Mid-Q Response Study
Phase: NA
Conditions: Heart Failure, Left Bundle-Branch Block, Heart Failure With Reduced Ejection Fraction (HFrEF), Heart Failure NYHA Class II, Heart Failure NYHA Class III, Heart Failure NYHA Class IV
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  Mid-Q Response 
Study Product Name 
Market released CRT-P and CRT-D devices containing 
the AdaptivCRT algorithm. 
Medtronic market released LV lead, and any market 
released RA and RV leads. 
Sponsor/Local Sponsor 
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 Japan Co., Ltd.  
Office: +81-3-6774-4611 
1-2-70 Konan, Minato-ku, Tokyo, 108-0075, Japan 
 
Medtronic (Shanghai) Management Co., Ltd. 
Floor 6-17, Building B, The New Bund World Trade 
Center Phase I , No. 5, Lane 255, Dong Yu Road, 
Pudong, Shanghai 200126, China 
 
Medtronic (Taiwan) Ltd. 
2F, No.2, Sec.1, Dunhua S. Rd. Songshan Dist. 
Taipei City 105, Taiwan (R.O.C.) 
 
Medtronic Korea Co. Ltd 
17F, Glass Tower, #534 
Teneran‐ro, Gangnam‐gu 
Seoul, 06181, Korea 
 

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Medtronic Hong Kong Medical Ltd.  
1104-11, 11/F, Tower 1,  
The Gateway,  
Harbour City, Kowloon,  
Hong Kong SAR, China 
 
Medtronic Malaysia Sdn Bhd 
B‐23‐1 Level 23, The Ascent, Paradigm 
No 1 Jalan SS7/26A Kelaena Jaya 46301 Petaling Jaya, 
Selangor, Malaysia 
 
PT Medtronic Indonesia 
Gandaria 8 Office Tower, 36th Floor Unit A 
Jl. Sultan Iskandar Muda, Kebayoran Lama 
Jakarta 12240 ‐ Indonesia 
 
Medtronic Philippines Inc. 
29th Floor One World Place  
32nd St., City Center North 
Bonifacio Global City Taguig City 
1634 Philippines 
 
Medtronic International Ltd (Singapore Branch) 
49 Changi South Avenue 2 
Singapore 486056 
Document Version 
Version 2.0, 29-DEC-2020 
Lead Principal Investigator(s) 
Mid-Q Response study lead PI: 
Kengo Kusano, M.D., Ph.D. 
Director, Division of Arrhythmia and Electrophysiology 
National Cerebral and Cardiovascular Center 
6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, 
Japan 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it 
is confidential and that it may not be further disclosed by them. 

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Table of Contents  
 
Table of Contents....................................................................................................................... 3 
Listing of Tables ........................................................................................................................ 7 
Listing of Figures ....................................................................................................................... 7 
Sponsor Contact Information .................................................................................................... 8 
CROs and Core Laboratories ...................................................................................................... 9 
Steering Committee ................................................................................................................... 9 
1. 
Glossary ............................................................................................................................ 10 
2. 
Synopsis ............................................................................................................................ 12 
3. 
Introduction ..................................................................................................................... 16 
3.1. Background ........................................................................................................................... 16 
3.2. Purpose ................................................................................................................................ 19 
3.3. Study scope .......................................................................................................................... 19 
3.4. Study oversight ..................................................................................................................... 20 
4. 
Objectives ......................................................................................................................... 20 
4.1. Primary Objective(s) .............................................................................................................. 20 
4.2. Secondary Objectives ............................................................................................................ 20 
4.3. Ancillary objectives: ............................................................................................................... 21 
5. 
Study Design ..................................................................................................................... 21 
5.1. Duration ............................................................................................................................... 22 
5.2. Rationale .............................................................................................................................. 22 
5.3. Randomization ...................................................................................................................... 23 
5.4. Crossover.............................................................................................................................. 23 
5.5. Blinding ................................................................................................................................ 23 
5.6. Minimization of Bias ............................................................................................................... 23 
6. 
Product Description .......................................................................................................... 24 
6.1. General ................................................................................................................................. 24 
6.2. Medtronic CRT-D and CRT-P devices ...................................................................................... 25 
6.3. Medtronic left ventricular leads ............................................................................................... 25 
6.4. Market released right ventricular (defibrillation) lead ............................................................... 25 
6.5. Market released right atrial lead ............................................................................................. 25 
6.6. Medtronic CareLink programmer............................................................................................. 25 

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6.7. Medtronic CareLink home monitors and Network ..................................................................... 25 
6.8. Market-released Pacing System Analyzer................................................................................. 26 
7. 
Selection of Subjects ........................................................................................................ 26 
7.1. Study Population ................................................................................................................... 26 
7.2. Subject Enrollment ................................................................................................................ 26 
7.3. Inclusion Criteria ................................................................................................................... 26 
7.4. Exclusion Criteria ................................................................................................................... 27 
8. 
Study Procedures ............................................................................................................. 28 
8.1. Site activation ....................................................................................................................... 28 
8.2. Equipment requirements ........................................................................................................ 29 
8.3. Schedule of Events ................................................................................................................ 29 
8.4. Subject Consent .................................................................................................................... 31 
8.5. Enrollment ............................................................................................................................ 34 
8.6. Baseline ................................................................................................................................ 34 
8.6.1. 
Baseline ECG ................................................................................................................... 35 
8.7. Implant ................................................................................................................................. 35 
8.7.1. 
Implant Requirements and Recommendations ................................................................... 36 
8.7.2. 
CRT Optimization ............................................................................................................. 36 
8.8. Randomization and Treatment Assignment ............................................................................. 36 
8.8.1. 
Programming Requirements and Recommendations ........................................................... 37 
8.9. Scheduled follow-up visits ...................................................................................................... 38 
8.9.1. 
3, 6 and 12 month Follow-up visits ................................................................................... 40 
8.10. 
Device Interrogation (Interrogate All) ............................................................................... 40 
8.11. 
Adverse Events ................................................................................................................ 40 
8.12. 
System Modification ......................................................................................................... 40 
8.13. 
Study Exit ....................................................................................................................... 41 
8.13.1. 
Subject Withdrawal or Discontinuation ........................................................................... 41 
8.13.2. 
Study completed .......................................................................................................... 42 
8.13.3. 
Lost to follow-up .......................................................................................................... 42 
8.14. 
Assessment of Safety ....................................................................................................... 42 
8.15. 
Recording Data ................................................................................................................ 43 
8.16. 
Deviation Handling........................................................................................................... 43 

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9. 
Risks and Benefits ............................................................................................................ 44 
9.1. Potential Risks ....................................................................................................................... 44 
9.2. Risk minimization .................................................................................................................. 45 
9.3. Potential Benefits .................................................................................................................. 46 
9.4. Risk-Benefit Rationale ............................................................................................................ 46 
10. 
Adverse Events ............................................................................................................... 46 
10.1. 
Adverse Event Definitions ................................................................................................. 47 
10.1.1. 
Adverse Events ............................................................................................................ 47 
10.1.2. 
Processing Updates and Resolution ............................................................................... 47 
10.2. 
Definitions, Classification and Reporting of Adverse Events ................................................. 48 
10.2.1. 
Adverse Event Definitions ............................................................................................. 48 
10.2.2. 
Adverse Events Classification and Reporting ................................................................... 52 
10.3. 
Subject Death .................................................................................................................. 53 
10.3.1. 
Death data collection .................................................................................................... 53 
10.3.2. 
Death classification and reporting .................................................................................. 54 
10.4. 
Adverse Event Records and Reporting Requirements ......................................................... 55 
10.5. 
Product Complaint Reporting ............................................................................................ 55 
11. 
Data Review Committees ............................................................................................... 56 
12. 
Statistical Design and Methods ..................................................................................... 56 
12.1. 
Rationale for Study Design ............................................................................................... 56 
12.2. 
General Aspects of Analysis .............................................................................................. 57 
12.3. 
Primary Objective ............................................................................................................ 57 
12.3.1. 
Primary Endpoint .......................................................................................................... 57 
12.3.2. 
Hypothesis and Analysis Methods .................................................................................. 58 
12.3.3. 
Analysis Set ................................................................................................................. 59 
12.4. 
Sample Size rationale ....................................................................................................... 59 
12.4.1. 
Historical Data .............................................................................................................. 59 
12.4.2. 
Sample Size Assumptions .............................................................................................. 59 
12.5. 
Secondary Objectives ....................................................................................................... 60 
12.5.1. 
Evaluate Change in NYHA Class ..................................................................................... 60 
12.5.2. 
Characterize Occurrence of HF Hospitalization ................................................................ 60 
12.5.3. 
Characterize All-Cause and Cardiovascular Mortality ....................................................... 60 

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12.5.4. 
Ancillary Objectives ...................................................................................................... 61 
13. 
Ethics .............................................................................................................................. 61 
13.1. 
Statement(s) of Compliance ............................................................................................. 61 
14. 
Study Administration ..................................................................................................... 62 
14.1. 
Monitoring ....................................................................................................................... 62 
14.1.1. 
Monitoring visits ........................................................................................................... 62 
14.2. 
Data Management ........................................................................................................... 63 
14.3. 
Confidentiality ................................................................................................................. 63 
14.4. 
Liability ........................................................................................................................... 64 
14.5. 
CIP Amendments ............................................................................................................. 66 
14.6. 
Record Retention ............................................................................................................. 66 
14.7. 
Publication and Use of Information ................................................................................... 66 
14.8. 
Suspension or Early Termination ....................................................................................... 67 
14.8.1. 
Planned study closure ................................................................................................... 67 
14.8.2. 
Early termination or suspension ..................................................................................... 67 
14.8.2.1. 
Study-wide termination or suspension ........................................................................ 67 
14.8.2.2. 
Investigator/center termination or suspension ............................................................ 67 
14.8.3. 
Procedures for termination or suspension ...................................................................... 68 
14.8.3.1. 
Medtronic-initiated and regulatory authority-initiated ................................................... 68 
14.8.3.2. 
Investigator-initiated ................................................................................................. 68 
14.8.3.3. 
Ethics committee-initiated .......................................................................................... 69 
15. 
Required Records and Reports ...................................................................................... 69 
15.1. 
Investigator records ......................................................................................................... 69 
15.2. 
Investigator reports ......................................................................................................... 70 
15.3. 
Sponsor records .............................................................................................................. 71 
15.4. 
Sponsor reports ............................................................................................................... 72 
16. 
References ..................................................................................................................... 73 
17. 
Appendices ..................................................................................................................... 76 
APPENDIX A. 
FORESEEABLE ADVERSE EVENT LIST ........................................................... 76 
APPENDIX B. 
CLINICAL INVESTIGATION PLAN SIGNATURE PAGE (IF APPLICABLE) ............ 85 
18. 
Version History ............................................................................................................... 86 
 

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Listing of Tables 
Table 1 Study sponsor contact information ........................................................................................... 8 
Table 2 CRO and Core Laboratory information ....................................................................................... 9 
Table 3 Adaptive CRT study post-hoc sub-analysis results .................................................................... 17 
Table 4 Data collection and study procedure requirements at subject visits ........................................... 30 
Table 5 Programming Requirements and Recommendations ................................................................ 37 
Table 6 post-randomization follow-up windows ................................................................................... 39 
Table 7 Adverse Event definitions ....................................................................................................... 48 
Table 8 Classification definition of heart failure hospitalization .............................................................. 51 
Table 9 Adverse Event classification responsibilities ............................................................................. 53 
Table 10 Investigator reports applicable for all countries per Medtronic requirements ............................ 70 
Table 11 Sponsor reports ................................................................................................................... 72 
Table 12 Observed  Adverse Events in Adaptive CRT clinical study ....................................................... 79 
Table 13 Frequent Major and Minor Complications ............................................................................... 82 
Table 14 Bi-V ICD Adverse Events – ACC-NCDR ICD Quarterly Report .................................................. 83 
 
Listing of Figures 
Figure 1 Study Flow Chart .................................................................................................................. 22 
Figure 2: Visit Timelines ..................................................................................................................... 39 
Figure 3 Clinical Composite Score Flowchart ........................................................................................ 58 
 
 

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Sponsor Contact Information 
Medtronic Inc. and Medtronic Japan Co., Ltd. are sponsoring the Mid-Q Response study. 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. 
Table 1 Study sponsor contact information 
Study contacts 
Global clinical study lead 
 
Methee Schreuder, Clinical Research Specialist 
Phone: +31 61 1597 388 
Fax: +31(0)43-356 6514 
methee.schreuder@medtronic.com 
Japan 
 
Kazuhiro Hidaka, Sr. Clinical Research Specialist 
Phone: +81 90 6486 6761 
Fax: +81 3 6774 4705 
kazuhiro.hidaka@medtronic.com 
Taiwan 
 
Pam Lee, Sr. Clinical Research Specialist 
Phone:  +88 6905219779 
Fax: +886 2 2752 3668 
pam.lee@medtronic.com 
Korea 
 
Seoyoung Youn, Clinical Research Specialist 
Phone: +82 2 3404 7761 
seoyoung.youn@medtronic.com 
Hong Kong 
 
Tina Ling, Clinical Research Specialist 
Phone: +852 2919 1326 
Fax: +852 2907 3998 
tina.ling@medtronic.com 
China 
 
Peter Tang, Sr. Clinical Research Specialist 
Phone: +86 21 2032 5216 
peter.tang@medtronic.com 
South East Asia 
 
Vinay Rajan, Sr, Clinical Research Manager 
Phone: +91 9619332703 
vinay.rajan@medtronic.com 
 
Study monitors and contacts 
Monitoring leader 
 
Alexander Zielinski,  Clinical Research Monitor 
Phone: +49  171 8635243 
alexander.zielinski@medtronic.com 
 
 
 

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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.  
CROs and Core Laboratories 
Table 2 CRO and Core Laboratory information 
Contact Information  
Duties performed 
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. 
 
Steering Committee 
A Steering Committee (SC) Roster and Charter will be available under separate cover. 
 
 

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1. Glossary 
Term 
Definition 
ACE-I 
Angiotensin Converting Enzyme Inhibitor 
aCRT 
AdaptivCRT® 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ARB 
Angiotensin II Receptor Blocker 
ARNi 
Angiotensin-Receptor/ Neprilysin inhibitor 
AV 
Atrioventricular 
Bi-V, BiV 
Biventricular 
CABG 
Coronary Artery Bypass Graft 
CCS 
Clinical Composite Score 
CIP 
Clinical Investigation Plan 
CRT 
Cardiac Resynchronization Therapy 
CRT-D 
Cardiac Resynchronization Therapy Defibrillator 
CRT-P 
Cardiac Resynchronization Therapy Pacemaker 
CTA 
Clinical Trial Agreement 
CV 
Cardiovascular 
DD 
Device Deficiency 
DMC 
Data Monitoring Committee 
EC/MEC/IRB/HREC 
Ethics Committee 
ECG 
Electrocardiogram 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
HF 
Heart Failure 
ICF 
Informed Consent Form 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LBBB 
Left Bundle Branch Block 
LV 
Left Ventricular 

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Term 
Definition 
LVEF 
Left Ventricular Ejection Fraction 
LVESV 
Left Ventricular End-Systolic Volume 
MI 
Myocardial Infarction 
MRA 
Mineralocorticoid Receptor Antagonist 
MSM 
Medtronic Secure Messaging 
NYHA 
New York Heart Association 
PGA 
Patient Global Assessment 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
QoL 
Quality of Life 
RA 
Right Atrial 
RV 
Right Ventricular 
S2D 
Save-to-Disk (device interrogation, .pdd/.pkg file) 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 

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2. Synopsis 
Title 
Mid-Q Response Study  
Clinical Study Type 
Post-Market Clinical Study 
Product Name 
Market released CRT-P and CRT-D devices containing the AdaptivCRT 
(aCRT) algorithm, Medtronic market released LV leads, and any market 
released RA and RV leads 
Sponsor  
Medtronic Inc., Medtronic, Bakken Research Center B.V., 
and Medtronic Japan Co., Ltd. 
Local Sponsor 
Medtronic (Shanghai) Management Co., Ltd. 
Medtronic (Taiwan) Ltd. 
Medtronic Korea Co. Ltd 
Medtronic Hong Kong Medical Ltd. 
Medtronic Malaysia Sdn Bhd 
Medtronic International Ltd (Singapore Branch) 
PT Medtronic Indonesia 
Medtronic Philippines Inc. 
Investigation 
Purpose 
The purpose of the Mid-Q Response study is to test the hypothesis that the 
AdaptivCRT algorithm is superior to standard CRT therapy regarding patient 
outcomes in CRT indicated patients with moderate QRS duration, preserved 
atrioventricular (AV) conduction and left bundle branch block (LBBB). 
Primary Objective 
To test the hypothesis that aCRT ON (“Adaptive Bi-V and LV”) increases the 
proportion of patients that improve on the Clinical Composite Score (CCS) 
compared to aCRT OFF (“Nonadaptive CRT”) at 6 months of follow-up. 
Secondary 
Objectives 
• 
To evaluate the change in NYHA class at 6 and 12 months between 
the aCRT ON group and the aCRT OFF group. 
• 
To characterize the occurrence of hospitalizations for worsening 
heart failure in the aCRT ON group and the aCRT OFF group at 12 
months. 
• 
To characterize all-cause and cardiovascular related mortality in the 
aCRT ON group and the aCRT OFF group at 12 months. 

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Ancillary 
Objectives 
• 
To evaluate the change in quality of life at 6 and 12 months, 
measured by the KCCQ, between the aCRT ON group and the aCRT 
OFF group. 
• 
To assess the combined effects of height, QRS duration, and aCRT 
on clinical outcomes, as measured by the Clinical Composite Score. 
• 
To characterize the incidence of AF in the aCRT ON group and the 
aCRT OFF group. 
• 
To characterize cardiovascular adverse events that occur in the 
aCRT ON and aCRT OFF groups. 
• 
To characterize reverse remodeling as measured via 
echocardiography, between the aCRT ON group and the aCRT OFF 
group. 
Study Design and 
Scope 
The Mid-Q Response study is a prospective, multi-center, randomized 
controlled, interventional, single-blinded, post-market study.  
The study will be executed at approximately 60 centers in Asia including but 
not limited to centers in Japan, South Korea, Taiwan, Hong Kong, Indonesia, 
Malaysia, Singapore, Brunei, the Philippines, and China.  
 
Study flow: 
 
Randomization 
The subjects will be randomly assigned in a 1:1 ratio to the aCRT ON (Adaptiv 
Bi-V and LV) group or the aCRT OFF (Nonadaptiv CRT) group. 

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Sample Size 
A total of 220 randomized patients followed through 6 months are needed 
for the study primary analysis. To achieve this, we expect to need 232 
enrolled patients. A maximum of 50 randomized patients is allowed at each 
site. 
Inclusion/Exclusion 
Criteria 
Inclusion Criteria: 
• 
Subject is willing to sign and date the study Informed Consent Form 
(ICF). 
• 
Subject is indicated for a CRT device according to local guidelines. 
• 
Subject has minimally: 
• 
Sinus rhythm at time of enrollment. 
• 
LBBB as documented on an ECG (preferably within 30 days prior to 
enrollment but up to 50 days is accepted) with moderately wide QRS:  
• 
Intrinsic QRS duration ≥120 ms and <150 ms 
• 
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.  
• 
Intrinsic, normal AV conduction as documented on a recent ECG by a 
PR interval ≤200 ms (within 30 days prior to enrollment). 
• 
Left ventricular ejection fraction ≤35% (documented within 180 days 
prior to enrollment). 
• 
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 MRA. 
 
Exclusion criteria: 
• 
Subject is less than 18 years of age (or has not reached minimum age 
per local law if that is higher). 
• 
Subject is not expected to remain available for at least 1 year 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. 
 

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• 
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. 
 
 

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3. Introduction  
3.1. 
Background  
Cardiac Resynchronization Therapy (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 acute [5] and 
randomized chronic [6] 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 LV [5] [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 allows 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] An additional post-hoc analysis of the Adaptive CRT study focused 
on the patients with moderately wide QRS of 120–150 ms, which comprised 40% of the patients. In 

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this subgroup, the proportion of patients that had an improved CCS was greater in the aCRT arm 
than in the echo arm (79% vs. 50%) [14]. 
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 months (81% 
vs.69%, p=0.041) and 12 months (77% vs. 66%, p=0.076) than echocardiography-optimized control 
patients. [15]  
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 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. [16] 
Table 3 Adaptive CRT study post-hoc sub-analysis results 
CRT Response [12] 
  
Improvement in Packer Clinical Composite 
Score  
12% higher response* 
HF Hospitalizations  
or Death [15] 
Reduced risk* 
30-day Readmissions [16] 
59% reduction in odds 
Atrial Fibrillation [17] [18] 
  
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 Atrial Fibrillation (AF) and aCRT 
patients without history of AF were less likely to develop persistent AF. In a sub-analysis of the 
Adaptive CRT study, Birnie D. et al compared 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 

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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. [17] [18] 
Further investigation of clinical outcomes over longer follow-up is needed to support the benefit of 
aCRT. Therefore, the AdaptResponse study was 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. [19]  
The inclusion criteria of AdaptResponse are similar to the Mid-Q Response study except for the 
QRS duration, which in AdaptResponse is ≥ 130ms for women and ≥ 140ms for men. In the past, a 
wide QRS was typically defined as a QRS duration ≥120 ms. In recent years new clinical evidence 
raised doubts about benefit of CRT in women with a QRS duration <130 ms and men with a QRS 
duration <140 ms. This has led to implementation of stricter QRS criteria in ACCF/AHA/HRS 
guidelines and ESC guidelines for CRT implantation [20] [21].  
The guidelines do not consider any ethnic differences. Ethnic differences have been observed in 
QRS duration. In the general population, Asian adults were found to have narrower QRS complexes 
compared to white adults, possibly related to smaller heart sizes in Asians [22].  In addition, 
association between LVEF and QRS duration have been observed between white and Asian patients 
with HF [23]. Asian heart failure patients had shorter QRS duration, had smaller body size and had 
more severely impaired LVEF. 
In the Japanese CRT guidelines, the QRS duration for CRT indication for patients with drug resistant 
heart failure, LBBB, sinus rhythm, EF ≤35% and NYHA III or IV is set to ≥ 120ms [24]. In some other 
Asian countries, it is also permissible to implant a CRT device in HF patients from a QRS duration of 
120 ms. 
A recent individual-patient data meta-analysis by Linde et al. of five randomized controlled trials 
looked at the associations of sex, QRS duration and patient height with benefit of CRT [25]. For all-
cause mortality, QRS duration was the only independent predictor of CRT benefit. For the 
composite of all-cause mortality or first hospitalization for HF, height and QRS duration, but not 
sex, were independent predictors of CRT benefit. Further analysis suggested increasing benefit 
with increasing QRS duration amongst shorter patients. Also, this analysis suggests that smaller 
men might still benefit from CRT even with QRS duration below 140 ms. 
In a retrospective analysis, 510 patients from the Japanese multicenter CRT database were divided 
in five subgroups: LBBB and QRS ≥150 ms (n=200, 39%); LBBB and QRS 120-149 ms (n=60, 16%); 
non-LBBB with QRS ≥150 ms (n=61, 12%); Non-LBBB with QRS 120-149 ms (n=54, 11%) and  
narrow QRS complex with QRS <120 ms (n=115, 23%). Echocardiographic response, defined as a 
relative reduction of left ventricular end-systolic volume (LVESV) ≥15% at 6-12 months after CRT 
implantation, in the subgroups was 74%, 51%, 38%, 52%, and 50% respectively, with P<0.001. The 

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incidence of the primary endpoint (composite of all-cause death or hospitalization because of HF) 
was significantly different between the groups as well, also after adjusting for other baseline 
characteristics (28.6%, 42.3%, 45.9%, 55.6%, and 55.3% respectively, P<0.001) [26]. 
From the above studies it was hypothesized that patients in Asia can benefit from CRT in general 
and from aCRT in particular, even at the lower end of the QRS duration spectrum, because the 
population is smaller in height compared to the average patient population in the landmark CRT 
studies, and because aCRT is more effective than standard BiV pacing in the subgroup of patients 
with a mid-range QRS of 120-150 ms. 
Showing the benefit of aCRT therapy in the moderately wide QRS cohort through this study may 
help to give all heart failure patients who would benefit from CRT access to this therapy. In relation 
to this, it may provide additional insights for CRT guidelines in Asian countries. 
3.2. 
Purpose 
Medtronic Inc. and Medtronic Japan Co., Ltd. are sponsoring the Mid-Q Response study; a 
prospective, randomized, controlled, interventional, single-blinded, multi-center, post-market 
Cardiac Resynchronization Therapy in heart failure clinical study. 
The purpose of this study is to assess if CRT indicated patients with normal AV conduction, LBBB, 
and QRS ≥120 and <150 ms treated with aCRT (aCRT ON: Adaptive Bi-V and LV), have a better 
Clinical Composite Score at 6 months than patients treated with standard BiV pacing (aCRT OFF: 
Nonadaptive CRT).  
To assess the superiority of CRT devices containing the aCRT algorithm, the primary objective of 
the Mid-Q Response study is 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. 
Eligible subjects will be randomized after baseline assessment and implant of a CRT system 
containing the aCRT algorithm. Randomization will be done in a 1:1 ratio to either treatment (aCRT 
ON, Adaptive Bi-V and LV) or control (aCRT OFF, Nonadaptive CRT) groups. All subjects, 
independent of randomization assignment, will have a CRT system. Study subjects will be followed 
for 12 months. 
3.3. 
Study scope 
The study is expected to be conducted at approximately 60 centers in Asia, including Japan, China, 
Taiwan, South Korea, Hong Kong, Malaysia, Singapore, Indonesia, Brunei, and the Philippines. 
Proposed study start is mid-2019. 

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A total of 220 randomized patients followed through 6 months are needed for the study primary 
analysis. To achieve this, we expect to need 232 enrolled patients. 
To ensure a widespread distribution of data to minimize bias in the study results, the maximum 
number of patients at a single center is 50 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. 
3.4. 
Study oversight 
The Steering Committee (SC) is involved in the scientific content and providing input for the 
execution of the study. The SC will also approve requests for crossovers and will review accuracy 
rates of LBBB (as determined by the ECG Core Laboratory). 
The ECG Core Laboratory will review all baseline ECGs for presence of LBBB with QRS duration 
≥120 ms and <150 ms and normal AV conduction. Feedback on accuracy rates will be presented to 
the Steering Committee and to the sites.  
 
4. Objectives  
The listed objectives will test the hypothesis that the aCRT algorithm is superior to standard CRT 
therapy in regard to patient outcomes.   
4.1. 
Primary Objective(s) 
The primary objective of the Mid-Q Response study is 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 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. 
4.2. 
Secondary Objectives  
• 
To evaluate the change in NYHA class at 6 and 12 months between the aCRT ON group and 
the aCRT OFF group. 
• 
To characterize occurrence of hospitalizations for worsening heart failure in the aCRT ON 
group and the aCRT OFF group at 12 months. 

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• 
To characterize all-cause and cardiovascular related mortality in the aCRT ON group and 
the aCRT OFF group at 12 months. 
4.3. 
Ancillary objectives: 
• 
To evaluate the change in the quality of life, measured by the KCCQ, at 6 and 12 months 
between the aCRT ON group and the aCRT OFF group. 
• 
To assess the combined effects of height, QRS duration, and aCRT on clinical outcomes, as 
measured by the Clinical Composite Score. 
• 
To characterize the incidence of AF in the aCRT ON group and the aCRT OFF group. 
• 
To characterize cardiovascular adverse events that occur in the aCRT ON and aCRT OFF 
groups 
• 
To characterize reverse remodeling as measured via echocardiography, between the aCRT 
ON group and the aCRT OFF group. 
 
5. Study Design  
The Mid-Q Response study is a prospective, randomized controlled, interventional, single-blinded, 
multi-center, clinical study, performed in Asian countries as described in section 3.3. 
CRT indicated patients with moderately wide QRS (≥120 and <150 ms), preserved AV conduction 
(PR interval ≤200ms) and LBBB will be randomized in a 1:1 ratio to either treatment (aCRT ON: 
Adaptive Bi-V and LV) or control (aCRT OFF: Nonadaptive CRT) groups. The flow chart for this 
clinical study is shown in Figure 1. 
 
 
 
 
 
 
 
 

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Figure 1 Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
5.1. 
Duration 
Enrollment is expected to start early 2020 and enrollment completion is estimated to occur 2 to 3 
years later. Due to the unknown duration and impact of the COVID-19 pandemic on CRT implants in 
the participating countries, the enrollment period may be longer than 3 years. Follow up completion 
(estimated to take place in early 2024) will take place 12 months after enrollment completion. 
Details on study duration per the definition of Clinical Trial Act in Japan will be provided under 
separate cover. 
5.2. 
Rationale  
As explained in section 3.1, results from retrospective analyses of the Adaptive CRT study [23] [24] 
[12] and a meta-analysis by Linde [25] led to the hypothesis that Asian CRT-indicated patients with 
LBBB and normal AV conduction can benefit from CRT even at the lower end of the QRS duration 
spectrum because the population is smaller in height and because aCRT is more effective than 
standard Bi-V pacing in this subgroup. 
The Mid-Q Response study is therefore designed as a prospective randomized study in Asian 
countries, including patients with a moderately wide QRS with LBBB and normal AV conduction. The 
primary endpoint is the Clinical Composite Score at 6 months post implant. 

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5.3. 
Randomization 
Subjects will be randomized in a 1:1 ratio to treatment (aCRT ON, with AdaptivCRT programmed to 
“Adaptive Bi-V and LV”) or control (aCRT OFF, with AdaptivCRT programmed to “Nonadaptive 
CRT”) group. 
Refer to section 8.8 for further details on randomization and programming requirements and 
recommendations. 
5.4. 
Crossover 
Crossovers significantly 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 interrogation 
files must be sent to Medtronic with a copy being maintained at the center in the subject’s file. 
Subjects will be analyzed per their randomly assigned treatment in accordance with the intention-
to-treat principle. 
5.5. 
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.  
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. 
5.6. 
Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of 
bias. Methods incorporated in the study design to minimize potential bias include (but are not 
limited to): 
• 
Patients will be evaluated to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to randomization. 

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• 
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. 
• 
To ensure a widespread distribution of data between centers, the maximum number of 
randomized subjects allowed per center is no more than 50. 
• 
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.  
• 
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 5.4.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 other local required registry databases e.g. 
Japan Registry of Clinical Trials) 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. 
 
6. Product Description 
6.1. 
General 
The study will be 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. The device accountability for 
this study purpose is not required. 

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6.2. 
Medtronic CRT-D and CRT-P devices  
Medtronic commercially available CRT-D and CRT-P devices containing the aCRT algorithm are 
required.   
6.3. 
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. 
6.4. 
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.  
6.5. 
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.  
6.6. 
Medtronic CareLink programmer 
The Medtronic CareLink Model 2090 Programmer (with associated software) and/or CareLink 
SmartSync™ Device Manager are used to program the CRT device. Programmers from other 
manufacturers are not compatible with Medtronic devices. 
6.7. 
Medtronic CareLink home monitors and Network 
The transfer of patient and device data from implanted Medtronic devices can be executed by using 
any of the compatible Medtronic CareLink home monitors: CareLink Monitor Model 2490C, 
MyCareLink Relay™ Home Communicator, and MyCareLink Heart™ mobile app (used with 
smartphones). The CareLink home monitor 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 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 
home monitors are not programmers and cannot be used to program implanted device parameters. 
CareLink home 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. 

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Medtronic CRT devices used in this study qualify for use with the Medtronic CareLink home 
monitors 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. 
6.8. 
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. 
 
7. Selection of Subjects 
7.1. 
Study Population 
The Mid-Q Response study will include heart failure patients in Asian countries indicated for CRT 
per local guidelines with moderately wide QRS (duration ≥120ms and <150ms), preserved AV 
conduction (PR interval ≤ 200 ms) and LBBB.  
7.2. 
Subject Enrollment 
Patients will be screened to ensure they meet all the Mid-Q Response inclusion- and none of the 
exclusion criteria prior to study enrollment. 
No study-specific procedures may be performed prior to obtaining the signed patient Informed 
Consent Form (ICF). Refer to section 8.5 for details on enrollment. 
7.3. 
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 Informed Consent Form (ICF). 
• 
Subject is indicated for a CRT device according to local guidelines. 
• 
Subject has minimally: 
• 
Sinus rhythm at time of enrollment. 
• 
Left Bundle Branch Block (LBBB) as documented on an ECG (preferably within 30 days 
prior to enrollment but up to 50 days is accepted) with moderately wide QRS: 
▪ 
Intrinsic QRS duration ≥120 ms and <150 ms 

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▪ 
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.  
• 
Intrinsic, normal AV conduction as documented on an ECG by a PR interval ≤200ms 
(preferably within 30 days prior to enrollment but up to 50 days is accepted). 
• 
Left ventricular ejection fraction ≤35% (documented within 180 days prior to 
enrollment). 
• 
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 MRA. 
7.4. 
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 if that is 
higher). 
• 
Subject is not expected to remain available for at least 1 year 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, 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. 
 

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8. 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 
8.1. 
Site activation  
During the activation process (prior to enrollment of subjects in the study), Medtronic will provide 
clinical study materials (e.g. Investigator Site File, database access codes etc.) and train site 
personnel on the CIP, relevant standards and regulations, informed consent process 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 ICF 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Signed/dated CTA on file with sponsor 

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• 
Current, signed and dated Curriculum Vitae (CV) of investigators 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 
 
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.  
8.2. 
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 (version 11 or 
higher), Google Chrome, and/or Safari for data entry  
• 
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. 
8.3. 
Schedule of Events 
Subjects enrolled in the Mid-Q Response study will be followed through 12 months. A high-level 
overview of events is provided in Table 4. 
 
 

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Table 4 Data collection and study procedure requirements at subject visits 
Study Procedure 
Enrollment# Baseline 
Implant# Randomization 3, 6 and 12 
Months Visit  
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 
 
Blood*** 
 
X 
 
 
X 
 
Echocardiographic 
data*** 
 
X 
From within 6 months 
prior to enrollment 
 
 
X 
 
Cardiovascular (CV) 
medications**** 
 
X 
 
 
 
X 
Medical history 
 
X 
 
 
 
 
Current heart failure 
symptoms status 
 
X 
 
 
X 
X 
Final implanted 
system configuration 
and LV lead 
placement 
 
 
X 
 
 
 
Device interrogation 
(and CareLink data if 
available) 
 
 
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 (KCCQ) 
 
X 
 
 
X 
 

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Study Procedure 
Enrollment# Baseline 
Implant# Randomization 3, 6 and 12 
Months Visit  
Study Exit***** 
NYHA assessment 
 
X* 
 
 
X 
 
Patient global 
assessment 
 
 
 
 
X 
 
Vital status 
 
 
 
 
 
 
X 
Crossover 
 
 
 
As it occurs 
System modifications  
 
As they occur  
Adverse events (AEs) 
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 
*** Data only collected if procedure is standard of care and if allowed per local regulations. In China, this data will not be 
collected. 
****Including daily dose at baseline and study exit 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. 
See also section 8.6. 
***** Study Exit:  To be completed at/after 12 months visit is completed. A separate exit CRF is required, a separate exit 
visit is not needed. 
****** Death: In case of death complete only a Death CRF and corresponding AE CRF, no Exit CRF should be completed. 
# Enrollment and Implant: although it is strongly recommended to perform the implant after enrollment, it is allowed to 
enroll subjects within 3 days after implant as implant is not a study related procedure. Please make sure all study related 
procedures are done after enrollment, and the baseline KCCQ is performed within 5 days after implant. 
8.4. 
Subject Consent 
Patient informed consent 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 signed Informed Consent Form  and an Authorization to Use and Disclose 
Personal Health Information /Research Authorization/ other privacy language (“Data Protection 
Authorization”) ,as required by local law, that has been approved by the applicable Ethics 
Committee and signed and personally dated by the subject (or their legally authorized 
representative or guardian, per local requirements) and by the person who conducted the informed 
consent discussion, as applicable to 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.  

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Prior to enrolling subjects, each applicable Ethics Committee will be required to approve the 
Informed Consent Form and Data Protection Authorization where applicable, 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 ICF 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, a signed ICF must be obtained from the subject 
(or their legally authorized representative or guardian, per local requirements) and by the person 
who conducted the informed consent discussion, as applicable to 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 ICF and 
Data Protection Authorization where applicable,  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: 
• 
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 ICF 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  
• 
Include any other locally required signatories, such as witnesses, as indicated by country 
specific legislations  

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• 
Provide the subject with a copy of the consent form and Data Protection Authorization 
where applicable, 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 ICF 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 ICF The ICF shall be obtained through a 
supervised oral process. An independent witness must be present throughout the process. The ICF 
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 ICF 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 ICF as well. The ICF 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 ICF must be filed in the hospital/clinical chart and/or with the subject’s 
study documents.  
The ICF (in Japan, the signature page only) and Data Protection Authorization where applicable, 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 ICF 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 ICF 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. 

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8.5. 
Enrollment 
A subject is considered enrolled in the Mid-Q Response when the Mid-Q Response consent process 
has been finalized. Enrollment can be a stand-alone visit or can occur on the same day as the 
baseline visit. If enrollment occurs on the same date as any study specific procedures, time of 
enrollment and study specific procedures should be clearly indicated in patient medical record. 
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. 
8.6. 
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. When a subject is enrolled after 
implant, the baseline data should reflect the patient status pre-implant and the baseline visit must 
be completed within 5 days after implant. 
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) 
• 
Quality of Life and Health outcome Measures  
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ)  
• 
Blood measurements (only collected when standard of care) 
• 
Echocardiography data (only collected when standard of care and originating from up to 6 
months prior to enrollment) 
• 
Report AEs and Study Deviations (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, SGLT2 inhibitors and 
vasodilators.  

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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. 
8.6.1. 
Baseline ECG 
LBBB with moderate QRS duration has to be diagnosed (per investigator assessment) per the 
following criteria: QRS duration ≥120 ms and <150 ms, 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 (12 lead ECG, 
original size, auto saved PDF format) must be sent to the ECG Core Laboratory for review of 
these criteria. Details on the review process will be provided under separate cover. 
8.7. 
Implant 
It is strongly recommended to perform the implant after enrollment, however, it is allowed to enroll 
subjects within 3 days after implant. All study related procedures should be done after enrollment.  
When implant is performed after enrollment, implant 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 and is not 
considered a study related procedure. 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,  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 collection following the implant 
procedure is required when the subject is enrolled pre-implant and recommended when the subject 
is enrolled post-implant. When collected, 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 implant i is not considered an adverse event. Events occurring during an 
unsuccessful implant (e.g. dissection, perforation) are adverse events and will be recorded and 
 
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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classified. Subjects experiencing unsuccessful implant procedures must be followed for 30 days 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. Randomization may only be done after a successful implant. 
8.7.1. 
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. 
8.7.2. 
CRT Optimization 
Optimization of the AV-VV intervals may be completed and documented. Additional features to 
optimize CRT may be used upon market commercialization. 
8.8. 
Randomization and Treatment Assignment 
Subjects who meet all inclusion and none of the exclusion criteria, and have a successfully 
implanted CRT device, will be assigned to a treatment at random during the randomization visit, 
which must occur within 7 days after a successful implant. Subjects will be randomized using the 
randomization schedule determined by a Medtronic statistician. 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 and Crossovers (as they occur) 
 

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When implant is performed after enrollment, randomization should occur within 37 days after 
enrollment. When randomization is done later, verification of all inclusion and all exclusion criteria 
must be repeated. 
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. 
8.8.1. 
Programming Requirements and Recommendations 
The following programming requirements and recommendations are applicable to study 
subjects, according to their respective randomization assignment. Any deviation from the 
programming requirements will constitute a study deviation, whereas deviations from 
programming recommendations are not considered study deviations. 
Table 5 Programming Requirements and Recommendations 
Parameter 
Treatment Group  
Control Group  
Adaptive CRT 
Adaptive Bi-V and LV 
Nonadaptive CRT  
Mode 
DDD required, with DDDR only if 
clinically needed  
DDD required, with DDDR only if 
clinically needed  
V. Blank Post VP 
≥ 200 ms 
No requirement 
SAV 
NA (field disabled when Adaptive 
Bi-V and LV selected) 
Per preferred in-office /physician 
method 
PAV 
NA (field disabled when Adaptive 
Bi-V and LV selected) 
Per preferred in-office /physician 
method 
VV Delay 
NA (field disabled when Adaptive 
Bi-V and LV selected) * 
Per preferred in-office /physician 
method 
V. Pacing 
NA (field disabled when Adaptive 
Bi-V and LV selected) 
LV→RV or RV→LV  
Left Ventricular Capture 
Management (LVCM) 
Adaptive 
Adaptive 
Lower Rate 
≤60 bpm  
 
≤60 bpm  
 
Upper Tracking Rate 
≤140 bpm  
 
≤140 bpm  
 
Upper Sensor Rate 
≤140 bmp 
≤140 bmp  

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Ventricular Sense Response 
ON 
ON 
Conducted AF response 
ON 
ON 
Lead polarity for quadripolar LV 
leads 
Dual cathode pacing is not allowed 
Dual cathode pacing is not allowed 
Multiple Point Pacing (MPP) 
OFF recommended 
OFF recommended 
EffectivCRT During AF 
OFF recommended 
OFF recommended 
* For CRT devices with programmable VV Delay in Adaptive mode: Program to Auto 
8.9. 
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 3 and are based on days post-randomization.  
Required visits post-randomization include follow-up visits at 3 months, 6 months, and 12 months 
as shown inFigure 2. During these visits information will be collected about adverse events (AE), 
Cardiovascular (CV) medications, and Heart Failure (HF) assessment, as well as additional 
information and procedures which vary by visit (see Table 4). Quality of Life (QoL) and Health 
outcome will be addressed using the KCCQ questionnaire, 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.  

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Figure 2: Visit Timelines 
  
 
The post-randomization follow-up windows are provided in Table 6. 
Table 6 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 
77 
91 
105 
6 Month follow-up 
183 
183 
211 
12 Month follow-up* 365 
365 
393 
*12 Month follow-up visit in the second half of the window is preferred but not required 
 

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8.9.1. 
3, 6 and 12 month Follow-up visits  
• NYHA HF assessment 
• Physical examination 
• Blood measurements (only collected when standard of care) 
• Echocardiography data (only collected when standard of care) 
• 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)  
• Patient Global Assessment 
• Report AEs and hospitalizations, System Modifications, Study Deviations, and Crossovers 
(as they occur) 
8.10. Device Interrogation (Interrogate All) 
For the implant (if performed after enrollment), randomization and follow-up visits, a final full 
“Interrogate ALL” device interrogation file (.pdd or .pkg) 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. 
8.11. Adverse Events 
All serious and all system, procedure, and/or cardiovascular related Adverse Events (AEs) will be 
collected throughout the study duration. These are reported upon center awareness and assessed 
at scheduled follow-up visits to ensure all applicable AEs have been reported. 
Refer to section 10 for adverse event details. 
8.12. 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: 
• 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)  

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• 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. 
8.13. Study Exit  
Subjects should be exited from the study when the 12 months visit is completed. 
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 and Study Deviations (as they occur) 
*Note: this does not need to be collected separately when exit occurs on same date as the 12 month visit. 
Subjects will not be replaced with newly enrolled subjects upon exit. As described in Section 12.4.2 
0, the sample size accounts for attrition.  
8.13.1. 
Subject Withdrawal or Discontinuation 
A subject can withdraw from the study at any time. If a subject is withdrawn from the clinical 
study, the reason for withdrawal will be recorded in the Exit CRF and in the subject’s hospital 
record. In addition, centers should follow the regulations set forth by their Ethics Board.  
Possible reasons for premature withdrawal or exit from the study are: 
• Study completed 

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• Subject chooses to withdraw (i.e. consent withdrawal)  
• Subject did not meet eligibility criteria after consent but prior to randomization (once 
randomized, subjects should stay in the study) 
• Investigator withdrew subject from the study for medical reasons 
• Subject did not have a successful CRT implant and no attempt at re-implant is made. If 
randomization is completed prior to successful implant by error, the subject should not be 
exited. 
• Subject lost to follow-up (not expected to occur due to the short study duration for 
individual subjects) 
• Subject death 
• Subject did not provide consent or data protection authorization 
 
Exits after randomization should be avoided as much as possible. Prior to exiting a subject from 
the study, pre-approval should be obtained from the Medtronic study manager, unless subject 
chooses to withdraw. 
8.13.2. 
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. 
The study will continue until the predetermined number of randomized patients has completed 
the 12-month visit, unless Medtronic determines to stop earlier. The study may be stopped 
early due to lack of enrollment, e.g. if the average enrollment rate is less than 0.15 subjects 
enrolled per active center per month over any 6 consecutive months during the study. 
8.13.3. 
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.   
8.14. Assessment of Safety 
Aggregate safety data will be reviewed internally at a minimum annually following first subject 
enrollment. The Safety Representative, Medical Advisor, Clinical Study Manager, and other 

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appropriate functional groups (e.g., Regulatory Affairs, Quality) as needed will participate in the 
Internal Safety Data Review/Trending meetings. 
The following are the key safety events identified a priori that will be reviewed for this study: 
• 
(Worsening) Heart Failure events 
• 
Events with outcome death 
The type of data for aggregate review is as follows: 
• 
Aggregate presentation of all AEs filtered by relatedness, seriousness, etc. 
• 
Aggregate presentation of all Deaths filtered by death classification through last data 
collection/modification. 
Important safety findings or signals identified will be reported per local requirements. 
8.15. Recording Data 
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 4. 
8.16. Deviation Handling 
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 5.4. 
Prior approval by Medtronic is expected in situations where the investigator anticipates, 
contemplates, or makes a conscious decision to deviate. Prior approval is not required when a 
deviation is necessary to protect the safety, rights or well-being of a subject in an emergency or in 
unforeseen situations beyond the investigator’s control (e.g. subject failure to attend scheduled 
follow-up visits, inadvertent loss of data due to computer malfunction, inability to perform required 
procedures due to subject illness). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going 
forward. This may also apply for other unforeseen situations (e.g. the subject permanently refuses 
to complete a study required procedure and the data will not contribute to the primary endpoint 
analysis). However, prior approval from Medtronic is required for such situations.  

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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 section 15.2 and 15.3 for 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. 
 
9. Risks and Benefits 
9.1. 
Potential Risks 
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. 

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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 
• 
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. 
9.2. 
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 

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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.  
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.  
9.3. 
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 
management of heart failure. Additionally, information collected from this study may assist in the 
design of new products, therapies and/or instructions for use.  
9.4. 
Risk-Benefit Rationale 
There is no incremental risk or benefit for subjects participating in the study. 
                  
10. Adverse Events 
All serious and all system, procedure, and/or cardiovascular related adverse events (AEs) will be 
collected throughout the study duration, starting at the time of signing the ICF.  These AEs should 
be reported timely, accurately and completely. Reporting and review of safety information for 
clinical studies are crucial for the protection of subjects. The products used in the clinical trial are 
market approved and used within the current indications for use as indicated in the product 
labeling. Sections below define the clinical event reporting requirements for the study.  

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10.1. Adverse Event Definitions 
10.1.1. 
Adverse Events 
Adverse Event (AE) definitions are provided in Table 7. 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 ICF. Reporting of these events to Medtronic will occur on an AE Form, 
including a description of the AE, date of onset of the AE, date of site awareness, signs and 
symptoms, treatment, resolution, and investigator assessment of both the seriousness and the 
relatedness to heart failure, the implant or system modification procedure, and to the system. 
Each AE must be recorded on a separate AE Form.  
Subject deaths are also required to be reported. Refer to section 10.3 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. However, episodes of symptomatic AF need to be reported. In all 
geographies, Unavoidable Adverse Events, listed in Table 7 need not be reported unless the 
adverse event worsens or is present outside the stated timeframe post-implant. For AEs that 
require immediate reporting, 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.  
10.1.2. 
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 is exited from the study prior to the 12 month visit or 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.  
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”. 

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10.2. Definitions, Classification and Reporting of Adverse Events 
10.2.1. 
Adverse Event Definitions 
The clinical study will collect all serious and all system, procedure, and/or cardiovascular related 
adverse events.  Where the definition indicates “device”, it refers to any market released device 
used in the study to provide CRT. This might be any market released component of the system 
and includes but is not restricted to: the CRT-P or CRT-D device, the RA, RV or LV leads, the 
programmer, and implant tools. 
Table 7 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 
(ISO 14155:2011, 3.2) 
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 
and programmers as defined in the 
Clinical Investigation Plan) 
 
Device-related: An adverse event that results from the presence or 
performance (intended or otherwise) of the CRT 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, including but not limited to Atrial Fibrillation, Myocardial 
Infarction, stroke, perivascular problems. 
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 

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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 fetal distress, fetal 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. 
(ISO 14155:2011, 3.37) 
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. 
(ISO 14155:2011, 3.1) 
Serious Adverse Device Effect (SADE)  
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
(ISO 14155:2011, 3.36) 
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. 
(ISO 14155:2011, 3.42) 
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 
 
For hospitalizations associated with applicable adverse events, investigators should classify 
whether a hospitalization is a heart failure hospitalization, according to the following definition: 
Intervention for heart failure decompensation is defined as an event that (i) occurred primarily 
because of new or worsening signs and symptoms of HF, or biomarker or imaging evidence of 
HF, and (ii) received additional or increased pharmacological or mechanical intervention to treat 
HF. In case the patient is not hospitalized, the treatment is required to be intravenous or 
invasive. 
More details on the classification of heart failure related hospitalization and outpatient invasive 
intervention for heart failure decompensation are provided in Table 8 and documented on the AE 
CRF. 

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Table 8 Classification definition of heart failure hospitalization 
Term 
Definition 
Heart Failure related 
hospitalization 
 
Hospitalization due to heart failure will be defined as a therapeutic 
admission lasting >24hrs that occurred primarily because of the 
documented presence of:  
• 
Use of additional or increased pharmacologic or mechanical 
interventions directed at the treatment of heart failure, and at least 1 
of the following 2 criteria: 
• 
Clinical manifestations of heart failure 
• 
Biomarker or radiographic evidence consistent with heart failure 
 
Clinical manifestations of heart failure include the following signs and 
symptoms: New or worsening 
• 
Dyspnea 
• 
Orthopnea 
• 
Paroxysmal nocturnal dyspnea 
• 
Edema 
• 
Pulmonary rales 
• 
Jugular venous distension 
• 
Third heart sound or gallop rhythm 
• 
Hypotension or cardiogenic shock not occurring in the context of an 
acute myocardial infarction or as the consequence of an arrhythmia, or 
• 
Other clinical evidence of new or worsening heart failure, e.g., weight 
gain, or confinement to bed predominantly due to heart failure 
symptoms 
 
Biomarker results consistent with heart failure include documented 
increased or increasing levels of a natriuretic peptide (BNP or NTproBNP). 
Radiographic evidence consistent with heart failure includes documented 
worsening pulmonary congestion or pulmonary edema on chest X-ray or 
other generally recognized imaging pattern. 
The use of additional or increased pharmacologic or mechanical 
interventions directed at the treatment of heart failure includes: 
• 
Initiation of intravenous diuretic, inotropic, or vasodilator therapy 
• 
Significant addition or increase in oral heart failure therapy 
• 
Up-titration of intravenous therapy, if already on therapy 
• 
Initiation of mechanical or surgical intervention (mechanical 
circulatory or ventilatory support, heart transplantation or ventricular 
pacing to improve cardiac function), or the use of ultrafiltration, 

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hemofiltration, or dialysis that is specifically directed at treatment of 
heart failure. 
Invasive intervention for 
HF decompensation 
This category will be defined as a clinical event where invasive treatment 
provided in an ambulatory setting for signs and/or symptoms of heart 
failure decompensation but where the patient is not hospitalized. The 
definition of signs and symptoms will be the same as the heart failure 
definition for hospitalization (see above). Invasive treatments will include 
any intravenous or invasive therapy directed at the management of heart 
failure (e.g., IV diuretics, IV vasodilators, IV inotropes, ultrafiltration, etc).   
 
10.2.2. 
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.  
Regulatory reporting of AEs will be completed according to local regulatory requirements. 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 A: 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 in 
Table 9.  

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Table 9 Adverse Event classification responsibilities 
What is classified? Who classifies? Classification Parameters 
Relatedness 
Investigator 
System, procedure, or heart failure related 
Sponsor 
System, procedure, heart failure related, cardiovascular 
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 
Sponsor 
Sudden Cardiac, Non-sudden Cardiac, Non-Cardiac, 
Unknown 
 
10.3. Subject Death 
10.3.1. 
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.   

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• 
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 returned product reporting 
systems may be used to gather additional information about the returned device/component. 
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) 
10.3.2. 
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 section 10.4 for investigator and sponsor reporting requirements. 

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10.4. 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.  
Investigator will submit to sponsor: 
• 
SAEs: Report to the sponsor, without unjustified delay, all serious adverse events 
• 
SADEs: Immediately after the investigator learns of the event or of new information in relation 
to an already reported event. 
• 
USADEs: Immediately after the investigator learns of the event or of new information in relation 
to an already reported event. 
 
All SAEs, SADEs and USADEs will be submitted by investigator and/or sponsor to Regulatory 
Authority, Head of Medical Institution, EC per local reporting requirement. 
10.5. 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 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. 
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). 

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• 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 
impairment to a body structure or a body function 
 
11. Data Review Committees  
The Mid-Q Response ECG Core Laboratory will review all baseline ECGs from patients enrolled in 
the Mid-Q Response study for presence of LBBB and normal AV conduction. Feedback on accuracy 
will be reported to Medtronic and the sites. 
No other committees will review data during the course of the study. Adverse Events will be 
reviewed and classified by Investigators and Medtronic. A Data Monitoring Committee (DMC) is not 
considered needed for Mid-Q Response, due to the well-understood risk profile of CRT therapy, 
short follow up duration and no interim analyses are planned. 
 
12. Statistical Design and Methods 
Medtronic employed statisticians will perform the statistical analyses described in this section. No 
interim analyses will be performed for the Mid-Q Response study and there are no criteria defined 
for termination of the study on statistical grounds. 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 Mid-Q Response Statistical Analysis Plan (SAP) will be created 
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. 
12.1. Rationale for Study Design 
The CCS is selected as the primary endpoint because it is an established endpoint in the research of 
CRT that can be assessed in all patients with 6 months of follow up. The study is randomized to 
ensure comparable groups between aCRT On and aCRT Off. Patients are blinded to exclude bias. 
However, investigators are not blinded to recognize that blinding would involve a prohibitive burden 
to clinical practice. 

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The secondary and ancillary endpoints are NYHA class, hospitalizations for worsening heart failure, 
all-cause and cardiovascular death, KCCQ, AF and cardiovascular adverse events. Death and HF 
hospitalizations are components of the CCS and frequently used as endpoint in pivotal trials in 
heart failure [27]. The NYHA class measures severity of heart failure symptoms and is also a 
component of the CCS. KCCQ is a measure of Quality of Life specific to heart failure. AF is common 
in HF patients and there is preliminary evidence that aCRT reduces the incidence of AF worsening 
[18]. Finally, cardiovascular adverse events are collected to allow for reporting and review of safety 
information. 
12.2. General Aspects of Analysis 
The final report will include descriptive summaries of patient characteristics at baseline, follow-up 
experience, attrition, adverse events, and study deviations. 
Statistical methods used for analysis of objectives will include Chi-square test, mixed-effects 
logistic regression, ordinal proportional odds logistic regression, and competing-risk survival 
analysis using Cumulative Incidence Functions.  
Subgroups may be considered, which will include age, gender, body height, heart failure etiology, 
LVEF, NYHA class, and QRS duration. Note that race and ethnicity are not collected in this study. 
All data will be reported. Data that is not used for the analysis of objectives, such as data from 
subjects that were not randomized, will be summarized separately. Missing data will be identified 
and the number of patients with missing data will be reported. No imputation of missing data will be 
done for the main analyses. However, multiple imputation may be used for sensitivity analyses. 
Note that the CCS is defined for all subjects, also if there is contributing data missing. The algorithm 
determining CCS (see below) uses last observation carried forward (LOCF) for the NYHA class. Data 
management procedures will be used to detect and correct spurious data. 
12.3. Primary Objective 
The primary objective of the study is to test the hypothesis that aCRT ON increases the proportion 
of patients with moderately wide QRS, LBBB and intact AV conduction that improve on the Clinical 
Composite Score (CCS) compared to aCRT OFF at 6 months of follow-up.  
12.3.1. 
Primary Endpoint 
The primary endpoint for the study will be the Clinical Composite Score (CCS) at 6 months. The 
CCS classifies patients according their clinical status at 6 months post-randomization into 
categories Improved, Unchanged, and Worsened. 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 

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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 including all 
patients that miss NYHA class and Global Assessment Score data and are not classified 
Worsened because of death, HF hospitalization, exit or crossover (see flowchart in Figure 3). 
The main analysis will look at the percentage of patients with Improved CCS. 
Figure 3 Clinical Composite Score Flowchart 
 
12.3.2. 
Hypothesis and Analysis Methods 
The null-hypothesis that will be tested is that the proportion of patients with Improved CCS is 
not different between the randomized arms: 
 
H0 : 
paCRT  =  pcontrol 
 
HA : 
paCRT  ≠  pcontrol 
The analysis will use a Chi-square test comparing the proportion Improved between randomized 
arms. The null-hypothesis will be rejected when the p-value is < 0.05. It will be concluded that 
aCRT is associated with a higher proportion Improved in case the null-hypothesis is rejected and 
the proportion Improved is higher in the aCRT ON arm. 

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A sensitivity analysis may be done using a logistic regression model with randomized arm, 
gender and NYHA class as fixed effects and site as random effect. Sites with a low number of 
enrollments will be grouped into clusters.  
12.3.3. 
Analysis Set 
All randomized patients will be included in the analysis. Patients will be analyzed in the arm that 
the patient was randomized to irrespective of the actual treatment that the patient received 
(intent-to-treat principle). 
The primary 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. 
12.4.  Sample Size rationale 
12.4.1. 
Historical Data 
The MIRACLE trial was a randomized trial in NYHA class III patients, comparing CRT vs control. 
CCS was Improved in 67% of the CRT patients and 39% of the control patients [1]. 
The REVERSE trial was a randomized trial in mostly NYHA class II patients, comparing CRT vs 
control. CCS at 6 months was Improved in 55% of the CRT patients and 42% of the control 
patients [28]. (Note that the primary analysis of REVERSE was at 12 months.) 
The Adaptive CRT trial was a randomized trial in NYHA class III patients comparing AdaptivCRT 
vs echo-optimized CRT. In the subgroup of patients with QRS ≤ 150ms, CCS was Improved in 
79% of the AdaptivCRT patients and 50% of the echo-optimized CRT patients, with Odds Ratio 
(OR) = 3.76.  
12.4.2. 
Sample Size Assumptions 
• 
The CRT arms from MIRACLE and REVERSE have CCS Improved in 67% and 55% of the 
patients. It is assumed that this represents the difference between NYHA classes II and III, 
and that the corresponding OR = 1.66 will be the same for both arms of the Mid-Q Response 
study. 
• 
Based on the Adaptive CRT trial results, it is conservatively assumed that CCS would be 
Improved for 59% of the NYHA III patients in the regular CRT control arm. Applying the OR = 

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1.66 for NYHA III vs II would give a CCS Improved rate of 46% for NYHA class II patients with 
regular CRT. 
• 
Similarly, the percentage improved for NYHA II patients in the AdaptivCRT arm would be 
69%, compared to 79% for the NYHA III patients. 
• 
The expected enrollment in the Mid-Q Response study is 55% NYHA class III and 45% NYHA 
class II, so that the overall CCS Improved rate will be 53% in the regular CRT arm and 75% in 
the AdaptivCRT arm. To add conservatism, for sample size calculation, the rate in the 
regular CRT arm is raised to 55%. 
• 
Assuming CCS is improved in 75% of patients in the AdaptivCRT arm and in 55% of patients 
in the regular CRT arm, a minimum of 220 patients must be randomized to achieve a power 
of 80% to demonstrate a significant difference in presence of 3% crossover in both arms. 
Pre-randomization attrition is expected to be at most 5%, so that approximately 232 
patients will be enrolled to fulfil the sample size requirements for the primary analysis. Up to 
3% post-randomization drop out is expected; however, subjects who drop out post 
randomization contribute to primary objective because, by definition, CCS is not impacted 
by missing data. 
12.5. Secondary Objectives 
12.5.1. 
Evaluate Change in NYHA Class 
NYHA class will be collected at baseline and at the 3, 6, and 12-month follow-up visits. The 
follow-up assessments will be analyzed with an ordinal proportional odds logistic regression 
model that will account for the correlation of subsequent assessments within each patient. The 
treatment arm allocation will be included as a main effect. The baseline NYHA class will also be 
included in the model as fixed effect. Analysis will be corrected for time trends if needed. 
12.5.2. 
Characterize Occurrence of HF Hospitalization 
Hospitalizations will be classified as heart failure-related by the investigators. The incidence of 
HF hospitalizations will be estimated with Cumulative Incidence Functions for both randomized 
arms separately, treating death as a competing risk. Incidence will be reported with a figure and 
with estimates with 95% confidence interval at 12 months post randomization. 
12.5.3. 
Characterize All-Cause and Cardiovascular Mortality 
All-cause mortality will be estimated by the Kaplan-Meier method for both randomized arms 
separately and reported with a figure and with estimates with 95% confidence interval at 12 
months post randomization. 
Death will be classified as cardiovascular or non-cardiovascular by the investigators. 
Cardiovascular mortality will be estimated with Cumulative Incidence Functions, treating non-
cardiovascular death as a competing risk. 

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12.5.4. 
Ancillary Objectives 
Analysis methods for ancillary objectives will be defined in the Statistical Analysis Plan. 
 
13. Ethics 
13.1. Statement(s) of Compliance  
The Mid-Q Response 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 Mid-Q Response clinical study is designed with good clinical practice (GCP) principles 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 process, 
EC/MEC/IRB/HREC (all henceforth referred to as an” Ethics Committee”) approval, study training, 
clinical trial registration, risk benefit assessment, and publication policy. 
In all participating countries, local laws and regulations (including Declaration of Helsinki 2013) will 
be followed. In Japan, the study will be conducted in compliance with Clinical Trials Act. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and 
Drug Administration Amendments Act (FDAA) and Declaration of Helsinki on 
http://clinicaltrials.gov.  
In addition, the study may be registered in local regulatory databases where required by local law, 
including but not limited to Japan Registry of Clinical Trials (jRCT) for Japan. 
Approval of the CIP is required from the following groups prior to any study procedures at a study 
center:  
• Medtronic 
• 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. 
Any additional requirements imposed by the EC/IRB or regulatory authority shall be followed. 
14. Study Administration 
14.1. 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. 
14.1.1. 
Monitoring visits 
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, and any suspected inconsistency in data that requires 
investigation. Monitoring for the study, including but not limited to interim monitoring visits, 
and closeout visits will be done in accordance to the study-specific monitoring plan. 
The Principal Investigator and site personnel will provide the Medtronic monitor(s) with 
complete access to primary source data (e.g., paper and electronic hospital/clinical charts, 
laboratory records etc.) that support the data on the eCRFs as well as other documentation 
supporting the conduct of the study. The monitor will perform source data verification and 
routine reviews of study related regulatory documents during scheduled monitoring visits, and 
work to secure compliance. Planned extent of source data verification will be performed 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 

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determine appropriate corrective action recommendations and to identify trends within the 
study or at a particular center. 
14.2. Data 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 investigator must ensure accuracy, completeness and timeliness of the data reported in the e-
CRFs. Only authorized persons can complete and sign e-CRFs, as specified on the Delegated Tasks 
List included in the Investigator Site File. 
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 Baseline ECGs, device interrogation files, worksheets, and lab results, must be created and 
maintained by the investigational site team.  
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. For Japan, audit related procedures and plans will be provided under separate cover. 
Study sites should inform Medtronic upon notification of an audit by a regulatory body immediately. 
14.3. Confidentiality 
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 (Cognizant Technology Solutions, ECG Core Laboratory) 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. 

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Confidentiality of data will be observed by all parties involved at all times throughout the clinical 
study. All data shall be secured against unauthorized access. The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any data. 
The Informed Consent Form and the process for conducting this study will be in compliance with 
any applicable local law. To maintain confidentiality, the subject’s name or any other identifying data 
should not be recorded on any study document other than the ICF. This scenario will be covered in 
the ICF. In the event a subject’s name or other identifying data is included for any reason, it will be 
blinded as applicable. In the event of inability to blind the identification (e.g. digital media), it will be 
handled in a confidential manner by the authorized personnel.  Data relating to the study might be 
made available to third parties (for example in case of an audit performed by regulatory authorities), 
provided the data are treated as confidential and that the subject’s privacy is guaranteed. No 
identifiable subject information will be published.  
14.4. Liability 
Warranty information is provided in the product packaging for the commercially released CRT-P or 
CRT-D devices and leads, and additional copies are available upon request. 
Insurance (Japan) 
Information regarding warranty and compensation will be provided under separate cover per the 
local regulation. 
 
Insurance (South 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 Committee. 
 
Insurance (China) 
Medtronic (Shanghai) Management 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 Committee. 
 
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 

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custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 
 
Insurance (Hong Kong) 
Medtronic Hong Kong Medical Ltd. is a wholly owned subsidiary of Medtronic Inc., which as the 
parent company of such entity maintains appropriate clinical trial liability insurance coverage as 
required under applicable laws and regulations and will comply with applicable local law and 
custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 
 
Insurance (Malaysia) 
Medtronic Malaysia Sdn Bhd. is a wholly owned subsidiary of Medtronic Inc., which as the parent 
company of such entity maintains appropriate clinical trial liability insurance coverage as 
required under applicable laws and regulations and will comply with applicable local law and 
custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 
 
Insurance (Indonesia) 
 PT Medtronic Indonesia 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 
 
Insurance (Singapore & Brunei) 
Medtronic International Ltd Singapore. is a wholly owned subsidiary of Medtronic Inc., which as 
the parent company of such entity maintains appropriate clinical trial liability insurance coverage 
as required under applicable laws and regulations and will comply with applicable local law and 
custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 
 
custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 
 
Insurance (Philippines) 
Medtronic Philippines Inc. is a wholly owned subsidiary of Medtronic, which as the parent 
company of such entity maintains appropriate clinical trial liability insurance coverage as 
required under applicable laws and regulations and will comply with applicable local law and 
custom concerning specific insurance coverage. If required, a Clinical Trial insurance 
statement/certificate will be provided to the Ethics Committee. 

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14.5. CIP Amendments 
Medtronic will submit any significant amendment to the CIP, including a justification for this 
amendment, to the appropriate regulatory authorities and to the investigators to obtain approval 
from their Ethics Board, if applicable. Administrative amendments to the Clinical Investigation Plan 
will be submitted to the Ethics Board and appropriate regulatory authorities for notification, if 
applicable. Any revisions or amendments to the CIP or ICF, along with a statement of justification 
for the changes, will be submitted to all affected Regulatory Authorities and governing Ethics 
Boards, according to applicable regulations. All amendments to the CIP shall be agreed between 
Medtronic and the principal investigator(s).  Approval by regulatory agencies and Ethics Board 
(where applicable) must be obtained prior to implementing a CIP revision at the site. 
In case the investigator will propose any appropriate modification(s) of the CIP or investigational 
software or investigational software use, Medtronic will review this proposal and decide whether 
the modification(s) will be implemented. 
14.6. Record Retention 
All study-related documents must be retained for a period of at least 2 years after study closure (or 
longer if required by local law/regulation hospital administration requirements). Medtronic will 
inform the investigator/site when these documents are no longer required to be retained. 
No study document or image will be destroyed without prior written agreement between Medtronic 
and the investigator. The investigator should take measures to prevent accidental or premature 
destruction of documents. Should the investigator wish to assign the study records to another 
party or move them to another location, advance written notice must be given to Medtronic. 
Medtronic will retain the study records according to Medtronic policy. 
14.7. Publication and Use of Information 
Results may be submitted for publication. If results from the Mid-Q Response study will be 
published, they will be handled according to Medtronic Standard Operating Procedures and as 
indicated in the Clinical Trial Agreement. 
Refer to the Mid-Q Response publication plan for additional details, including general statements 
regarding publication committee, publication management, authorship and transparency. 

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14.8. Suspension or Early Termination 
14.8.1. 
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 local Lead PI submits the summary of the Final Report which was 
reviewed by the authorized EC in advance, to the Minister of Health, Labor and Welfare for 
posting the study results in the local registry database (jRCT), the local Lead PI informs this to 
the other PIs in Japan, and subsequently each PI reports this to the HOMI and Medtronic thereof 
in writing. In all geographies, ongoing Ethics Committee oversight is required until the overall 
study closure process is complete. 
14.8.2. 
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. 
14.8.2.1. 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)  
• 
(Temporary) unavailability of the study devices 
• 
Medtronic may stop the study due to lack of enrollment, e.g. if the average enrollment 
rate is less than 0.15 subjects enrolled per active center per month over any 6 
consecutive months during the study. 
14.8.2.2. 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 

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• 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.  
• 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)  
14.8.3. 
Procedures for termination or suspension 
14.8.3.1. 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 local Lead PI, will 
promptly inform the applicable Ethics Committee.   
• 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 
14.8.3.2. Investigator-initiated 
• The investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension.  

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• The investigator (or in Japan the local Lead PI), will promptly inform the institution, or in 
Japan the HOMI (where required per regulatory requirements)  
• The investigator or the local Lead PI will promptly inform the Ethics Committee 
• The investigator or the local Lead PI will promptly inform the regulatory authorities 
(where required) 
• 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. 
14.8.3.3. Ethics committee-initiated 
• The investigator (or in Japan the local Lead PI) 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, or in Japan the HOMI (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. 
 
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 

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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 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 ICF 
• 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, where required per local law  
• Final Study Report including the statistical analysis  
• Any other records that local regulatory agencies require to be maintained 
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 the Adverse Events section 10. 
Table 10 Investigator reports applicable for all countries per Medtronic requirements 

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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. 
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, where required per local law  
• Names/contact addresses of monitors 
• Statistical analyses and underlying supporting data 
• Final report of the clinical study 
• The Clinical Investigation Plan, Informed Consent Form, 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  

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15.4. Sponsor reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in 
the tables below, as required by local laws and Ethics Committees. 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 the Adverse Event section. 
Table 11 Sponsor reports 
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. 
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 
N/A  
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.   
 
Electronic versions of the Medtronic records and 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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16. References 
 
[1]  "Abraham W.T., et al. Cardiac Resynchronization in Chronic Heart Failure. N Engl J Med 2002; 
346:1845-1853".  
[2]  "J.B. Young et al. 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 et al. '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 et al. '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 et al., and Investigators Evalutation 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.".  
[8]  "K.L. Lee et al., '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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[11] "B. Vidal et al. '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.".  
[12] "D.O. Martin et al., 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. 2012; 9: 1807-14.".  
[13] "Singh J.P., et al. 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".  
[14] "Yamasaki H, et al. Adaptive CRT in patients with normal AV conduction and left bundle branch 
block: Does QRS duration matter? Int J Cardiol. 2017; 240: 297-301".  
[15] "D. Birnie et al., 'Clinical Outcomes with Synchronized Left Ventricular Pacing: Analysis of the 
Adaptive CRT Trial', Heart Rhythm, 10 (2013), 1368-74.".  
[16] "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".  
[17] "D. O. Martin et al., 'Clinical Outcomes with Adaptive Cardiac Resynchronization Therapy: 
Final Results of the Adaptive CRT Trial', HFSA Late Breaking (2013).".  
[18] "D. Birnie et al., ‘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".  
[19] "G. Filippatos et al., ‘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".  
[20] "Epstein AE, et al. 2012 ACCF/AHA/HRS Focused Update Incorporated Into the 
ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm 
Abnormalities. JACC 2013; 61: e6-75.".  
[21] "Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic 
heart failure. European Heart Journal 2016; 37: 2129-2200".  

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[22] "Tan E, Xu CF, Liang F, et al. Association of ethnicity, age and body size with 
electrocardiographic values in the community. J Am Coll Cardiol 2014;63:A1636".  
[23] "Gijsberts CM, Benson L, Dahlstrom U, et al. Ethnic differences in the association of QRS 
duration with ejection fraction and outcome in heart failure. Heart 2016; 102: 1464-1471".  
[24] "JCS Joint Working Group. Guidelines for Diagnosis and Treatment of Acute and Chronic 
Heart Failure (JCS 2017/JHFS 2017): Issued March 23, 2018; 46 - 48.".  
[25] "Linde C, et al. The interaction of sex, height, and QRS duration on the effects of cardiac 
resynchronization therapy on morbidity and mortality: an individual-patient data meta-
analysis. Eur J of Heart Failure 2018: doi: 10.1002/ejhf.113".  
[26] "Oka T, et al. Effect of QRS Morphology and Duration on Clinical Outcomes After Cardiac 
Resynchronization Therapy, Analysis of Japanese Multicenter Registry. Circ J. 2018; doi: 
10.1253/circj.CJ-17-1383".  
[27] "F. Zannad et al., 'Clinical outcome endpoints in heart failure trials: a European Society of 
Cardiology Heart Failure Association consensus document', Eur, J Heart Fail. (2013) 15, 1082-
1094".  
[28] "Linde C, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart 
failure patients and in asymptomatic patients with left ventricular dysfunction and previous 
heart failure symptoms. J Am Coll Cardiol. 2008 Dec 2;52(23):1834-43".  
 
 
 
 

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17. Appendices  
APPENDIX A. FORESEEABLE ADVERSE EVENT LIST 
The information provided in this section pertains to foreseeable adverse events that may be 
observed in Mid-Q Response 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 
Implant site fibrosis 

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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).  
 

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Table 12 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.  
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. 
 
 

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Table 12 Observed  Adverse Events in Adaptive CRT clinical study 
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 
Complications1 
Events 
Complications 
Events 
Complications 
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%) 
Diarrhea 
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%) 
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%) 

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Events 
Complications1 
Events 
Complications 
Events 
Complications 
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%) 
1 An adverse event is considered a complication when it a) results in death, b) involves any termination of significant device function, or c) required an 
invasive intervention 
 
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 
        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 

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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 13. 
Table 13 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 
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 

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*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. 
Table 14 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) 
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) 

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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 ( %) 
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 B. CLINICAL INVESTIGATION PLAN SIGNATURE PAGE (IF APPLICABLE) 
Mid-Q Response Study 
The Mid-Q Response study is a prospective, randomized, controlled, interventional, single-blinded, 
multi-center, post-market, Cardiac Resynchronization Therapy (CRT) in heart failure (HF) clinical 
study performed in Asian countries. 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, 29-DEC-2020. 
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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18. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
28-MAR-2019 
• 
Not Applicable, New Document 
Loes 
Schoenmakers, 
Clinical Research 
Specialist 
 
Lidwien Vainer, 
Principal Clinical 
Research Specialist 
 
Mireille van 
Ginneken, Principal 
Clinical Research 
Specialist 
 
Bart Gerritse, 
Senior Principal 
Statistician 
2.0 
29-DEC-2020 
• 
CIP template transitioned from v A to v B; 
• 
Minor editorial updates; 
• 
Updated Lead Principal Investigator address; 
• 
Updated Table 1: Study sponsor contact 
information; 
• 
Removed “Cognizant Technology Solutions” as CRO 
from Table 2: CRO and Core Laboratory information; 
• 
Updated synopsis to reflect updates to the CIP; 
• 
Approximate number of centers increased from 55 
to 60 in section 3.3; 
• 
Section 4.3 updated to include an additional ancillary 
objective to characterize reverse remodeling 
measured via echocardiography; 
• 
Section 5.1 language updated to accurately capture 
enrollment start and to extend study duration as 
necessary due to the unforeseen impact of COVID-
19; 
 
Methee Schreuder,  
Clinical Research 
Specialist 
 
Lidwien Vainer,  
Clinical Research 
Manager 
 
Bart Gerritse,  
Sr. Principal 
Statistician 
 
Kazuhiro Hidaka,  
Sr. Clinical 
Research Specialist 

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• 
Section 6.6 updated to include CareLink 
SmartSync™ Device Manager as a Medtronic 
CareLink programmer; 
• 
Section 6.7 updated to include MyCareLink Relay™ 
Home Communicator and MyCareLink Heart™ 
mobile app as suitable Medtronic CareLink home 
monitors; 
• 
Section 7.3 updated to accept ECGs up to 50 days 
prior to enrollment; 
• 
Section 8.2 updated to clarify that a Google Chrome 
and/or Safari are also suitable for data entry; 
• 
Table 4 (Section 8.3) updated to include 
Echocardiography data collection; 
• 
Sections 8.6 and 8.7 updated to clarify that baseline 
data should reflect pre-implant data when a patient 
is enrolled post-implant; 
• 
Echocardiography data collection (only if standard of 
care) added to sections 8.6 (Baseline) and 8.9.1 (3, 6, 
and 12 month Follow-up visits); 
• 
Section 8.8.1 updated to clarify that deviations from 
programming recommendations are not considered 
study deviations; 
• 
Section 8.10 updated to include .pkg files as an 
acceptable device interrogation file; 
• 
Row added to Table 9: Adverse Event classification 
responsibilities to capture sponsor responsibilities 
for death classifications; 
• 
Section 13.1 updated to remove reference to ISO 
14155:2011; 
• 
Since a Mid-Q Response Publication Plan has been 
finalized, Appendix A was removed.