AdaptResponse Clinical Trial
Phase: NA
Conditions: Heart Failure With Left Bundle Branch Block
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

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Clinical Investigation Plan 
 
Medtronic Confidential 
 
 
 
AdaptResponse 
 
Clinical Investigation Plan 
 
Version 2.0  
28 February 2018 
Regional Sponsors and Contacts  
Medtronic, Inc. 
Cardiac Rhythm and Heart Failure 
Clinical Research 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
Medtronic, Bakken Research Center 
B.V. 
Cardiac Rhythm and Heart Failure 
Clinical Research 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
+31-43-35-66-566 
Medtronic Australasia Pty Ltd 
2 Alma Rd,  
Macquarie Park NSW 2113Australia+61-
2-9857-9000 
Medtronic of Canada, Ltd. 
99 Hereford Street 
Brampton, Ontario, L6Y 0R3 Canada 
+1-905-460-3800 
Medtronic Japan Co., Ltd. 
Shinagawa Season Terrace 22 F, 1-
2-70 Konan, , Minato-ku 
Tokyo, 108-0075 
JAPAN 
+81-3-6776-1313 
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 Latin America HQ 
Medtronic USA, Inc., 
Doral Corporate Center II 
3750 NW 87th Avenue, Suite 700 
Miami, FL U.S.A. 33178 
+305 500-9328
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
LISTING OF TABLES ..................................................................................................... 6 
LISTING OF FIGURES ................................................................................................... 7 
SPONSOR CONTACT INFORMATION .......................................................................... 8 
CROS AND CORE LABORATORIES ........................................................................... 10 
STEERING COMMITTEE .............................................................................................. 11 
1. 
INTRODUCTION .................................................................................................. 13 
1.1 
Study purpose and description 
13 
1.2 
Study scope 
13 
1.3 
Study oversight 
14 
2. 
BACKGROUND AND JUSTIFICATION .............................................................. 15 
3. 
SYSTEM DESCRIPTION AND INTENDED USE ................................................. 17 
3.1 
Medtronic CRT-D and CRT-P devices 
17 
3.2 
Medtronic left ventricular leads 
17 
3.3 
Market released right ventricular (defibrillation) lead 
17 
3.4 
Market released right atrial lead 
17 
3.5 
Medtronic CareLink programmer 
17 
3.6 
Medtronic CareLink Home Monitor 2490C and Network 
17 
3.7 
Market-released Pacing System Analyzer 
18 
4. 
REGULATORY COMPLIANCE ........................................................................... 19 
5. 
METHODOLOGY ................................................................................................. 20 
5.1 
Study objectives 
20 
5.1.1 
Primary objective 
20 
5.1.2 
Secondary objectives 
20 
5.1.3 
Ancillary objectives 
21 
5.2 
Primary endpoint 
21 
5.2.1 
Primary endpoint definition 
21 
5.2.2 
Endpoint Adjudication Committee 
21 
5.3 
Subject selection criteria 
22 
5.3.1 
Inclusion criteria 
22 
5.3.2 
Exclusion criteria 
22 
5.4 
Randomization 
23 
5.5 
Crossover 
23 
5.6 
Blinding 
24 
5.7 
Minimization of Bias 
24 

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6. 
STUDY PROCEDURES ....................................................................................... 26 
6.1 
Site activation 
26 
6.2 
Equipment requirements 
27 
6.3 
Data collection 
27 
6.4 
Patient informed consent process 
29 
6.5 
Enrollment 
31 
6.6 
Baseline 
31 
6.6.1 
Baseline ECG 
32 
6.7 
Implant 
32 
6.7.1 
Implant Requirements and Recommendations 
33 
6.7.2 
CRT Optimization 
33 
6.8 
Randomization 
33 
6.8.1 
Programming Requirements and Recommendations 
33 
6.9 
Scheduled follow-up visits 
35 
6.9.1 
3 and 6 month Follow-up visits 
37 
6.9.2 
12, 18, 24 month Follow-up visits 
37 
6.9.3 
Follow-up visit every 6 months until study closure 
37 
6.10 
Device Interrogation (Interrogate All) 
38 
6.11 
Adverse Events 
38 
6.12 
Healthcare Utilization 
38 
6.13 
System Modification 
38 
6.14 
Conditional Disengagement 
39 
6.15 
Study Exit 
39 
6.15.1 Study completed 
40 
6.15.2 Lost to follow-up 
40 
6.15.3 Subject chooses to exit (i.e. revokes consent) 
40 
7. 
STUDY DEVIATIONS .......................................................................................... 42 
8. 
ADVERSE EVENTS ............................................................................................ 43 
8.1 
Adverse Event definitions 
43 
8.1.1 
Adverse Events 
43 
8.1.2 
Processing Updates and Resolution 
43 
8.2 
Definitions, Classification and Reporting 
44 
8.2.1 
Adverse Event Definitions 
44 
8.2.2 
Adverse Events Classification and Reporting 
46 
8.3 
Subject Death 
48 
8.3.1 
Death data collection 
48 
8.3.2 
Death classification and reporting 
49 
8.4 
Adverse Event Records and Reporting Requirements 
49 
8.5 
Product Complaint Reporting 
56 
9. 
RISK ANALYSIS ................................................................................................. 58 

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9.1 
Risk Minimization 
59 
9.2 
Potential Benefits 
59 
9.3 
Risk-to-Benefit Analysis 
60 
10. 
PLANNED STUDY CLOSURE, EARLY TERMINATION OF STUDY OR STUDY 
SUSPENSION ............................................................................................................... 61 
10.1 
Planned study closure 
61 
10.2 
Early termination or suspension 
61 
10.2.1 Study-wide termination or suspension 
61 
10.2.2 Investigator/center termination or suspension 
61 
10.3 
Procedures for termination or suspension 
62 
10.3.1 Medtronic-initiated and regulatory authority-initiated 
62 
10.3.2 Investigator-initiated 
62 
10.3.3 Ethics committee-initiated 
63 
11. 
STATISTICAL METHODS AND DATA ANALYSIS ............................................. 64 
11.1 
General 
64 
11.2 
Study design 
64 
11.2.1 Rationale 
64 
11.2.2 Randomization 
65 
11.2.3 Sample size 
65 
11.2.4 Interim analyses 
65 
11.3 
Primary objective 
65 
11.3.1 Endpoint definition 
65 
11.3.2 Hypothesis, analysis methods and performance requirements 
65 
11.3.3 Determination of patients and data for analysis 
66 
11.3.4 Sample size rationale 
66 
11.4 
Interim analysis methodology 
67 
11.5 
Secondary and ancillary objectives 
68 
11.5.1 Secondary objectives 
68 
11.5.2 Ancillary objectives 
70 
12. 
DATA AND QUALITY MANAGEMENT ............................................................... 71 
13. 
WARRANTY/INSURANCE INFORMATION ........................................................ 72 
13.1 
Warranty 
72 
13.2 
Insurance (Europe, Russia and Middle East) 
72 
13.3 
Insurance (Japan) 
72 
13.4 
Insurance (Australia) 
72 
13.5 
Insurance (India) 
72 
13.6 
Insurance (Korea) 
72 
13.7 
Insurance (Taiwan) 
73 
13.8 
Insurance (Latin America) 
73 
14. 
MONITORING ...................................................................................................... 74 

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14.1 
Monitoring Visits 
74 
15. 
REQUIRED RECORDS AND REPORTS ............................................................. 75 
15.1 
Investigator records 
75 
15.2 
Investigator reports 
76 
15.3 
Sponsor records 
78 
15.4 
Sponsor reports 
79 
APPENDIX A: CASE REPORT FORMS ....................................................................... 83 
APPENDIX B: PRELIMINARY PUBLICATION PLAN .................................................. 84 
APPENDIX C: DATA MONITORING COMMITTEE (DMC) ........................................... 86 
APPENDIX D: ENDPOINT ADJUDICATION COMMITTEE (EAC) ............................... 88 
APPENDIX E: STUDY OVERVIEW .............................................................................. 89 
APPENDIX F: INFORMED CONSENT TEMPLATE...................................................... 94 
APPENDIX G: FORESEEABLE ADVERSE EVENT LIST ............................................ 95 
APPENDIX H: PARTICIPATING INVESTIGATORS AND INSTITUTIONS ................. 103 
APPENDIX I: ETHICS COMMITTEE LIST .................................................................. 104 
APPENDIX J: LABELING ........................................................................................... 105 
APPENDIX K: BIBLIOGRAPHY ................................................................................. 106 
APPENDIX L: ADDITIONAL INFORMATION FOR CENTERS BY COUNTRY .......... 107 
APPENDIX M: PREVIOUS CLINICAL INVESTIGATIONS ......................................... 108 
APPENDIX N: CLINICAL INVESTIGATION PLAN SIGNATURE PAGE (IF APPLICABLE)
 
109 
APPENDIX O: REFERENCES .................................................................................... 110 
APPENDIX P: DOCUMENT CHANGE HISTORY ....................................................... 113 
  
 
 

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LISTING OF TABLES 
 
Study sponsor contact information ............................................................................. 8 
 
CRO and Core Laboratory information ..................................................................... 10 
 
Steering Committee contact information ................................................................... 11 
 
Adaptive CRT study post-hoc sub-analysis results ................................................... 16 
 
Data collection and study procedure requirements at subject visits .......................... 28 
 
Programming Requirements and Recommendations ............................................... 34 
 
Post-randomization follow-up windows ..................................................................... 36 
 
Adverse Event definitions ......................................................................................... 44 
 
Adverse Event classification responsibilities............................................................. 47 
 Adverse event reporting requirements...................................................................... 49 
 Investigator reports applicable for all geographies per Medtronic requirements ....... 76 
 Investigator reports applicable to Japan ................................................................... 76 
 Investigator reports applicable to India ..................................................................... 78 
 Sponsor reports for Australia .................................................................................... 79 
 Sponsor reports for Canada ..................................................................................... 79 
 Sponsor reports for Europe, Russia, Middle East, Taiwan, Korea, Latin America ..... 80 
 Sponsor reports for Japan ........................................................................................ 81 
 Sponsor reports for the United States ...................................................................... 82 
 Observed System and Implant Procedure Related Adverse Events ......................... 97 
 Frequent Major and Minor Complications ............................................................... 100 
 Bi-V ICD Adverse Events – ACC-NCDR ICD Quarterly Report .............................. 101 
 
 
 

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LISTING OF FIGURES 
Figure 1: Visit Timeline .............................................................................................................. 35 
Figure 2. Statistical stopping boundaries ................................................................................... 67 
 

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SPONSOR CONTACT INFORMATION 
Medtronic, Inc. is sponsoring the AdaptResponse trial. Regional contact information is provided 
below. This information may be subject to change during the course of the clinical study. 
Periodic updates to study contact information will be sent to the centers as needed. 
 
Study sponsor contact information 
Study contacts 
Worldwide clinical study leader 
 
Lidwien Vainer, Sr. Clinical Research Specialist 
Phone: 
 
Fax: 
 
lidwien.vainer@medtronic.com  
US / Canada 
 
 
Phone: 
 
Fax: 
 
scott.a.sarazin@medtronic.com  
Japan 
 
 
 
 
  
Australia 
 
 
 
 
 
Taiwan 
 
 
 
 
 
India 
 
 
 
 
 
Latin America 
 
 
 
 
Korea 
 
 
 
 
Study monitors and contacts 
Worldwide monitoring leader 
 
 
 
 
  
US/Canada monitoring leader 
 
 
  
 
  
 
 
 

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Name and title of persons authorized to sign protocol and amendments for the sponsor:  
This information may be subject to change during the course of the clinical study. Updates will 
be sent to the centers as needed. 
Dan Schaber, Vice President Heart Failure Clinical Research  
Jeff Stein, Clinical Biostatistics Director responsible for oversight of the statistical aspects of the 
study  
Helma van den Berg, Sr Regulatory Affairs Specialist 
 
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 centers as needed. 
David Steinhaus, M.D., VP & GM Heart Failure  
Medtronic, Inc. 
Cardiac Rhythm and Heart Failure  
8200 Coral Sea Street N.E., MVC42 
Mounds View, MN 55112 
United States 
Phone: 
 
Fax: 
 
david.m.steinhaus@medtronic.com  
 
Names, titles, addresses and contact numbers of the investigators responsible for 
conducting the study: 
A complete list of participating investigators and institutions will be distributed under separate 
cover upon request.  
 
 

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CROs AND CORE LABORATORIES 
 
CRO and Core Laboratory information 
Contact Information  
Duties performed 
Cognizant Technology Solutions 
500 Frank W. Burr Blvd. 
Teaneck, NJ 07666 
United States 
Direct Phone: (201) 801-0233 
Direct Fax: (201) 801-0243 
• 
Development 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. 
ECG Core Laboratory 
Centre d’Investigation Clinique – 
Innovations Technologiques 
Cardiology Department, Level 0, 
Pontchaillou Hospital 
2, Rue H. Le Guilloux 
35033 Rennes Cedex 09 
France
• 
Review of baseline ECGs, determining LBBB presence, 
measuring P-R interval. 
  
 
 

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STEERING COMMITTEE 
 
Steering Committee contact information 
Committee Member  
Contact information 
Bruce Wilkoff, MD 
Chair, Steering Committee 
Address: The Cleveland Clinic Foundation, 9500 Euclid Avenue, 
Desk F15, Cleveland, Ohio, 44195 
Telephone: 
 
Fax: 
 
Email: wilkofb@ccfr.org  
Professional Position: Director of Cardiac Pacing and 
Tachyarrhythmia Devices 
Gerasimos Filippatos, MD 
Co-chair, Steering Committee 
Address: University of Athens, Department of Cardiology, Heart 
Failure Unit 
28 Doukissis Plakentias,  
11523 Athens, Greece 
Telephone: 
 
Email: geros@otenet.gr 
Professional Position: Head of Heart Failure Unit, Department of 
Cardiology, Athens University Hospital
David Birnie, MD 
 
Address: University of Ottawa Heart Institute, 40 Ruskin Street, 
Ottawa, Ontario K1Y 4W7 
Telephone: 
 
Fax: +
 
Email: dbirnie@ottawaheart.ca 
Professional Position: Staff Cardiac Electrophysiologist Director, 
Arrhythmia Service, University of Ottawa Heart Institute 
Michael Gold, MD 
Address: Medical University of South Carolina, 25 Courtenay Drive 
Suite 7031, Charleston, SC 29425-8911 
Telephone: 
 
 
Fax: 
 
Email: goldmr@musc.edu  
Professional Position: Director, Division of Cardiology, Medical 
University of South Carolina 
Ahmed Hersi, MD 
Address: King Saud University, Faculty of Medicine, P.O. Box 
7805 (92), Riyadh, 11472, Saudi Arabia 
Telephone: 
 
Fax: 
 
Email: ahersi@ksu.edu.sa 
Professional Position: Associate Professor of Cardiac Sciences, 
Consultant Electrophysiologist 
 Kengo Kusano, MD 
Address: National Cerebral and Cardiovascular Center 5-7-1 
Fujishiro-dai, Suita, Osaka 565-8565, Japan. 
Telephone: 
 
Fax: 
 
Email: kusanokengo@hotmail.com 
Professional Position: Director, Division of Arrhythmia and 
Electrophysiology, Department of Cardiovascular Medicine,  
Christophe Leclercq, MD 
Address: University of Rennes, CHU Pontchaillou, Rue Henri le 
Guilloux 2, 35033, Rennes, Cédex 09, France 
Telephone:
 
Fax: 
 
Email: christophe.leclercq@chu-rennes.fr 
Professional Position: Professor of Cardiology

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Wilfried Mullens, MD 
Address: Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, 
Belgium 
Telephone: 
  
Fax: 
 
Email: wilfried.mullens@gmail.com 
Professional Position: Professor Cardiologist Heart Failure 
 
 
 

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1. INTRODUCTION 
1.1 
Study purpose and description 
Medtronic, Inc. is sponsoring the AdaptResponse study; a prospective, randomized, controlled, 
interventional, single-blinded, multi-center, post-market, global Cardiac Resynchronization 
Therapy (CRT) in heart failure (HF) clinical study. The purpose of this clinical study is to test the 
hypothesis that market released CRT devices which contain the AdaptivCRT® (aCRT) algorithm 
have a superior outcome compared to standard CRT devices in CRT indicated patients with 
normal atrio-ventricular (AV) conduction and left bundle branch block (LBBB). 
To assess the superiority of CRT devices containing the aCRT algorithm, the primary objective 
of the AdaptResponse study is to test the hypothesis that AdaptivCRT® reduces the incidence of 
the combined endpoint of all-cause mortality and intervention for heart failure decompensation, 
compared to standard CRT therapy, in patients with a CRT indication, LBBB and normal AV 
conduction. The secondary endpoints will include the components of the primary endpoint, 
Clinical Composite Score (CCS) and time to atrial fibrillation (AF).  
Intervention for heart failure decompensation (HF event) is defined as an event requiring 
invasive intervention (i.e. IV diuretics, ultrafiltration, or equivalent) or inpatient hospitalization. 
Following enrollment and baseline assessment, eligible subjects will be implanted with a CRT 
system containing the aCRT algorithm and randomized in a 1:1 fashion to either treatment 
(aCRT ON, Adaptive Bi-V and LV) or control (aCRT OFF, Nonadaptive CRT) groups. All 
subjects, independent of randomization assignment, will receive a CRT system. Study subjects 
will be followed until the minimally required number of endpoint events is reached or until study 
closure, whichever occurs first. 
1.2 
Study scope 
The study is expected to be conducted at approximately 250 centers including Australia, 
Canada, Europe, Russia, India, Japan, Korea, Latin America, Middle East, Taiwan and the US. 
Approximately 3500 subjects will be randomized in the study. Proposed study start date is 01 
June 2014. 
To ensure a widespread distribution of data to minimize bias in the study results, the maximum 
number of subjects randomized at a single center is 200 subjects. There is no specific minimum 
number of randomized subjects required, except where stated in the clinical trial agreement 
between the sponsor and the individual center. 
The study utilizes an “event-driven” study design. Enrollment will end when approximately 3500 
patients are randomized or there is reasonable certainty that the required number of events will 
be reached, as determined by the Data Monitoring Committee (DMC), whichever occurs first. 
The study may be stopped early if the average enrollment rate is less than 0.25 subjects 
enrolled per active center per month over any 6 consecutive months during the study. The study 
may also be stopped on recommendation of the DMC, see stopping guidelines in section 10.2. 
Study subjects will be followed until official study closure defined as when requirements have 

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been satisfied per the Clinical Investigation Plan (CIP) and/or a decision by Medtronic, Ethics 
Committee, or regulatory authority, whichever occurs first.  
Accordingly, the expected total study duration is approximately 8 years, representing 
approximately 4 years of enrollment and approximately 4 years of subject follow-up. The actual 
duration of the study will depend on the accrual of 1100 primary endpoint events. The duration of 
individual subject participation will vary based on timing of their enrollment; however, at a 
minimum, participation of an individual subject is expected to be 30 months unless early study 
exit occurs. 
1.3 
Study oversight 
The Steering Committee (SC) is responsible for the scientific content of the study and provides 
input for the execution. The SC will also approve requests for crossovers and will review 
accuracy rates of LBBB (as determined by the ECG Core Laboratory). 
The Data Monitoring Committee (DMC) provides oversight for the overall conduct of the study, 
and specifically for subject safety and scientific validity. The DMC will review interim results of 
the study. 
The Endpoint Adjudication Committee (EAC) will adjudicate the HF- and AF related 
endpoints. 
The ECG Core Laboratory will review all baseline ECGs for presence of LBBB and normal AV 
conduction. Feedback on accuracy rates will be presented to the Steering Committee and to the 
sites.  
 
 

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2. BACKGROUND AND JUSTIFICATION 
CRT is an established therapy for patients with HF symptoms, left ventricular systolic 
dysfunction, and a wide QRS.1,2   However, the magnitude of clinical and hemodynamic benefit 
of CRT varies significantly among its recipients with no clinical improvement in approximately 
one third.1 Patient-specific characteristics, such as severity and type of electrical conduction 
abnormalities, dyssynchrony and scar burden, have been associated with the degree of CRT 
benefit.3,4    
While CRT is most commonly achieved by using biventricular (BiV) pacing, multiple acute5 and 
randomized chronic6 studies have demonstrated that left-ventricular (LV) pacing can be at least 
as efficacious as BiV pacing.  In patients with sinus rhythm and normal AV conduction, pacing 
only the LV with appropriate AV delays can result in even superior LV5,7 and right-ventricular 
(RV)8,9 function compared to standard BiV pacing.  
Optimization of the AV and inter-ventricular (VV) intervals during BiV pacing is another option to 
maximize the positive effects of CRT.10,11 Optimization is usually accomplished by using 
echocardiography or other modalities. However, these methods can be resource-intensive and 
only a minority of clinicians routinely optimizes AV and VV delays. 
The AdaptivCRT (aCRT) algorithm has been developed to provide RV-synchronized LV pacing 
when intrinsic AV conduction is normal or BiV pacing otherwise. The algorithm also adjusts AV 
and VV delays based on periodic automatic evaluation of intrinsic conduction intervals. The 
algorithm is intended to provide ambulatory CRT optimization and allow more physiologic 
ventricular activation and greater device longevity in patients with normal AV conduction by 
reducing unnecessary RV pacing.  
The Medtronic Adaptive CRT pre-market approval study has demonstrated that aCRT-optimized 
CRT is at least as effective as echo-optimized BiV pacing in terms of CCS (73.6% improved in 
aCRT arm vs. 72.5% in echo optimized arm, with a non-inferiority margin of 12%, p=0.0007)12.  
Additionally, a comparison with a historical echocardiographic AV-optimized CRT cohort 
indicated that the aCRT algorithm increased the proportion of patients with an improved CCS by 
11.9% (95% CI: 2.7% to 19.2%).13  
A post-hoc sub-analysis of the Adaptive CRT study showed that in patients with sinus rhythm, 
normal AV conduction and LBBB, more aCRT patients improved in their CCS compared with the 
echo arm (80.7% vs. 68.4%, p=0.04). In this subgroup the aCRT patients received LV-only 
pacing 64.0% ± 32.8% of the time.12  
Additionally, in an unpublished analysis on extended follow-up duration in patients with normal 
AV conduction, 
. Also, a greater proportion of aCRT patients improved in CCS at 6 
months (81% vs.69%, p=0.041) and 12 months (77% vs. 66%, p=0.076) than echocardiography-
optimized control patients.14  
Use of the aCRT algorithm is associated with a significant reduction in the probability of a 30-day 
readmission after both HF and all-cause hospitalizations as demonstrated in another analysis of 

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the Adaptive CRT study. For HF hospitalizations, the 30-day readmission rate was 19.1% (17 of 
89) in the aCRT group and 35.7% (15 of 42) in the Echo group (odds ratio: 0.41; 95% 
confidence interval: 0.19 to 0.86; p = 0.02). For all-cause hospitalization, the 30-day readmission 
rate was 14.8% (35 of 237) in the aCRT group compared with 24.8% (39 of 157) in the Echo 
group (odds ratio: 0.54; 95% CI: 0.31 to 0.94; p = 0.03). The risk of readmission after HF or all-
cause index hospitalization with aCRT was also significantly reduced beyond 30 days.23 
 
 
Adaptive CRT study post-hoc sub-analysis results 
CRT Response12 
  
Improvement in Packer Clinical 
Composite Score  
12% higher response* 
HF Hospitalizations  
or Death14 
Reduced risk* 
30-day Readmissions23 
59% reduction in odds 
Atrial Fibrillation15,24 
  
Time to first 48 consecutive hours or 
more 
46% reduced risk of AF 
* in subgroups with prolonged AV conduction at baseline 
 
Furthermore, over the longer-term follow-up (20.2 + 5.9 months) the aCRT algorithm has been 
shown to reduce the risk of the incidence of 48 consecutive hours in AF (HR=0.54 [95% CI 0.31-
0.93]; p=0.03) and aCRT patients without history of AF were less likely to develop persistent AF 
(HR=0.44 [95% CI 0.19-1.03]; p=0.05).15  
Birnie D. et al compared in a sub-analysis of the Adaptive CRT study, the long-term effects of 
aCRT versus conventional CRT pacing on the incidence of AF. During the follow-up period, 
8.7% of patients with aCRT and 16.2% of patients with conventional CRT experienced the 
primary outcome of an AF event of >48 hours, which was a 46% reduced risk with aCRT (hazard 
ratio 0.54; 95% confidence interval 0.31–0.93; P = 0.03) compared with conventional CRT 
patients. 24 
Further investigation of clinical outcomes over longer follow-up is needed to support the benefit 
of aCRT. Therefore the AdaptResponse study is designed to test the hypothesis that the aCRT 
algorithm reduces the incidence of total mortality and heart failure decompensation events, 
increases the proportion of patients with an improved CCS and reduces the incidence of AF in 
CRT patients with normal AV conduction and LBBB.25 
 

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3. SYSTEM DESCRIPTION AND INTENDED USE 
The study will be conducted using market released CRT-P and CRT-D devices containing the 
aCRT algorithm, Medtronic market released LV leads, and any market released RA and RV 
leads. All system components will be implanted per intended use as specified in the respective 
manuals. Medtronic may incorporate additional Medtronic CRT-P and/or CRT-D devices 
containing the aCRT algorithm, or devices containing an update of the aCRT algorithm, LV 
leads, programmers and software into this clinical study as they become commercially available, 
provided the scientific soundness is not adversely affected as assessed by the Steering 
Committee. Additional commercially available devices should not be used until notification from 
Medtronic is received. Instructions for use of the devices used in this study are provided in their 
respective manuals. 
3.1 
Medtronic CRT-D and CRT-P devices  
Medtronic commercially available CRT-D and CRT-P devices containing the aCRT algorithm are 
required.   
3.2 
Medtronic left ventricular leads 
Medtronic commercially available LV transvenous pacing leads that are compatible with the CRT 
devices containing the aCRT algorithm are required. Epicardial leads can only be used if a 
transvenous lead cannot be placed. If investigators wish to use a non-Medtronic epicardial lead, 
it is recommended that they confirm device compatibility with a Medtronic representative. 
3.3 
Market released right ventricular (defibrillation) lead 
Commercially available RV (defibrillation) leads that are compatible with the CRT devices 
containing the aCRT algorithm are required. Medtronic commercially available RV (defibrillation) 
leads are recommended.  
3.4 
Market released right atrial lead 
Commercially available RA lead models that are compatible with the CRT devices containing the 
aCRT algorithm are required. Medtronic commercially available RA leads are recommended.  
3.5 
Medtronic CareLink programmer 
The Medtronic CareLink Model 2090 Programmer and software are used to program the CRT 
device. The programming head will be needed for communications with this device. 
Programmers from other manufacturers are not compatible with Medtronic devices. 
3.6 
Medtronic CareLink Home Monitor 2490C and Network 
The CareLink Monitor Model 2490C is an external monitor that is indicated for use in the transfer 
of patient and device data from implanted Medtronic devices. The CareLink Monitor Model 
2490C interrogates implanted devices and temporarily stores these data. It collaborates with the 
appropriate Medtronic server to confirm the establishment of an Internet connection with server 

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and performs any required file translation functions necessary for data transfer. It executes data 
file transfer and collaborates with the appropriate Medtronic server to confirm data file transfer 
through the Internet connection with the server. The CareLink Monitor 2490C is not a 
programmer and cannot be used to program implanted device parameters. CareLink monitors 
are not a substitute for appropriate medical attention in the event of an emergency and should 
only be used as directed by medical staff. 
Medtronic CRT devices used in this study qualify for use with the Medtronic CareLink Monitor 
and Medtronic CareLink Network; however, the use of CareLink in this clinical study is optional 
and does not replace the need for in-person follow-up visits.  
Medtronic may incorporate additional home monitors as they receive regulatory approval. 
3.7 
Market-released Pacing System Analyzer  
The system supports the use of the Medtronic CareLink Model 2290 Analyzer, an accessory of 
the Medtronic CareLink programmer. The system allows having a device session and an 
analyzer session running at the same time, to quickly switch from one to the other without having 
to end or restart sessions, and to send data from the analyzer to the programmer. 
 
 

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4. REGULATORY COMPLIANCE 
The AdaptResponse clinical study is a prospective, randomized, controlled, interventional single-
blinded, multi-center, post-market global study. This clinical study is required to be in compliance 
to the CIP, Clinical Trial Agreement (CTA) and local laws/regulations within the respective 
geography where the study is being conducted. 
The AdaptResponse clinical study is designed with the good clinical practice (GCP) principles 
outlined in ISO 14155:2011 as guidance. 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 investigation, 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. The principles of the 
Declaration of Helsinki are implemented in this study by means of the Patient Informed Consent 
(PIC) process, MEC/IRB/HREC (all henceforth referred to as an ”Ethics Committee”) approval, 
study training, clinical trial registration, risk benefit assessment, and publication policy. 
In Europe, local laws and regulations (including Declaration of Helsinki 2013) will be followed  
In Russia, 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 Australia, applicable local regulations will be followed. 
In Japan, the study will be conducted in compliance with the Ethical Guidelines for Medical and 
Health Research Involving Human Subjects and the Clinical Study Act. 
In India, applicable India laws and regulations will be followed. 
In Latin America, local laws will be complied with. 
In Taiwan and Korea, applicable laws and regulations will be followed. 
In Canada, the Canadian Medical Devices Regulations, 1998 (SOR/98-282), and the Canadian 
Regulatory Guidelines for Mandatory Problem Reporting of Medical Devices, 2011 (H164-
145/2011E) will be followed.  
The study has been publicly registered 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 center:  
• Medtronic 
• Steering Committee 
• Principal Investigators (where required by local law) 
• Geography-specific regulatory authorities (if regulatory approval is required)  
• An independent medical ethics committee or institutional review board 

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Similarly, approval of subsequent revisions to the CIP is required at each study center from the 
above-mentioned groups prior to implementation of the revised CIP at that center. 
5. METHODOLOGY 
5.1 
Study objectives 
The listed objectives will test the hypothesis that the aCRT algorithm is superior to standard CRT 
therapy in regards to patient outcomes.   
5.1.1 Primary objective 
The primary objective of the AdaptResponse Study is to test the hypothesis that 
AdaptivCRT® reduces the incidence of the combined endpoint of all-cause mortality and 
intervention for heart failure decompensation, compared to standard CRT therapy, in 
patients with a CRT indication, LBBB and normal AV conduction. Intervention for heart 
failure decompensation (HF event) is defined as an event requiring “invasive intervention 
(i.e. IV diuretics, ultrafiltration, or equivalent) or inpatient hospitalization”. 
The study will be event driven, comparing the rate of first events. The study will continue 
until a predetermined number of events has been observed, unless the DMC advises to 
stop earlier. 
The analysis will include all randomized patients and will follow the intent-to-treat principle. 
A secondary analysis will be done including only the patients for whom the ECG Core 
Laboratory confirmed the presence of LBBB. 
5.1.2 Secondary objectives 
• To test the hypothesis that aCRT ON reduces all-cause mortality compared to aCRT 
OFF. 
• To test the hypothesis that aCRT ON reduces the rate of intervention for heart failure 
decompensation compared to aCRT OFF. 
• To test the hypothesis that aCRT ON increases the proportion of patients that improve on 
the Clinical Composite Score (CCS) compared to aCRT OFF, at 6 months of follow-up. 
• To test the hypothesis that aCRT ON reduces the incidence of AF compared to aCRT 
OFF. 
• To test the hypothesis that the change in quality of life, measured by the KCCQ, in the 
aCRT ON group is better than the change in the aCRT OFF group. 
• To test the hypothesis that the change in health outcome, measured by the EQ-5D, in the 
aCRT ON group is better than the change in the aCRT OFF group. 
• To test the hypothesis that aCRT reduces the incidence of all-cause re-admissions after 
a heart failure (HF) admission within 30-days of the index event. 
• To assess cost-effectiveness of CRT devices with the aCRT algorithm relative to 
traditional CRT devices. 
 

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5.1.3 Ancillary objectives 
• To test the hypothesis that the change in NYHA class in the aCRT ON group is better 
than the change in the aCRT OFF group. 
• To test the hypothesis that the change in BNP/NT-proBNP in the aCRT ON group is 
better than the change in the aCRT OFF group. 
• To characterize cardiovascular adverse events that occur in the aCRT ON and aCRT 
OFF groups. 
• To test the hypothesis that aCRT reduces the incidence of all-cause re-admissions after 
an all-cause admission within 30-days of the index event.  
• To characterize occurrence of spontaneous VT/VF episodes and compare between the 
aCRT ON and aCRT OFF groups. 
5.2 
Primary endpoint 
5.2.1 Primary endpoint definition 
Intervention for heart failure decompensation (HF event) is defined as an event requiring 
“invasive intervention (i.e. IV diuretics, ultrafiltration, or equivalent) or inpatient 
hospitalization”. 
The primary endpoint is the composite of all-cause death and any intervention for heart 
failure decompensation as adjudicated by the EAC. The date of the endpoint will be the date 
of death or the date of initiation of treatment for decompensation as determined by the EAC.  
The EAC will determine if an endpoint has been met. Sites may adhere to their standard 
practice diagnosing heart failure, but are required to report all diagnostic assessments, tests 
and procedures done with supporting material as appropriate to allow the EAC to 
adjudicate.  
5.2.2 Endpoint Adjudication Committee 
All potential endpoints will be reviewed by the Endpoint Adjudication Committee (EAC). 
Please refer to Appendix D for an overview of the EAC’s tasks.  
 
 

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5.3 
Subject selection criteria 
Patients will be screened to ensure they meet all of the inclusion and none of the exclusion 
criteria prior to study enrollment.  
No study-specific procedures may be performed prior to obtaining written patient informed 
consent.  
5.3.1 Inclusion criteria 
Patients must meet the following inclusion criteria to be eligible to participate in the study: 
• Subject is willing to sign and date the study Patient Informed Consent (PIC) Form. 
• Subject is indicated for a CRT device according to local guidelines. 
• Subject has, minimally: 
o Sinus Rhythm at time of enrollment. 
o Left Bundle Branch Block (LBBB) as documented on an ECG (within 30 
days prior to enrollment). Criteria16 for complete LBBB must include: 
 
Intrinsic QRS duration ≥140 ms (men) or ≥130 ms (women),  
 
QS or rS in leads V1 and V2, 
and 
 
Mid-QRS notching or slurring in ≥2 of leads V1, V2, V5, V6, I, and 
aVL. 
o Intrinsic, normal AV conduction as documented on an ECG by a PR 
interval less than or equal to 200ms (within 30 days prior to enrollment). 
o Left ventricular ejection fraction less than or equal to 35% (documented 
within 180 days prior to enrollment). 
o NYHA class II, III or IV (documented within 30 days prior to enrollment) 
despite optimal medical therapy. Optimal medical therapy is defined as 
maximal tolerated dose of Beta-blockers and a therapeutic dose of ACE-I, 
ARB or Aldosterone Antagonist. 
5.3.2 Exclusion criteria 
Patients must not meet any of the following exclusion criteria to be eligible to participate in 
the study:  
• Subject is less than 18 years of age (or has not reached minimum age per local law). 
• Subject is not expected to remain available for at least 2 years of follow-up visits. 
• Subject has permanent atrial arrhythmias for which pharmacological therapy and/or 
cardioversion have been unsuccessful or have not been attempted. 
• Subject is, or previously has been, receiving cardiac resynchronization therapy. 
• Subject is currently enrolled or planning to participate in a potentially confounding drug or 
device trial during the course of this study.  Co-enrollment in concurrent trials is only 
allowed when documented pre-approval is obtained from the Medtronic study manager. 

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• Subject has unstable angina, or experienced an acute myocardial infarction (MI) or 
received coronary artery revascularization (CABG) or coronary angioplasty (PTCA) within 
30 days prior to enrollment. 
• Subject has a mechanical tricuspid heart valve or is scheduled to undergo valve repair or 
valve replacement during the course of the study. 
• Subject is post heart transplant (subjects on the heart transplant list for the first time are 
not excluded). 
• Subject has a limited life expectancy due to non-cardiac causes that would not allow 
completion of the study. 
• Subject is pregnant (if required by local law, women of child-bearing potential must 
undergo a pregnancy test within seven days prior to device implant). 
• Subject meets any exclusion criteria required by local law. 
5.4 
Randomization 
Subjects will undergo a CRT implant procedure after completion of the baseline assessment if all 
inclusion and none of the exclusion criteria are met. Subjects who have a successful CRT 
implant will be randomized within 7 days of completing the implant procedure. Subjects will be 
randomized in a 1:1 fashion to treatment (aCRT ON, with AdaptivCRT programmed to “Adaptive 
Bi-V and LV”) or control (aCRT OFF, with AdaptivCRT programmed to “Nonadaptive CRT”) 
group. Subjects will be randomized using the randomization schedule determined by a 
Medtronic statistician. The randomization schedule will be stratified by center and by NYHA 
class. Centers will receive this assignment electronically in the study database from Medtronic 
upon completion of the randomization case report form.  
Once a subject is assigned to a study group (treatment or control), he/she will remain in that arm 
and all efforts will be made to provide the optimal therapy specified for that treatment 
assignment. In the circumstance this is clinically or technically not feasible, the subject will 
remain in the assigned treatment arm for statistical analysis based on the intention-to-treat 
principle, as it represents a normal medical situation of success and failure of delivering the 
planned medical therapy. 
5.5 
Crossover 
Crossovers significantly increase the required number of events and therefore increase the 
sample size needed for the study. Every reasonable effort must be made to keep subjects in 
their blinded randomization assignment for the duration of the study. Unless required by clinical 
or technical urgency, the reprogramming of aCRT therapy in any subject must be approved by a 
member of the study’s Steering Committee. The study center must make reasonable effort to 
contact the study sponsor prior to reprogramming. Failure to gain prior approval for 
reprogramming of aCRT therapy (even if required urgently) constitutes a deviation and should 
be reported as such. Every reasonable effort should be made to prevent unblinding of the patient 
prior to and after reprogramming, unless clinically necessary. In the case of a permanent 
crossover (i.e. the programming will not be corrected to the original randomization assignment) 
to the other study arm, a Crossover CRF and Study Deviation CRF must be completed. Full 
device interrogation data will be collected reflecting the final programming, and a copy of the 
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subject’s file. Subjects will be analyzed per their randomly assigned treatment in accordance 
with the intention-to-treat principle. 
5.6 
Blinding 
The study will be single-blinded (i.e. subjects are blinded to randomization assignment) to 
reduce the effect of bias. Every effort must be made to ensure the randomization assignment is 
not revealed to the subject.  
The Data Monitoring Committee (DMC) will regularly review summarized adverse event data to 
address potential safety issues. The DMC will be unblinded to subject treatment assignments. 
However; the EAC will be blinded to the treatment designation when reviewing case files, 
wherever reasonably achievable.  
After all study tests and procedures have been completed just prior to subject exit from the 
study, the subject may be informed (verbally or in written form) of their randomization 
assignment. 
5.7 
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): 
• Patients will be evaluated at baseline to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to implant and randomization. 
• An ECG Core Laboratory will be used to confirm presence of LBBB and normal AV 
conduction. 
• Subjects will be randomized to ensure comparable treatment groups. 
• Subjects will be blinded to their treatment group. 
• Subject demographics will be collected at baseline and differences that may affect 
primary endpoints will be identified. 
• To ensure a widespread distribution of data between centers, the maximum number of 
randomized subjects allowed per center is no more than 200. 
• All implanters in the study will be experienced in the implant of CRT devices. 
• Data collection requirements and study procedures will be standardized across all 
centers and geographies. 
• All study center 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. 
• Monitoring visits will be conducted for adherence to the CIP and to verify the CRF data 
against the source data.  
• HF events and deaths will be adjudicated by an independent and blinded EAC. 
• An independent DMC will review endpoint and other data to monitor the overall integrity 
of the study. 

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• The Steering Committee members will not have influence on the HF treatment decisions 
by center investigators during the trial, except for approval for crossover, as described in 
Section 5.5. 
• The analysis will be intent-to-treat, following pre-defined statistical methods specified in 
this Clinical Investigation Plan and the Statistical Analysis Plan. 
• Registration of the trial on clinicaltrials.gov and the publication plan will ensure that study 
results will be reported. 
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 
All clinical investigators managing the subject’s heart failure must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with heart failure. All implanting 
physicians must be experienced and/or trained in the handling of CRT devices. Center 
personnel training and delegation will be completed prior to participation in this clinical study. 
Medtronic personnel or their representatives may perform the following activities at the study 
sites during the study, under supervision of site personnel: 
• Technical support at all visits (e.g. programming of the CRT device according to study 
requirements, performing device interrogations) 
• Monitoring activities 
6.1 
Site activation  
During the activation process (prior to enrollment of subjects in the study), Medtronic will train 
site personnel on the CIP, relevant standards and regulations, informed consent process, written 
Clinical Trial Agreements (CTAs) and on data collection and reporting tools. If new members join 
the study center team, they will receive training on the applicable clinical study requirements 
relevant to their role before contributing to the clinical study. 
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 and subsequent 
amendments.  
Prior to performing study related activities, all centers must have Ethics Committee approval, as 
applicable for that geography.  
All local and regional regulatory requirements will be fulfilled prior to center activation and 
enrollment of subjects into the study. Each study center must have written documentation of 
center and investigator readiness before beginning any study-related activities. Requirements for 
activation vary by geography, and may include, but are not limited to:  
• Ethics Committee approval (and voting list, as required by local law) of the current 
version of the CIP and PIC Form 
• Regulatory authority approval or notification (as required per local law) 
• Signed/dated CTA on file with sponsor 
• Current, signed and dated Curriculum Vitae (CV) of investigators and coordinator and 
other key members of investigation site team CV (as required by local law) 
• Documentation of delegated tasks 
• Signed/dated documentation of training of required study personnel 
• Site initiation visit, where required 

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Additional requirements imposed by the Ethics Committee and regulatory authority shall be 
followed, if appropriate.  
In addition, all participating site staff must be trained on the current version of the CIP pertinent 
to their role in the study and must be delegated by the principal investigator to perform study 
related activities, which must be documented on the Delegated Task List. Site personnel 
performing only standard of care procedures and no study related activities throughout the study 
(including but not limited to CRT implant, physical exam, device interrogations) do not need to 
be trained on the CIP.  
 
6.2 
Equipment requirements 
The following equipment must be available at each center to support study activities: 
• Computer with high speed internet access using Microsoft Internet Explorer for data entry 
(version 9 or higher) 
• Market-released Medtronic programmer (Model 2090 or future equivalent)  
• 12-lead ECG equipment 
 
The maintenance and calibration of the programmers used for this study will be assessed 
outside of this clinical study. Centers are responsible for maintaining and calibrating non-
programmer equipment used in the course of this study in accordance with established center 
practice. Clinical monitors will not monitor maintenance or calibration schedules. 
6.3 
Data collection 
Clinical data is collected at designated time points throughout the study. Data will be collected 
using an electronic data management system for clinical studies. 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 may be generated by Medtronic to monitor data quality 
and study progress. At the end of the study, the data will be frozen and retained by Medtronic. 
Data collection requirements are summarized in Table 5. 
 
 

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Data collection and study procedure requirements at subject visits 
Study Procedure 
Enroll 
ment
Baseline
Implant Randomi
zation 
3 and 6 
Months
12, 18, 24 
Months
Every 6 
Months
Study 
Exit
Subject Informed 
Consent 
x 
 
 
 
 
 
 
 
Inclusion/exclusion 
x
x
12- lead 
Electrocardiogram 
(ECG)* 
 
x 
 
 
 
 
 
 
Left Ventricular Ejection 
Fraction (LVEF) 
measurement** 
 
x 
 
 
 
 
 
 
Demographics
x
Physical examination
x
x
x
x
Blood*** 
x
x
x
x
Cardiovascular (CV) 
medications**** 
 
x 
 
 
x 
x 
x 
x 
Medical history
x
Current heart failure 
symptoms status 
 
x 
 
 
x 
x 
x 
x 
Final implanted system 
configuration and LV 
lead placement 
optimization method 
 
 
x 
 
 
 
 
 
Device interrogation 
(and CareLink data if 
available) 
 
 
x 
x 
x 
x 
x 
x 
Device programming per 
randomization 
assignment 
 
 
 
x 
 
 
 
 
Device optimization*** 
(Control Group only) 
 
 
 
 
As it occurs 
 
Quality of life and Health 
Outcome measures 
(EQ-5D and KCCQ) 
 
x 
 
 
x 
x 
 
 
NYHA assessment
x*
x
x
x
Patient global 
assessment 
 
 
 
 
x 
 
 
 
Vital status 
x
Crossover 
As it occurs
System modifications
As they occur
Adverse events (AEs)
As they occur
Healthcare utilizations
As they occur
Study Deviations
As they occur
Death 
As it occurs
*Unless done within 30 days prior to enrollment 
**Unless done within 180 days prior to enrollment 

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***Data only collected if procedure is standard of care 
****Including daily dose at baseline of guideline recommended medication, including but not limited to the following 
medications: diuretics, ß-blockers, ACE inhibitors, ARBs, MRAs, ARNi, If-channel blockers, cardiac glycosides 
 
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’s 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. 
6.4 
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, per local requirements) voluntary 
agreement to participate in a particular clinical study 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. This process includes obtaining a Patient Consent and a/an Authorization to Use and 
Disclose Personal Health Information/Research Authorization/HIPAA/other privacy language as 
required by local law that has been approved by the study center’s Ethics Committee and signed 
and personally dated by the subject (or their legally authorized representative or guardian, per 
local requirements). A subject may only consent after information has been given to the subject 
on all aspects of the clinical investigation that are relevant to the subject’s decision to participate. 
Informed consent may be given by the legally authorized representative in accordance with local 
law.  
Prior to enrolling subjects, each study center’s applicable Ethics Committee will be required to 
approve the PIC Form, and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/HIPAA/other privacy language as required by law. The 
document(s) must be controlled (i.e. versioned and dated) to ensure it is clear which version(s) 
were approved by the Ethics Committee. Any adaptation of the sample PIC Form must be 
reviewed and approved by Medtronic and the Ethics Committee reviewing the application prior to 
enrolling subjects. Geography specific Informed Consent form templates will be provided under 
separate cover. 
Prior to initiation of any study-specific procedures, patient informed consent must be obtained 
from the subject (or their legally authorized representative or guardian, per local requirements). 
Likewise, privacy or health information protection regulation may require subjects to sign 
additional forms to authorize centers to submit subject information to the study sponsor. The 
informed consent process must be conducted by the principal investigator or an authorized 
designee, and the PIC Form and Authorization to Use and Disclose Personal Health 
Information/Research Authorization/HIPAA/other privacy language as required by law must be 
given to the subject (or their legally authorized representative or guardian, per local 
requirements) in a language he/she is able to read and understand. The process of patient 
informed consent must be conducted without using coercion or undue improper influence on or 
inducement of the subject to participate by the investigator or other center personnel. 
The process of obtaining patient informed consent shall: 

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• Ensure that the principal investigator or his/her authorized designee conducts the 
informed consent process 
• Include all aspects of the clinical investigation that are relevant to the subject's decision 
to participate throughout the clinical investigation 
• Avoid any coercion or undue improper influence on, or inducement of, the subject to 
participate 
• Not waive or appear to waive subject’s legal rights 
• Use language that is non-technical and understandable to the subject 
• Provide ample time for the subject to read and understand the informed consent form 
and to ask questions, receive answers and consider participation 
• Include a personally dated signature of the subject (or legally authorized representative 
or guardian, per local requirements) 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 informed consent process (not applicable in US and 
Canada) 
• Include any other locally required signatories, such as witnesses, as indicated by country 
specific legislations  
• Provide the subject with a copy of the consent form, 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 important new information is provided to new and existing subjects throughout 
the clinical investigation 
If the PIC Form is obtained on the same day the subject begins participating in study-related 
procedures, it must be documented in the subject's case history that consent was obtained prior 
to participation in any study-related procedures. It is best practice for the informed consent 
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 patient informed consent. The 
PIC 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, per local 
requirements). 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 
Form as well. The PIC Form 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 PIC Form must be filed in the hospital/clinical chart and/or with the 
subject’s study documents.  

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The PIC Form (in Japan, the signature page only) and Authorization to Use and Disclose 
Personal Health Information/Research Authorization/HIPAA/other privacy language as required 
by law must be available for monitoring and auditing. Any Medtronic Field personnel who 
support the implant must be able to review the subject’s signed and dated PIC Form and verify 
its completeness prior to proceeding with the implant. In the event that Medtronic Field 
personnel identify patient informed consent as being incomplete, study procedures will not be 
allowed to occur until the consent of the subject can be adequately and appropriately obtained. 
In Japan, only the monitor assigned to this study may be able to review the signed informed 
consent prior to the implant procedure. 
Any changes to a previously approved PIC Form throughout the course of the study must be 
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. 
6.5 
Enrollment 
A subject is considered enrolled when the consent process has been finalized. Enrollment can 
be a stand-alone visit or can occur on the same day as the baseline visit.   
Each study center must document participation of each enrolled subject in subject’s source 
documentation and maintain a log of all subjects enrolled in the study, assigning an identification 
code linked to their names, alternative subject identification or contact information.  
6.6 
Baseline 
The baseline visit must occur within 14 days after subject enrollment. Baseline testing will occur 
after the consent process has been finalized. The baseline visit can be a stand-alone visit or can 
be performed on the same day of, but prior to the implant procedure. The following data are 
required to be collected at the baseline visit: 
• Subject demographics 
• Verification of all inclusion and exclusion criteria 
• Physical exam (including height, weight, heart rate and blood pressure) 
• Medical history, including comorbidities and cardiovascular, arrhythmia, and surgical 
history 
• Cardiovascular medications 
• Current heart failure symptoms status 
• NYHA HF assessment (unless documented within 30 days prior to enrollment) 
• 12-lead ECG recording (unless documented within 30 days prior to enrollment) 
• LVEF (unless documented within 180 days prior to enrollment) 
• Quality of Life and Utility Measures  
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ)  

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• 
EQ-5D 
• Blood measurements (only collected when standard of care) 
• Report AEs, Study Deviations and Healthcare Utilizations (as they occur) 
 
CV medications include ACE inhibitors, ARBs, MRAs, ARNi, antiarrhythmics, anti-coagulants 
and antiplatelets, antihypertensives, antilipidemics (incl. statins), ß-blockers, If-channel blockers, 
calcium channel blockers, diuretics, digitalis, inotropes, nitrates, digoxin, and vasodilators.  
For CV medications, daily dose is collected at baseline. Apart from CV medications, the use of 
insulin is collected. There are no medication restrictions in this study unless they are 
investigational and may confound the study results. 
6.6.1 Baseline ECG 
LBBB needs to be diagnosed using the Strauss criteria16. Criteria for complete LBBB should 
include QRS duration ≥140 ms (men) or ≥130 ms (women), QS or rS in leads V1 and V2, 
and mid-QRS notching or slurring in ≥2 of leads V1, V2, V5, V6, I, and aVL. 
The Baseline ECG must be sent to the ECG Core Laboratory for review. Details on the 
review process will be provided under separate cover. 
6.7 
Implant 
The implant visit must occur after the baseline visit, and within 30 days after subject enrollment. 
The implant will be performed according to the hospital’s standard implant practice. Implant 
guidelines can also be found in the device manuals. The following data are required to be 
collected at the implant visit: 
• Final system configuration (CRT-P or CRT-D device and lead models, serial numbers 
and locations) 
• LV lead placement optimization method 
• Adverse Events, Health Care Utilizations, and Study Deviations (as they occur) 
• Final device interrogation 
At implant, it is recommended that the device is programmed to CRT OFF until the subject is 
randomized. Full device interrogation (Interrogate ALL) data will be collected following the 
implant procedure, and a copy of the interrogation files must be sent to Medtronic with a copy 
being maintained at the center in the subject’s file. 
Note:  An unsuccessful implanti is not considered an adverse event. Events occurring during an 
unsuccessful implant (e.g. dissection, perforation) are adverse events and will be recorded and 
classified. Subjects experiencing unsuccessful implant procedures must be followed for 30 days 
                                               
i An implant procedure that results in one or more of the leads not placed, or where all leads are placed but not all are 
completely connected to the device, or where electrical measurements are unsatisfactory and an invasive intervention 
is planned for mitigation. 

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post implant attempt or until all implant and procedure-related AE’s are resolved, whichever 
comes last. A second attempt may be made, but is not required, after inclusion and exclusion 
criteria have been re-verified. 
6.7.1 Implant Requirements and Recommendations 
It is recommended that the LV lead placement is targeted for an LV lateral, anterolateral or 
posterolateral position. Data on LV lead placement decision and method will be collected. 
6.7.2 CRT Optimization 
Optimization of the AV-VV intervals may be completed and documented. Additional features 
to optimize CRT may be used upon market commercialization. Any deviation from the 
programming requirements outlined in section 6.9.1 will constitute a study deviation. 
6.8 
Randomization 
Subjects will be assigned to a treatment at random during the randomization visit, which must 
occur within 7 days after a successful implant. Centers will receive this assignment electronically 
in the study database from Medtronic upon completion of the randomization case report form.   
At the time of the randomization device programming, a device check will be conducted and the 
default settings will be verified. If subjects are assigned to the aCRT ON group, “Adaptive Bi-V 
and LV” will be programmed. If subjects are assigned to the aCRT OFF group, the delegated 
person will ensure that “Nonadaptive CRT” is programmed. Control group subjects will be 
optimized per physician’s discretion. The method of AV and VV optimization in the control group 
will be collected. Full device interrogation (Interrogate ALL) data will be collected reflecting the 
final programming, and a copy of the interrogation files must be sent to Medtronic with a copy 
being maintained at the center in the subject’s file.  
The following procedures will be completed / data will be collected at the randomization visit: 
• Device programming according to assignment 
• AV/VV optimization method (control group only, if optimization occurs per standard of 
care) 
• Final device interrogation (Interrogate All) 
• Report AEs, System Modifications, Study Deviations, Crossovers, and Healthcare 
Utilizations (as they occur) 
If randomization does not occur within 37 days after enrollment, verification of all inclusion and 
all exclusion criteria must be repeated before randomization. 
6.8.1 Programming Requirements and Recommendations 
The following programming requirements and recommendations are applicable to study 
subjects, according to their respective randomization assignment. 
 

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Programming Requirements and Recommendations 
Parameter 
Treatment Group  
Control Group  
Adaptive CRT 
Adaptive Bi-V and LV 
Nonadaptive CRT  
Mode 
 
  
 
  
V. Blank Post VP 
 
 
No requirement 
SAV 
 
 
Per preferred in-office /physician 
method 
PAV 
 
 
Per preferred in-office /physician  
method 
VV Delay 
 
 
Per preferred in-office /physician 
method 
V. Pacing 
 
 
  
Left Ventricular Capture 
Management (LVCM)
 
 
Lower Rate 
  
 
  
 
Upper Tracking Rate 
  
 
  
 
Upper Sensor Rate 
 
  
Ventricular Sense Response 
 
 
Conducted AF response 
 
 
Lead polarity for quadripolar  LV 
leads 
 
 
 
 
 
Multiple Point Pacing (MPP) 
 
 
EffectivCRT During AF 
 
 
                                               
ii For CRT devices with programmable VV Delay in Adaptive mode: Program to Auto 
recommended 

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6.9 
Scheduled follow-up visits 
After receiving randomization notice via the randomization CRF, Medtronic will provide the target 
dates and windows for each follow-up visit to the implanting center via the randomization CRF. 
Follow-up visit windows open on the Window Start date and remain open as defined below. It is 
recommended that subjects are scheduled as close as possible to the target date for a given 
follow-up visit.  
Should a subject visit fall 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, an early or 
late visit is preferred over a missed visit, but still must be accompanied by a deviation. Follow-up 
visit windows are listed in Table 7 and are based on days post-randomization.  
Required visits post-randomization include follow-up visits at 3 months, 6 months, and every 6 
months thereafter until study closure. During these visits information will be collected about 
adverse events (AE), health care utilization (HCU), Cardiovascular (CV) medications, and Heart 
Failure (HF) assessment, as well as additional information and procedures which vary by visit 
(see Table 5). Quality of Life (QoL) and Health outcome will be addressed using the KCCQ and 
the EQ-5D questionnaires, which subjects will complete during applicable study visits. Full 
device interrogation (interrogate ALL) data will be collected for subjects at the end of the visit 
(final interrogation) and a copy of the interrogation files (Save-to-Disk, S2D) must be sent to 
Medtronic, with a copy also being maintained at the center in the subject’s file.  
Figure 1: Visit Timeline 
 
 
 

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Post-randomization follow-up windows 
Study Follow-up 
Visit 
Window 
(Calculated days post-randomization) 
Window Start 
(days post-
randomization) 
Target 
(days post-
randomization) 
Window End 
(days post-
randomization) 
3 Month follow-up 
56 
91 
105 
6 Month follow-up 
153 
183 
213 
12 Month follow-up 
335 
365 
395 
18 Month follow-up 
518 
548 
578 
24 Month follow-up  
700 
730 
760 
30 Month follow-up 
883 
913 
943 
36 Month follow-up 
1066 
1096 
1126 
42 Month follow-up 
1249 
1279 
1309 
48 Month follow-up 
1431 
1461 
1491 
54 Month follow-up 
1614 
1644 
1674 
60 Month follow-up 
1796 
1826 
1856 
66 Month follow-up 
1979 
2009 
2039 
72 Month follow-up 
2162 
2192 
2222 
78 Month follow-up 
2344 
2374 
2404 
84 Month follow-up 
2527 
2557 
2587 
90 Month follow-up 
2709 
2739 
2769 

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6.9.1 3 and 6 month Follow-up visits  
• NYHA HF assessment 
• Physical examination 
• Blood measurements (if collected per standard of care) 
• Current CV medications 
• Current heart failure symptoms status 
• Final device interrogation (Interrogate All) 
• AV/VV optimization method (control group only, if optimization occurs per standard of 
care) 
• Quality of Life and Health Outcome Measures:  
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ)  
• 
EQ-5D 
• Patient Global Assessment 
• Report AEs, System Modifications, Study Deviations, Crossovers, and Healthcare 
Utilizations (as they occur) 
6.9.2 12, 18, 24 month Follow-up visits 
• NYHA HF assessment 
• Physical examination 
• Blood measurements (if collected per standard of care) 
• Current CV medications 
• Current heart failure symptoms status 
• Final device interrogation (Interrogate All) 
• AV/VV optimization method (control group only, if optimization occurs per standard of 
care) 
• Quality of Life and Health Outcome Measures  
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ)  
• 
EQ-5D 
• Report AEs, System Modifications, Study Deviations, Crossovers, and Healthcare 
Utilizations (as they occur) 
6.9.3 Follow-up visit every 6 months until study closure 
• NYHA HF assessment 
• Physical examination 
• Blood measurements (if collected per standard of care) 
• Current CV medications 
• Current heart failure symptoms status 
• Final device interrogation (Interrogate All) 

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• AV/VV optimization method (control group only, if optimization occurs per standard of 
care) 
• Report AEs, System Modifications, Study Deviations, Crossovers, and Healthcare 
Utilizations (as they occur) 
 
6.10 
Device Interrogation (Interrogate All) 
For the implant, randomization and follow-up visits, a final full “Interrogate ALL” device 
interrogation file (.pdd) must be obtained and saved in a digital format (e.g., USB). Store one 
copy at the site and send a copy to Medtronic. It is recommended that data are not cleared 
during any interrogation. 
6.11 
Adverse Events 
The primary objective depends on complete reporting of HF events, including interventions for 
heart failure decompensation and cardiovascular adverse events (AEs). These are reported 
upon center awareness and assessed at scheduled follow-up visits to ensure all applicable 
hospitalizations and AE’s have been reported. Refer to section 8 for adverse events details.  
6.12 
Healthcare Utilization 
Healthcare Utilization (HCU) information should be reported upon center awareness and 
assessed at all follow-up visits to ensure all applicable Healthcare Utilizations have been 
reported. All hospitalizations, emergency department visits, outpatient treatment involving 
overnight stay, cardiovascular-related urgent care and cardiovascular-related clinic visits will be 
considered reportable Healthcare Utilizations for this study. Any visit where changes occur to 
protocol-required programming parameters will be considered cardiovascular-related. For HCU’s 
involving changes to protocol-required programming parameters, both an initial and final device 
interrogation will be required, and a copy of the interrogation files must be sent to Medtronic with 
a copy also being maintained at the center in the subject’s file. Additionally, collection of current 
cardiovascular medications will be required for all HCU’s. Any remote transmissions via the 
Medtronic CareLink® system will also be collected.  
Healthcare Utilization information will be included in the review of potential HF related events 
and hospitalizations by the blinded Endpoint Adjudication Committee (EAC). Supporting source 
documentation may be requested if needed for study or endpoint evaluation. Relevant 
documentation may include but is not limited to: a copy of the hospital discharge summary 
report, and medical records such as chest x-ray reports, echocardiogram reports, medication 
documentation, lab results related to the event and consultation reports (e.g., Heart Failure, 
Renal, Cardiology, Pulmonary, etc.). 
6.13 
System Modification 
A system modification will be reported in the event the device and/or leads require invasive 
modification (e.g., device or lead explant, device or lead replacement, lead repositioning). In the 
event of a system modification, the follow-up schedule for the subject will remain unchanged. 
The following information is required to be collected for a system modification: 

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• Report reason for modification 
• Report the details of the system modification procedure 
• Device programming according to randomization assignment (aCRT ON for treatment 
group and aCRT OFF for control group)  
• Device interrogation (initial and final “interrogate ALL”; a copy of the interrogation files 
must be sent to Medtronic with a copy also being maintained at the center) 
• Report the associated AE 
It is recommended that all explanted Medtronic products (device, leads, etc.) are returned to 
Medtronic 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 CRF as separate system modifications. 
6.14 
Conditional Disengagement 
After a patient is randomized every effort should be made to keep the subject in the study. 
However, it is recognized that there are circumstances where limited data may be collected, or 
study exit will need to occur. In these cases we will consider either modified data collection 
requirements where subjects may conditionally disengage in study procedures but data from the 
subject can still be collected because the subject has not revoked consent, or exit when study 
participation is completely ended. In randomized subjects, modified data collection is always 
preferred over exit. 
Subjects may be conditionally disengaged from study procedures for any of the following 
reasons: 
• Subject chooses to disengage (e.g., follow-up schedule cannot be adhered to, study 
burden too large, relocation to another geographic location but telephone follow-up still 
acceptable)  
• Investigator deems conditional disengagement necessary (e.g. medically justified)  
If the subject wishes to disengage from the study, or the investigator deems it necessary, the 
center is required to document the reason. Prior approval from the study team is required and a 
Limited Data Collection CRF needs to be completed. Data collection requirements no longer 
apply, but sites are encouraged to collect as much data as possible on the regular CRFs. 
6.15 
Study Exit 
Subjects will be exited from the study for any of the following situations: 
• Study completed 
• Subject lost to follow-up 
• Subject death 
• Subject did not meet eligibility criteria and was not randomized 
• Subject did not have a successful implant and no attempt at re-implant is made 
• Subject did not provide consent or data protection authorization 

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• Subject chooses to exit (i.e. revokes consent)  
 
Prior to exiting a subject from the study, it is recommended to follow the subject until all ongoing 
system- and procedure-related AEs are resolved or are unresolved with no further actions 
planned. After all study tests and procedures have been completed just prior to subject exit from 
the study, the subject may be informed of their randomization assignment. Following exit, 
subjects will continue to receive standard medical care. There will be no further required study-
related follow-up visits for these subjects. All data available through the time of the subject’s exit 
will be used for the study analyses. The following procedures are required to be collected at the 
exit visit: 
• Report the reason for exit 
• Vital status check 
• Current CV medications 
• Current heart failure symptoms status 
• Initial and Final device interrogation, if available (Interrogate ALL) 
• Report AEs, Study Deviations and Healthcare utilization (as they occur) 
 
Subjects will not be replaced with newly enrolled subjects upon exit. As described in Section 
11.3.4, the sample size accounts for attrition.  
6.15.1 Study completed 
Upon study closure, subjects will be exited from the study. After all study tests and 
procedures have been completed just prior to subject exit from the study, the subject may 
be informed (verbally or in written form) of their randomization assignment. Subjects in the 
control group may have aCRT turned ON. For subjects within a visit window upon study 
closure, the exit visit and scheduled visit may be combined. For other patients a separate 
exit visit must be planned. For all subjects, a Study Exit CRF including Vital Status 
information will be completed. 
6.15.2 Lost to follow-up 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two 
attempts to contact the subject, and the method of attempt (e.g., one letter and one phone 
record or two letters) must be recorded. In addition, regulations set forth by the governing 
Ethics Committee must be followed.  
6.15.3 Subject chooses to exit (i.e. revokes consent)  
If the subject wishes to exit from the study (i.e. the subject revokes consent), the center is 
required to document the reason for exit.  
In addition, study centers shall follow the regulations set forth by the governing Ethics 
Committee. Adverse events, healthcare utilizations and study deviations should be 
assessed at the time of exit and recorded on the appropriate case report forms. In addition, 

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whenever possible, an initial and final full device interrogation (Interrogate ALL) should be 
collected prior to subject exit, and a copy of the interrogation files should be sent to 
Medtronic with a copy also being maintained at the center in the subject’s file. 
 
 

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7. 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. Crossover is considered a deviation, 
but additional requirements apply, see section 5.5. 
Prior approval by Medtronic is expected in situations where the investigator anticipates, 
contemplates, or makes a conscious decision to deviate. In all geographies, 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 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 Ethic Committee 
policies and/or local laws and deviations must be reported to Medtronic as soon as possible 
upon the center becoming aware of the deviation. Refer to Table 11 through 18 for geography-
specific deviation reporting requirements 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, terminate the 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 center-specific 
reports to investigators summarizing information on deviations that occurred at the 
investigational site on a periodic basis.  
 
 

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8. ADVERSE EVENTS   
Timely, accurate, and complete reporting of clinical events is of crucial importance for success of 
the study. To assess the superiority of CRT devices containing the aCRT algorithm, it is 
important that all information related to heart failure decompensation events, atrial fibrillation 
status, and other cardiovascular adverse events are reported. Additionally, reporting and review 
of safety information for clinical studies are crucial for the protection of subjects. Sections below 
define the clinical event reporting requirements for the study, and the geography specific safety 
reporting requirements.  
8.1 
Adverse Event definitions 
8.1.1 Adverse Events 
Adverse Event (AE) definitions are provided in Table 8. All serious and all system, 
procedure, and/or cardiovascular related AEs will be collected throughout the study 
duration, starting at the time of signing the PIC form. Reporting of these events to Medtronic 
will occur on an AE Form, including a description of AE, date of onset of AE, date of site 
awareness, signs and symptoms, treatment, resolution, and investigator assessment of both 
the seriousness and the relatedness to heart failure, the procedure, and to the system. Each 
AE must be recorded on a separate AE Form.  
Health Care Utilization will be reported on the Health Care Utilization Form. 
Subject deaths are also required to be reported. Refer to section 8.3 for Subject Death 
collection and reporting requirements. 
Documented pre-existing conditions are not considered AEs unless the nature or severity of 
the condition has worsened. Episodes of symptomatic AF need to be reported. In all 
geographies, Unavoidable Adverse Events, listed in Table 8 need not be reported unless 
the adverse event worsens or is present outside the stated timeframe post-implant. For AEs 
that require immediate reporting (see Table 10), initial reporting may be done by phone, fax, 
or on the CRF completing as much information as possible, with missing or follow-up 
information provided as soon as it becomes available. The AE CRF must be completed as 
soon as possible.  
8.1.2 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), information needs to be updated on, or 
added to the original AE form. 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 has conditionally disengaged or is exited from the study prior to 
study closure, all efforts should be made to continue following the subject until all 
unresolved system or procedure related adverse events, as classified by the investigator, 
are resolved or they are unresolved with no further actions planned.  

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At the time of study exit, all cardiovascular-related adverse events with an outcome of 
“Unresolved, further actions or treatment planned” must be reviewed and an update to the 
original AE must be reported. 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 closure”. 
8.2 
Definitions, Classification and Reporting 
8.2.1 Adverse Event Definitions 
The clinical study will collect all serious and all system, procedure, and/or cardiovascular 
related adverse events.   
 
Adverse Event definitions 
General 
Adverse Event (AE) 
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 medical 
device or the comparator. 
NOTE 2: This definition includes events related to the procedures 
involved 
Relatedness 
Procedure related 
An Adverse Event that occurs due to any procedure related to the 
implantation or surgical modification of the system. 
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. 
Cardiovascular related 
An Adverse Event relating to the heart and the blood vessels or 
the circulation, e.g. Atrial Fibrillation, Myocardial Infarction, stroke, 
perivascular problems. 

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Heart Failure related 
An adverse event related to worsening heart failure signs and 
symptoms such as hypervolemic and hypovolemic status requiring 
the administration, alteration, adjustment or augmentation of HF 
therapy (diuretics, inotropes and/or vasodilators etc.) or the 
utilization of ultrafiltration devices.
Seriousness 
Serious Adverse Event (SAE) 
 
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 1: 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. 
Adverse Device Effect (ADE) 
Adverse event related to the use of the 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 use 
error or from intentional misuse of the medical device. 
Serious Adverse Device Effect (SADE)  Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
 
Unanticipated Serious Adverse Device 
Effect (USADE) 
 
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 

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NOTE 1: 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. 
Other 
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 
Intervention for heart failure 
decompensation 
An event requiring inpatient hospitalization for heart failure, or 
requiring invasive intervention for heart failure (i.e. IV diuretics, 
ultrafiltration, or equivalent). 
Hospitalization 
A therapeutic admission lasting >24hrs. 
8.2.2 Adverse Events Classification and Reporting 
All study reportable adverse events will be reported on case report forms and will be 
reviewed by a Medtronic specialist. AEs will be classified according to the definitions 
provided.  
Upon receipt of adverse events at Medtronic, a Medtronic representative will review the 
adverse event 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.  

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Regulatory reporting of AEs will be completed according to local regulatory requirements. 
Refer to Table 10 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. 
Foreseeable Adverse Events are listed in Appendix G: 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 an SAE, contact a clinical study representative 
immediately (refer to the study contact list provided in the center’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:  
 
Adverse Event classification responsibilities 
What is classified? Who classifies?
Classification Parameters 
Relatedness 
Investigator 
System, procedure, or heart failure related 
Sponsor 
System, procedure, or heart failure related 
Seriousness 
Investigator 
SAE  
Sponsor 
SAE, SADE, USADE  
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 
 
The DMC will monitor adverse event rates and evaluate risk-benefit. 
The EAC will review all applicable Healthcare Utilizations and all study reportable events 
during the study, assessing outpatient treatment and hospitalizations, to determine HF 
relatedness and AF relatedness for the study objectives. 

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8.3 
Subject Death 
8.3.1 Death data collection 
All subject deaths must be reported by the investigator to Medtronic on a Subject Death 
form as soon as possible after the investigator first learns of the death. Document the 
Adverse Event that led to the subject death on an Adverse Event form. 
In the event of a subject’s death, it is recommended that the implanted system is explanted 
and returned to Medtronic 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, the system shall be interrogated and a full 
summary interrogation (Interrogate All) performed when possible.   
• Make the interrogation file before any programming to prevent overwriting information in 
the CRT device’s memory and/or distinguishing between events detected during versus 
before the explant procedure. 
If the system is not interrogated, an explanation must be entered on the Subject Death 
form. For CRT-D 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 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 center’s responsibility 
to attempt retrieval of information about the death. In summary, the following data will be 
collected: 
• 
Adverse Event leading to death 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to system and/or procedure 
• 
Device interrogation (Interrogate ALL) (if available) 
• 
Death summary/hospital records (if available and allowed by state/local 
law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 

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8.3.2 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. 
Regulatory reporting of Subject Deaths will be completed according to local regulatory 
requirements. Refer to Table 10 for a list of required investigator and sponsor reporting 
requirements and timeframes. 
 
8.4 
Adverse Event Records and Reporting Requirements 
Adverse Events should be recorded and reported according to local regulatory requirements. It 
is the responsibility of the Investigator to abide by the adverse event reporting requirements 
stipulated by local law and the center’s Ethics Committee.  
Relevant (adverse event related) and available copies of hospital records should be sent to 
Medtronic, when allowed by local law/regulations 
 Adverse event reporting requirements 
Serious Adverse Events (SAEs) 
Investigator submit to: 
Medtronic 
Canada: Investigators are required to report to the sponsor immediately except for those 
SAEs that the protocol or other document (e.g. Investigator’s Brochure) identifies as not 
needing immediate reporting.   The immediate reports should be followed promptly by detailed, 
written reports.  
Medical Devices Regulations, sections 59-61. A guidance for “immediately” is within 72 hours 
of the investigator becoming aware of the event; Report to sponsor, without unjustified delay 
(ISO 14155:2011, sec 9.8.b). 

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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). 
Taiwan: All SAEs should be reported to the sponsor immediately and a detailed written report 
should be provided to the sponsor as soon as possible. It is recommended for investigator to 
report all SAEs to the sponsor within 48 hours (Medical Device GCP Guidance (2016-01-01) 
Article 106). 
All SAEs should be reported to TFDA and ADR center (Regulatory authorities) within 7 days of 
first knowledge (Procedure for Reporting Severe Adverse Reactions to Medicines (2004-8-31) 
Article 5). 
Korea: The PI shall quickly report all SAEs (excluding what classified in the protocol or the IB 
as ones not requiring immediate report) as expedited reports of ADE under Attached Form No. 
35 to the sponsor within the period provided in the protocol (KGCP Article 8 item 18). 
It is recommended for the investigator to report safety events within 48 hours from become 
aware date.  
All geographies: Report to the sponsor, without unjustified delay, all serious adverse events. 
Regulatory 
Authority 
All geographies: Submit to regulatory authority per local reporting requirement 
Head of 
Medical 
Institution 
Japan: The principal investigator shall report to the Head of Medical Institution, with respect to 
the progress of the research and status of any adverse event which occurs in implementing of 
the research, in accordance with specifications prescribed in this CIP. (The Ethical Guidelines 
for Medical and Health Research Involving Human Subjects)  
When a principal investigator becomes aware of any serious adverse event while carrying out 
the research which involves any invasiveness, the principal investigator shall promptly report 
to the Head of Medical Institution and take appropriate measures following the operating 
procedures including this CIP and any direction from the Head of Medical Institution (The 
Ethical Guidelines for Medical and Health Research Involving Human Subjects).  
Reporting requirements of this study: Since this study is implemented with the market-
approved devices and under the approved indications, ONLY an unanticipated serious 
adverse event for which causal relationship with the device/system/procedure/Heart Failure 
cannot be ruled out shall be reported. In the case when the study site has any additional 
reporting requirements, the principal investigator shall follow them. The principal investigator 
shall report the status of any adverse event periodically which occurs in implementing of this 
study per the site procedure. 
EC 
All geographies:  Submit to EC per local reporting requirement. 
Sponsor submit to: 
Investigators Japan: The sponsor as the study leader shall share information on the occurrence of an 
unanticipated serious adverse event for which causal relationship with the 

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device/system/procedure/Heart Failure cannot be ruled out with the other principal 
investigators in Japan when such information has been reported by a principal investigator.  
All geographies:  Submit to investigator per local reporting requirement. 
Regulatory 
authorities 
Taiwan: All SAEs should be reported to TFDA and ADR center (Regulatory authorities) within 
15 days of first knowledge (Procedure for Reporting Severe Adverse Reactions to Medicines 
(2004-8-31) Article 6). 
Canada: Preliminary and final reporting to the Canadian Ministry of Health of events occurring 
inside (always) or outside Canada (in case of corrective actions) that is related to a failure of 
the device or a deterioration in its effectiveness, or any inadequacy in its labeling or its 
directions for use and has led to the death or a serious deterioration in the state of health of a 
patient, user or other person or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in the state of health of a 
patient, user or other person b) within 30 days, if incident has not led to led to death or a 
serious deterioration in the state of health of a patient, user or other person, but could do so 
were it to recur c) as soon as possible, if incident occurred outside of Canada and is related to 
a corrective action. (Canada Medical Device Regulations, SOR/98-282; Mandatory Problem 
Reporting 59(1), 59(2), 60 (1)) 
All geographies: Submit to regulatory authority per local reporting requirement. 
EC 
Japan: The sponsor shall report information on the occurrence of an unanticipated serious 
adverse event for which causal relationship with the device/system/procedure/Heart Failure 
cannot be ruled out to the applicable EC when such information has been reported by a 
principal investigator. 
All geographies: Submit to EC per local reporting requirement. 

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Serious Adverse Device Effects (SADEs)  
Investigator submit to: 
Medtronic 
Canada: Investigators are required, to submit as soon as possible and per local requirements. 
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. 
Taiwan:  All SADEs should be reported to the sponsor, TFDA and ADR center (Regulatory 
authorities) within 7 days of first knowledge (Procedure for Reporting Severe Adverse 
Reactions to Medicines (2004-8-31) Article 5). 
Korea: SADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. SADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies:  Immediately after the investigator learns of the event or of new information 
in relation to an already reported event. 
Regulatory 
Authority 
All geographies: Submit to regulatory authority per local reporting requirement. 
Head of 
Medical 
Institution 
Japan: Since this study is implemented with market-approved devices and under the 
approved indications, ONLY an unanticipated serious adverse event for which causal 
relationship with the device/system/procedure/Heart Failure cannot be ruled out shall be 
reported. In the case when the study site has any additional reporting requirements, the 
principal investigator shall follow them. The principal investigator shall report the status of any 
adverse event periodically which occurs in implementing of this study per the site procedure. 
EC 
All geographies: Submit to EC per local reporting requirement. 
Sponsor submit to: 
Investigator 
Japan: The sponsor as the study leader shall share information on the occurrence of an 
unanticipated serious adverse event for which causal relationship with the 
device/system/procedure/Heart Failure cannot be ruled out with the other principal 
investigators in Japan when such information has been reported by a principal investigator. 
Korea:   SADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. SADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies:  Submit to investigator per local reporting requirement. 
Regulatory 
authorities 
Canada: Preliminary and final reporting to the Canadian Ministry of Health of events occurring 
inside (always) or outside Canada (in case of corrective actions) that is related to a failure of 
the device or a deterioration in its effectiveness, or any inadequacy in its labeling or its 
directions for use and has led to the death or a serious deterioration in the state of health of a 
patient, user or other person or could do so were it to recur. Report a) within 10 days after 

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awareness, if incident has led to death or a serious deterioration in the state of health of a 
patient, user or other person b) within 30 days, if incident has not led to led to death or a 
serious deterioration in the state of health of a patient, user or other person, but could do so 
were it to recur c) as soon as possible, if incident occurred outside of Canada and is related to 
a corrective action. (Medical Devices Regulation Mandatory Problem Reporting 59 (1), 59 (2), 
60 (1)) 
Taiwan: All SADEs should be reported to TFDA and ADR center (Regulatory authorities) 
within 15 days of first knowledge (Procedure for Reporting Severe Adverse Reactions to 
Medicines (2004-8-31) Article 6). 
Korea: SADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. SADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies: Submit to regulatory authority per local reporting requirement. 
EC 
Japan: The sponsor shall report information on the occurrence of an unanticipated serious 
adverse event for which causal relationship with the device/system/procedure/Heart Failure 
cannot be ruled out to the applicable EC when such information has been reported by a 
principal investigator. 
All geographies:  Submit to EC per local reporting requirement. 
Unanticipated Serious Adverse Device Effects (USADEs) 
Investigator submit to: 
Medtronic 
Canada: Investigators are required to submit as soon as possible and per their local 
requirements. 
India: All USADEs 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.   
Taiwan: All USADEs should be reported to the sponsor, TFDA and ADR center (Regulatory 
authorities) within 7 days of first knowledge (Procedure for Reporting Severe Adverse 
Reactions to Medicines (2004-8-31) Article 5). 
Korea: USADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. USADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies: Immediately after the investigator learns of the event or of new information 
in relation to an already reported event. 
Regulatory 
Authority 
Taiwan: All USADEs should be reported to the sponsor, TFDA and ADR center (Regulatory 
authorities) within 7 days of first knowledge (Procedure for Reporting Severe Adverse 
Reactions to Medicines (2004-8-31) Article 5). 

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All geographies: Submit to regulatory authority per local reporting requirement. 
Head of 
Medical 
Institution 
Japan: Since this study is implemented with market-approved devices and under the 
approved indications, ONLY an unanticipated serious adverse event for which causal 
relationship with the device/system/procedure/Heart Failure cannot be ruled out shall be 
reported. In the case when the study site has any additional reporting requirements, the 
principal investigator shall follow them. The principal investigator shall report the status of any 
adverse event periodically which occurs in implementing of this study per the site procedure.  
EC 
All geographies: Submit to EC per local reporting requirement. 
Sponsor submit to: 
Investigator 
Japan: The sponsor as the study leader shall share information on the occurrence of an 
unanticipated serious adverse event for which causal relationship with the 
device/system/procedure/Heart Failure cannot be ruled out with the other principal 
investigators in Japan when such information has been reported by a principal investigator.  
Korea: USADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. USADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies:  Submit to investigator per local reporting requirement. 
Regulatory 
authorities 
Canada: Preliminary and final reporting to the Canadian Ministry of Health of events occurring
inside (always) or outside Canada (in case of corrective actions) that is related to a failure of 
the device or a deterioration in its effectiveness, or any inadequacy in its labeling or its 
directions for use and has led to the death or a serious deterioration in the state of health of a 
patient, user or other person or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in the state of health of a 
patient, user or other person b) within 30 days, if incident has not led to led to death or a 
serious deterioration in the state of health of a patient, user or other person, but could do so 
were it to recur c) as soon as possible, if incident occurred outside of Canada and is related to 
a corrective action. (Canada Medical Device Regulations, SOR/98-282; Mandatory Problem 
Reporting 59 (1), 59 (2), 60 (1)).  
Taiwan: All USADEs should be reported to TFDA and ADR center (Regulatory authorities) 
within 15 days of first knowledge (Procedure for Reporting Severe Adverse Reactions to 
Medicines (2004-8-31) Article 6). 
Korea: SADEs which have caused death or life threatening should be reported within 7 
calendar days from the date when the investigator had relevant effects reported or informed. A 
detailed report should be submitted within 8 calendar days from the initial report. SADEs 
excluding death or life threatening should be reported within 15 calendar days from the date 
when the investigator had relevant effects reported or informed (KGCP Article 8 item 18). 
All geographies: Submit to regulatory authority per local reporting requirement. 
Head of 
Study 
Implementin
g Entity 
Japan: Information on the occurrence of an unanticipated serious adverse event for which 
causal relationship with the device/system/procedure/Heart Failure cannot be ruled out shall 
be reported when such information has been reported by a principal investigator. 

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EC 
Japan: The sponsor shall report information on the occurrence of an unanticipated serious 
adverse event for which causal relationship with the device/system/procedure/Heart Failure 
cannot be ruled out to the applicable EC when such information has been reported by a 
principal investigator. 
 
For US: Notification as soon as possible, but not later than 10 working days after the 
sponsor first learns of the effect. (21 CFR 812.150(b)(1)) 
All geographies: Submit to EC per local reporting requirement. 

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8.5 
Product Complaint Reporting 
All devices used in this study are market released. Therefore, vigilance and Medical Device 
Reporting (MDR) reporting is applicable and AEs related to any market-released device during 
                                               
iii For Japan, required reports per Clinical Study Act which will be in effect from April 2018 will be provided 
under separate cover 
All other study reportable Adverse Events (system, procedure and cardiovascular-related) 
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. 
Head of 
Medical 
Institution 
Japan: Since this study is implemented with market-approved devices and under the 
approved indications, ONLY an unanticipated serious adverse event for which causal 
relationship with the device/system/procedure/Heart Failure cannot be ruled out shall be 
reported. In the case when the study site has any additional reporting requirements, the 
principal investigator shall follow them. The principal investigator shall report the status of any 
adverse event periodically which occurs in implementing of this study per the site procedure. 
EC 
All geographies: Submit to EC 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 geographies: Submit in a timely manner after the investigator first learns of the 
information. 
EC 
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 geographies: Submit to EC per local reporting requirement. 
Sponsor submit to: 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
EC 
All geographies: Submit to EC per local reporting requirementiii . 

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the study must be reported. The reporting of product complaints is not part of the clinical study 
and 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 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 according to local Product Complaint Handling SOPs. 
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 (device deficiency). 
• Any technical or medical reason resulting in withdrawal of a device from the market by 
the manufacturer. 
A serious deterioration in the state of health 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 
 
 
 

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9. RISK ANALYSIS 
The safety and clinical performance of the Medtronic market-released CRT systems have been 
demonstrated through previous pre-clinical testing and previous clinical studies. Specifically, 
safety of the AdaptivCRT® algorithm was demonstrated in the Adaptive CRT study. All products 
used within this study are market-released. Therefore, it is not anticipated that subjects enrolled 
in this study will be exposed to any risks beyond those normally associated with CRT systems, 
transvenous and subcutaneous lead systems, or their implant procedure.   
With the exception of the risks associated with the device and implant procedure, there are no 
risks associated with study-related procedures (e.g. quality of life questionnaires), since these 
are not incremental to standard of care treatment and monitoring of patients with symptomatic 
heart failure. Therefore, the risk analysis in this section is specific to the implantation, 
management and therapy from the implanted CRT-P/D system. 
The potential risks to subjects implanted with CRT-P or CRT-D system include, but are not 
limited to, the following: 
Air embolism 
Cardiac dissection or perforation 
Cardiac tamponade 
Coronary sinus dissection 
Death 
Endocarditis or pericarditis 
Erosion through the skin 
Exit block 
Extracardiac muscle or nerve stimulation 
Fibrillation or other arrhythmias 
Heart block 
Heart wall or vein wall rupture 
Hematoma/seroma 
Infection 
Lead dislodgement 
Lead conductor fracture or insulation failure 
Loss of capture 
Myocardial irritability 
Myopotential sensing 
Pericardial effusion or rub 
Pneumothorax 
Rejection phenomena 

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Threshold elevation 
Thrombosis 
Thrombotic embolism 
Valve damage 
 
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. 
There may be other discomforts and risks related to the CRT device and/or this study that are 
not foreseen at this time. 
A summary of the risk analysis and risk assessment will be listed in the Investigator Brochure. 
The Investigator’s Brochure will be available upon request.  
9.1 
Risk Minimization 
There is no additional risk for the patient by participating in this clinical study as compared to a 
standard CRT implant. The potential risks associated with the commercially available CRT 
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 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 
implanted with the CRT system.  
Risks will be minimized by careful assessment of each subject prior to, during, and after implant 
of the CRT system.  
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 protocol required follow-up, in all 
subjects, the investigator must interrogate the CRT device to verify appropriate CRT function 
and to evaluate pacing and sensing characteristics and to assess any adverse events.  
9.2 
Potential Benefits 
There is no direct benefit for the subjects participating in the study as the devices are already 
commercially available. The information gained from this study could result in the improved 

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management of heart failure. Additionally, information collected from this study may assist in the 
design of new products, therapies and/or instructions for use.  
9.3 
Risk-to-Benefit Analysis 
There is no incremental risk or benefit for subjects participating in the study. 
 
 
 

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10. PLANNED STUDY CLOSURE, EARLY TERMINATION OF 
STUDY OR STUDY SUSPENSION 
10.1 
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 Clinical Investigation Plan requirements 
have been satisfied and/or by a decision by Medtronic or regulatory authority, whichever occurs 
first. In all geographies, except Japan, the study closure process is complete upon distribution of 
the Final Report or after final payments, whichever occurs last. In Japan, the study closure 
process is completed when the HOMI notifies the Ethics Committee and Medtronic thereof in 
writing. In all geographies, ongoing Ethics Committee oversight is required until the overall study 
closure process is complete. 
10.2 
Early termination or suspension 
Early Termination is the closure of a clinical study that occurs prior to meeting CIP-defined 
endpoints. This is possible for the whole study or a single center. Suspension is a temporary 
postponement of study enrollment. This is possible for the whole study or a single center. 
10.2.1 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 or concerns about study enrollment or conduct, or event rates. 
• (Temporary) unavailability of the study devices 
• Medtronic may stop the study due to lack of enrollment, if the average enrollment rate is 
less than 0.25 subjects enrolled per active center per month over any 6 consecutive 
months during the study. 
10.2.2 Investigator/center termination or suspension 
Possible reasons for clinical investigator or center 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 investigation plan (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups) 
• Failure to accurately diagnose LBBB as determined by the ECG Core Laboratory.  

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• 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 center 
• Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
• Investigator request (e.g. no longer able to support the study)  
10.3 
Procedures for termination or suspension 
10.3.1 Medtronic-initiated and regulatory authority-initiated 
• Medtronic will promptly inform the clinical investigators of the 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 approval lapse, the investigator, or in Japan the HOMI, will promptly inform 
the Ethics Committee of Medical Institution  
• In the case of study termination, the investigator must inform the subjects/legally 
authorized representatives and may inform the personal physician of the subjects to 
ensure appropriate care and follow-up is provided 
• In the case of study termination, subjects may be informed of their randomization 
assignment 
• 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 
• In the case of study suspension, enrolled subjects should stay on their randomized 
programming, if possible 
• CRT device therapy may be managed and reprogrammed as deemed appropriate at the 
discretion of the investigator upon study termination. 
• In case the suspension is lifted, the investigator should assess whether or not to 
continue the study at the respective site 
10.3.2 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 regulatory authorities (where required) 

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• The investigator will promptly inform the subjects, or legally-authorized representative or 
guardians and 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 
• CRT device therapy may be managed and reprogrammed as deemed appropriate at the 
discretion of the investigator upon study termination. 
10.3.3 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 representative or 
guardians and the personal physician of the subjects, with the rationale for the study 
termination or suspension  
• CRT device therapy may be managed and reprogrammed as deemed appropriate at the 
discretion of the investigator upon study termination. 
 
 

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11. STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
General 
Medtronic employed statisticians will perform the statistical analyses described in this section. 
Interim analyses will be performed by a Medtronic statistician other than the lead statistician for 
the study. The lead study statistician will be blinded to all interim analyses. All tests of treatment 
effects will be conducted in order to preserve an overall two-sided alpha level of 0.05 unless 
otherwise stated. An Intention-to-Treat analysis will be performed and will serve as the primary 
analysis for all objectives in this study. The Intention-to-Treat cohort will include all randomized 
subjects. 
A Statistical Analysis Plan (SAP) will be created before the first interim analysis to specify 
analyses in further detail. In case the SAP deviates from this Clinical Investigation Plan (CIP), or 
the actual analysis deviates from CIP and/or SAP, this will be explained in the Final Report.  
11.2 
Study design  
The AdaptResponse study is a prospective, randomized, controlled, interventional, single-
blinded, multi-center, post-market, global Cardiac Resynchronization Therapy (CRT) in heart 
failure (HF) clinical study. Patients will be randomized in equal numbers between a treatment 
arm that will receive CRT therapy with ambulatory optimization and preferential LV-only pacing 
(aCRT ON, programmed to “Adaptive Bi-V and LV”) and a control arm that will receive standard 
bi-ventricular CRT therapy (aCRT OFF, programmed to “Nonadaptive CRT”). Further details are 
given in section 5.4. Study subjects will be followed until the required number of endpoint events 
is reached. 
11.2.1 Rationale 
As described in detail in section 2, the Adaptive CRT study has demonstrated equivalence 
of aCRT with echo-optimized bi-ventricular CRT, with respect to the Clinical Composite 
Score at 6 months post-implant. A retrospective analysis on the subgroup of patients with 
LBBB and normal AV conduction suggested the hypothesis that aCRT reduces the 
incidence of the combined endpoint of death or heart failure hospitalization. The 
AdaptResponse study is designed to prospectively test this hypothesis.  
The primary endpoint is the composite of all-cause death and any intervention for heart 
failure decompensation. The heart failure event definition is broader than the more 
traditional heart failure hospitalization, adding in-patient treatment for decompensation with 
oral diuretics and out-patient treatment with IV diuretics. The reasons for this choice are that 
the incidence rate of heart failure hospitalizations has decreased over the years due to 
advances in the treatment of heart failure, and the fact that there are geographic differences 
in the treatment of heart failure and the definition of hospitalization that lead to different 
rates of heart failure hospitalization. The broader definition is intended to ensure that the 
event rate is high enough to have an achievable sample size and to accommodate 
geographic differences due to differing health care systems. Independent blinded endpoint 
adjudication will ensure an unbiased comparison between randomized arms. 

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11.2.2 Randomization 
Patients will be randomized in a 1:1 ratio using permuted blocks with random block sizes. 
Randomization will be stratified by center and by NYHA class. Randomization schedules will 
be generated by a Medtronic statistician using computer-generated random numbers.  
11.2.3 Sample size 
The AdaptResponse study will be event-driven. The study is designed to observe a primary 
endpoint in 1100 patients. To that end, the study will randomize approximately 3500 
patients. The DMC will review accruing data and will advise on continuation of enrollment 
and patient follow up.  
11.2.4 Interim analyses 
Three interim analyses are planned to be performed after 275, 550, and 825 first primary 
endpoints. Under the assumptions of the sample size calculation, the interim analyses will 
take place approximately 3.5, 5.0, and 6.5 years after first enrollment. See section 11.4 for 
more details. 
11.3 
Primary objective 
The primary objective is to test the hypothesis that aCRT reduces the incidence of the combined 
endpoint of all-cause mortality and intervention for heart failure decompensation, compared to 
standard CRT therapy, in patients with a CRT indication, LBBB and normal AV conduction. 
11.3.1 Endpoint definition 
The primary endpoint is the composite of all-cause death and any intervention for heart 
failure decompensation as adjudicated by the EAC. The date of the endpoint will be the date 
of death or the date of initiation of treatment for decompensation as determined by the EAC.  
11.3.2 Hypothesis, analysis methods and performance requirements 
The null hypothesis that will be tested is that the hazard ratio for aCRT versus control is 
equal to 1. It will be tested against the alternative hypothesis that the hazard ratio is unequal 
to 1.  
Let ST(t) and SC(t) denote the proportion of patients in the treatment arm and control arm, 
respectively, that have not experienced a primary endpoint up to time t. Let hT(t) and hC(t) 
be the associated hazard functions. Under the proportional hazards model, hT(t) = HR hC(t), 
where HR is the hazard ratio of treatment compared to control. The null and alternative 
hypotheses can be expressed as: 
H0 :  HR = 1 
HA :  HR ≠ 1 

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The hypothesis will be tested using a Cox proportional hazards regression model with a 
random center effect (frailty), stratified by baseline NYHA class. The hazard ratio for 
treatment arm versus control arm will be reported with its associated p-value and 95% 
confidence interval. The null hypothesis will be rejected when the p-value is below the 
critical value for the (interim or final) analysis, and it will be concluded that aCRT reduces 
the incidence of the primary endpoint when the hazard ratio is below 1. Kaplan-Meier 
graphs for incidence will also be reported, together with an estimate for the absolute event 
rate difference at 2 years post randomization. 
Two further analyses of the primary objective are planned. First, a Cox regression model will 
be reported with a random center effect and a risk score as fixed effect. The risk score will 
be derived from baseline data. Second, an analysis will be done including only the patients 
for whom the ECG Core Laboratory confirmed the presence of LBBB. 
11.3.3 Determination of patients and data for analysis 
The primary analysis will follow the intent-to-treat principle. All randomized patients will be 
included in analysis, and for each patient the endpoints will be attributed to the arm that the 
patient was randomized to irrespective of the actual treatment that the patient received. 
Event dates will be entered in the analysis relative to the date of randomization (which will 
be time zero for the survival analysis). Patients will be censored if no primary endpoint has 
occurred prior to the end-of-study exit visit, or the last documented follow-up visit if the 
patient was exited early. 
11.3.4 Sample size rationale 
A total of 1100 patients experiencing a primary endpoint will give 90% power to show a 
significant reduction of the incidence of the primary endpoint, accounting for 3 equally 
spaced interim analyses and assuming a true intent-to-treat hazard ratio of 0.82 for aCRT 
ON compared to aCRT OFF. 
Version 1.0 of the CIP specified the total number of patients randomized as follows: With 
the inclusion of 2874 randomized patients enrolled over 3 years and followed for 2.3 more 
years, 1100 primary endpoint events are expected when the true control arm event-free rate 
is 75% at 2 years.  
Version 2.0 of the CIP increases the total number of patients randomized to accommodate a 
lower event rate: With the inclusion of 3326 randomized patients enrolled over 4 years and 
followed for 3.5 more years, 1100 primary endpoint events are expected when the true 
control arm event-free rate is 85% at 2 years.  
The study will randomize approximately 3500 patients in order to accommodate attrition due 
to early exit. The study will be event-driven and the DMC may advise to stop enrollment 
early when the primary endpoint rate is higher than expected. 
Through simulation it was confirmed for version 1.0 of the CIP that the study will have 90% 
power under the following assumptions: 
• 3000 patients randomized in 3 years with a uniform rate 

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• control arm event-free rate is 75% at 2 years 
• LBBB is not confirmed by the ECG Core Laboratory in 10% of patients 
• aCRT hazard ratio is 0.78 in confirmed LBBB patients, 1.0 in unconfirmed patients 
• crossover rate is 5% at 2 years in aCRT arm and 8% at 2 years in control arm 
• loss-to-follow-up rate is 5% at 2 years in both arms 
• final analysis is done when 1100 events are accrued 
 
For version 2.0 of the CIP, the simulation was updated and the power of 90% was 
confirmed with updated control group event rate expectation. 
11.4 
Interim analysis methodology 
The 3 interim analyses will follow a symmetric group sequential design using the alpha-spending 
methodology of Lan and DeMets17 with O’Brien-Fleming18 type boundaries. The statistical 
stopping rules are illustrated in the figure below.  
Figure 2. Statistical stopping boundaries 
 

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The horizontal axis shows the number of events, indicating the timing of interim analyses after 
275, 550, and 825 events, and the final analysis when 1100 events are accrued. If at any interim 
analysis the standardized Z statistic for the primary objective is in the darker blue area with solid 
boundary line, the DMC may advise to stop the study claiming the null hypothesis is rejected. 
This corresponds to a cumulative α-level of 0.00002, 0.00304, 0.0193 and 0.05 spent at the 
subsequent stages. If the Z Statistic is in the lighter blue area with dashed boundary line, the 
DMC may advise to stop the study for futility. 
In case the study is stopped for efficacy after an interim analysis, the secondary objectives will 
be analyzed using a total significance level derived from a Pocock-type alpha-spending function. 
This corresponds to a cumulative α-level of 0.018, 0.031, 0.041 and 0.05 spent at the 
subsequent stages19. 
11.5 
Secondary and ancillary objectives 
Interpretation of results will be guided by a formal multiple testing procedure to achieve strict 
control of the family wise error rate, also accounting for the interim analysis plan. Secondary 
objectives will be analyzed when the study has stopped after an interim analysis or has reached 
the final analysis stage. A Hommel procedure20,21 will be applied to the secondary objectives 
(excluding the cost-effectiveness objective) using an overall α-level as determined by the stage 
in the interim analysis plan as described in section 11.4 above.  
Secondary objectives for which the hypothesis is rejected under the adjusted significance level 
of the Hommel procedure will be reported as significant with strictly controlled family wise error 
α=0.05. 
Secondary objectives include the components of the primary endpoint, patient status at 6 
months, the incidence of atrial fibrillation, and cost-effectiveness.  
11.5.1 Secondary objectives 
To assess all-cause mortality in the aCRT ON arm compared to aCRT OFF. 
Mortality will be illustrated with Kaplan-Meier graphs. A Cox proportional hazards regression 
model will be used to estimate the HR of aCRT compared to control, which will be reported 
with its p-value and 95% confidence interval. The model will include the stratification 
variables also included in the primary objective model. 
To assess the rate of intervention for heart failure decompensation for aCRT ON compared 
to aCRT OFF. 
Incidence of intervention for heart failure decompensation will be illustrated with cumulative 
incidence graphs. A Cox regression model will be used to estimate the cause-specific HR of 
aCRT compared to control, which will be reported with its p-value and 95% confidence 
interval. The model will include the stratification variables also included in the primary 
objective model. Additionally, recurrent event survival analysis will be performed to compare 
rates of interventions for heart failure decompensation. 

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To test the hypothesis that aCRT ON increases the proportion of patients that improve on 
the Clinical Composite Score (CCS) compared to aCRT OFF, at 6 months of follow-up. 
The Clinical Composite Score classifies patients according their clinical status at 6 months 
post randomization into categories Improved, Unchanged, and Worsened22. A patient is 
classified Worsened in case of death, hospitalization for worsening heart failure, worsened 
NYHA class (using last observation carried forward), or worsened status on the Global 
Assessment Score. Also patients that exit the study or cross over because of worsening 
heart failure are classified Worsened. A patient is classified Improved when not Worsened 
and there is an improvement in NYHA class or Global Assessment Score. Patients that are 
not Worsened or Improved are Unchanged. 
The proportion of patients who Improved will be compared between the arms of the study 
with a logistic regression model, correcting for the stratification variables also included in the 
primary objective model. 
To test the hypothesis that aCRT reduces the incidence of AF compared to aCRT OFF. 
Incidence of AF will be determined from device data, and the endpoint for the primary 
analysis will be the first day after randomization on which there is >6 hrs of AF reported in 
the device’s Cardiac Compass Trends. The analysis will compare incidence of AF using 
survival analysis methods. As secondary analyses device measured AF burden and 
treatment for AF will be analyzed.  
To test the hypothesis that the change in quality of life, measured by the KCCQ, in the 
aCRT ON group is better than the change in the aCRT OFF group. 
The parameter of interest is the KCCQ overall summary score (range, 0 to 100; higher 
scores indicate better health status) which will be assessed at baseline and at the 3, 6, 12, 
18, and 24 months follow-up visits. The summary score at the follow-up visits will be 
analyzed using a linear mixed effects regression model that will account for the correlation 
of scores within each patient. The treatment arm allocation will be included as a main effect. 
The baseline KCCQ score as well as the stratification variables included in the primary 
objective model will be included as covariates in the model. Analysis will be corrected for 
time trends if needed. 
To test the hypothesis that the change in health outcome, measured by the EQ-5D, in the 
aCRT ON group is better than the change in the aCRT OFF group. 
The parameter of interest is the EQ-5D index, which will be assessed at baseline and at the 
3, 6, 12, 18, and 24 months follow-up visits. Derivation of the index will follow instructions 
provided by the EuroQol Group (www.euroqol.org). The index at the follow-up visits will be 
analyzed using a linear mixed effects regression model that will account for the correlation 
of measurements within each patient. The treatment arm allocation will be included as a 
main effect. The baseline EQ-5D index as well as the stratification variables included in the 
primary objective model will be included as covariates in the model. Analysis will be 
corrected for time trends if needed. 

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To test the hypothesis that aCRT reduces the incidence of all-cause re-admissions after a 
heart failure (HF) admission within 30-days of the index event. 
A negative binomial model will be used to estimate and compare incidence rates of all-
cause re-admissions after an HF admission. For each patient the number of hospital 
admissions that falls within 30 days of discharge from an HF admission (as classified by the 
investigator) will be determined. All patients will be included in the model, with a count of 
zero in case no 30-day readmissions occurred. The model will include an offset based on 
the total follow-up experience of all patients.  
To assess cost-effectiveness of CRT devices with the aCRT algorithm relative to traditional 
CRT devices. 
Analysis method for this objective will be defined in the Economic Analysis Plan. There will 
be no hypothesis test and therefore the objective will not be included in the Hommel multiple 
testing procedure. 
11.5.2 Ancillary objectives 
Analysis methods for ancillary objectives will be defined in the Statistical Analysis Plan. 
 
 
 

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12. DATA AND QUALITY MANAGEMENT 
Data will be collected using an electronic data management system for clinical studies.  Case 
Report Form (CRF) 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 centers 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 by Medtronic. 
The data reported on the CRFs shall be derived from source documents and be consistent with 
these source documents, and any discrepancies shall be explained in writing. Source 
documents, such as patient charts, ECGs, device interrogation files, worksheets, and lab results, 
must be created and maintained by the investigational site team. For source documentation, the 
investigational center 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. 
The sponsor or a regulatory authority may audit or inspect the study center 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. 
 
 

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13. WARRANTY/INSURANCE INFORMATION 
13.1 
Warranty 
Warranty information is provided in the product packaging for the commercially released CRT 
devices and leads, and additional copies are available upon request. 
13.2 
Insurance (Europe, Russia and Middle East) 
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. 
13.3 
Insurance (Japan) 
Information regarding warranty and compensation will be provided under separate cover per the 
local regulation. Documentation explaining compensation to the subjects in the event of study-
related injuries will be submitted to Ethics Board if required.  
13.4 
Insurance (Australia) 
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. 
13.5 
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. 
13.6 
Insurance (Korea) 
Medtronic Korea Co., 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 Board. 

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13.7 
Insurance (Taiwan) 
Medtronic Taiwan 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 Board. 
13.8 
Insurance (Latin America) 
Medtronic USA Inc. 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 Board. 
 
 
 

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14. 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 center in order to ensure that the study is conducted in accordance with the CIP, the 
Clinical Trial Agreement, and applicable regulatory and local requirements. Trained Medtronic 
personnel, 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 Subject 
Informed Consent, Research Authorization (where applicable) and Clinical Trial Agreement. The 
principal investigator should also be available during monitoring visits.    
14.1 
Monitoring Visits 
The study follows a risk-based monitoring approach. The frequency of monitoring visits will be 
based upon subject enrollment, duration of the study, study compliance, number of adverse 
events, number of deviations from previous monitoring visits, remote monitoring findings, risk 
based analysis, and any suspected inconsistency in data that requires investigation. Monitoring 
for the study, including but not limited to site qualification visits, site initiation visits, interim 
monitoring visits, and closeout visits will be done in accordance to the study-specific monitoring 
plan. 
Monitoring visits will be conducted to assess 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, review of source documents against subject CRFs, and 
subjects’ compliance. 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 center.  
 
 

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15. REQUIRED RECORDS AND REPORTS 
15.1 
Investigator records 
The investigator is responsible for the preparation and retention of 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. CRFs 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 
the date on which the investigation is terminated. Measures will be taken to avoid loss or 
premature destruction. 
• All correspondence between the Ethics Committee, sponsor, monitor, and/or the 
investigator that pertains to the investigation, including required reports.  
• Subject’s case history records, including:  
o Signed and dated informed consent form (In U.S. and Canada, signed by subject. 
In Europe, Russia, Middle East, Taiwan, Australia, Korea, Latin America, and 
Japan, signed by subject and investigator).  
o Observations of adverse events/adverse device effects/device deficiencies 
o Medical history, including comorbidities and cardiovascular, arrhythmia, and 
surgical history 
o Baseline, implant and follow-up data (if applicable) 
o Documentation of the dates and rationale for any deviation from the protocol 
• Electronically signed and dated CRFs and blank set of CRFs where required by local law  
• All approved versions of the CIP and PIC 
• All approved versions of the Investigator’s Brochure, if required by local law 
• Signed and dated Clinical Trial Agreement (CTA)  
• Current curriculum vitae of principal investigators and key members of investigation site 
team (as required by local law, signed and dated if required by local law) 
• Documentation of delegated tasks 
• Ethic 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 Board 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 (Europe, Russia, Middle East, India, Australia, Korea, Taiwan and 
Latin America only) 
• Final Study Report including the statistical analysis  
• List of investigational sites 
• Any other records that local regulatory agencies require to be maintained 

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15.2 
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), 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 immediately. 
Reports are subject to inspection and to the retention requirements as described above for 
investigator records.  
Safety data investigator reporting requirements are listed in section 8.4 of the Adverse Event 
section.  
 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. 
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.  
Final Report 
Ethics Committee 
and relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination. 
 Investigator reports applicable to Japan  

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Investigator reports applicable to Japan per Ethical Guidelines for Medical and Health 
Research Involving Human Subjectsiv 
Report  
Submit to 
Description/Constraints 
Withdrawal of Ethics 
Committee approval 
Head of Medical 
Institution 
The principal investigator must report a withdrawal of 
Ethics Committee approval which occurred in other study 
site. 
Progress Report 
Head of Medical 
Institution 
The investigator shall submit written summaries of the 
status of the study and record retention information 
relevant to the study to the Head of Medical Institution 
periodically per the site procedure. 
Study Deviations  
Head of Medical 
Institution 
When an investigator, etc. becomes aware of any serious 
concern with respect to human rights of the study subject, 
etc. or with respect to implementing of the study, such as 
leakage of information related to the study, the investigator, 
etc. shall report promptly to the Head of Medical Institution 
and the principal investigator.  
When a principal investigator becomes aware of any fact or 
obtains any information that ethical justification or scientific 
validity of the study is, or might be, impaired, and if the 
continuation of the study will be hindered, the principal 
investigator shall report to the Head of Medical Institution 
without delay and, as necessary, suspend or terminate the 
study or revise the CIP. 
When a principal investigator becomes aware of any fact or 
obtains any information that appropriateness of 
implementing the study he/she is engaged in or reliability of 
results of the research is, or might be, impaired, the 
principal investigator shall report to the Head of Medical 
Institution promptly and, as necessary, suspend or 
terminate the study or revise the CIP. 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation and 
report if required by the site procedure. 
Study closure and/or 
premature 
termination 
Head of Medical 
Institution 
When a principal investigator has completed or terminated 
any study, the principal investigator shall submit to the 
Head of Medical Institution without delay, in writing, a 
statement to that effect and a summary of the results of the 
study. 
Study registration 
and publication 
Head of Medical 
Institution 
If the study involves invasiveness (not including minor 
invasiveness) and intervention, the principal investigator 
shall, without delay, report to the Head of Medical 
Institution, when the final publication of results of the study 
is done. 

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 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) 
Final report 
Institution and 
Ethics Committee
The completion of the study should be informed by the 
investigator to the institution, the sponsor and the ethics 
committee. (India GCP section 3.3.8)  
15.3 
Sponsor records 
Medtronic shall maintain the following accurate, complete, and current records: 
• All correspondence which pertains to the investigation 
• Signed Clinical Trial Agreements (CTA) 
• Current signed and dated curriculum vitae of principal investigator and key members of 
the investigation site team (as required by local law) 
• Documentation of delegated tasks 
• All signed and dated case report forms submitted by investigator 
• Approved templates of informed consents, and other information provided to the subjects 
and advertisements, including translations 
• Copies of all IRB/MEC approval letters and relevant Ethics Committee correspondence 
and Ethic Committee voting list/roster/letter of assurance 
• Names of the institutions in which the clinical study will be conducted 
• Regulatory authorities correspondence, notifications and approvals as required by 
national legislation 
• Insurance certificates (Europe, Russia, Middle East, India, Australia, Korea, Taiwan and 
Latin America only) 
                                               
iv Required reports per Clinical Study Act which will be in effect from April 2018 will be provided under 
separate cover 

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• Names/contact addresses of monitors 
• 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 
• Sample of CRFs 
• Any other records that local regulatory agencies require to be maintained  
15.4 
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 study. Safety data Medtronic reporting requirements 
are listed in section 8.4 of the Adverse Event section. 
 Sponsor reports for Australia 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators,  
Ethics Committee 
and relevant 
authorities 
Provide prompt notification of termination or suspension 
and reason(s).  
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 investigation.   
Site specific study deviations will be submitted to 
investigators periodically.   
 Sponsor reports for Canada 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
Ethics Committee
 
Provide prompt notification of termination or suspension 
and reason(s). (ISO 14155:2011)  

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Report  
Submit to 
Description/Constraints 
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 investigation.  Site specific 
study deviations will be submitted to investigators 
periodically.   
Recall and device 
disposition 
Investigators, 
Ethics 
Committee, 
 
Notification within 30 days and will include the reasons for 
any request that an investigator return, repair, or otherwise 
dispose of any devices. (Mandatory Devices Regulation 
Mandatory Problem Reporting 63-65.1) 
 Sponsor reports for Europe, Russia, Middle East, Taiwan, Korea, Latin America 
Report  
Submit to 
Description/Constraints 
(Premature) 
termination or 
suspension of the 
clinical investigation 
Investigators, 
Ethics 
Committee, 
Relevant 
authorities and 
Head of the 
Institution 
Provide prompt notification of termination or suspension 
and reason(s).  
Withdrawal of Ethics 
Committee approval 
Investigators, 
Ethics 
Committee,  
Relevant 
authorities and 
Head of the 
Institution 
Investigators, Ethics Committees will be notified only if 
required by local laws or by the Ethics Committee. 
Withdrawal of CA 
approval 
Investigators, 
Ethics 
Committee, 
Relevant 
authorities and 
Head of the 
Institution 
Investigators, Ethics Committees will be notified only if 
required by local laws or by the Ethics Committee. 

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Report  
Submit to 
Description/Constraints 
Progress Reports 
Ethics Committee 
and relevant 
authorities 
This will be submitted to the Ethics Committee only if 
required by the Ethics Committee. 
Final report 
Investigators,  
Ethics Committee 
and Regulatory 
authorities upon 
request 
For studies with sites complying to ISO 14155:2011: 
• 
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 
center should be obtained.    (ISO 14155:2011) 
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 investigation.  Site specific 
study deviations will be submitted to investigators 
periodically.   
 Sponsor reports for Japanv 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators and 
Ethic Committees 
Provide prompt notification of termination or suspension 
and reason(s).  
Recall and device 
disposition 
Ethics Committee Submit per local reporting requirement. 
Audit report 
Principal 
investigator and 
Head of Medical 
Institution 
Those engaged in audit shall report to the principal 
investigator and the Head of Medical Institution concerning 
results of the audit. (Ethical Guidelines for Medical and 
Health Research Involving Human Subjects) 
Final report 
Investigators and 
Ethics Committee
A final report will be submitted if requested after completion 
or termination of this study.  
                                               
v Required reports per Clinical Study Act which will be in effect from April 2018 will be provided under 
separate cover 

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Report  
Submit to 
Description/Constraints 
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 investigation.  Site specific 
study deviations will be submitted to investigators 
periodically, if requested.   
 Sponsor reports for the United States 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators 
IRB/MEC 
Relevant 
authorities 
Head of the 
Institution 
Provide prompt notification of termination or suspension 
and reason(s).  
Withdrawal of Ethics 
Committee approval 
Investigators 
Ethics Committee
Relevant 
authorities 
Investigators, Ethics Committees will be notified only if 
required by local laws or by the Ethics Committee. 
Final report 
Investigators, 
IRB/MEC,  
Regulatory 
authorities upon 
request 
A final report will be submitted to investigators, and 
IRBs/MECs 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 investigation.  
Site specific study deviations will be submitted to 
investigators periodically.   
 
Medtronic records and reports will be stored in locked file cabinets at Medtronic during the 
course of the study. Electronic versions of the reports will be kept on a password-protected 
document management system. After closure of the study, all records and reports will be 
archived indefinitely. Measures will be taken to avoid loss or premature destruction. 

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APPENDIX A: CASE REPORT FORMS 
Case report forms for the AdaptResponse study will be provided under separate cover upon 
request.  
 

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APPENDIX B: PRELIMINARY PUBLICATION PLAN 
Publications from the AdaptResponse study will be handled according to Medtronic Standard 
Operating Procedures and as indicated in the Clinical Trial Agreement. 
Publication Committee 
For AdaptResponse the Steering Committee will comprise the Publication Committee. Medtronic 
personnel may serve as members of the committee. 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 including writing group selection criteria, 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 at regular intervals. 
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 
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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. 
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; AND 
• Drafting the article or revising it critically for important intellectual content; AND 
• Final approval of the version to be published; AND 
• Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
 
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 AdaptResponse 
Study Investigators” and will be individually listed according to the guidelines of the applicable 
scientific journal when possible. 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, MECs 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 financial interests of the co-authors of publications according to the policies set 
forth by the corresponding journals and conferences  
• making an individual center’s study data accessible to the corresponding investigator 
after the completion of the study, if requested 
 

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APPENDIX C: 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).  
Who will be 
involved 
The DMC will have one statistician, at least one physician specializing in 
electrophysiology and at least one specializing in heart failure management.  
None of the DMC members are participating in the AdaptResponse study. A 
chairperson from among those members will be identified.   
Responsibility of 
the DMC 
The DMC will be responsible for monitoring patient safety and treatment 
efficacy data while the AdaptResponse study is ongoing.  
The DMC will safeguard the interests of study participants and the scientific 
soundness of the study, by reviewing the accumulating data including interim 
analysis results, monitoring the overall conduct of the clinical study, and 
reviewing external developments.  
The DMC will regularly review data on patient safety and study conduct, 
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. 
 
Recommendations The DMC will be advisory to the sponsor and the Steering Committee. The 
DMC may provide recommendations for early termination of the study. 
Review and consensus by the entire committee is required to recommend 
that the study should be stopped.   
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 will monitor the event rates of the study, and if necessary, they 
may recommend randomizing more subjects and/or extending follow-up in 
order to ensure the minimum number of events occurs. 

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Point  
Examples 
Decision 
Boundaries  
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 should continue as no 
statistical methods can adequately capture the complexity of all data in a 
clinical study. 
The DMC may provide recommendations for early termination of the study. 
At interim analyses, the DMC assessment will balance the evidence on the 
primary objective and the secondary objectives of all-cause mortality and 
heart failure decompensation incidence. If a mortality benefit is detected 
early, the study will stop. In addition other considerations for early stopping 
for efficacy will include, but are not limited to, the magnitude of effect, 
secondary objectives, data quality, and consistency of results across 
subgroups. 
 
Operation 
Together with the Steering Committee and Medtronic, the DMC will develop a 
charter that defines in further detail the role and operation of the DMC. The 
charter may deviate from the above, in which case the DMC charter takes 
priority. 
 
 

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APPENDIX D: ENDPOINT ADJUDICATION COMMITTEE (EAC) 
Point  
Examples 
EAC will be used Ongoing review of events contributing to the primary endpoint for this study 
will be provided by an independent blinded Endpoint Adjudication Committee 
(EAC).  
Who will be 
involved 
The EAC will have at least three members, including at least one physician 
specializing in electrophysiology, and at least one specializing in heart failure 
management. A chairperson from among those members will be identified. 
None of the EAC members will be participating investigators in the 
AdaptResponse study.    
Responsibility of 
the EAC 
The EAC will establish standards for adjudicating HF events, using the 
ACC/AHA and ESC Guidelines as a basis for diagnosis and adjudication. 
  
The EAC will be responsible for assessing applicable Healthcare Utilizations 
and events during the study, assessing the cause of hospitalizations and 
outpatient treatment, to determine HF relatedness for study objectives. 
The EAC will meet at regular intervals throughout the course of the study to 
assess events, and determine whether these events should contribute to the 
primary and secondary endpoints of the AdaptResponse Study. 
Recommendations The EAC will be advisory to the sponsor and the Steering Committee. The 
EAC will determine events that will contribute to the primary and secondary 
endpoints of the study. Review and quorum adjudication by the committee is 
required to govern any event to the primary and/or secondary endpoint(s).   
Heart Failure 
Relatedness 
definition 
 
The category for heart failure relatedness will include worsening heart failure 
signs and symptoms such as hypervolemic and hypovolemic status requiring 
the administration, alteration, adjustment or augmentation of HF therapy 
(diuretics, inotropes and/or vasodilators etc.) or the utilization of certain 
treatment devices. Intervention for heart failure decompensation (HF event) 
is defined as an event requiring “invasive intervention (i.e. IV diuretics, 
ultrafiltration, or equivalent) or inpatient hospitalization” 
Decision 
Boundaries  
The EAC will make decisions as to the relatedness of the HF event. They will 
not be responsible for evaluating adverse events, deaths or the safety of the 
patients in the study (See DMC). 
 
 
 

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APPENDIX E: STUDY OVERVIEW 
Title 
AdaptResponse Clinical Study 
Study 
Purpose 
The AdaptResponse study is a prospective, randomized, controlled, interventional, 
single-blinded, multi-center, post-market, global Cardiac Resynchronization Therapy 
(CRT) in heart failure (HF) clinical study. The purpose of this clinical study is to test the 
hypothesis that market released CRT devices which contain the AdaptivCRT® (aCRT) 
algorithm have a superior outcome compared to standard CRT devices in CRT indicated 
patients with normal AV conduction and left bundle branch block (LBBB). 
Background 
CRT is an established therapy for patients with HF symptoms, left ventricular systolic 
dysfunction, and a wide QRS.1,2   However, the magnitude of clinical and hemodynamic 
benefit of CRT varies significantly among its recipients with no clinical improvement in 
approximately one third.1 Evidence from the Medtronic pre-market approval Adaptive 
CRT study has demonstrated that aCRT-optimized CRT is at least as effective as echo-
optimized BiV pacing in terms of CCS (73.6% improved in aCRT arm vs. 72.5% in echo 
optimized arm, with a non-inferiority margin of 12%, p=0.0007)12. Additionally, a 
comparison with a historical echocardiographic AV-optimized CRT cohort indicated that 
the aCRT algorithm increased the proportion of patients with an improved CCS by 
11.9% (95% CI: 2.7% to 19.2%).13 Importantly, a post-hoc sub-analysis of the Adaptive 
CRT Clinical Study showed that in patients with sinus rhythm, normal AV conduction and 
LBBB, more aCRT patients improved in their CCS compared with the echo arm (80.7% 
vs. 68.4%, p=0.04). In this subgroup the aCRT patients received LV-only pacing 64.0% 
± 32.8% of the time.12 Additionally, in an unpublished analysis on extended follow-up 
duration in patients with normal AV conduction, there was a lower risk of death or HF 
hospitalization (HR=0.71, 95% CI: 0.40-1.27, p=0.25) with aCRT. Also a greater 
proportion of aCRT patients improved in CCS at 6 (81% vs.69%, p=0.041) and 12 
months (77% vs. 66%, p=0.076) than echocardiography-optimized control patients.14 
Furthermore, over the longer term follow-up (20.2 + 5.9  months) the aCRT algorithm 
has been shown to reduce the risk of the incidence of 48 consecutive hours in AF 
(HR=0.54 [95% CI 0.31-0.93]; p=0.03) and aCRT patients without history of AF were 
less likely to develop persistent AF (HR=0.44 [95% CI 0.19-1.03]; p=0.05).15 Further 
investigation of clinical outcomes over longer follow-up is needed to support the benefit 
of aCRT. Therefore the AdaptResponse study is designed to test the hypothesis that the 

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aCRT algorithm reduces the incidence of total mortality and heart failure 
decompensation events, increases the proportion of patients with an improved CCS and 
reduces the incidence of AF in CRT patients with normal AV conduction and LBBB. 
Study 
Components 
The following components will be used in the clinical study:  
• 
Market-released Medtronic CRT-P and CRT-D devices containing the AdaptivCRT® 
(aCRT) algorithm. 
• 
Compatible market-released right atrial, right ventricular, and Medtronic left ventricular 
pacing leads 
• 
Medtronic Model 2090 CareLink programmer 
Study Design 
 
 
Following enrollment and baseline assessment, eligible subjects will be implanted with a 
CRT system containing the aCRT algorithm and randomized in a 1:1 fashion to either 
treatment (aCRT ON, programmed Adaptiv Bi-V and LV) or control (aCRT OFF, 
programmed Nonadaptiv CRT) groups. Study subjects will be followed until 1100 
primary endpoints are accrued or until study closure, whichever comes first. Refer to the 
figure below for an overview of the study design. 
 

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Study Scope 
The study is expected to be conducted at approximately 250 centers including Australia, 
Canada, Europe, Russia, India, Japan, Korea, Latin America, Middle East, Taiwan and 
the US. Approximately 3500 subjects will be randomized in the study.   The study utilizes 
an “event-driven” study design. Enrollment will end when approximately 3500 patients are 
randomized or there is reasonable certainty that the required number of events will be 
reached as determined by the Data Monitoring Committee (DMC), whichever occurs first.
Study 
Objectives 
 
 
 
Primary objective 
To test the hypothesis that AdaptivCRT® reduces the incidence of the combined endpoint 
of all-cause mortality and intervention for heart failure decompensation, compared to 
standard CRT therapy, in patients with a CRT indication, LBBB and normal AV conduction. 
Intervention for heart failure decompensation (HF event) is defined as an event requiring 
“invasive intervention (i.e. IV diuretics, ultrafiltration, or equivalent) or inpatient 
hospitalization”. 
Secondary Objectives 
• 
To test the hypothesis that aCRT ON reduces all-cause mortality compared to aCRT 
OFF. 
• 
To test the hypothesis that aCRT ON reduces the rate of intervention for heart failure 
decompensation compared to aCRT OFF. 
• 
To test the hypothesis that aCRT ON increases the proportion of patients that improve 
on the Clinical Composite Score (CCS) compared to aCRT OFF, at 6 months of follow-
up. 
• 
To test the hypothesis that aCRT ON reduces the incidence of AF compared to aCRT 
OFF. 
• 
To test the hypothesis that the change in quality of life, measured by the KCCQ, in 
the aCRT ON group is better than the change in the aCRT OFF group. 
• 
To test the hypothesis that the change in health outcome, measured by the EQ-5D, 
in the aCRT ON group is better than the change in the aCRT OFF group. 
• 
To test the hypothesis that aCRT reduces the incidence of all-cause re-admissions 
after a heart failure (HF) admission within 30-days of the index event. 
• 
To assess cost-effectiveness of CRT devices with the aCRT algorithm relative to 
traditional CRT devices. 

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Inclusion Criteria 
 
Subject is willing to sign and date the study 
Patient Informed Consent (PIC) Form. 
 
Subject is indicated for a CRT device 
according to local guidelines. 
 
Subject has minimally: 
o 
Sinus rhythm at time of enrollment. 
o 
Left Bundle Branch Block (LBBB) as 
documented on an ECG (within 30 
days prior to enrollment). Criteria for 
complete LBBB should include: 
 
Intrinsic QRS duration ≥140 
ms 
(men) 
or 
≥130 
ms 
(women),  
 
QS or rS in leads V1 and V2,
 
Mid-QRS notching or slurring 
in ≥2 of leads V1, V2, V5, V6, 
I, and aVL. 
o 
Intrinsic, normal AV conduction as 
documented on an ECG by a PR 
interval less than or equal to 200ms 
(within 30 days prior to enrollment). 
o 
Left ventricular ejection fraction less 
than or equal to 35% (documented 
within 180 days prior to enrollment). 
o 
NYHA class II, III or IV (documented 
within 30 days prior to enrollment) 
despite optimal medical therapy. 
Optimal medical therapy is defined 
as maximal tolerated dose of Beta-
blockers and a therapeutic dose of 
ACE-I, 
ARB 
or 
Aldosterone 
Antagonist. 
 
Exclusion criteria 
 
Subject is less than 18 years of age (or has 
not reached minimum age per local law). 
 
Subject is not expected to remain available 
for at least 2 years of follow-up visits. 
 
Subject has permanent atrial arrhythmias 
for which pharmacological therapy and/or 
cardioversion have been unsuccessful or 
have not been attempted 
 
Subject is, or previously has been, receiving 
cardiac resynchronization therapy. 
 
Subject is currently enrolled or planning to 
participate in a potentially confounding drug 
or device trial during the course of this study.  
Co-enrollment in concurrent trials is only 
allowed when documented pre-approval is 
obtained from the Medtronic study manager.
 
Subject 
has 
unstable 
angina, 
or 
experienced an acute myocardial infarction 
(MI) 
or 
received 
coronary 
artery 
revascularization 
(CABG) 
or 
coronary 
angioplasty (PTCA) within 30 days prior to 
enrollment. 
 
Subject has a mechanical tricuspid heart 
valve or is scheduled to undergo valve 
repair or valve replacement during the 
course of the study. 
 
Subject is post heart transplant (subjects on 
the heart transplant list for the first time are 
not excluded). 
 
Subject has a limited life expectancy due to 
non-cardiac causes that would not allow 
completion of the study. 
 
Subject is pregnant (if required by local law, 
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undergo a pregnancy test within seven days 
prior to device implant). 
 
Subject 
meets 
the 
exclusion 
criteria 
required by local law. 
 
 

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APPENDIX F: INFORMED CONSENT TEMPLATE 
Geography specific Informed Consent form 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 AdaptResponse subjects and may assist in identifying those events for a given 
device or therapy that are unexpected in nature. The implantation of the CRT devices involves 
surgery, therefore, standard adverse events associated with a surgical procedure may be 
experienced (e.g. anesthesia complications, injury, infections, bleeding, exacerbation of pre-
existing conditions, healing complications, etc). However, the focus of this section is to 
specifically address in more detail, those events that are foreseeable due to the implantation, 
use, performance, and/or presence of the CRT system.  
Potential risks associated with the implantation of the CRT devices as well as risk minimization 
are discussed in section 9. 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 adverse events associated with the use of CRT systems include, but are not 
limited to, the following: 
Foreseeable 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 

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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 
 
Previous Clinical Data 
The listing below provides an example of reported system and procedure related adverse 
events associated with the use of CRT systems reported in the Adaptive CRT clinical study. It 
summarizes more commonly occurring adverse events (≥1% prevalence) by MedDRA preferred 
term. The adverse event relatedness adjudications are not mutually exclusive. Adverse events 
can be adjudicated as being related to multiple causes (e.g. an event can be related to both a 
lead and an implant procedure).  Table 23 provides a summary of adverse events by preferred 
term, by highest incidence of event rate. Cardiac failure was the most frequently occurring event 
(218 events in 129 subjects). 
All events were collected and reviewed during the study phase and have been reclassified 
utilizing MedDRA, the Medical Dictionary for Regulatory Activities, to allow coding to a standard 
set of medical terms. The MedDRA Lowest Level Term (LLT) and the Preferred Terms (PT) are 
provided. The LLT is the specific granular term or verbatim term, and the PT is the linked parent 
term for the LLT that is the single medical concept.  

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Due to limitations in the included patient population, this data may be used in combination with 
current event reporting information and published literature to assess for an unexpected 
increase in occurrence. 
 Observed System and Implant Procedure Related Adverse Events 
Adverse Event Preferred 
Term 
Number of Events (Number, % of Subjects) 
Adaptive CRT 
(n=318) 
Total years of follow-up = 534.6 
Control 
(n=160) 
Total years of follow-up = 272.7 
Total Subjects 
(n=478) 
Total years of follow-up = 807.3 
 
Events 
Complications††
Events 
Complications 
Events 
Complication
s 
Cardiac failure 
145 (84, 
26.4%)
117 (66, 20.8%)
73 (45, 28.1%)
56 (36, 22.5%)
218 (129, 
27.0%)
173 (102, 
21.3%)
Atrial fibrillation 
15 (13, 4.1%)
5 (3, 0.9%)
23 (17, 10.6%)
10 (8, 5.0%)
38 (30, 6.3%)
15 (11, 2.3%)
Pneumonia 
24 (19, 6.0%)
19 (15, 4.7%)
12 (9, 5.6%)
11 (9, 5.6%)
36 (28, 5.9%)
30 (24, 5.0%)
Device stimulation issue 
19 (16, 5.0%)
4 (4, 1.3%)
16 (12, 7.5%)
2 (2, 1.3%)
35 (28, 5.9%)
6 (6, 1.3%)
Ventricular tachycardia 
20 (17, 5.3%)
4 (4, 1.3%)
11 (9, 5.6%)
5 (3, 1.9%)
31 (26, 5.4%)
9 (7, 1.5%)
Chest pain 
18 (16, 5.0%)
7 (7, 2.2%)
10 (9, 5.6%)
6 (6, 3.8%)
28 (25, 5.2%)
13 (13, 2.7%)
Device dislocation 
11 (11, 3.5%)
11 (11, 3.5%)
11 (8, 5.0%)
10 (7, 4.4%)
22 (19, 4.0%)
21 (18, 3.8%)
Bronchitis 
14 (14, 4.4%)
6 (6, 1.9%)
8 (7, 4.4%)
3 (2, 1.3%)
22 (21, 4.4%)
9 (8, 1.7%)
Chronic obstructive pulmonary 
disease 
8 (6, 1.9%)
7 (5, 1.6%)
13 (8, 5.0%)
7 (4, 2.5%)
21 (14, 2.9%)
14 (9, 1.9%)
Urinary tract infection 
11 (10, 3.1%)
6 (6, 1.9%)
10 (9, 5.6%)
4 (4, 2.5%)
21 (19, 4.0%)
10 (10, 2.1%)
Renal failure acute 
12 (10, 3.1%)
9 (7, 2.2%)
7 (7, 4.4%)
5 (5, 3.1%)
19 (17, 3.6%)
14 (12, 2.5%)
Dyspnoea 
8 (8, 2.5%)
1 (1, 0.3%)
9 (8, 5.0%)
1 (1, 0.6%)
17 (16, 3.3%)
2 (2, 0.4%)
Hypotension 
11 (11, 3.5%)
1 (1, 0.3%)
5 (5, 3.1%)
1 (1, 0.6%)
16 (16, 3.3%)
2 (2, 0.4%)
Anaemia 
8 (8, 2.5%)
6 (6, 1.9%)
6 (6, 3.8%)
5 (5, 3.1%)
14 (14, 2.9%)
11 (11, 2.3%)
Renal failure 
9 (8, 2.5%)
6 (5, 1.6%)
3 (3, 1.9%)
2 (2, 1.3%)
12 (11, 2.3%)
8 (7, 1.5%)
Atrial flutter 
9 (8, 2.5%)
5 (5, 1.6%)
3 (3, 1.9%)
1 (1, 0.6%)
12 (11, 2.3%)
6 (6, 1.3%)
Gastrointestinal haemorrhage 
5 (5, 1.6%)
5 (5, 1.6%)
6 (4, 2.5%)
6 (4, 2.5%)
11 (9, 1.9%)
11 (9, 1.9%)
Sepsis 
9 (7, 2.2%)
9 (7, 2.2%)
2 (2, 1.3%)
2 (2, 1.3%)
11 (9, 1.9%)
11 (9, 1.9%)
Dehydration 
6 (6, 1.9%)
5 (5, 1.6%)
4 (4, 2.5%)
2 (2, 1.3%)
10 (10, 2.1%)
7 (7, 1.5%)
Ventricular fibrillation 
5 (5, 1.6%)
1 (1, 0.3%)
5 (5, 3.1%)
1 (1, 0.6%)
10 (10, 2.1%)
2 (2, 0.4%)
Upper respiratory tract 
infection 
4 (2, 0.6%)
0 (0, 0.0%)
6 (4, 2.5%)
0 (0, 0.0%)
10 (6, 1.3%)
0 (0, 0.0%)
Diarrhoea 
5 (5, 1.6%)
2 (2, 0.6%)
4 (2, 1.3%)
1 (1, 0.6%)
9 (7, 1.5%)
3 (3, 0.6%)
Hyperglycaemia 
4 (4, 1.3%)
4 (4, 1.3%)
4 (4, 2.5%)
4 (4, 2.5%)
8 (8, 1.7%)
8 (8, 1.7%)
                                               
†† An adverse event is considered a complication when it a) results in death, b) involves any termination of significant 
device function, or c) requires an invasive intervention 

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Events 
Complications††
Events 
Complications 
Events 
Complication
s 
Angina pectoris 
6 (6, 1.9%)
3 (3, 0.9%)
2 (2, 1.3%)
2 (2, 1.3%)
8 (8, 1.7%)
5 (5, 1.0%)
Implant site infection 
3 (3, 0.9%)
1 (1, 0.3%)
5 (5, 3.1%)
4 (4, 2.5%)
8 (8, 1.7%)
5 (5, 1.0%)
Intracardiac thrombus 
4 (4, 1.3%)
1 (1, 0.3%)
4 (4, 2.5%)
3 (3, 1.9%)
8 (8, 1.7%)
4 (4, 0.8%)
Non-cardiac chest pain 
6 (6, 1.9%)
2 (2, 0.6%)
2 (2, 1.3%)
1 (1, 0.6%)
8 (8, 1.7%)
3 (3, 0.6%)
Coronary artery disease 
7 (7, 2.2%)
7 (7, 2.2%)
0 (0, 0.0%)
0 (0, 0.0%)
7 (7, 1.5%)
7 (7, 1.5%)
Hyperkalaemia 
4 (4, 1.3%)
2 (2, 0.6%)
3 (3, 1.9%)
1 (1, 0.6%)
7 (7, 1.5%)
3 (3, 0.6%)
Implant site haematoma 
3 (3, 0.9%)
2 (2, 0.6%)
4 (4, 2.5%)
1 (1, 0.6%)
7 (7, 1.5%)
3 (3, 0.6%)
Device pacing issue 
4 (4, 1.3%)
0 (0, 0.0%)
3 (3, 1.9%)
1 (1, 0.6%)
7 (7, 1.5%)
1 (1, 0.2%)
Syncope 
3 (3, 0.9%)
0 (0, 0.0%)
4 (3, 1.9%)
1 (1, 0.6%)
7 (6, 1.3%)
1 (1, 0.2%)
Oversensing 
4 (4, 1.3%)
0 (0, 0.0%)
3 (3, 1.9%)
0 (0, 0.0%)
7 (7, 1.5%)
0 (0, 0.0%)
Acute myocardial infarction 
4 (4, 1.3%)
4 (4, 1.3%)
2 (2, 1.3%)
2 (2, 1.3%)
6 (6, 1.3%)
6 (6, 1.3%)
Cellulitis 
3 (3, 0.9%)
3 (3, 0.9%)
3 (3, 1.9%)
3 (3, 1.9%)
6 (6, 1.3%)
6 (6, 1.3%)
Gastritis 
3 (3, 0.9%)
2 (2, 0.6%)
3 (3, 1.9%)
2 (2, 1.3%)
6 (6, 1.3%)
4 (4, 0.8%)
Abdominal pain 
3 (3, 0.9%)
1 (1, 0.3%)
3 (3, 1.9%)
2 (2, 1.3%)
6 (6, 1.3%)
3 (3, 0.6%)
Back pain 
2 (2, 0.6%)
1 (1, 0.3%)
4 (4, 2.5%)
1 (1, 0.6%)
6 (6, 1.3%)
2 (2, 0.4%)
Supraventricular tachycardia 
6 (6, 1.9%)
2 (2, 0.6%)
0 (0, 0.0%)
0 (0, 0.0%)
6 (6, 1.3%)
2 (2, 0.4%)
Dizziness 
5 (5, 1.6%)
0 (0, 0.0%)
1 (1, 0.6%)
0 (0, 0.0%)
6 (6, 1.3%)
0 (0, 0.0%)
Sinusitis 
4 (4, 1.3%)
0 (0, 0.0%)
2 (2, 1.3%)
0 (0, 0.0%)
6 (6, 1.3%)
0 (0, 0.0%)
Cardiac arrest 
4 (4, 1.3%)
4 (4, 1.3%)
1 (1, 0.6%)
1 (1, 0.6%)
5 (5, 1.0%)
5 (5, 1.0%)
Transient ischaemic attack 
3 (3, 0.9%)
2 (2, 0.6%)
2 (2, 1.3%)
2 (2, 1.3%)
5 (5, 1.0%)
4 (4, 0.8%)
Deep vein thrombosis 
3 (3, 0.9%)
2 (2, 0.6%)
2 (2, 1.3%)
1 (1, 0.6%)
5 (5, 1.0%)
3 (3, 0.6%)
Implant site pain 
4 (4, 1.3%)
3 (3, 0.9%)
1 (1, 0.6%)
0 (0, 0.0%)
5 (5, 1.0%)
3 (3, 0.6%)
Diabetes mellitus 
3 (3, 0.9%)
2 (2, 0.6%)
2 (2, 1.3%)
0 (0, 0.0%)
5 (5, 1.0%)
2 (2, 0.4%)
Hypertension 
2 (2, 0.6%)
1 (1, 0.3%)
3 (3, 1.9%)
1 (1, 0.6%)
5 (5, 1.0%)
2 (2, 0.4%)
Orthostatic hypotension 
4 (4, 1.3%)
2 (2, 0.6%)
1 (1, 0.6%)
0 (0, 0.0%)
5 (5, 1.0%)
2 (2, 0.4%)
Chest discomfort 
4 (4, 1.3%)
1 (1, 0.3%)
1 (1, 0.6%)
0 (0, 0.0%)
5 (5, 1.0%)
1 (1, 0.2%)
Nasopharyngitis 
3 (3, 0.9%)
0 (0, 0.0%)
2 (2, 1.3%)
0 (0, 0.0%)
5 (5, 1.0%)
0 (0, 0.0%)
 
Adverse events in literature 
Potential adverse events and patient complications associated with the implantation of CRT 
systems have been documented in various literature articles. 
1. 
Ahsan, Syed, et al., Early and Late Complications of Cardiac Resynchronization Therapy: A Single 
Centre Experience Over 8 Years of 402 Patients; Circulation. 2009;120:S787  
Retrospective data were analyzed for all acute and chronic complications occurring over 490 
consecutive CRT device procedures in 402 patients, from 2000 through 2008.  Associated 
complications were reported by timeframe. 

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2. 
Dickstein, Kenneth, et al. The European Cardiac Resynchronization Therapy Survey; European Heart 
Journal (2009) 30, 2450–2460 
The primary aim of this survey is to describe current European practice associated with CRT 
implantations. A total of 140 centers from 13 European countries contributed data from 
consecutive patients successfully implanted with a CRT device with or without an ICD between 
November 2008 and June 2009. The total number of patients enrolled was 2438. 
Event 
% 
Peri-procedural complications  
 10 
        Bleeding  
1 
        Pocket haematoma  
3 
        Pneumothorax  
1 
        Pericardial tamponade  
0.3 
        Coronary sinus dissection  
1 
        Phrenic nerve pacing  
2 

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        Lead dislocation  
3 
Post –implantation device related complications  
4 
        Lead displacement  
2 
        Lead malfunction  
0 
        Phrenic nerve stimulation  
2 
 
3. 
Romeyer-Bouchard, Cecile, et al. Prevalence and risk factors related to infections of cardiac 
resynchronization therapy devices; European Heart Journal (2010) 31, 203–210 
This study included an evaluation of the prevalence of CRT device-related infections (DRI). 
Between January 2001 and May 2007, the study included CRT implantations performed in 303 
patients (247 men, 82%). Thirteen patients developed a DRI: endocarditis in four, pocket 
erosion in three, pocket abscess in five and septicemia in one. The prevalence of DRI was 4.3 
at 2.6 years (1.7% per year incidence). The study results showed the risk of CRT infection is 
twice that of a standard pacemaker implant risk.  
4. 
Lee DS, Krahn AD, Healey JS, et al. Evaluation of early complications related to de novo cardioverter 
defibrillator implantation. J Am Coll Cardiol 2010;55:774-82. 
The Ontario ICD Database was a prospective, multi-center registry of 3,340 new ICD implants 
and major complications were reported in 4.1% of procedures. The events most frequently 
experienced are displayed in Table 20.  
 Frequent Major and Minor Complications 
 
Number of 
Occurrences 
Number of 
Patients Affected 
% Patients With 
Complications 
Major complications* 
 
 
 
Lead replacement 
94 
90 
2.7 
Lead repositioning 
67 
67 
2.0 
Pocket infection requiring 
debridement 
40 
32 
1.0 
Electrical storm 
33 
29 
0.9 
Lead dislodgement with 
repositioning 
29 
28 
0.8 
Lead extraction 
23 
23 
0.7 

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Pulmonary edema 
24 
21 
0.6 
Myocardial perforation 
15 
14 
0.4 
Pneumothorax/hemothorax 
13 
13 
0.4 
Post-implant myocardial infarction 
8 
8 
0.2 
Sepsis 
8 
7 
0.2 
Cardiogenic shock 
7 
6 
0.2 
Minor complications* 
 
 
 
Incisional infection 
38 
35 
1.1 
Pocket hematoma 
41 
33 
1.0 
Lead dislodgement not 
repositioned† 
28 
27 
0.8 
Subclavian vein thrombosis 
8 
8 
0.2 
*Only complications with frequency >5 are shown.  
†Lead dislodgement without replacement or repositioning. 
 
5. 
American College of Cardiology (ACC) National Cardiovascular Data Registry ICD Report 1st Quarter 
2010 (30Aug2010) 
The American College of Cardiology (ACC) National Cardiovascular Data Registry (ACC-
NCDR™) contains a suite of several hospital-based cardiovascular data registries including the 
ICD Registry™. The ICD Registry allows tracking of implantable cardioverter defibrillator 
procedures within the United States including associated adverse events. 
 Bi-V ICD Adverse Events – ACC-NCDR ICD Quarterly Report 
Registry Variables for 
Bi-V Systems 
Primary Prevention
Cumulative To Date
(N = 183259) 
n ( %) 
Secondary 
Prevention 
Cumulative To Date
(N = 29815) 
n ( %) 
Total 
Cumulative To Date
(N = 213074) 
n ( %) 
AV Fistula 
9 (<0.005) 
 
9 (<0.005) 
CVA/Stroke 
111 (0.06) 
25 (0.08) 
136 (0.06) 
Cardiac Arrest 
573 (0.31) 
184 (0.62) 
757 (0.36) 
Cardiac Perforation 
142 (0.08) 
24 (0.08) 
166 (0.08) 
Cardiac Valve Injury 
2 (<0.005) 
 
2 (<0.005) 
Conduction Block 
73 (0.04) 
5 (0.02) 
78 (0.04) 

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Registry Variables for 
Bi-V Systems 
Primary Prevention
Cumulative To Date
(N = 183259) 
n ( %) 
Secondary 
Prevention 
Cumulative To Date
(N = 29815) 
n ( %) 
Total 
Cumulative To Date
(N = 213074) 
n ( %) 
Coronary Venous Dissection 
363 (0.2) 
51 (0.17) 
414 (0.19) 
Drug Reaction 
167 (0.09) 
24 (0.08) 
191 (0.09) 
Hematoma 
1907 (1.04) 
245 (0.82) 
2152 (1.01) 
Hemothorax 
192 (0.1) 
21 (0.07) 
213 (0.1) 
Infection Related to Device 
52 (0.03) 
15 (0.05) 
67 (0.03) 
Lead Dislodgement 
2338 (1.28) 
317 (1.06) 
2655 (1.25) 
MI 
48 (0.03) 
7 (0.02) 
55 (0.03) 
Pericardial Tamponade 
183 (0.1) 
21 (0.07) 
204 (0.1) 
Peripheral Embolus 
57 (0.03) 
15 (0.05) 
72 (0.03) 
Peripheral Nerve Injury 
7 (<0.005) 
2 (0.01) 
9 (<0.005) 
Phlebitis - Deep 
56 (0.03) 
12 (0.04) 
68 (0.03) 
Phlebitis - Superficial 
48 (0.03) 
18 (0.06) 
66 (0.03) 
Pneumothorax 
795 (0.43) 
113 (0.38) 
908 (0.43) 
TIA 
47 (0.03) 
5 (0.02) 
52 (0.02) 
 
Additional Adverse Events 
The above incidences of each adverse event were reported from the Adaptive CRT study or 
published papers.  Other events that have been experienced in other studies or have the 
potential to be experienced by subjects, but were not recorded in the Medtronic studies (or may 
have been reported with different terminology) also include: 
Cardiac rupture, cardiac tamponade, depression, device battery issue, device rejection, 
dysplasia, electrical conduction disorders, emotional distress, implant tool delivery problem, 
tissue fibrosis, tissue necrosis, implant site seroma, inappropriate device therapy, inappropriate 
shocks, keloid scar, lead abrasion and discontinuity, insulation or conductor failure, mortality 
due to inability to deliver therapy, myocardial irritability or damage, nerve damage, pacemaker 
syndrome, pericardial rub, transient ischemic attack, valve damage, or venous stenosis.  
 
 

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APPENDIX H: PARTICIPATING INVESTIGATORS AND 
INSTITUTIONS 
A complete list of participating investigators and institutions where study activities are conducted 
will be distributed under separate cover. 
 
 

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APPENDIX I: ETHICS COMMITTEE LIST 
A complete list of participating Ethics Committee and the Chairperson(s) will be distributed 
under separate cover. 

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APPENDIX J: LABELING 
Labeling for all market approved system components can be found with each package insert. 
Manuals can be found on http://manuals.medtronic.com. 

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APPENDIX K: BIBLIOGRAPHY 
A complete bibliography, summary of relevant literature, and summary and results of previous 
clinical investigations is provided in the Investigator’s Brochure. The Investigator’s Brochure is 
available upon request. 

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APPENDIX L: ADDITIONAL INFORMATION FOR CENTERS BY 
COUNTRY 
Regulations for the conduct of clinical trials vary by country. Required information for centers in 
each country, such as detailed sponsor contact information, names of monitors, detailed CRF 
instruction, etc. not outlined in the Clinical Investigational Plan will be provided under separate 
cover. 
 

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APPENDIX M: PREVIOUS CLINICAL INVESTIGATIONS 
A summary and results from the Adaptive CRT study, which is the clinical study evaluating the 
AdaptivCRT algorithm, are provided in the Investigator’s Brochure. The Investigator’s Brochure 
is available upon request. 

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APPENDIX N: CLINICAL INVESTIGATION PLAN SIGNATURE 
PAGE (IF APPLICABLE) 
AdaptResponse Study 
The AdaptResponse study is a prospective, randomized, controlled, interventional, single-
blinded, multi-center, post-market, global Cardiac Resynchronization Therapy (CRT) in heart 
failure (HF) clinical study. The study is being conducted to test the hypothesis that market 
released CRT devices which contain the AdaptivCRT®  (aCRT) algorithm have a superior 
outcome compared to standard CRT devices in CRT indicated patients with normal AV 
conduction and left bundle branch block (LBBB).   
Clinical Investigation Plan Version 2.0, 28 February 2018  
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 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX O: REFERENCES 
 
1 
W. T. Abraham, W. G. Fisher, A. L. Smith, D. B. Delurgio, A. R. Leon, E. Loh, D. 
Z. Kocovic, M. Packer, A. L. Clavell, D. L. Hayes, M. Ellestad, R. J. Trupp, J. 
Underwood, F. Pickering, C. Truex, P. McAtee, J. Messenger, and Miracle Study 
Group. Multicenter InSync Randomized Clinical Evaluation, 'Cardiac 
Resynchronization in Chronic Heart Failure', N Engl J Med, 346 (2002), 1845-53. 
2 
J. B. Young, W. T. Abraham, A. L. Smith, A. R. Leon, R. Lieberman, B. Wilkoff, 
R. C. Canby, J. S. Schroeder, L. B. Liem, S. Hall, K. Wheelan, and I. C. D. 
Randomized Clinical Evaluation Trial Investigators Multicenter InSync, 
'Combined Cardiac Resynchronization and Implantable Cardioversion 
Defibrillation in Advanced Chronic Heart Failure: The Miracle ICD Trial', JAMA, 
289 (2003), 2685-94.  
3 
C. Ypenburg, S. D. Roes, G. B. Bleeker, T. A. Kaandorp, A. de Roos, M. J. 
Schalij, E. E. van der Wall, and J. J. Bax, 'Effect of Total Scar Burden on 
Contrast-Enhanced Magnetic Resonance Imaging on Response to Cardiac 
Resynchronization Therapy', Am J Cardiol, 99 (2007), 657-60. 
4 
W. Zareba, H. Klein, I. Cygankiewicz, W. J. Hall, S. McNitt, M. Brown, D. 
Cannom, J. P. Daubert, M. Eldar, M. R. Gold, J. J. Goldberger, I. Goldenberg, E. 
Lichstein, H. Pitschner, M. Rashtian, S. Solomon, S. Viskin, P. Wang, A. J. Moss, 
and Madit-CRT Investigators, 'Effectiveness of Cardiac Resynchronization 
Therapy by QRS Morphology in the Multicenter Automatic Defibrillator 
Implantation Trial-Cardiac Resynchronization Therapy (Madit-CRT)', Circulation, 
123 (2011), 1061-72. 
5 
D. A. Kass, C. H. Chen, C. Curry, M. Talbot, R. Berger, B. Fetics, and E. Nevo, 
'Improved Left Ventricular Mechanics from Acute VDD Pacing in Patients with 
Dilated Cardiomyopathy and Ventricular Conduction Delay', Circulation, 99 
(1999), 1567-73. 
6 
B. Thibault, A. Ducharme, F. Harel, M. White, E. O'Meara, M. C. Guertin, J. 
Lavoie, N. Frasure-Smith, M. Dubuc, P. Guerra, L. Macle, L. Rivard, D. Roy, M. 
Talajic, P. Khairy, and Investigators Evaluation of Resynchronization Therapy for 
Heart Failure, 'Left Ventricular Versus Simultaneous Biventricular Pacing in 
Patients with Heart Failure and a QRS Complex ≥120 Milliseconds', Circulation, 
124 (2011), 2874-81. 
7 
B. M. van Gelder, F. A. Bracke, A. Meijer, and N. H. Pijls, 'The Hemodynamic 
Effect of Intrinsic Conduction During Left Ventricular Pacing as Compared to 
Biventricular Pacing', J Am Coll Cardiol, 46 (2005), 2305-10. 

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8 
K. L. Lee, J. E. Burnes, T. J. Mullen, D. A. Hettrick, H. F. Tse, and C. P. Lau, 
'Avoidance of Right Ventricular Pacing in Cardiac Resynchronization Therapy 
Improves Right Ventricular Hemodynamics in Heart Failure Patients', J 
Cardiovasc Electrophysiol, 18 (2007), 497-504. 
9 
N. Varma, P. Jia, C. Ramanathan, and Y. Rudy, 'RV Electrical Activation in Heart 
Failure During Right, Left, and Biventricular Pacing', JACC Cardiovasc Imaging, 
3 (2010), 567-75. 
10 
N. S. Sawhney, A. D. Waggoner, S. Garhwal, M. K. Chawla, J. Osborn, and M. 
N. Faddis, 'Randomized Prospective Trial of Atrioventricular Delay Programming 
for Cardiac Resynchronization Therapy', Heart Rhythm, 1 (2004), 562-7. 
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B. Vidal, M. Sitges, A. Marigliano, V. Delgado, E. Diaz-Infante, M. Azqueta, D. 
Tamborero, J. M. Tolosana, A. Berruezo, F. Perez-Villa, C. Pare, L. Mont, and J. 
Brugada, 'Optimizing the Programation of Cardiac Resynchronization Therapy 
Devices in Patients with Heart Failure and Left Bundle Branch Block', Am J 
Cardiol, 100 (2007), 1002-6. 
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D. O. Martin, B. Lemke, D. Birnie, H. Krum, K. L. Lee, K. Aonuma, M. Gasparini, 
R. C. Starling, G. Milasinovic, T. Rogers, A. Sambelashvili, J. Gorcsan, 3rd, M. 
Houmsse, and Adaptive CRT Study Investigators, 'Investigation of a Novel 
Algorithm for Synchronized Left-Ventricular Pacing and Ambulatory Optimization 
of Cardiac Resynchronization Therapy: Results of the Adaptive CRT Trial', Heart 
Rhythm, 9 (2012), 1807-14. 
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J.P.  Singh, W.T. Abraham, E.S. Chung, T. Rogers, A. Sambelashvili, J.A. Coles 
Jr, and D.O. Martin, 'Clinical Response with Adaptive CRT Algorithm Compared 
with CRT with Echocardiography-Optimized Atrioventricular Delay: a 
Retrospective Analysis of Multicentre Trials', Europace, 15 (2013), 1622-1628. 
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D. Birnie, B. Lemke, K. Aonuma, H. Krum, K. L. Lee, M. Gasparini, R. C. Starling, 
G. Milasinovic, J. Gorcsan, 3rd, M. Houmsse, A. Abeyratne, A. Sambelashvili, 
and D. O. Martin, 'Clinical Outcomes with Synchronized Left Ventricular Pacing: 
Analysis of the Adaptive CRT Trial', Heart Rhythm, 10 (2013), 1368-74. 
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Starling, J. Gorcsan, 3rd, T. Rogers, A. Sambelashvili, H. Hudnall, and D. Birnie, 
'Clinical Outcomes with Adaptive Cardiac Resynchronization Therapy:  Final 
Results of the Adaptive CRT Trial', HFSA Late Breaking (2013). 
16 
D. G. Strauss, R. H. Selvester, G. S. Wagner, 'Defining Left Bundle Branch Block 
in the Era of Cardiac Resynchronization Therapy', Am J Cardiol, 107 (2011), 927-
934. 
17 
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18 
P. C. O’Brien and T. R. Fleming, 'A Multiple Testing Procedure for Clinical Trials', 
Biometrics, 35 (1979),549–556. 
19 
Glimm E, Maurer W and Bretz F. Hierarchical testing of multiple endpoints in 
group-sequential trials. Statistics in Medicine 2009; 29:219-28. 
20 
Hommel G. A stagewise rejective multiple test procedure based on a modified 
Bonferroni test. Biometrika 1988; 75:383–386. 
21 
Dmitrienko A and d’Agostino R. Traditional multiplicity adjustment methods in 
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22 
M. Packer, 'Proposal for a New Clinical End Point to Evaluate the Efficacy of 
Drugs and Devices in the Treatment of Chronic Heart Failure', Journal of Cardiac 
Failure. Vol. 7 No. 2, 2001, 176-182. 
23. 
Starling, R. C., H. Krum, S. Bril, S. I. Tsintzos, T. Rogers, J. H. Hudnall, and D. 
O. Martin. ‘Impact of a Novel Adaptive Optimization Algorithm on 30-Day 
Readmissions: Evidence from the Adaptive CRT Trial’. JACC Heart Fail 3, no. 7 
(Jul 2015): 565-72  
 
24. 
D. Birnie, H. Hudnall, B. Lemke, K. Aonuma, K. Lai-Fun Lee, M. Gasparini, J. 
Gorcsan III, J. Cerkvenik, D. O. Martin. ‘Continuous optimization of cardiac 
resynchronization therapy reduces atrial fibrillation in heart failure patients: 
results of the Adaptive Cardiac Resynchronization Trial’, Heart Rhythm. 2017 
Dec;14(12):1820-1825 
 
25. 
G. Filippatos, D. Birnie, M. R. Gold, B. Gerritse, A. Hersi, S. Jacobs, K. Kusano, 
C. Leclercq, W. Mullens, B. L. Wilkoff, on behalf of the AdaptResponse 
Investigators. ‘Rationale and design of the AdaptResponse trial: a prospective 
randomized study of cardiac resynchronization therapy with preferential adaptive 
left ventricular-only pacing’, Eur, J Heart Fail. (2017) 19, 950–957 
 
 
 
  
 
 
 

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APPENDIX P: DOCUMENT CHANGE HISTORY 
 
Revision 
Description of Change 
Author 
1.0 
First issue 
 
 
2.0 
1. 
General:  
a. 
Updated information related to sponsor contact, Core 
laboratory, Steering Committee to reflect the current 
situation 
b. 
Updated availability of study related documents to the 
current situation 
c. 
Updated regulatory requirements to reflect the current 
situation 
d. 
Used the wording in the device manuals to explain the 
programming in the 2 arms 
e. 
Corrected typo’s 
2. 
Paragraph 1.1: Study purpose and description 
a. 
Used the wording in the device manuals to 
explain the programming in the 2 arms 
b. 
Removed sentence referring to the number of 
CRT systems in the study as not aligned with the 
study change to enroll 3500 randomized subjects 
3. 
Paragraph 1.2: Study scope 
a. 
Aligned the text with the study change: 
randomization increase from 3000 to 3500 
randomized subjects, an increase of participating 
sites from 200 to approximately 250, and an 
increase in study duration 
b. 
Added Russia to the participating regions 
4. 
Paragraph 2: Background and justification 
a. 
Updated with analyses results and aCRT related 
manuscripts published since 
b. 
Updated aCRT study post-hoc sub-analysis 
results table  
5. 
Paragraph 3.1: System description and intended use 
a. 
Removed the name of the CRT devices used in 
the study, as the study is about the aCRT 
algorithm, not about the devices itself. All CRT 
devices used in the study are commercially 
available. 
6. 
Paragraph 4: Regulatory compliance 
a. 
Updated local laws and regulations to the current 
situation 
7. 
Paragraph 6.1: Site activation 
a. 
Added clarity regarding study training for site 
personnel 
8. 
Paragraph 6.2: Equipment requirements 
a. 
Updated computer requirements to be compatible 
with the current data base 
9. 
Paragraph 6.3: Data collection 
Lidwien Vainer 

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Revision 
Description of Change 
Author 
a. 
Explained acronyms 
b. 
Added cardiovascular medications which are 
recommended for heart failure treatment 
according to the current guideline 
10. Paragraph 6.4: Patient Informed Consent process 
a. 
Due to regional regulation differences, added “per 
local requirements” to the informed consent sign 
off possibility of a legally authorized 
representative or guardian 
11. Paragraph 6.5: Enrollment 
a. 
Added the need to document subject’s 
participation in the source docs, per current 
regulations 
12. Paragraph 6.6: Baseline 
a. 
Changed names of medication to CV medication 
to also include newly guideline recommended CV 
medication 
13. Paragraph 6.8: Randomization 
a. 
Table Programming requirements: Corrected and 
updated programming requirements according to 
the current available devices, added 
recommended programming 
14. Paragraph 6.9: Scheduled follow-up visits 
a. 
Added follow-up visit windows to table 7 to 
implement the longer participation of some 
patients 
15. Paragraph 8.4: Adverse event records and reporting 
requirements 
a. 
Added the need for source docs for endpoint 
adjudication 
b. 
Updated tables to the current local reporting 
requirements 
16. Paragraph 10.3: Procedures for termination or suspension 
a. 
Added sentence to implement new MDT CIP 
requirements  
17. Paragraph 11.2: Study design  
a. 
Added stratification by NYHA class: this was 
implemented from the start of the study, on 
request of the Steering Committee.  
b. 
Updated timelines for interim analyses based on 
the current actuals 
18. Paragraph 11.3: Primary objective 
a. 
Updated sample size rationale to align with the 
study change (increase randomized subjects from 
3000 to 3500) 
19. Paragraph 11.5: Secondary and ancillary objectives 
a. 
Changed type of regression model 
20. Paragraph 13: Warranty/insurance information 
a. 
Added Russia 
b. 
Updated insurance sections according to current 
local regulations 
21. Paragraph 15: Required records and reports 
a. 
Updated according to current local regulations 
22. Appendix A:  

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Revision 
Description of Change 
Author 
a. 
Removed “draft” as the Case Report Forms are 
final 
23. Appendix E: Study overview 
a. 
Aligned with CIP V2.0 
24. Updated appendix H, I, to the actual status 
25. Updated appendix O with new references