.1 Secondary Objective #1 ....................................................................................... 14 
3.3.1.1 
Hypothesis ............................................................................................................ 14 
3.3.1.2 
Endpoint ............................................................................................................... 14 
3.3.1.3 
Analysis Methods ................................................................................................. 15 
3.3.1.4 
Power to test the objective ................................................................................... 15 
3.3.1.5 
Determination of Subjects’ Data for Analysis ....................................................... 17 
3.3.1.6 
Missing Data ......................................................................................................... 17 
3.3.1.7 
Subgroup Analyses .............................................................................................. 17 
3.3.2 Secondary Objective #2 ....................................................................................... 18 
3.3.2.1 
Hypothesis ............................................................................................................ 18 
3.3.2.2 
Endpoint Definition ............................................................................................... 18 
3.3.2.3 
Analysis Methods ................................................................................................. 18 
3.3.2.4 
Determination of Subjects’ Data for Analysis ....................................................... 19 
3.3.2.5 
Missing Data ......................................................................................................... 19 
3.3.2.6 
Subgroup Analyses .............................................................................................. 19 
3.3.3 Secondary Objective #3 ....................................................................................... 19 
3.3.3.1 
Hypothesis ............................................................................................................ 19 
3.3.3.2 
Endpoint Definition ............................................................................................... 20 
3.3.3.3 
Analysis Methods ................................................................................................. 20 
3.3.3.4 
Determination of Subjects’ Data for Analysis ....................................................... 20 
3.3.3.5 
Missing Data ......................................................................................................... 20 
3.3.3.6 
Subgroup Analyses .............................................................................................. 21 

3 
 
3.4 Ancillary Objectives ......................................................................................................... 21 
3.4.1 Ancillary Objective #1:  Mortality .......................................................................... 21 
3.4.1.1 
Endpoint ............................................................................................................... 21 
3.4.1.2 
Hypothesis ............................................................................................................ 21 
3.4.1.3 
Analysis Methods ................................................................................................. 21 
3.4.1.4 
Determination of Subjects for Analysis ................................................................ 22 
3.4.2 Ancillary Objective #2:  CIED procedure success rate ......................................... 22 
3.4.2.1 
Analysis Methods ................................................................................................. 22 
3.4.2.2 
Determination of Data for Analysis ....................................................................... 23 
3.4.3 Ancillary Objective #3:  Summarize adverse events ............................................ 23 
3.4.3.1 
Analysis Methods ................................................................................................. 23 
3.4.3.2 
Determination of Data for Analysis ....................................................................... 24 
3.4.4 Ancillary Objective #4:  Predictors of CIED infection............................................ 24 
3.4.4.1 
Analysis Methods ................................................................................................. 24 
3.4.4.2 
Determination of Data for Analysis ....................................................................... 24 
3.4.5 Ancillary Objective #5: Quality of Life ................................................................... 24 
3.4.5.1 
Analysis Methods ................................................................................................. 24 
3.4.5.2 
Determination of Data for Analysis ....................................................................... 25 
3.4.6 Ancillary Objective #6:  Healthcare System Cost Effectiveness .......................... 25 
3.5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
APPENDIX ............................................................................................................................. 34 
4.1 Sample Size Simulation Program ................................................................................... 34 
4.2 Information Fraction Simulation Program........................................................................ 45 
4.3 Sample Size Simulation Program ..................................... Error! Bookmark not defined. 
 

4 
 
1 
PURPOSE 
This Statistical Analysis Plan (SAP) has been designed to document, before data are analyzed, 
the rationale for the study design of the WRAP-IT study, and the planned analyses that will be 
included in study reports. This SAP does not limit the analysis in reports, and additional analysis 
of the study data beyond this plan is expected. 
2 
RATIONALE FOR STUDY DESIGN 
The World-wide Randomized Antibiotic EnveloPe Infection PrevenTion Trial (WRAP-IT) is a 
randomized, prospective, multi-center, single blinded, post-market, interventional clinical study.  
The study has three purposes.  First, the WRAP-IT study will serve as a post-approval study for 
those geographies requiring a post-approval study to facilitate collection of complications related 
to the Cardiovascular Implantable Electronic Device (CIED) procedure or system in subjects 
randomized to receive the TYRXTM Absorbable Antibacterial Envelope (henceforth referred to as 
TYRX envelope).  Next, this study will evaluate the ability of the TYRX envelope to reduce major 
CIED infections through 12-months post-procedure following CIED generator replacement, 
upgrade, or revision, or the implant of a de novo CRT-D.  Subjects undergoing CIED generator 
replacement, upgrade, or revision or the implant of a de novo CRT-D system will be randomized 
to either receive the TYRX envelope or not to receive the TYRX envelope.  Randomization will be 
1:1 and be stratified by study site and device type, high power (ICD and CRT-D) vs. low power 
devices (IPG and CRT-P).  Finally this large device study provides the unique opportunity to 
prospectively characterize the performance of Medtronic’s lead monitoring features in subjects 
whose CIED system includes a transvenous RV defibrillation lead.  These features include the 
lead integrity alert (LIA), lead noise alert (LNA), RV pacing impedance, and high voltage (HV) 
pacing impedance to detect events that affect a RV lead’s pacing, sensing, or defibrillation circuit 
lead system events (LSE).   
 
The study is expected to be conducted at up to 225 sites worldwide with up to 7,764 subjects 
enrolled in order to randomize approximately 6,988 subjects.  Enrollment of subjects receiving a 
replacement low power device (i.e. IPG or CRT-P) will be capped at approximately 25% of the 
total randomized study population (i.e. approximately 1,746 subjects).  Relative to high power 
device recipients, patients receiving a low power device may be at reduced risk of a major CIED 
infection. Thus, to ensure an adequate CIED infection event rate in the control arm, there is a 
desire to include a higher proportion of high power devices in the trial.  
The WRAP-IT study utilizes a group sequential design and has up to two planned analyses of the 
primary objective.  The first analysis will occur when a minimum of 3,200 randomized subjects 
complete the 6-month visit and the final analysis will occur when all randomized subjects have the 
opportunity to complete the 12-month study visit.  The study may be considered successful at the 
first analysis in which the primary objective is met.  An independent Data Monitoring Committee 
(DMC) will periodically review the accumulating data and review the results of the analysis of the 
primary objective at each pre-specified analysis time point.  Should the DMC indicate that the 
study is successful at the interim analysis, the study may continue to enroll and follow subjects to 
evaluate the effect of the TYRX envelope on CIED infections that develop post-12 months as well 
as collect additional follow-up in subjects with a defibrillation system in which to evaluate the lead 
monitoring features.  However, subjects enrolled following review of the interim analysis may no 
longer be randomized upon recommendation of the DMC if the TYRX envelope is found to have a 
clear benefit.   
 
The WRAP-IT Study Clinical Investigational Plan Version 1.0 was used to develop the SAP. 
 

5 
 
3 
DESCRIPTION OF ANALYSIS 
3.1 General Summaries 
3.1.1 Description of Baseline Variables 
Standard baseline and relevant medical history will be collected on the eCRFs for all enrolled 
subjects.  Baseline and medical history variables to be summarized include, but are not limited to:  
age, sex, race, device type (CRT-D, ICD, CRT-P, and IPG), number of previous CIED devices, 
NYHA class, arrhythmia history, and baseline medication use. 
 
For continuous variables, mean, standard deviation, median, and range will be reported.  For 
categorical variables, frequency and percentage will be reported.  Baseline information will be 
summarized for all randomized subjects.  The TYRX envelope and control groups will be 
compared using T-tests for continuous variables and the Chi-square test for categorical variables 
to quantify any imbalance in treatment groups. 
 
3.1.2 Special Considerations 
3.1.2.1 
Pooling 
The study may be conducted at up to 225 sites worldwide.  Data from all centers that participate 
in this protocol will be combined for analysis. Expected participating geographies include, but are 
not limited to, the United States (US), Europe, the Middle East and Africa (EMEA), Greater China 
(Hong Kong), New Zealand, Latin America, the Association of South East Asian Nations (ASEAN) 
(Singapore and Malaysia), and India. However, since the majority of study centers will come from 
the US and the primary endpoint is likely to be rare, the primary objective results for US and 
outside the US (OUS) geographies will be presented and poolability analysis will be done. If a 
differential treatment effect (P<0.05) is observed, we will investigate the cause of the differential 
treatment effect (e.g. by comparing baseline characteristics, procedure information and the 
medical practice etc).  
 
3.1.2.2 
Missing Data 
If applicable, treatment of missing data is addressed within each objective. 
 
3.1.2.3 
Visit Windows 
As the visit windows are meant as a guideline for centers, data from CRFs dated outside of the 
prescribed visit windows in the CIP will be used in all analyses.       
3.1.2.4 
Database Freeze 
The visit cut-off date for the database freeze for the interim analysis will be the first date when  a 
minimum of 3200 randomized subjects complete the 6-month visit.  The visit cut-off date for the 
database freeze for the final analysis will be the date when all randomized subjects have had the 
opportunity to complete the 12-month study visit.      
 
3.1.2.5 
Randomization Date 
There may be instances where the date and timestamp for the randomization process in 
the electronic database where randomization is performed may be after the date of the 
CIED procedure.  This occurs when randomization is performed outside of the database 
(e.g. cases where Oracle Clinical is not accessible by the site) and the randomization 

6 
 
routine in the electronic database is executed to document the randomization process on a 
later date.   For such cases, the randomization date will come from the randomization or 
implant procedure eCRF, which ever came first. 
 
3.1.2.6 
Interim Analysis Type I Error Control 
The study has up to two planned analyses of the primary objective.  The study may be considered 
successful at the first analysis in which the primary objective is met.   
 
The first analysis will occur when approximately 50% of the total follow-up within 12-months of 
randomization occurs; based on enrollment projections described below this is defined as the 
point where 3200 randomized subjects complete the 6-month post-procedure visit.  The purpose 
of this first analysis is two-fold: 
 
1. To assess whether the study’s primary objective has been met.  If the DMC indicates that 
the study has met its objective, the study may continue to enroll and follow subjects to 
study the effect of the TYRX envelope on long-term CIED infections as well as 
accumulate LSEs.  However, subjects enrolling following review of the interim analysis 
may no longer be randomized upon recommendation of the DMC if the TYRX envelope is 
found to have a clear benefit.  
  
2. To assess whether the study may end earlier than planned for futility. 
 
The timing of the interim analysis was selected so that sufficient data is collected to contribute to 
the interim analysis before decisions that impact the study are made.  The Hwang-Shih-DeCani 
alpha spending function with a gamma parameter of negative 4 (-4) is used to control the overall 
alpha level at 5% (two-sided; 2.5% one-sided in the direction favorable to the TYRX envelope).  
This function spends the alpha at a level analogous to the O’Brien-Fleming boundary.  The 
boundary condition at the interim analysis will be based on the information fraction at the interim 
analysis and computed by dividing the accrued number of major CIED infections observed at the 
interim analysis by the total number of major CIED infections anticipated at the final analysis.   
 
To obtain the information fraction, a simulation will be performed to estimate the anticipated 
number of events pooled across both treatment groups which are expected to happen after the 
interim analysis.  The event-free survival function is assumed to be piecewise exponential with 
two intervals (interval cutoff to be determined at interim analysis based on observed data).  The 
hazard parameter in each interval will be estimated by data observed at interim analysis.  Then 
complete follow-up data will be simulated to estimate of number of events by end of study. 
Sample R code for performing this simulation is found in section 4.2. 
 
Assuming the information fraction at the interim analysis is 50%, the boundary condition at the 
interim analysis is 0.003 (2.75 on the Z-scale or 0.006 on the two-sided p-value scale) and is 
purposely low to allow early claims of study success only when the TYRX envelope is highly 
effective.  At the final analysis, the boundary condition is 0.0238 (1.98 on the Z-scale or 0.0476 
on the two-sided p-value scale) when the information fraction is 50% at the interim analysis.  
Since the analytical methods for the secondary objectives also utilize survival analysis methods, 
the same alpha spending function will be used to compute the success boundaries for the 
secondary objectives. 
 
If the primary objective of the study is met, the secondary objectives will be tested using the Holm 
procedure to protect the overall type I error rate of the study and allow statistically valid claims of 
significance.  Specifically, at analysis k (k=1,2), the ordered hypotheses H(1k), H(2k), H(3k) 
corresponding to the ordered p-values p(1k), p(2k), p(3k) of the secondary objectives will be 
tested based off the sequentially rejective algorithm.  The hypothesis H(1k) is rejected if p(1k) ≤

7 
 
𝛼𝑘3
⁄ .  Futher, H(jk) is rejected at the jth step if p(jk) ≤𝛼𝑘(3 −𝑗+ 1)
⁄
. Otherwise, H(jk),…H(3k) are 
retained and the algorithm terminates. 
 
To help assess whether the study may end earlier than planned for futility, stochastic curtailment 
methods will be used to calculate the futility index for the primary objective.  The futility index (1-
P1, where P1 is the predictive power observed at the interim analysis) is based on predictive 
power as computed as: 
 
𝑃1 = Φ {𝑍1 √𝐼2 −𝑧𝛼√𝐼1
√𝐼2 −𝐼1
} 
 
where Z1 is the test statistic at the interim analysis, I1 is the information fraction at the interim 
analysis, I2 is the information fraction at the final analysis (will be considered 1 at the interim 
analysis), and zα is the critical value at the final analysis based on the alpha spending function.  
Although non-binding, a futility index greater than 0.9 at the interim analysis provides strong 
evidence that the study will not achieve its primary objective if the study were to continue to its full 
sample size and follow-up. 
3.1.3 Early Study Success 
Should the DMC indicate that the study is successful at the interim analysis, the study may 
continue to enroll and follow subjects to evaluate the effect of the TYRX envelope on CIED 
infections that develop post 12 months as well as collect additional follow-up in subjects with a 
defibrillation system in which to evaluate the lead monitoring features.  If the study were to 
continue to enroll, it is anticipated that all subjects enrolled after the interim analysis would 
receive the TYRX envelope.  Thus, for the final report, only those subjects randomized prior to 
the decision to end randomized allocation of the TYRX envelope would be included in the 
analysis of the primary and secondary objectives as well as ancillary objective #1.   
3.1.4 Reports for which this Statistical Analysis Plan applies 
This SAP applies to the interim analysis report and final report.  However, the interim analysis 
report will likely evaluate the primary and secondary objectives as well as ancillary objective #1.  
This SAP also applies to the main study manuscript, though not everything specified here will be 
included in the manuscript.  
3.1.5 Analysis Cohort 
 
Intention-to-Treat (ITT):  The ITT analysis cohort will include all randomized subjects in the 
groups to which they are randomized regardless of treatment received and will serve as 
the primary analysis cohort for each objective unless otherwise specified.  The ITT cohort 
will likely be the only cohort evaluated at the time of the interim analysis. 
 
As Treated (AT):  The AT cohort includes subjects in the ITT cohort but will be defined 
using the treatment actually received at the time of their final index procedure.  
Randomized subjects without a procedure attempt and randomized subjects without a 
device remaining in the pocket at their final index procedure will be excluded from the AT 
cohort.  Thus the number of subjects in the AT cohort will be less than the number of 
subjects in the ITT cohort.   Furthermore, subjects with a device and with a TYRX envelope 
remaining in the device pocket following their procedure will be considered members of the 
TYRX group in the AT cohort regardless of randomization assignment.  Similarly, subjects 
with a device, but without a TYRX envelope in their device pocket following procedure will 
be considered members of the control group in the AT cohort regardless of randomization 
assignment.     For analyses stratified by device class (high power or low power) the 
analyses will stratify by the device class received at the index procedure implant unless the 

8 
 
device class is unknown (e.g., device not manufactured by Medtronic) in which case the 
device class as randomized will be used. 
 
modified As Treated (mAT):  The mAT cohort includes all subjects and follow-up time in the 
AT cohort that were successfully implanted with a CIED system (including the TYRX 
envelope if subject had a successfully placed TYRX envelope) up until the point where a 
CIED modification (i.e. system modification) occurred.  Thus, subjects with a system 
modification for reasons other than device infection will be considered censored at the time 
of the system modification. 
 
modified Intent-to-Treat: The mITT cohort will exclude all enrolled subjects from the ITT 
cohort who, after enrollment become a higher risk for infection. This excludes subjects who 
meet any of the following criteria: 
• 
Have an ongoing infection post-enrollment, but during procedure, 
• 
Receive a heart transplant post-enrollment but prior to procedure, 
• 
Receive a VAD (defined as LVAD, RVAD, or BiVAD) post-enrollment but prior to 
procedure, 
• 
 Initiate dialysis after enrollment but prior to procedure. 
The mITT cohort will be used in a sensitivity analysis on the primary objective to show the 
effects of including subjects with a higher risk of infection and excluding them. 
 
 
3.2 Primary Objective 
The primary study objective is to compare the rate of major CIED infections through 12-
months post-procedure between the TYRX envelope group and the control group (no 
TYRX envelope). 
 
3.2.1  Hypothesis 
The primary study objective will be tested with the following hypothesis: 
 
Ho: T(t) = c(t) for all t ≤ 12 months (365 days), versus 
Ha: T(t)  c(t) for some t ≤ 12 months (365 days) 
 
where T(t) is the hazard function for major CIED infection in the TYRX envelope group and 
c(t) is the hazard function for major CIED infection in the control group. 
3.2.2 Endpoint Definition 
CIED infections are defined as: (1) superficial cellulitis in the region of the CIED pocket 
with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space 
(generator pocket) surgical site infection (SSI) that meet the Centers for Disease Control 
and Prevention (CDC) criteria, independent of time from surgery (3) persistent bacteremia 
or (4) endocarditis.  
 
Major CIED infections are defined as CIED infections resulting in one or more of the 
following: 
• CIED system removal 
• Any invasive procedure (e.g. pocket opened) without system removal 

9 
 
• Treatment with antibiotic therapy if the subject is not a candidate for system removal 
and infection recurrence after completion of antibiotic therapy or evidence of deep 
infection with wound dehiscence, erosion, or purulent drainage. 
• Death 
 
3.2.3 Performance Requirements 
If the hazard ratio : T(t) /c(t) is significantly different from 1 (and less than 1), the major 
infection rate will be considered lower in the TYRX group.  
3.2.4 Rationale for Performance Criteria 
This study will evaluate the ability of the TYRX envelope to reduce major CIED infections 
through 12-months post-procedure following CIED generator replacement, upgrade, or 
revision, or the implant of a de novo CRT-D system.  The hazard ratio is significantly 
different if the nominal p-value is less than the specified type I error boundary as 
determined by the Hwang-Shih-DeCani alpha spending function described above. 
 
3.2.5 Analysis Methods 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the primary endpoint.  The primary method to be used to test the primary 
objective will be the Cox proportional hazard model.  The Cox model will be stratified by 
device type (low power versus high power) the subject is to receive as documented on the 
randomization eCRF and include treatment as an independent variable.  This stratified Cox 
model assumes that the baseline hazard may be different for each device type, but that the 
underlying treatment effect is constant across device type.  Days of follow-up for each 
subject will be set to the minimum of days from last procedure attempt (or randomization if 
the subject was randomized but no procedure attempt) to: (1) onset date of a subject’s first 
CIED infection meeting the primary endpoint, (2) study exit date (if exited), (3) date of 
death (if death occurs), (4) date of last follow-up, or (5) 365 days post-procedure.  
However, if a subject has a major CIED infection during an unsuccessful procedure 
attempt; days of follow-up will be set to zero.    Subjects not meeting the primary endpoint 
during the follow-up period will be considered censored at the end of their follow-up period 
as derived above.  Based on this statistical test, it will be claimed that the TYRX envelope 
reduces major CIED infection if the hazard ratio estimate is less than one and the resulting 
p-value from the Wald test falls below the specified type I error boundary as determined by 
the Hwang-Shih-DeCani alpha spending function.  Kaplan-Meier plots of freedom from 
major CIED infection will be presented by treatment group and by treatment group within 
each device type. 
 
The following sample syntax in SAS will be used to evaluate the primary objective: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     strata device; 
     *different baseline h0 but same HR across device** 
run;  
 
Sample R-code to fit the stratified Cox model is also displayed below: 
 
coxph(Surv(survData$survDays,survData$survStatus)~survData$trt + 
strata(survDat$device)) 
 

10 
 
 
If the primary objective is met at either the interim or final analysis time point, the following 
two assumptions will be tested: 
 
 
1. Heterogeneity of the hazard ratio across device type: 
The following sample syntax in SAS will be used to evaluate the homogeneity of 
treatment effect across device types for primary objective.  If the interaction effect 
is significant at 0.05 level the treatment effect will not be assumed constant across 
device type and separate analyses will be performed for each device type. 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt device trt*device; 
run;  
 
2. Proportional hazards between treatment groups: 
The proportional hazards assumption for the treatment effect will be examined 
graphically by examining plots of the complementary log-log CIED infection free 
time versus log time.  Additionally, an interaction between event time and 
treatment group will be added to the model.  If this interaction term is significant at 
the 0.05 level then this may provide evidence that the proportional hazards 
assumption is violated.  Should the proportional hazards assumption be violated, 
inference regarding the effect of the TYRX envelope may be made at several 
different time points (e.g. 1-month, 6-months, and 12-months post-procedure).  
The following SAS code implements the test of the proportional hazards 
assumption: 
 
*** PLOT THE COMPLEMENTARY LOG LOG; 
 proc lifetest data=<data> plot=(s, lls) noprint; 
   
      time time*censor(0); 
  
      strata trt; 
  
      group device; 
 run;  
 
*** TEST THE TIME VERSUS TREATMENT EFFECT; 
proc phreg data=<data>; 
 
CLASS trt device; 
 
model eventtime*event(0)=trt trtTime; 
 
trtTime = trt*log(eventtime); 
 
strata device; 
run; 
 
 
3.2.6 Sample Size 
 
Background 
The reported prevalence rate of CIED infection varies widely in the literature and is 
dependent on the nature of data collection (retrospective vs prospective, single center vs 
multi-center), CIED infection definition, and population studied.  The REPLACE study 
prospectively evaluated CIED infection requiring system removal or intravenous antibiotics 
in 1744 subjects undergoing a device replacement or upgrade.  The infection rate at 6-
months post-procedure for subjects receiving a device replacement was 1.4% and 1.1% for 
those subjects undergoing a device upgrade.  

11 
 
 
Analysis of 103,020 device implant claims from Medicare evaluated for Medtronic by 
Truven Analytics suggested that subsequent invasive procedures related to device 
infection occurred at a rate of 4.0% for CRT-D, 3.9% for ICDs, and 2.6% for pacemakers 
through 12-months.  The 12-month CIED infection rate associated with replacement 
devices was 4.1% for CRT-D, 5.4% for ICDs, and 3.4% for pacemakers with 12-month 
infection rates associated with initial device implants ranging from 4.0% in CRT-Ds to 2.2% 
in pacemakers.  However, examination of CIED infections reported in Medtronic studies, 
suggests that the Medicare claims data may overestimate the CIED infection rate that may 
be observed in clinical trials for initial implants by at least 50% (Table 1).   
 
Table 1: 12-Month Infection Rates for Initial Implants by Device Type and Data Source 
 
Data Source 
Device 
Medicare Claims 
Data 
12-Month CIED 
Infection Rate 
Medtronic Studies (12-
month CIED Infection Rate  
(95% CI)) 
CRT-D 
4.1% 
2.0% (1.2% - 3.4%)1 
ICD 
3.0% 
1.5% (0.3% - 6.7%)2 
Pacemaker 
2.2% 
1.2% (0.8% - 1.7%)3 
1Based on 753 subjects with an attempted CRT-D implant in the REVERSE and 
BLOCK-HF studies.  
2Based on 246 subjects from the Model 6947, 6948, and 6949 RV defibrillation lead 
studies 
3Based on 2799 subjects from the 3830, 4074, 5076, Advisa MRI, EnRhythm, 
EnRhythm MRI, and SAVEPACe studies. 
 
Based on the assumption that the Medicare claims data may overestimate the actual CIED 
infection rate that may be observed in a clinical trial, it is hypothesized that the 12-month 
infection rate for initial CRT-D implants, replacement (or upgrade) CRT-D implants, and 
replacement (or upgrade) ICD implants is 2.4% and is 0.6% for replacement pacemaker 
implants.  Since low power replacement procedures (i.e. pacemaker and CRT-P 
replacement procedures) will be capped at 25% of the total sample size, an overall 12-
month CIED infection rate for the control group is assumed to be 2% for sample size 
calculation purposes. 
 
Retrospective evidence from the COMMAND study demonstrated that in 624 subjects 
consecutively implanted with the TYRX envelope the CIED infection rate was 0.48% and 
ranged from 0% during initial implant procedures to 1.05% during ICD/CRT-D 
replacement/revision procedures.  Additionally, recently published data from Mittal, et. al 
showed that the CIED infection rate was 1.1% in 275 subjects that received the TYRX 
envelope compared to 3.6% in 275 propensity matched control subjects over a 6-month 
period across both low power and high power devices.  Finally, early evidence from the 
CITADEL/CENTURION studies suggests that CIED infection rate among a cohort of 1000 
ICD/CRT-D subjects receiving the TYRX envelope is 0.2% at 6-months post-
replacement/upgrade; a 9-fold decrease compared to published controls at 6-months.  
Based on this experience, it is assumed that the TYRX envelope will reduce the risk of 
CIED infection by 50% through 12-months post-procedure. 
 
Sample Size Calculation 
The sample size is derived based on the following assumptions: 
1. One-to-one randomization to the TYRX envelope or control group 
2. Power to test the primary objective is at least 90% 
3. One interim analysis and final analysis 

12 
 
4. The interim analysis will occur when approximately 50% of the statistical information 
has been accrued 
5. One-sided alpha level of 2.5% 
6. Hwang-Shih-DeCani alpha spending function with a gamma parameter of negative 4 
(-4) which approximates O’Brien-Fleming boundaries 
7. Assumed control CIED infection rate of 2% at 12-months 
a. 2.4% for high power (CRT-D/ICD) devices 
b. 0.6% for low power (pacemaker/CRT-P) devices 
c. Low power devices are capped at 25% of the required sample size 
8. TYRX envelope assumed to reduce the control infection rate by 50% 
9. Non-binding futility assessment based on stochastic curtailment at the interim 
analysis 
10. 15% annualized attrition rate that is independent of treatment group and infection 
status 
 
The method of Lakatos (1988) as implemented in the POWER procedure of SAS v9.2, 
indicated 6,988 randomized subjects (3,494 randomized to each group) are required to test 
the primary objective based on the assumptions described above.  Thus, up to 7,764 
subjects may be enrolled to allow for up to a 10% discontinuation rate between enrollment 
(i.e. subject consent) and randomization.   
 
A simulation study was performed to confirm the sample size calculation.  In addition to the 
sample size assumptions described above, the simulation assumed that 50% of CIED 
infections occur within the first month of device procedure.  Simulations were performed 
when the CIED infection risk reduction associated with the TYRX envelope ranged from 
0% (null case) to 60%.  Figure 1 confirms the sample size calculation and demonstrates 
that the type I error rate is well controlled.  The program used to conduct the simulation 
analysis is found in section 4.1. 
 
Figure 1:  Empirical Power to Test the Primary Objective (n=6,988)   
 
 

13 
 
3.2.7 Determination of Subjects’ Data for Analysis 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention-to-Treat principle). Sensitivity 
analyses may be conducted by evaluating the performance of the TYRX envelope in the 
mITT, AT, or mAT cohorts as described above. 
 
Sensitivity analyses will be performed for the mITT, AT, and mAT cohorts as necessary. 
3.2.8 Missing Data 
The primary analysis cohort will include all follow-up from all randomized subjects through 
the 12-month visit or 365 days post-randomization, whichever occurs first. Since the 
primary statistical methods involve survival methods all follow-up from all randomized 
subjects will be included.  However, missing data could arise if a randomized subject exits 
the study or dies prior to the 12-month visit without experiencing a CIED infection meeting 
the primary endpoint.  The log-rank test will be used to compare the study attrition rate for 
any reason (study exit or death) between randomized treatment groups to evaluate the 
pattern of data missingness by treatment group.  
 
Additionally, as many cardiology journals are now requesting sensitivity analyses that 
include competing risk for death, a competing risks model will be used to test the effect of 
the TYRX envelope in the presence of competing risk of death unrelated to CIED infection 
should the study meet its primary objective.  Sample R code for implementing the stratified 
competing risks model is as follows as recently described by Zhou et. al1 is provided 
below: 
 
R syntax below will be used to evaluate treatment effect on CIED infection with 
consideration of competing risk of death unrelated to CIED infection: 
 
Library(crrSC) 
Crrs(time, status, cov,strata,failcode=2,cencode=0)   
 
# Status: 0 censor, 1 death unrelated to CIED infection, 2 CIED infection 
# Cov: 0 control, 1 envelope 
# Strata: low=1 high=2 
 
3.2.9 Subgroup analysis 
Subgroup analysis will be performed for subjects within high power (CRT-D, ICD) devices 
and patients with low power (pacemaker, CRT-P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
low to high power ) and patients without device upgrade will be analyzed separately.  
Additional subgroup analyses may also be performed on a post hoc basis. 
 
The following sample syntax in SAS will be used for the subgroup analysis: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     by device; 
run;  
 
                                                     
1 B. Zhou, A. Latouche, V. Rocha, J. Fine.  2011.  Competing risks regression for stratified data.  Biometrics 67: 
661-670. 

14 
 
Additionally, an interaction between the treatment group and subgroup will be added to the 
model to test for homogeneity of the treatment effect across subgroups.  If this interaction 
term is significant at the 0.05 level the treatment effect will be considered heterogeneous 
between subgroups. 
 
proc phreg data=<data>; 
    CLASS trt subGroup; 
    model eventtime*event(0)=trt subgroup trt*subGroup; 
    run; 
 
3.3 Secondary Objectives 
The following secondary objectives will be evaluated to gain additional information about 
the safety and efficacy of the TYRX envelope in the study population.  Provided the 
primary objective of the study is met with a statistically significant p-value, then the 
secondary objectives will be assessed.  The Holm procedure will be used to control the 
family-wise type I error rate as described in section 3.1.2.6 in order to make statistically 
valid claims of significance. 
3.3.1 Secondary Objective #1 
 
Confirm that the TYRX envelope does not increase the CIED procedure-related or system-
related complication rate through 12-months post-procedure.   
3.3.1.1 
Hypothesis 
 
The first secondary objective will be tested with the following non-inferiority hypothesis: 
 
Ho: T(t)/c(t) ≥ 1.33 for t ≤ 12 months (365 days), versus 
Ha: T(t)/c(t) < 1.33 for t ≤ 12 months (365 days) 
 
where T(t) is the hazard function for CIED system- or procedure-related complications in 
the TYRX envelope group and c(t) is the hazard function for CIED system-related 
complications in the control group.  Rejecting the null hypothesis would indicate that the 
TYRX envelope does not increase the CIED system- or procedure-related complication 
rate by more than 33% on a relative scale or 4.4% on a linear scale when the underlying 
CIED system or procedure complication freedom rate at 12-months is 85%.  
 
3.3.1.2 
Endpoint 
 
A CIED system-related complication is defined as an adverse event that meets the 
complication definition as determined by the CEC and is considered by the CEC to be 
related to one of the implanted CIED system components (i.e. device, RV lead, RA lead, 
LV lead, other lead, or the TYRX envelope). 
 
A CIED procedure-related complication is defined as an adverse event that meets the 
complication definition as determined by the CEC and is considered by the CEC to be 
related to the CIED procedure (i.e. replacement/upgrade/new implant/revision) or a system 
modification including the TYRX envelope (if applicable). 
 

15 
 
3.3.1.3 
Analysis Methods 
 
All potential adverse events potentially related to the implanted system (i.e. device, leads), 
the TYRX envelope, or the CIED replacement/upgrade/implant or system modification 
procedure will be reported on the eCRFs as they occur.  The CEC will adjudicate each 
reported adverse event for its relationship to the CIED system and CIED procedure.  
Additionally, the CEC will classify each CIED system-related or procedure-related adverse 
event as a complication or observation.  Days of follow-up for each subject will be set to 
the minimum of days from last procedure attempt (or randomization if a subject was 
randomized but not implanted) to:  (1) onset date of a subject’s first CIED system related or 
procedure related complication (including the TYRX envelope where applicable), (2) study 
exit date (if exited), (3) date of death (if death occurs), , 4) date of last follow-up, or (5) 365 
days post-procedure.  Subjects with a procedure- and/or system-related complication 
occurring prior to their last CIED procedure attempt will their event date set to day zero.  
Subjects not having a CIED system-related or procedure-related complication during the 
follow-up period will be considered censored on the day as derived above. 
 
The effect of the TYRX envelope on the rate of CIED system- or procedure-related 
complications will be tested using a Cox proportional hazards regression model stratified 
by device type (low power versus high power) containing an indicator term for treatment 
group.  The observed hazard ratio from the Cox model will be compared to the non-
inferiority margin of 1.33.  The null hypothesis will be rejected in favor of the alternative and 
the TYRX envelope will be considered non-inferior to the control group if the p-value 
computed from the non-inferiority test is less than the type I error boundary as determined 
by the Hwang-Shih-DeCani alpha spending function and Holm adjustment for multiple 
comparisons.  Kaplan-Meier plots of freedom from system- or procedure-related 
complications will be presented by treatment group and by treatment group within each 
device type. 
 
 
The following sample syntax in SAS will be used to evaluate the second objective #1: 
 
proc phreg; 
     class trt device; 
     model eventtime*event(0)=trt; 
     estimate trt 1/testvalue=0.285 lower;  **ln(1.33)=0.285** 
     strata device; 
run;  
 
If secondary objective #1 is met at either the interim or final analysis time point, the 
following two assumptions will be tested in an analogous fashion as described for the 
primary objective: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 
3.3.1.4 
Power to test the objective 
 
Background 
Table 2 displays the procedure- or system-related complication rates from several 
Medtronic and non-Medtronic sponsored studies.  These data indicate that complications 
related to the implanted system (i.e. device and leads) or procedure range from 4.0% to 

16 
 
24.7% depending on complication definition, devices studied, and study population.  Based 
on these data it appears reasonable based on the mix of devices and population under 
investigation in the WRAP-IT study that the underlying system or procedure complication 
free rate could range from 80% to 90% at 12-months post-procedure. 
 
Table 2: System or Procedure-Related Complications Reported Previous Studies 
Study 
Devices 
Studied 
Population 
Time 
Frame 
Complication Rate (95% 
CI) 
Gould et. al 20081 
ICD (n=451) 
Replacements 
12-months 
9.1% (NR) 
REPLACE2 
IPG (n=515) 
ICD (n=327) 
CRT-D (n=175) 
CRT-P (n=14) 
Replacements 
6-months 
4.0% (2.9%-5.4%) 
REPLACE 
IPG (n=329) 
ICD (n=320) 
CRT-D (n=49) 
CRT-P (n=15) 
Upgrades 
6-months 
15.3% (12.7% - 18.1%) 
BLOCK-HF 
CRT-D (n=230) 
New Implants 
12-months 
22.9% (18.0% - 29.0%) 
BLOCK-HF 
CRT-P (n=531) 
New Implants 
12-months 
17.7% (14.7% - 21.3%) 
REVERSE 
CRT-D (n=523) 
New Implants 
12-months 
17.0% (14.0% - 20.5%) 
REVERSE 
CRT-P (n=104) 
New Implants 
12-months 
24.7% (17.5% - 34.4%) 
4074 Study 
IPG (n=132) 
New Implants 
6-months 
13.9% (9.0% - 21.1%) 
EnRhythm MRI3 
IPG (n=469) 
New Implants 
12-months 
11.3% (8.8% - 14.6%) 
Advisa MRI3 
IPG (n=269) 
New Implants 
6-months 
9.2% (6.3% - 13.4%) 
1Gould et. al.  2008. Heart Rhythm 5: 1675-1681.  Major complication defined as post-operative death, nonfatal 
MI, cardiogenic shock, or event requiring reoperation. 
2Poole et. al. 2010. Circulation 122:1553-1561.  Major complications defined as an event defined in Table 1 of 
the manuscript.  In general major complications required invasive intervention. 
3Does not include system complications related to the RA lead only. 
 
Power Calculation 
Since the primary objective of the study dictates the sample size for the study, the power to 
test this secondary objective under several scenarios was determined based on the 
method of Lakatos as implemented in PASS 2008.  The following assumptions were made 
in the power calculation: 
1. Sample size of 6,988 subjects randomized 1:1 to the TYRX envelope or control 
group 
2. One interim analysis and final analysis 
3. The interim analysis will occur when approximately 50% of the follow-up is accrued 
4. One-sided alpha level of 2.5% 
5. Hwang-Shih-DeCani alpha spending function with a gamma parameter of negative 4 
(-4) which approximates O’Brien-Fleming boundaries and means the final test will 
be conducted at a one-sided alpha-level of 0.0238 which is analogous to a two-
sided alpha level of 0.0476. 
6. 15% annualized attrition rate that is independent of treatment group and system-
related complication 
7. 12-month system- or procedure-related complication rate in the control group could 
range from 10% to 20% 
8. The TYRX envelope has no effect on the system- or procedure-related complication 
rate 

17 
 
9. Non-inferiority margin of 33% on a relative scale or 4.4% on a linear scale when the 
underlying CIED system complication freedom rate at 12-months is 85% 
Table 3 indicates that the statistical power to test the non-inferiority hypothesis associated 
with secondary objective #1 is greater than 94% based on the assumptions above across a 
range of plausible control group event rates. 
 
Table 3:  Power to Test Secondary Objective #1 with Sample Size of 6,988 Subjects 
12-month system-
related Complication 
Free Rate 
Control Group 
Hazard Rate 
Non-inferiority 
Margin (Relative 
Scale) 
Non-inferiority Margin  
(Linear Scale)1 
Power 
90% 
0.1054 
1.33 
3.1% 
94.9% 
88% 
0.1278 
3.6% 
97.6% 
86% 
0.1508 
4.2% 
98.9% 
85% 
0.1625 
4.4% 
99.3% 
84% 
0.1744 
4.7% 
99.5% 
82% 
0.1985 
5.2% 
99.8% 
80% 
0.2231 
5.7% 
99.9% 
1The non-inferiority margin on the linear scale is defined as the difference in the survival curves for the event rate at 12-
months post-randomization between the control group and the TYRXTM Absorbable Antibacterial Envelope group. 
 
3.3.1.5 
Determination of Subjects’ Data for Analysis 
Since non-inferiority tests based on intention-to-treat principles may be anti-conservative, 
the results of the non-inferiority test will be reported for both the ITT and AT cohorts as 
recently suggested2.  However, statistical inference for this objective will be based on the 
AT cohort.  All randomized subjects and all follow-up from randomized subjects is included 
in the ITT cohort regardless of treatment received.  For the AT cohort, all follow-up from all 
subjects will be included, but the analysis will be based on the treatment the subject 
actually received at the time of their original CIED procedure. 
3.3.1.6 
Missing Data 
 
The analysis cohorts will include all follow-up from all randomized subjects through the 12-
month visit or 365 days post-randomization, whichever occurs first.  Since the statistical 
methods involve survival methods all follow-up from all randomized subjects will be 
included.  However, missing data could arise if a randomized subject exits the study or dies 
prior to the 12-month visit without experiencing a CIED system- or procedure-related 
complication.  As described in section 0 the log-rank test will be used to compare the study 
attrition rate for any reason between randomized treatment groups to evaluate the pattern 
of data missingness. 
 
3.3.1.7 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high power (CRT-D, ICD) devices 
and patients with low power (pacemaker, CRT-P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
lower to high power) and patients without device upgrade will be analyzed separately using 
the methods described in section 3.2.9. 
                                                     
2 Head, SJ et al.  2012.  Non-inferiority study designs:  lessons to be learned from cardiovascular trials.  European 
Heart Journal 33(11): 1318-1325. 

18 
 
3.3.2          Secondary Objective #2 
 
Compare the major CIED infection rate during the entire follow-up between the TYRX 
envelope group and the control group. 
 
3.3.2.1 
Hypothesis 
The second secondary objective will be tested with the following hypothesis: 
 
Ho: T(t) = c(t) for all t ≤ T, versus 
Ha: T(t)  c(t) for some t ≤ T 
 
where T(t) is the hazard function for major CIED infection in the TYRX envelope group 
and c(t) is the hazard function for major CIED infection in the control group during the 
entire follow-up period.  
 
 
3.3.2.2 
Endpoint Definition 
 
Major CIED infection is defined in section 3.2.2. 
3.3.2.3 
Analysis Methods 
 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  The primary method to be used to 
test this objective will be the Cox proportional hazard model.  The Cox model will be 
stratified by device type (low power versus high power) and include treatment as an 
independent variable.  Days of follow-up for each subject will be set to the minimum of 
days from last procedure attempt (or randomization if a subject was randomized but not 
implanted) to: (1) onset date of a subject’s first CIED infection meeting the primary 
endpoint, (2) study exit date (if exited), (3) date of death (if death occurs), or, (5) date of 
last follow-up.  Subjects who meet the endpoint prior to their last CIED procedure attempt 
will be considered to have met the endpoint on day zero.  Subjects not having a major 
CIED infection during the follow-up period will be considered censored at their last follow-
up day.  Based on this statistical test, it will be claimed that the TYRX envelope reduces 
major CIED infection during the entire study period if the hazard ratio estimate is less than 
one and the resulting p-value from the Wald test falls below the specified type I error 
boundary as determined by the Hwang-Shih-DeCani alpha spending function and Holm 
adjustment for multiple comparisons.  Kaplan-Meier plots of freedom from major CIED 
infection will be presented by treatment group and by treatment group within each device 
type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5.  
 
If secondary objective #2 is met at either the interim or final analysis time point, the 
following two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 

19 
 
 
 
 
3.3.2.4 
Determination of Subjects’ Data for Analysis 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention-to-Treat principle).   
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT/mAT 
cohorts. 
 
3.3.2.5 
Missing Data 
The primary analysis cohort for this objective will include all follow-up from all randomized 
subjects through the end of the study or visit cutoff for the interim analysis (i.e. Intention-to-
Treat principle).  Since the statistical methods involve survival methods all follow-up from 
all randomized subjects will be included.  However, missing data could arise if a 
randomized subject exits the study or dies prior to the end of the study (or visit cutoff) 
without experiencing a major CIED infection.  The log-rank test will be used to compare the 
study attrition rate for any reason (study exit or death) between randomized treatment 
groups to evaluate the pattern of data missingness by treatment group.   
 
Additionally, a competing risks model will be used to test the effect of the TYRX envelope 
in the presence of the competing risk of death unrelated to CIED infection should this 
objective be met as described in section 0. 
 
3.3.2.6 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high power (CRT-D, ICD) devices 
and patients with low power (pacemaker, CRT-P) devices to assess the performance of the 
TYRX envelope within each of these device types.  In addition, subgroups of subjects with 
device upgrade (e.g single chamber to dual chamber, or dual chamber to triple chamber, or 
low to high power) and subjects without device upgrade will be analyzed separately using 
the methods described in section 3.2.9. 
 
3.3.3          Secondary Objective #3 
 
Compare the rate of major and minor CIED infections through 12-months post-procedure 
between the TYRX envelope group and the control group.   
 
3.3.3.1 
Hypothesis 
The third secondary objective will be tested with the following hypothesis: 
 
Ho: T(t) = c(t) for all t ≤ 12 months (365 days), versus 
Ha: T(t)  c(t) for some t ≤ 12 months (365 days) 
 
where T(t) is the hazard function for major and minor CIED infection in the TYRX envelope 
group and c(t) is the hazard function for major and minor CIED infection in the control 
group.  
 

20 
 
3.3.3.2 
Endpoint Definition 
 
CIED infections, including major CIED infections are defined in section 3.2.2.  Minor CIED 
infections are CIED infections that are not classified as major CIED infections. 
3.3.3.3 
Analysis Methods 
 
All potential CIED infections will be collected on the eCRFs as they occur.  The CEC will 
adjudicate each potential CIED infection for its relationship to the CIED and determine 
whether it meets the major CIED infection definition.  Those infections related to the CIED 
that do not meet the major CIED infection will be considered minor CIED infections.  The 
primary method to be used to test this objective will be the Cox proportional hazard model.  
The Cox model will be stratified by device type (low power versus high power) and include 
treatment as an independent variable.  Days of follow-up for each subject will be set to the 
minimum of days from last procedure attempt (or randomization if a subject is randomized 
but not implanted) to:  (1) onset date of a subject’s first major or minor CIED infection, (2) 
study exit date (if exited), (3) date of death (if death occurs), (4) date of last follow-up, or 
(5) 365 days post-procedure.  Subjects who meet the endpoint prior to their last CIED 
procedure attempt will be considered to have met the endpoint on day zero.  Subjects not 
having a major or minor CIED infection during the follow-up period will be considered 
censored on the day as derived above.  Based on this statistical test, it will be claimed that 
the TYRX envelope reduces major or minor CIED infection if the hazard ratio estimate is 
less than one and the resulting p-value from the Wald test falls below the specified type I 
error boundary as determined by the Hwang-Shih-DeCani alpha spending function and 
Holm adjustment for multiple comparisons.  Kaplan-Meier plots of freedom from major or 
minor CIED infection will be presented by treatment group and by treatment group within 
each device type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5. 
 
If secondary objective #3 is met at either the interim or final analysis time point, the 
following two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
 
3.3.3.4 
Determination of Subjects’ Data for Analysis 
 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention-to-Treat principle).   
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT/mAT 
cohorts. 
3.3.3.5 
Missing Data 
The primary analysis cohort for this objective will include all follow-up from all randomized 
subjects through the 12-month visit or 365 days post-randomization, whichever occurs first.  
Since the statistical methods involve survival methods all follow-up from all randomized 
subjects will be included.  However, missing data could arise if a randomized subject exits 
the study or dies prior to the 12-month visit without experiencing a major or minor CIED 
infection.  The log-rank test will be used to compare the study attrition rate for any reason 

21 
 
(study exit or death) between randomized treatment groups to evaluate the pattern of data 
missingness by treatment group.   
 
Additionally, a competing risks model will be used to test the effect of the TYRX envelope 
in the presence of the competing risk of death unrelated to CIED infection should this 
objective be met as described in section 0. 
 
3.3.3.6 
Subgroup Analyses 
Subgroup analysis will be performed for subjects within high-power (CRT-D, ICD) devices 
and subjects with low-power (pacemaker, CRT-P) devices to assess the performance of 
the TYRX envelope within each of these device types.  In addition, subgroups of subjects 
with device upgrade (e.g. single chamber to dual chamber, or dual chamber to triple 
chamber, or low to high power) and subjects without device upgrade will be analyzed 
separately using the methods described in section 3.2.9. 
 
3.4 
Ancillary Objectives 
The following ancillary objectives are intended to gain additional information about the 
performance of the TYRX envelope.  The type I error rate is not controlled for the ancillary 
objectives.  Not all ancillary objectives may be evaluated if the study’s primary objective is 
not met. 
3.4.1 Ancillary Objective #1:  Mortality 
 
To compare all-cause mortality rates between the TYRX envelop group and the control 
group. 
3.4.1.1 
Endpoint  
 
Death for any cause 
 
3.4.1.2 
Hypothesis 
 
This ancillary objective will be tested with the following hypothesis: 
 
Ho: T(t) = c(t) for all t ≤ T, versus 
Ha: T(t)  c(t) for some t ≤ T 
 
where T(t) is the hazard function for death for any cause in the TYRX envelope group and 
c(t) is the hazard function for death any cause in the control group during the entire follow-
up period. 
 
3.4.1.3 
Analysis Methods 
The primary method to be used to evaluate the hypothesis above will be the Cox 
proportional hazard model.  The Cox model will be stratified by device type (low power 
versus high power) and include treatment as an independent variable.  Days of follow-up 
for each subject will be set to the minimum of days from last procedure attempt (or 
randomization if a subject was randomized but not implanted) to the (1) date of death or (2) 
last study contact date.  Subjects alive at their last follow-up day will be censored on their 
last day as derived above.  A p-value less than 0.05 will be considered statistically 

22 
 
significant.  Kaplan-Meier plots of subject survival will be presented by treatment group and 
by treatment group within each device type. 
 
The SAS code for implementing the stratified Cox regression model will be similar to the 
sample code described in 3.2.5 
  
If ancillary objective #1 is met at either the interim or final analysis time point, the following 
two assumptions will be tested as described above: 
 
1. Heterogeneity of the hazard ratio across device type 
 
2. Proportional hazards between treatment groups 
3.4.1.4 
Determination of Subjects for Analysis 
All randomized subjects will be included in the primary analysis regardless of the treatment 
they actually receive or their study compliance (i.e. Intention-to-Treat principle). 
 
If the objective is not met for the ITT cohort, the analysis will be conducted for the AT 
cohort. 
 
3.4.2 Ancillary Objective #2:  CIED procedure success rate 
 
Evaluate the CIED procedure success rate in the TYRX envelope group and the control 
group  
 
3.4.2.1 
Analysis Methods 
Information related to the CIED procedure (i.e., initial implant or index 
replacement/upgrade or index system revision) will be collected on the procedure eCRF.  A 
procedure attempt is defined as any CIED procedure where the device pocket is opened or 
venous access was gained (i.e., skin was cut).  A successful procedure is defined as an 
implant attempt where the device is successfully connected to the system’s leads and the 
CIED system remains in the body and the device pocket is closed.  Additionally, for those 
subjects randomized to the TYRX envelope group, the TYRX envelope must also remain in 
the device pocket following pocket closure to qualify as a successful CIED procedure.  
 
Specifically, for all subjects with a procedure attempt, a CIED procedure can only be 
considered successful if the question on the procedure CRF “Was a generator in the 
pocket following the procedure?” is answered as “Yes”.  Additionally, for those subjects 
randomized to the TYRX envelope group and with an attempted implant of the TYRX 
envelope, the question “Was the TYRX envelope in the device pocket following the implant 
procedure?” must also be answered as “Yes”.  Note that for purposes of determining 
procedure success, subjects with a CRT device where the LV lead cannot be placed 
adequately may still be considered a success if the generator remains in the pocket.  In 
these cases, a system modification form would be required if another LV lead implant 
attempt is made during a separate procedure.  
 
The CIED procedure success rate will be defined on a per subject basis as the number of 
subjects with their last CIED procedure considered successful divided by the number of 
subjects with at least one CIED procedure attempt.  Fisher’s exact test will be used to 
compare the procedure success rate between the TYRX envelope group and the control 
group. 
 

23 
 
The following sample syntax in SAS will be used to evaluate the ancillary objective #2: 
 
proc freq; 
     tables trt*success /exact cmh; 
     weight count; 
run; 
 
Fisher’s exact test will also be used to compare the percentage of subjects with more than 
one procedure attempt (i.e. more than one CIED procedure CRF) by randomized treatment 
group.  For each randomized treatment group the denominator will be the number of 
subjects with a successful procedure and the numerator will be the number of subjects with 
a successful procedure requiring more than one procedure to obtain the successful 
procedure. 
  
3.4.2.2 
Determination of Data for Analysis 
The primary analysis cohort will be the ITT population with the following additional 
requirements: 
1. A subject must have a CIED procedure attempt (e.g., skin cut) 
2. Subjects randomized to the TYRX group must have had an attempt to implant the TYRX 
envelope.  Specifically, subjects who crossed over to the control group without an 
attempted TYRX envelope implant were excluded from this analysis.  For example, this 
includes subjects who were crossed over due to TYRX inventory issues or site error.   
3. Subjects randomized to the control group that crossed over to the TYRX envelope group 
during their implant attempt will be conservatively excluded from the analysis cohort for 
this objective since it is not possible to accurately determine the number of control group 
subjects with an attempted crossover to the TYRX envelope group where the TYRX 
envelope was not successfully implanted. 
 
3.4.3 Ancillary Objective #3:  Summarize adverse events 
To summarize adverse events by treatment group 
 
3.4.3.1 
Analysis Methods 
Subjects will be queried for AEs at all scheduled and unscheduled visits.  All AEs 
potentially related to the CIED system, CIED implant or system modification procedure, 
and all SAEs regardless of their relationship to the CIED system or CIED procedure 
(including the TYRX envelope if applicable) will be collected.  Medtronic safety specialists 
will ensure that at a minimum all AEs that are potentially related to the CIED system 
(including the TYRX envelope), or CIED procedure, or death are classified by the CEC.  
Summary tables will be compiled categorizing the AEs with respect to procedure 
relatedness, CIED relatedness (including CIED component), and TYRX envelope 
relatedness.  For events classified by the CEC, the CEC classification will be used in the 
analysis.  In cases where only the investigator classifies the event, the investigator’s 
classification will be used.  In addition, the number of events and number of subjects with 
events by MedDRA term will be displayed.  Additionally, the nominal p-value from the log-
rank test will be used to identify system- or procedure-related AEs occurring on or after a 
CIED procedure attempt by MedDRA preferred term that may differ between treatment 
groups.  This test does not protect the type I error, but may help identify specific AEs that 
differ between randomized treatment group for further evaluation.  These tests will only be 
performed for preferred terms that occur in more than five subjects. 

24 
 
 
3.4.3.2 
Determination of Data for Analysis 
All adverse events collected during the study will be included in this analysis. 
 
3.4.4 Ancillary Objective #4:  Predictors of CIED infection 
To identify predictors of major CIED infection 
 
3.4.4.1 
Analysis Methods 
Subject demographics and medical history including previous device history will be 
collected at baseline.  CIED procedure-related variables such as antibiotic prophylaxis, 
surgical site preparation, procedure duration, device type, and number of leads will be 
collected for each CIED procedure.  Additionally, device characteristics such as 
impedance, optivol fluid status, and heart rate variability etc. will be collected via device 
interrogations at each follow-up visit.  Cox regression models will be employed using 
subjects in the control group to identify factors that may be associated with major CIED 
infection.  Additionally, multivariable Cox models may be used to develop a risk model for 
major CIED infection.  For any such multivariable Cox model, the number of degrees of 
freedom available and hence the number of candidate predictors available (and their 
functional form) for modelling will be determined by the number of major CIED infections in 
the control group.  This analysis will be exploratory in nature. 
 
3.4.4.2 
Determination of Data for Analysis 
All subjects randomized to the control group with a CIED procedure attempt who do not 
receive the TYRX envelope during their CIED procedure. 
 
3.4.5 Ancillary Objective #5: Quality of Life 
 
Summarize quality of life. 
3.4.5.1 
Analysis Methods 
Subjects will be asked to complete the EQ-5D questionnaires at baseline and at the 12-
month visit (or study exit if the subject exits the study for reasons other than lost to follow-
up prior to completing the 12-month visit).  Additionally, subjects with a CIED infection will 
be asked to complete the EQ-5D within two weeks following their CIED infection diagnosis 
and at 1-month, 3-months, and 6-months post-CIED infection diagnosis.   
The EQ-5D summary health score is calculated based on five “dimension” questions: 
mobility, self-care, usual activities, pain/discomfort, anxiety/depression.  For subjects 
completing the EQ-5D-3L questionnaire (primarily OUS subjects) each dimension has 
three options, which are in general: 1=no problem, 2=some problem, 3=extreme problem.  
For subjects completing the EQ-5D-5L questionnaire (primarily US subjects) each 
dimension has five options which are in general: 1=no problem, 2=slight problem, 
3=moderate problem, 4=severe problem, 5=unable to perform.   
 
For purposes of the final study report, EQ-5D summary scores will be standardized to the 
EQ-5D-3L summary health score using EQ-5D-5L to EQ-5D-3L crosswalk value set current 
at the time the final report is prepared, unless EQ-5D-5L value sets become available from 
EuroQoL during the WRAP-IT study for geographies using the EQ-5D-5L.   

25 
 
Each subject’s summary health score will be standardized to the same country value set 
(e.g. US) regardless of the subject’s origin using the appropriate EQ-5D-3L value set. 
 
Medtronic’s healthcare economics group may request additional summaries of the EQ-5D 
data following study completion for conducting cost effectiveness analyses described in the 
healthcare economics analysis plan. 
 
Descriptive statistics will be used to summarize the change in EQ-5D scores from baseline 
to the 12-month visit by infection status.  Additionally, the changes in EQ-5D between 
CIED infection and post-CIED infection will be computed using summary statistics for all 
subjects with a major CIED infection as classified by the CEC. More detailed analysis 
methods will be described in the health economics Statistical Analysis Plan.  
 
Bar charts will be used to present results from the EQ-5D descriptive system as a health 
profile.  Summary health score will be presented in tables similar to shown below: 
 
EQ-5D 
 
Baseline 
12-months 
Change 
 
 
N 
 
Mean 
± Std. 
Median 
Range 
N 
 
Mean ± 
Std. 
Median 
Range 
N 
 
Mean ± 
Std. 
95%  CI  
 
EQ-5D 
Health 
Score  
Infection 
 
 
 
 
 
 
 
 
 
 
 
 
No Infection 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D 
Visual 
Analog 
Scale 
Infection 
 
 
 
 
 
 
 
 
 
 
 
No Infection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4.5.2 
Determination of Data for Analysis 
Completed EQ-5D questionnaires from all randomized subjects will be used to describe the 
changes in EQ-5D score from baseline.  All completed EQ-5D questionnaires following an 
adjudicated CIED infection will be used to summarize the change in EQ-5D score from 
baseline following CIED infection. 
 
3.4.6 Ancillary Objective #6:  Healthcare System Cost Effectiveness 
Objective 
To assess the cost-effectiveness of the TYRX envelope. 
 
Analysis Methods 
Health care utilizations (HCUs) related to suspected CIED infection will be collected on the 
eCRFs.  HCUs related to CIED infection include all hospitalizations, emergency 
department visits, urgent care, or unscheduled follow-up visits associated with the 
suspected CIED infection regardless of location of care. 
For each major CIED infection as classified by the CEC, the following information will be 
compiled and provided to Medtronic’s healthcare economics group: 
• 
Subject identifier, randomized treatment group, and treatment actually received 
• 
For each inpatient hospitalization the hospitalization admission date, discharge date, total 
hours in ICU, and total hours in cardiac ward 

26 
 
• 
For each outpatient visit the type of outpatient visit, provider type, and visit date 
• 
Date and type of any long-term health care facility stay 
• 
Start date, stop date, frequency per week, and frequency per day for each session of 
home health care 
• 
Medications used to treat the CIED infection as recorded on the AE eCRF associated 
with the major CIED infection 
Medtronic’s healthcare economics group (or their designees) will use this information to 
evaluate the cost-effectiveness of the TYRX envelope and develop subsequent ancillary 
study publications.  The methodology for the cost-effectiveness models is detailed in the 
WRAP-IT health economics analysis plan. 
For purposes of the final report, the following healthcare utilization parameters will be 
summarized by randomized treatment group for subjects with a major CIED infection within 
12-months, major CIED infection during the entire follow-up period, any major or minor 
CIED infection within 12-months, and any major or minor CIED infection during the entire 
follow-up period: 
• 
Total days hospitalized for hospitalizations exceeding 24 hours 
• 
Days in intensive care unit (24 hours = 1 day and fractional days rounded up) 
• 
Days in cardiac ward (24 hours = 1 day and fractional days rounded up) 
• 
Total days hospitalized for hospitalization less than 24 hours 
• 
Number of emergency department visits 
• 
Number of urgent clinic visits 
• 
Number of clinic visits 
For each healthcare utilization parameter, the rate of healthcare contacts per year (e.g., 
hospitalized days per year, number of emergency department visits) in each randomized 
treatment group will computed by dividing the total number of contacts by the cumulative 
total duration of the follow-up in years across all subjects in the treatment group. 
Additionally, the distribution of healthcare utilization related to major CIED infection within 
12-months (or during the entire follow-up period) and related to major or minor CIED 
infection within 12-months (or during the follow-up period) will be compared between 
randomized treatment groups using negative binomial hurdle models for the following 
healthcare utilization parameters: 

27 
 
• 
Total days hospitalized for hospitalizations exceeding 24 hours 
• 
Total outpatient visits where outpatient visits were defined as the sum of all 
hospitalizations less than 24 hours, emergency department visits, urgent clinic visits, and 
clinic visits. 
 
Each negative binomial hurdle model will include the number of healthcare utilizations as 
the response, randomized treatment group as the independent predictor for both the zero 
distribution and negative binomial components of the model, and natural log of follow-up 
months as the offset.  Under this parameterization, each hurdle model provides two 
estimates of the effect of the TYRX envelope on healthcare utilization:  specifically (1) a 
measure of the change in the log odds of having at least one utilization in the TYRX group 
relative to the control group, and (2) a measure of the change in the intensity of healthcare 
utilization in the TYRX group relative to the control group.  Exponentiated, the model 
estimates (1) and (2) can be interpreted as an odds ratio and conditional relative risk 
respectively. 
 
The R package pscl will be used to fit each negative binomial hurdle model using the 
syntax below: 
 
hurd.out <- hurdle(hcuParameter ~ trtgrp | trtgrp 
                       offset=logMonths, 
                       link="logit", 
                       dist="negbin") 
 
where “hcuParameter” represents the count of the number health care utilization contacts 
for a subject, “trtgrp” is the randomized treatment group (parameterized as 1 = TYRX 
group, 0 = Control group), and “logMonts” is the natural log of the follow-up months.  A link 
of “logit” requests that the logit link function be used for the zero component of the hurdle 
model, and a distribution of “negbin” requests that the negative binomial distribution be 
used to model the positive integer component of the hurdle model. 
 
 
3.5 
 
 
 
 
 
 
   
 
  
 
   
 
  
 
  
 
 
 
 
 
 
 
 

28 
 
 
 
   
 
 
 
 
 
3.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
SAS syntax for this analysis will be similar to below: 
 

29 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.2 
 
 
 
 
 
 
 

30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 

31 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.5.4 
 
 
 
 
 
 
 
 
 
 
 
 
3.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

33 
 
 
 
 
 
 

 
4 
APPENDIX 
4.1 Sample Size Simulation Program 
 
 
 
 
  
                                                               
 
                                                                                   
 
  
                                                                
 
                
                                               
  
                  
 
  
                                       
 
                                      
 
  
                                                                               
 
  
                                            
 
                                                                       
 
     
       
        
       
                         
 
     
       
 
                  
   
   
                              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
  
                          
 
 
 
 
 
   
  
 
  
 
  
 

 
 
Statistical Analysis Plan 
 
 
 
  
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
                                  
 
   
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
  
 
  
 
   
  
 
  
 
   
  
 
  
 
    
 
    
 
    
 
      
 
     
    
 
      
 
     
   
   
   

 
 
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4.3 Change History 
 
Table 4:  Change History 
 
Applicable 
Sections 
Change 
Rationale 
Amendment 1 – 08JAN2018 
Section 
3.1.5 
Modified the definition of As Treated 
cohort 
The original text in version 1.0 of the WRAP-IT SAP was 
unclear as to whether subjects without a procedure attempt 
or with no successful procedure attempts would be included 
in the AT cohort.  Additionally, the original text did not 
indicate whether the analysis of the AT cohort would stratify 
by the device type (high power or low power) as randomized 
or by the device type as actually implanted. 
Section 
3.4.2.1 
Modified the definition of 
Analysis Cohort for Ancillary 
Objective #2 (CIED Procedure 
Success) 
The DMC informed Medtronic on 25 February 2017 that 
Medtronic may want to consider revising the analysis cohort 
for the analysis of the procedure success rate (ancillary 
objective #2), as several subjects randomized to the TYRX 
envelope group never had a TYRX envelope implant attempt. 
Reasons for not having a TYRX envelope implant attempt 
included “TYRX envelope inventory issues” and “study site 
error”.   
Section 
3.4.2.2 
Modified the determination of 
Subjects for Analysis for Ancillary 
Objective #2 (CIED Procedure 
Success) 
Section 
3.4.6 
Analysis Methods for Ancillary 
Objective #6:  (Healthcare System 
Cost Effectiveness) 
There were two reasons for modifying the original text in 
version 1.0 of the WRAP-IT SAP.   
First, the blinded study statistician noticed that the distribution 
of healthcare utilization parameters had many more zeros 
(i.e., subjects with value of zero for healthcare utilization 
parameter) than could be accommodated by a negative 
binomial distribution.  Specifically, the distribution of these 
variables was highly zero inflated.  Thus, it was necessary to 
change from the originally specified negative binomial model 
to a negative binomial hurdle model to account for the zero 
inflation.   
Secondly, the healthcare cost effectiveness analyses are 
being specified in the healthcare economics analysis plan.  
Moreover, since many of the healthcare cost effectiveness 
analyses will likely occur following distribution of the WRAP-
IT final clinical study report, it was necessary to identify which 
healthcare utilization analyses would appear in the final 
report. 
Amendment 2 – 31JUL2018 
Section 
3.1.5 
Added the modified Intent-to-Treat 
cohort definition 
The original text in version 1.0 of the WRAP-IT SAP indicates 
subjects with complications post enrollment would be 
included for analysis. Subjects with complications after 
enrollment are defined as having an ongoing infection at 
procedure, receiving a heart transplant or a VAD, or receiving 
dialysis initiated after enrollment, but prior to procedure. 
These subjects are at a higher risk for infection and will be 
analyzed separately. A sensitivity analysis will be included to 
show differences between the ITT population and the cohort 
defined by these subjects. 

 
 
Statistical Analysis Plan 
 
 
 
Section 
3.2.7 
Added the modified intent-to-treat 
to the list of cohorts to be analyzed 
if the primary objective is not met 
The initial text did not take into consideration subjects who 
accumulate exclusion criteria after enrollment. An additional 
cohort is necessary to exclude subjects who are considered a 
higher risk for infection, and would have been excluded from 
the trial.