Registry to Improve the Adoption of Consensus Treatment Guideline (Brady MX)
Conditions: Sinus Node Disfunction
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

Signed By
Meaning of Signature
Date/Time (UTC)
APPROVALS
CONFIDENTIAL
  
DOCUMENT/RECORD 
 
 
This document/record is electronically controlled; printed copies are considered uncontrolled. 
System of Record: Regulatory Affairs Domain 
 
Document Name
Version
Title
Document Approver
Document Approver
1.0
Brady MX CIP V1
Document Approver
Sparks, Brandon
04/28/2016 18:13:25
Fagioli, Hugo
05/13/2016 12:51:50
Bergemann, Tracy
Hernandez, Maria [MMX]
04/28/2016 19:05:01
05/02/2016 16:39:48
Document Approver
Brady MX CIP V1

VERSION 1 
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Clinical Investigation Plan 
 
 
Medtronic Confidential 
 
 
 
 
 
 
 
 
 
 
Brady MX 
Clinical Investigation Plan 
Version 1 
31 MARCH 2016 
 
 
 
 
 
 
 
 
 

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Contents 
CONTACT INFORMATION ................................................................................................................ 4 
ADVISORY COMMITTEE ................................................................................................................... 4 
 
INTRODUCTION ....................................................................................................................... 4 
1.
 
Study Scope ..................................................................................................................... 4 
1.2.
 
BACKGROUND AND JUSTIFICATION ........................................................................................ 5 
2.
 
SYSTEM DESCRIPTION AND INTENDED USE ............................................................................ 6 
3.
 
Device Description ........................................................................................................... 6 
3.1.
 
METHODOLOGY ....................................................................................................................... 6 
4.
 
Study Objectives .............................................................................................................. 7 
4.1.
 
Subject Selection ............................................................................................................. 8 
4.2.
 
Study Design .................................................................................................................... 9 
4.3.
 
Minimization of Bias ...................................................................................................... 10 
4.4.
 
STUDY PROCEDURES ............................................................................................................. 11 
5.
 
Informed Consent/Patient Data Release Process ......................................................... 12 
5.1.
 
Data Collection .............................................................................................................. 13 
5.2.
 
Enrollment/Baseline Procedures ................................................................................... 13 
5.3.
 
Diagnostic Assessment Visit(s) ...................................................................................... 14 
5.4.
 
Implant Visit................................................................................................................... 14 
5.5.
 
Study Exit ....................................................................................................................... 14 
5.6.
 
Subject Follow-up after Withdrawal ............................................................................. 15 
5.7.
 
Medications ................................................................................................................... 15 
5.8.
 
STUDY DEVIATIONS ............................................................................................................... 15 
6.
 
ADVERSE EVENTS ................................................................................................................... 16 
7.
 
Vigilance Reporting ........................................................................................................ 16 
7.1.
 
SUBJECT DEATH ..................................................................................................................... 16 
8.
 
RISK ANALYSIS........................................................................................................................ 17 
9.
 
Potential Benefits .......................................................................................................... 17 
9.1.
 
PLANNED STUDY CLOSURE, EARLY TERMINATION ............................................................ 17 
10.

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Planned Study Closure ............................................................................................... 17 
10.1.
 
Early Termination OR Suspension ............................................................................. 17 
10.2.
 
STATISTICAL METHODS AND DATA ANALYSIS ................................................................... 19 
11.
 
Primary Objective(s) .................................................................................................. 19 
11.1.
 
Secondary Objective .................................................................................................. 21 
11.2.
 
Ancillary Objectives ................................................................................................... 22 
11.3.
 
DATA AND QUALITY MANAGEMENT ................................................................................. 24 
12.
 
WARRANTY/ INSURANCE INFORMATION ......................................................................... 25 
13.
 
Insurance (Latin America) .......................................................................................... 25 
13.2.
 
MONITORING .................................................................................................................... 25 
14.
 
Monitoring Visits ....................................................................................................... 25 
14.1.
 
Required Records and Reports .......................................................................................... 26 
15.
 
Sponsor Records ........................................................................................................ 27 
15.1.
Appendix A:  Patient Informed Consent and Patient Data Release .............................................. 28 
Appendix B:  Case Report Forms ................................................................................................... 29 
Appendix C:  Preliminary Publication Plan .................................................................................... 30 
Appendix D:  Participating Investigators and Institutions ............................................................. 32 
Appendix E:  IRB/MEC List ............................................................................................................. 33 
Appendix F:  Bibliography ............................................................................................................. 34 
  
FIGURES 
Figure 1: IMPROVE Brady Study Design ......................................................................................... 9 
 
TABLES 
Table 1: Data Collection and Study Procedure Requirements at Subject Visits .............. 13 
 
 
 
 
 
 

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Medtronic, plc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
Medtronic USA, Inc. 
9850 Doral Blvd – Suite 450 
Miami, FL 33178 USA 
Latin America HQ 
Medtronic Mexico 
Insurgentes 863, piso 16 
Ciudad de México, CP 03810 
 
 
CONTACT INFORMATION 
Medtronic contact information will be provided under separate cover.  
ADVISORY COMMITTEE  
Medtronic, Mexico will assemble an independent scientific advisory committee 
comprised of local health care professionals to consult on this initiative.   
 INTRODUCTION 
1.
 
 Study Purpose 
1.1.
Medtronic, is sponsoring a quality improvement study called Brady MX. 
It is hypothesized that lack of awareness of treatment and diagnostic pathways 
results in lower number of referrals to implanters of IPGs 
 
 
Education and process improvement initiatives can improve the diagnosis 
and increase appropriate therapy applications for SND 
 
The quality improvement methods to be studied will have general applicability 
which can be utilized beyond the Brady MX study.  
 Study Scope 
1.2.
The study may be conducted in up to10 sites under oversight by the “Secretaria de 
Salud” in Mexico. The study will be conducted in two phases, with Phase I serving as 
control subjects and Phase II measuring the impact of the intervention.  Up to 500 
subjects will be enrolled in the study with at least 210 enrolled per phase. An 
enrollment target of 45  subjects per center in total is desired to make center-specific 
outcomes more meaningful and reliable in measuring changes in diagnostic rates 
and patient acceptance of indicated therapy. Centers that enroll faster than others 
will be allowed to enroll up to 42 subjects within each phase of the study. 
 

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All study subjects will be followed until the study exit criteria are met or until official study 
closure.  Study closure is defined as closure of a clinical study that occurs when 
Medtronic and/or regulatory requirements have been satisfied per the Clinical 
Investigation Plan and/or by a decision by Medtronic or regulatory authority, whichever 
occurs first. The expected study duration from first enrollment to last follow-up, is 
approximately 26 months. 
 
 BACKGROUND AND JUSTIFICATION 
2.
 
The World Health Survey of Cardiac Pacing and Cardioverter-Defibrillators suggests that 
adoption of pacing therapy in emerging countries is lower than that of developed 
countries.  New device implants per million in emerging countries are 17, 31, 159 and 
287 for India, China, Russia and Argentina respectively compared to 702, 782, 744 and 
627 for the respective developed countries of Sweden, France, Italy and Belgium.  The 
population for these countries in millions is as follows: 1,200 in India, 1,300 in China, 142 
in Russia, and 40 in Argentina, 9 in Sweden, 62 in France, 60 in Italy and 10 in Belgium1.  
Mexico there are 25 Brady implants per million ( documented in Seguro Popular).  The 
size of the population in the emerging countries combined with data from the World 
Health Survey, suggests that there is an opportunity to improve adoption to consensus 
treatment guidelines in the emerging countries.  Adoption of the pacing indications for 
Sinus Node Dysfunction (SND) may not be optimal due to the chronic non-specific 
nature of the symptoms and the lack of conclusive randomized trials supporting the 
efficacy of pacemaker therapy in SND patients2,3,4.  Within the developed geographies, 
21-40% of subjects participating in clinical studies receiving pacing therapy had met the 
indication for sinus node dysfunction.  The wide range may demonstrate that SND can 
be a difficult indication to identify1, 5, 6, 7, 8, 9.  
                                                          
1 Mond HG and Proclemer A. The 11th World Survey of Cardiac Pacing and Implantable Cardiac Defibrilators: Calendar Year 2009 A 
World Society of Arrhythmia’s Project. Pacing Clin Electrophysiol 20011 Aug;34:1013-1027 
2 Mangrum JM. The Evaluation oand Management of Bradycardia. New England Journal of Medicine 2010 May;342(10):703-709 
3 Epstein et al.  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities. Heart Rhythm 
2008;5:e1-e62. 
4 Vardas PE. Guidelines for cardiac pacing and cardiac resynchronization therapy. European Heart Journal 2007 Sep;28(18):2256-95. 
5 Nowak et al. Do gender differences exist in pacemaker implantation?. Europace 2010 Feb;12(2):210-5) 
6 Levander-Lindgren et al. Bradyarrhythmia profile and associated disease in 1265 patients with cardiac pacing. Pacing Clin 
Electrophysiol 1988 Dec;11(12):2207-15 
7 Sutton et atl. Electrophysiological and haemodynamic basis for application of new pacemaker technology in sick sinus syndrome 
and AV block. Br Heart J 1979 May;41(5):600-12 
8 Coma et al. Spanish Pacemaker Registry. Fifth Official Report of the Spanish Society of Cardiology Working Group on Cardiac 
Pacing. Rev Esp Cardiol 2008 Dec;61(12):1315-28 
9 Hartel G. Treatment of sinoatrial syndrome with permanent cardiac pacing in 90 patients. Acta med Scand. 1975 Nov;198(5):341-7 

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A recent process improvement clinical study, IMPROVE HF, demonstrated that 
implementation of a defined and scalable practice-specific quality improvement process 
in the outpatient heart failure cardiology setting significantly improved the use of 
evidence-based therapies in eligible patients with systolic heart failure10. A baseline 
chart review was conducted at 167 sites, involving 34,810 patients. Physicians then 
attended an educational workshop, where they set treatment goals and developed a 
customized clinical care pathway for their practice. Sites were also provided with heart 
failure disease state management tools that were designed to help improve the quality of 
care administered to their heart failure patients. Participation did not require that any 
specific procedure or assessment be done11. After the intervention occurred, there was 
evidence of significant improvements in the adoption of guideline based care. Perhaps a 
similar clinical trial on SND developed for the emerging countries could improve the 
adoption of the American College of Cardiology (ACC)/American Heart Association 
(AHA)/Heart Rhythm Society (HRS) Guidelines for Device Based Therapy of Cardiac 
Rhythm Abnormalities2 and the European Society of Cardiology (ESC) Guidelines for 
cardiac pacing and cardiac resynchronization therapy3. 
 
The aim of Brady MX is to improve adoption of consensus treatment guidelines in  
Mexico for SND indicated patients as described in the ACC/AHA/HRS guidelines2 and 
ESC guidelines3. Implantable Pulse Generator (IPG) therapy has been integrated into 
the ACC/AHA/HRS guidelines and ESC guidelines without evidence from large 
randomized clinical trials (RCT). While the RCT is considered the gold standard for 
establishing that a therapy causes a clinical outcome effect, the scientific community is 
calling for clinical research beyond the RCT. A manuscript in Circulation in 200812 states 
that the external validity of RCTs must be supplemented by real world “effectiveness 
research”, including pragmatic studies, meta-analyses and observational trials.  
Guidelines and major publications help with awareness of what is possible when treating 
disease and an important component of adoption is the physician’s personal experience 
with the therapy. As such, the evidence in this study will provide personal experience, 
powerful information for the individual physician, and an aggregated analysis. 
 
 SYSTEM DESCRIPTION AND INTENDED USE 
3.
 
Device Description 
3.1.
Subjects meeting an ACC/AHA/HRS or ESC indication for pacing therapy may be 
implanted with any pacemaker from the Medtronic family of devices that are market 
released and any market released lead. There are no programming requirements for this 
study. All devices are used according to medical, technical and ethical standards without 
any change to the approved use of the device. 
 
 
 METHODOLOGY 
4.
The Brady MX study is a prospective, sequential, post market study with an educational 
phase and any market released pacemaker from the Medtronic family of devices may be 
used in this study. It is hypothesized that the use of a practice-specific process 
improvement intervention consisting of education, diagnostic algorithm(s) and 

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documentation tools that advocate and reinforce adherence to consensus treatment 
guidelines will improve the quality of care for patients with sinus node dysfunction (SND).  
The study will be conducted in two phases, with Phase I serving as control subjects and 
Phase II measuring the impact of the intervention. 
 
The study will be conducted in compliance with the Clinical Investigation Plan, Clinical 
Trial Agreement, approved labeling, latest version of the Declaration of Helsinki, and 
laws and regulations of the country in which the study is conducted, including data 
protection laws. 
 
Principles of the Declaration of Helsinki have been incorporated into this study by means 
of the patient informed consent/Patient Data Release process, IRB/MEC approval (if 
required); study training, clinical trial registration, risk benefit assessment, and 
publication policy, etc. 
 
The study may enroll up to 500 Mexican subjects. with at least 210 subjects enrolled per 
study phase. Once enrolled, Phase I subjects should be followed for approximately 6 
months and Phase II subjects should be followed for approximately 6 months. Brady MX 
is anticipated to be completed in mid-2018. 
Subject data will be collected at enrollment/baseline, diagnostic assessment visits and 
implant visit. Data will continue to be collected until one of the exit criteria has been met. 
Brady MX does not mandate specific requirements regarding any other procedures, 
subject visits to the clinic, clinical treatment of subjects or device programming. Clinical 
data will be collected using electronic case report forms. 
 
Centers will be eligible to enroll subjects in Brady MX upon Medtronic’s receipt of 
required center activation materials and written approval. 
 
 Study Objectives 
4.1.
 
Primary Objectives 
1. Evaluate the impact of the intervention on the diagnosis of SND  
2. Evaluate the impact of the intervention on SND subjects receiving a referral 
for an  indicated IPG device 
 
Secondary Objective 
The secondary objectives to be measured include: 
1. Evaluate the impact of the intervention on whether SND subjects undergo an 
IPG implant 
 
Ancillary Objectives 
1. Characterize the patient population that declines indicated IPG therapy  
2. Characterize the usage and impact of interventional tools (e.g., diagnostic 
algorithm(s), patient education tools) on the management of SND 
3. Evaluate device pacing mode of subjects receiving indicated IPG device 
before and after intervention  
4. Characterize the impact of the intervention on screening strategies and the 
impact on enrollment. 

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 Subject Selection 
4.2.
Subjects of both genders meeting all the inclusion criteria and none of the 
exclusion criteria are eligible for the study. 
Inclusion Criteria: 
Patient is at least 18 years of age 
Patient's heart rate meets at least one of the following: 
 
Patient has a sinus rate ≤50 OR a junctional escape rhythm no 
faster than 50 
 
Patient has a history of exercise intolerance 
Patient complains of general fatigue, shortness of breath, shortness of 
breath with exertion, syncope, light headed dizziness, palpitations, 
lethargy, dyspnea OR malaise within the last 30 days that are not related to 
other discovered causes (such as untreated hypothyroidism or anemia). 
Patient (or patient’s legally authorized representative) is willing and able to 
sign and date written Patient Consent Form/Patient Data Release Consent 
 
Exclusion Criteria: 
Patient has recent history of blood loss 
Patient has a medical history leading to suspicion of neurological disorder 
Patient has a history of Chronic Atrial Fibrillation 
Patient is enrolled or planning to participate in a concurrent drug and/or 
device study at any time during the course of this clinical study without 
documented pre-approval from the Medtronic study manager 
Patient is not expected to survive for 12 months 
Patient is anticipated to be unwilling or unable to comply with the clinical 
investigation plan 
 
Subjects will be screened to ensure they meet all of the inclusion and none of the 
exclusion criteria. Subjects are considered enrolled upon signing the Informed 
Consent Form/Patient Data Release. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Study Design 
4.3.
There are two phases for Brady MX 
 
Figure 1: IMPROVE Brady Study Design 
 
 
 
 
Phase I: This phase of the study serves as a control period. During Phase I 
physicians will assess and treat subjects per their site’s standard care practice. 
 
Enrollment for Phase I is anticipated to occur for approximately 6 months but will 
continue until a minimum of 210 subjects have been enrolled. For subjects 
enrolled during Phase I, collection of diagnostic assessment and implant data will 
be complete 6 months after the last enrollment. At that time, all Phase I subjects 
will be exited 
 
Phase II: 
The objective of the Brady MX study is to provide investigators with 
comprehensive resources that may be adapted by the Principal Investigator and 
his/her colleagues to create a practice specific process improvement intervention 
to improve the quality of care for patients. 

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At the completion of Phase I, the Principal Investigator and co-investigators will 
complete an educational workshop and be given access to the Brady MX toolkit. 
In addition, the Principal Investigator and his/her colleagues are encouraged to 
adapt tools from the Brady MX toolkit to create a practice specific process 
improvement intervention. 
 
Immediately following completion of the educational workshop, study 
investigators will receive written authorization from Medtronic that they are 
authorized to enroll subjects in Phase II. Enrollment during this phase is 
anticipated to occur for approximately 6 months but will continue until a minimum 
of 210 subjects have been enrolled.  
 
 
The Brady MX process improvement intervention toolkit may include an 
education workshop, diagnostic algorithm(s), patient video and tools for 
investigators to educate their patients on their disease state, available therapy 
options, and benefits and risks associated with the therapy options. 
 
For subjects enrolled during Phase II collection of diagnostic assessment data 
will be complete 6 months after last enrollment. At that time, any subjects without 
a diagnosis will be exited from the study. 
 
 Minimization of Bias 
4.4.
Potential sources of bias in this study may result from the Hawthorne effect, selection 
of study centers, selection of subjects, treatment of subjects, and evaluation of study 
data. The following methods have been incorporated into the study to minimize 
potential bias. 
 
 
Center selection criteria, documented under separate cover, will need to be 
met prior to participation in Brady MX. Study center characteristics will be 
collected at activation on possible differences that may affect the primary 
endpoints. Centers will be used as their own control 
 
Subjects will be screened to confirm eligibility with the help of screening logs, 
for enrollment with defined inclusion/exclusion criteria prior to enrollment 
 
Subject demographics will be collected at baseline on possible differences 
that may affect the primary endpoints 
 
It is anticipated that the distribution of subjects with various co-morbidities will 
vary by study centers. To minimize potential bias, all sites will be encouraged 
to enroll at least 5 subjects in each study Phase and enrollment at a site 
cannot exceed 42 subjects per phase to ensure a more even distribution of 
data 
 
All study Clinicians will be required to follow the Clinical Investigation Plan 
 
All study clinicians and Medtronic personnel will be trained on their respective 
aspects of the clinical investigation plan using standardized training materials. 
 
 
 
 

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 STUDY PROCEDURES 
5.
 
All local requirements will be fulfilled prior to center activation and enrollment of 
subjects into the study. Each study site must have written documentation of site and 
investigator readiness, including (but not limited to): 
 
Medical Ethics Committee (MEC), or Head of the Medical Institution written approval 
of the current version of the Clinical Investigation Plan and Patient Informed 
consent/Patient Data Release (what is applicable depending on the site) 
 
When MEC or Head of the Medical Institution written approval is submitted to 
Medtronic the following needs to be included: 
 
 The approval letter must contain enough information to identify the version/date of 
the documents approved or it must be retrievable from the submission letter. 
 
 Approval letter must be accompanied by a roster or written documentation that 
center staff participating in the study did not participate in the approval process 
 
Investigator Curriculum Vitae on file with the sponsor (signed and dated as required 
per geography/country) 
 
Signed/dated Clinical Trial Agreement on file with the sponsor 
 
Signed/dated documentation of training of required personnel 
 
All clinical investigators managing the subjects must be qualified practitioners that 
will be involved in the diagnosis and/or treatment of subjects with SND. All implanting 
physicians must be experienced in the handling of market released pacemakers. All 
participating Clinicians will complete study training regarding the Informed Consent 
Process (if applicable), case report forms and Clinical Investigation Plan. 
 
Medtronic will inform the investigator in writing when all requirements have been 
fulfilled for center activation. 
 
The following study equipment may be useful to have available at each center to support 
study activities. 
: 
 
 
Electrocardiography machine 
Echocardiography machine 
Holter monitor, Event Monitor or Insertable Cardiac Monitor  
Ergometer or treadmill. 
 
 
 

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 Informed Consent/Patient Data Release Process 
5.1.
 
Patient Informed Consent(PIC)/Patient Data Release (PDR) is defined as legally 
effective, documented confirmation of a subject’s (or their legally authorized 
representative or guardian) voluntary agreement to participate in a particular clinical 
investigation 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. 
A PDR can only be used when ethics committee approval of the study is not needed 
or when local laws allow. 
 
Prior to enrolling patients, each investigational center’s Medical Ethics Committee 
(MEC), or Head of the Medical Institution must approve the Clinical Investigation 
Plan 
(CIP) and Patient Informed Consent/Patient Data Release (PIC/PDR). Any changes 
to the PIC/PDR consent must be approved by Medtronic and the MEC or Head of the 
Medical Institution reviewing the application before being used to consent a 
prospective study subject. The document(s) should be controlled (i.e. versioned 
and/or dated) to ensure it is clear which version(s) were approved by the MEC/IRB or 
Head of the Medical Institution. 
 
Prior to initiation of any study-specific procedures, subjects (or their legally 
authorized representative or guardian) must sign and date the data protection 
authorization and/or other privacy language where required by law and the MEC or 
Head of Medical Institution and Medtronic approved Patient Informed 
Consent/Patient Data Release. A copy of the PIC/PDR form or a signed copy where 
required by law, will be given to all subjects (or their legally authorized representative 
or guardian) in a language he/she is able to read and understand. 
 
The process of obtaining patient informed consent shall: 
 
Avoid coercion and undue influence of subjects to participate 
Answer all questions to the subject’s satisfaction 
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 consider participation 
Include a dated signature of the subject acknowledging that their participation in  
      the study is voluntary 
 
Include a dated signature by the clinical investigator or authorized designee  
 
If the PIC/PDR is obtained the same day the subject begins participating in study 
related procedures, it should be documented in the subject’s case history that 
consent was obtained prior to participation in any study-related procedures. In the 
event the subject cannot read and/or write, witnessed (impartial third party) informed 
consent will be allowed, provided detailed documentation of the process is recorded 
in the subject’s case history, the witness was present during the entire discussion 
and the witness signs and dates the PIC/PDR to attest that the information was 
accurately explained, and clearly understood by the patient and that consent was 
freely given. The original or a copy of the signed PIC/PDR must be filed in the 
hospital/clinical chart or with the subject’s study documents. A copy of the signed 

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PIC/PDR and data protection authorization/or other privacy language where required 
by law must be provided to the subject. 
The PIC/PDR consent form and data protection authorization and/or other privacy 
language where required by law must be available for monitoring and auditing. Any 
Medtronic Field personnel who supports the study must be able to review the 
subject’s signed and dated consent form and verify it’s completeness prior to 
proceeding with study related activities. In the event the Medtronic Field personnel 
identify a consent as being incomplete, the study activities will not be allowed to 
occur until the consent of the subject can be adequately and appropriately obtained. 
 
 Data Collection 
5.2.
Table 1 depicts the data collection requirements for the study. 
 
Table 1: Data Collection and Study Procedure Requirements at Subject Visits 
 
Study procedure 
Enrollment Baseline 
Diagnostic 
Assessment 
Implant 
Informed Consent/ 
Medical release 
X 
 
 
Inclusion / Exclusion X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Symptoms 
X 
 
 
Vitals (HR, BP) 
X 
 
 
Cardiovascular 
Medications 
X 
X 
X 
Diagnostic tests/ 
results 
X if applicable 
X 
 
Final Diagnosis 
 
X 
 
Device Indication 
 
X 
 
System information 
 
 
X 
Pt Education tool 
used (Phase II only) 
 
X 
 
Treatment decision 
 
X 
 
Death  
As they occur 
Reason for exit 
 
 
 Enrollment/Baseline Procedures 
5.3.
The investigator or designated study coordinator will evaluate patients for inclusion 
and exclusion criteria. Patients who meet these criteria may be invited to participate 
in the study. Each study subject or legal representative must sign an informed 
consent/Patient Data Release prior to any study procedures taking place. 
 

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Enrollment is anticipated to occur prior to a final diagnosis of the patient being 
known, however, the patient may be enrolled at any time after the Brady MX 
inclusion/exclusion criteria are met. 
 
When a subject signs and dates the patient consent form/Patient Data Release, 
he/she is considered a subject enrolled in the study. The date the subject signed the 
consent form must be reported in the CRF. The Baseline assessment will be utilized 
to collect subject demographic data, cardiovascular medical history, symptoms, vital 
signs and cardiovascular medication use. 
 
 Diagnostic Assessment Visit(s) 
5.4.
 
A diagnostic assessment is any post enrollment visit to the study center for continued 
diagnostic assessment or management. During these visits information about 
utilization of diagnostic tests, results and cardiovascular medication use will be 
collected. Information about the final diagnosis and treatment decision will also be 
collected during the diagnostic assessment visit. The diagnostic assessment visit 
data will be complete: 
 
 
When the subject meets study exit criteria 
 
6 months after the last Phase I enrollment for Phase I subjects 
 
6 months after the last Phase II enrollment for Phase II subjects 
 
Patient education tools have been reviewed with the patient by the investigator 
(Phase II only) 
 
The study protocol does not dictate when the Diagnostic Assessment(s) is/are to 
occur. 
 
 Implant Visit 
5.5.
The implant visit is when the IPG is implanted in the study subject and will only occur 
for those subjects meeting the ACC/AHA/HRS and ESC pacing indications for sinus 
node dysfunction. 
The implant will be performed according to the hospital’s standard implant practice. 
Brady MX does not have device programming requirements. Information about the 
device and lead configuration, as well as serial number will only be collected for 
Medtronic and Vitatron devices.  
 
 Study Exit 
5.6.
Subjects may be exited from the study for any of the following situations, including 
but not limited to: 
 
Subject does not meet an indication for pacing therapy 
Subject meets an indication for pacing but not a SND indication for pacing 
therapy 

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Subject has met a SND indication for pacing therapy but will not be receiving 
pacing  therapy 
Subject diagnosis meets an SND indication for IPG Therapy and a non-
Medtronic/Vitatron device was implanted. 
Completion of study follow-up with no diagnosis made 
Study Closure 
 
Subject lost to follow-up, patient doesn’t come back after baseline for diagnosis 
test decision 
Subject death 
Subject did not meet inclusion/exclusion criteria 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another 
geographic location) 
Investigator deems withdrawal necessary (e.g., medically justified, failure of 
subject to maintain adequate study compliance) 
 
 
 Subject Follow-up after Withdrawal 
5.7.
Upon withdrawal from the study, no further study data will be collected or study visits 
will occur for the subject. 
 
 Medications 
5.8.
There are no medications that are required for this study. All cardiovascular 
medications will be collected.  
 
 STUDY DEVIATIONS 
6.
A study deviation is defined as an event within a study that did not occur according to 
the Clinical Investigation Plan or the Clinical Trial Agreement. 
 
Prior approval by the Medtronic study manager 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 life or physical 
wellbeing 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, etc.). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-
required procedure, it may be permitted to complete only one deviation Case Report 
Form which will apply to all visits going forward. This may also apply for other 
unforeseen situations (e.g. the subject permanently refuses to complete a study required 
procedure and the data will not contribute to the primary end point analysis, etc.). 
However, prior approval from Medtronic is required for such situations. 
 
All study deviations must be reported on the Case Report Form regardless of whether 
medically justifiable, pre-approved by Medtronic, an inadvertent occurrence, or taken to 
protect the subject in an emergency. The deviation must be recorded with an 
explanation for the deviation and corrective/ preventative action(s). 

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In the event the deviation involves a failure to obtain a subject’s consent, or is made to 
protect the life or physical wellbeing of a subject in an emergency, the deviation must be 
reported to the MEC/IRB (where applicable) as well as Medtronic within five (5) working 
days. Reporting of all other study deviations should comply with MEC/IRB policies 
and/or local laws and must be reported to Medtronic as soon as possible upon the 
center becoming aware of the deviation. Reporting of deviations must comply with IRB/ 
MEC policies, local laws, and or regulatory agency requirements.  
 
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 investigation, etc.). 
Repetitive or serious investigator compliance issues may represent a need to initiate a 
corrective action plan with the investigator and site, and in some cases, necessitate 
freezing 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. 
 
 ADVERSE EVENTS 
7.
The collection of adverse event data is not required to meet the objective(s) of this 
clinical trial. The products used in the clinical trial are market approved and used 
within the current indications for use as indicated in the product labeling. 
However, it is the responsibility of the Investigator to abide by any adverse event 
reporting requirements stipulated by local laws and regulations and the site’s 
Investigational Review Board (IRB) or Medical Ethics Committee (MEC). 
User (Investigator) reporting of events to regulatory authorities related to market 
approved products may be required. 
 
 
 Vigilance Reporting 
7.1.
It is the responsibility of the investigator to report all product complaints and 
malfunctions immediately via the regular channels for CE marked products. The 
reporting of product complaints and malfunctions of these CE-labeled devices is not 
part of the clinical study and should be done by the investigator. 
 
 SUBJECT DEATH 
8.
 Data Collection 
8.1.
Subject deaths will be documented on the Study Exit form. The date of death and 
classification of cardiovascular relatedness, if known, will also be documented. It is 
the responsibility of the Investigator to abide by any death reporting requirements 
stipulated by local laws and regulations and the site’s Medical Ethics Committee 
(MEC). 
 
User (Investigator) reporting of deaths to regulatory authorities related to market 
approved products may be required. 
 

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 RISK ANALYSIS 
9.
All implantable systems (pacemaker and lead(s)) utilized in this study are market 
released and are used according to medical, technical and ethical standards without 
any change to the approved use of the system. The safety and clinical performance 
of the market released systems have been demonstrated through previous pre-
clinical testing and clinical studies in similar populations, but not necessarily the 
same population as this study. The risks are described in the informed consent. 
 
 Potential Benefits 
9.1.
There are no direct benefits to the patient for participating in IMPROVE Brady. 
However, information gained from the study will contribute to the body of knowledge 
regarding diagnosis and treatment of patients with SND and may help improve the 
quality of care for these patients. 
 
 PLANNED STUDY CLOSURE, EARLY TERMINATION 
10.
OF STUDY OR STUDY SUSPENSION 
 
Planned Study Closure 
10.1.
Study Closure is a process initiated by distribution of an initial study closure letter. 
Study closure is defined as closure of a clinical study that occurs when Medtronic 
and/or regulatory requirements have been satisfied per the Clinical Investigation Plan 
and/or by a decision by Medtronic or regulatory authority, whichever occurs first. The 
study closure process is complete upon distribution of the Final Report or after final 
payments, whichever occurs last. IRB/MEC re-approvals are required until the 
overall study closure process is complete. 
 
 
Early Termination OR Suspension 
10.2.
Early Termination of the Study is the closure of a clinical study that occurs prior to 
meeting defined endpoints. This is possible for the whole study, or a single center. 
Study Suspension is a temporary postponement of study activities related to 
enrollment. This is possible for the whole study or a single center. 
 
 
Criteria 
Study Termination or Suspension 
Possible reasons for considering study suspension or early termination of the study 
may include: 
None of the study subjects have been implanted with an indicated IPG at the 
completion of Phase I 
Enrollment is slower than anticipated 
 
Investigator/Center Termination or Suspension 
Possible reasons for clinical investigator or center termination or suspension include 
but are not limited to: 

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 
Failure to obtain initial MEC/Head of Medical Institution approval or annual 
renewal of the study (where applicable) 
 
Consistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups, 
etc.) 
 
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.) 
 
MEC 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) 
 
Procedures 
If Medtronic terminates or prematurely suspends the study: 
Medtronic will promptly inform the clinical investigators of the termination or 
suspension and the reasons and inform the regulatory authority (ies) (where required 
per regulatory requirements). In the case of study termination or suspension for 
reasons other than a temporary MEC approval lapse, the investigator will promptly 
inform the MEC. 
 
In the case of study termination, the investigator must inform the subjects and 
may inform the personal physician of the subjects to ensure appropriate care and 
follow-up is provided. 
 
In the case of a study suspension, subjects already enrolled should continue to 
be followed out of consideration of their safety, rights and welfare. 
 
If the investigator terminates or suspends the study without prior agreement of 
Medtronic: 
 
The investigator will promptly inform Medtronic and provide a detailed written 
explanation of the termination or suspension. 
 
The investigator will promptly inform the institution (where required per regulatory 
requirements). 
 
The investigator will promptly inform the MEC (where applicable). 
 
 
If the MEC terminates or suspends its approval of the study: 
 
The investigator will promptly inform Medtronic and provide a detailed written  
explanation of the termination or suspension within 5 business days. 
 
Subject enrollment must stop until the MEC suspension is lifted. 
 
Subjects already enrolled should continue to be followed in accordance with 
IRB/MEC policy or its determination that an overriding safety concern or ethical 
issue is involved. 
 
The investigator will inform his/her institution (where required per local 
requirements). 
 
The investigator will promptly inform the subjects and/or the personal physician 
of the subjects, with the rationale for the study termination or suspension. 
 
 

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 STATISTICAL METHODS AND DATA ANALYSIS 
11.
Medtronic statisticians or designees will conduct all statistical analysis. The sample 
size package PASS 2008 was used for sample size evaluation. In this study, it is 
hypothesized that the use of a practice-specific process improvement intervention 
consisting of education, diagnostic algorithm(s) and documentation tools that 
advocate and reinforce adherence to consensus treatment guidelines will improve 
the quality of care for patients with sinus node dysfunction (SND). The two primary 
endpoints are the impact of the intervention on the diagnosis of subjects with SND 
and whether SND indicated subjects receive a referral for an IPG therapy. In current 
practice, both of these proportions are unknown but have been estimated for a set of 
patients meeting the study inclusion criteria. The sample size calculations will use 
exact confidence intervals and tests to compare rates and binomial proportions.  
 
 
Primary Objective(s) 
11.1.
Primary Objective #1 
Evaluate the impact of the intervention on the diagnosis of SND. 
 
Hypothesis 
The primary objective will be tested with the following hypothesis: 
H0:   p1t = p2t  
HA:   p1t ≠ p2t 
where p1t is the proportion of patients with SND in Phase I and p2t is the proportion of 
patients with SND in Phase II at time point t.   
 
Endpoint Definition 
The absolute change in the proportion of subjects diagnosed with SND at pre-
specified time points (%=number diagnosed/number enrolled x 100 at time point t  = 
6, or t is a multiple of 6 representing any additional 6-month interval for which there is 
sufficient follow-up information) and the absolute change in the number of subjects 
diagnosed with SND per person-year. 
 
Analysis Methods 
A. Statistical Methodology 
To compare the proportion of subjects with an SND diagnosis pre-intervention 
(Phase I) to the proportion post-intervention (Phase II), a binomial exact test will 
determine statistical significance. The proportion of subjects diagnosed will be 
evaluated at multiple time points because the time to diagnosis is expected to vary 
by hospital. Thus, times are pre-specified starting at 6 months and any additional 6-
month interval thereafter for which there is sufficient follow-up data available to 
compare study phases. Proportions calculated at all available time points will be 
reported. Additionally a Poisson regression will compare the average number of 
subjects with an SND diagnosis in Phase I and Phase II where the subject time in 
study is treated as an offset in the model. The above described tests will be 
performed separately within site as well as overall. 
 

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B. Determination of Patients/Data for Analysis 
All subjects that are enrolled in the study and that meet study inclusion/exclusion 
criteria will be included in the determination of the proportion estimates. The 
proportion estimates will be calculated based on information from fixed time points at 
6 months of follow-up, and any additional 6-month interval thereafter for which there 
is sufficient follow-up data available to compare study phases. The number of 
subjects that obtain a SND diagnosis by pre-specified time point t is included in the 
numerator and the number of subjects enrolled is included in the denominator. 
 
 
Sample Size Methods and Assumptions 
The proportion of SND diagnoses in subjects with bradycardia is currently unknown. 
The power calculations conservatively assume that the SND diagnosis will be 10% at 
six months of follow-up, or equivalently an SND incidence of 0.2 diagnoses per 
person-year. If 200 subjects are collected each in Phase I and in Phase II, assuming 
a type I error of 0.05 and power of 0.80, a binomial exact test will detect an increase 
in SND diagnosis of at least 10%. For example, the study will find a statistically 
significant difference between a Phase I SND percentage of 10% at 6 months and a 
Phase II SND percentage of 20% at 6 months. If the proportion of SND diagnoses is 
smaller than 10%, there will be more power to detect significant differences in the 
diagnosis proportion. It is expected that the study attrition rate may be 5% of the 
study population. To account for attrition, the sample size for Phase I will be a 
minimum of 210 subjects and for Phase II will be a minimum of 210 subjects. 
 
Primary Objective #2 
Evaluate the impact of the intervention on SND subjects receiving a referral for an 
indicated IPG device. 
 
Hypothesis 
The primary objective will be tested with the following hypothesis: 
H0:   p1t = p2t  
HA:   p1t ≠ p2t 
where p1t is the proportion of patients referred for an IPG in Phase I and p2t is the 
proportion of patients in Phase II at time point t.   
 
Endpoint Definition 
The absolute change in the proportion of subjects receiving therapy referral for an 
indicated IPG at pre-specified time points (% = number receiving IPG/number with 
SND diagnosis x 100 at time point t where t = 3, 6, and any additional 3-month 
interval for which there is sufficient follow-up information) and the absolute change in 
the number of subjects implanted per person-year. 
 
 
 
 
 

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Analysis Methods 
Statistical Methodology 
To compare the proportion of SND subjects that receive a referral for indicated 
therapy pre-intervention (Phase I) to the proportion post-intervention (Phase II), a 
binomial exact 
test will determine statistical significance. The proportion of subjects diagnosed will 
be evaluated at multiple time points because the time from diagnosis to implant is 
expected to vary by hospital. Shorter time intervals will be used to evaluate the 
proportion of referrals than for the proportion of diagnosis because implants typically 
occur more quickly than the SND diagnosis. Thus, times are pre specified starting at 
3 months and any additional 3-month interval thereafter for which there is sufficient 
follow-up data available to compare study phases. Proportions calculated at all 
available time points will be reported. Additionally, a Poisson regression will compare 
the average number of subjects with an implant where the subject time in study 
beginning at the time of SND diagnosis is treated as an offset in the model.  
 
Determination of Patients/Data for Analysis 
The number of subjects that meet inclusion criteria and obtain an SND diagnosis 
shall be included in this analysis. The proportion estimates will be calculated based 
on information from fixed time points at 3 months of follow-up, 6 months of follow-up, 
and any additional 3-month interval thereafter for which there is sufficient follow-up 
data available to compare study phases. The number of subjects that obtain an IPG 
referral by pre-specified time point t = 3, 6, etc., will be included in the numerator and 
the number of subjects with an SND diagnosis will be included in the denominator. 
 
 
 
Secondary Objective 
11.2.
Secondary Objective #1 
Evaluate the impact of the intervention on whether SND subjects undergo an IPG 
implant  
 
Hypothesis 
The secondary objective will be tested with the following hypothesis: 
H0:   p1t = p2t  
HA:   p1t ≠ p2t 
where p1t is the proportion of patients with an IPG in Phase I and p2t is the proportion 
of patients with an IPG in Phase II at time point t.   
 
Endpoint Definition 
The absolute change in the proportion of SND subjects receiving indicated therapy at 
pre-specified time points (% = number receiving IPG/number with SND diagnosis x 
100 at time point t where t = 3, 6, and any additional 3-month interval for which there 
is sufficient follow-up information) and the absolute change in the number of subjects 
implanted per person-year.  

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Analysis Methods 
A.  Statistical Methodology  
To compare the proportion of SND subjects that receive indicated therapy pre-
intervention (Phase I) to the proportion post-intervention (Phase II), a binomial exact 
test will determine statistical significance.  The proportion of subjects diagnosed will 
be evaluated at multiple time points because the time from diagnosis to implant is 
expected to vary by site.  Shorter time intervals will be used to evaluate the 
proportion of implants than for the proportion of diagnosis because implants typically 
occur more quickly than the SND diagnosis.  Thus, times are pre-specified starting at 
3 months and any additional 3-month interval thereafter for which there is sufficient 
follow-up data available to compare study phases.  Proportions calculated at all 
available time points will be reported.  Additionally, a Poisson regression will 
compare the average number of subjects with an implant where the subject time in 
study beginning at the time of SND diagnosis is treated as an offset in the model.  
The above described tests will be performed separately within geography/country as 
well as overall.  Further, similar tests will compare the differences in the types of 
therapy received in Phase I and Phase II.  For example, a binomial exact test will 
compare the frequency of dual chamber device use pre- and post-intervention.   
B.  Determination of Patients/Data for Analysis 
The number of subjects that meet inclusion criteria and obtain an SND diagnosis 
shall be included in this analysis. The proportion estimates will be calculated based 
on information from fixed time points at 3 months of follow-up, 6 months of follow-up, 
and any additional 3-month interval thereafter for which there is sufficient follow-up 
data available to compare study phases. The number of subjects that obtain an IPG 
by pre-specified time point t = 3, 6, etc., will be included in the numerator and the 
number of subjects with an SND diagnosis will be included in the denominator. 
 
Ancillary Objectives 
11.3.
 
Ancillary Objective #1 
Characterize the patient population that declines indicated IPG therapy. 
Endpoint Definition 
Decision to receive/decline therapy & why or why not 
 
 Analysis Methods 
A. Statistical Methodology 
Descriptive statistics will be used to describe the number of subjects that receive or 
decline an indicated therapy split by the reasons subjects provide for their decision. 
 
 
 

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B. Determination of Patients/Data for Analysis 
Subjects in either study phase who receive a diagnosis of SND will be characterized. 
The subjects will be asked for their reasons to either receive or decline indicated 
therapy. 
 
Ancillary Objective #2 
Characterize the usage and impact of interventional tools (e.g., diagnostic 
algorithm(s), patient education tools) on the management of SND. 
 
Endpoint Definition 
Use of diagnostic tools; use of patient education materials, use of diagnostic 
algorithm(s), use of other tools 
 
Analysis Methods 
A. Statistical Methodology 
Descriptive statistics will be used to describe the frequency of usage of interventional 
tools that assist in the diagnosis and management of SND. 
B.  Determination of Patients/Data for Analysis 
Subjects in Phase II will be characterized. For each subject, the education tools 
provided to the subject and the interventional tools used by the patient’s physicians 
that are applicable will be recorded. 
 
Ancillary Objective #3 
Evaluate device pacing mode of subjects receiving indicated IPG device before and 
after intervention 
 
Endpoint Definition 
Change in pacing mode set at time of implant  
Analysis Methods 
Statistical Methodology 
Descriptive statistics will be used to describe the pacing mode implemented by 
implanting physicians.   
Determination of Patients/Data for Analysis 
Subjects in either study phase who receive indicated therapy for SND will be 
characterized.  The device pacing mode set by the implanting physician will be 
recorded on the Implant CRF at the time of implant. 
 
 
 
 
 
 

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Ancillary Objective #4 
Characterize the impact of the intervention on screening strategies and the impact on 
enrollment. 
 
 
Endpoint Definition 
 
Change in the proportion of subjects enrolled out of those screened  by site 
 
Analysis Methods 
 
A. Statistical Methodology 
 
Descriptive statistics will be used to describe the proportion of subjects enrolled out 
of those screened per site. 
 
B. Determination of Patients/Data for Analysis 
 
All subjects screened and enrolled in each study phase. 
 
 
 DATA AND QUALITY MANAGEMENT 
12.
Data will be collected using an electronic data management system for clinical trials. 
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 indefinitely by 
Medtronic. 
Procedures in the CIP require source documentation. In some cases, items on the 
CRFs may be considered source as long as there is evidence of the visit in the 
subject’s record. Even when the CRF may be considered as source, an alternate 
method of source documentation is always strongly encouraged. 
Save-to-disk data collected prior to discharge from the hospital will be sent to 
Medtronic, if available. Upon receipt, device data will be maintained with databases 
and retrieved for analysis and reporting. 
The sponsor or a regulatory authority may audit the study center to evaluate the 
conduct of the study. The Clinical Investigator must immediately notify Medtronic 
when it learns that a regulatory authority will be auditing the site. The clinical 
investigator(s)/institution(s) shall allow trial related monitoring, audits, Ethics Board 
review, and regulatory inspection(s) by providing direct access to source 
data/documents. 
 
 
 
 
 

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 WARRANTY/ INSURANCE INFORMATION 
13.
 
Warranty 
13.1.
Warranty information is provided in the product packaging for the commercially 
released system and additional copies are available upon request. 
 
 
Insurance (Latin America) 
13.2.
Medtronic Latin America., 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/Institutional Review Board. 
 
 
 MONITORING 
14.
It is the responsibility of Medtronic to ensure proper monitoring of the study per 
regulations. Appropriately trained Medtronic personnel or delegates appointed by 
Medtronic will 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 (CTA), 
and applicable regulatory requirements. Medtronic must therefore be allowed access 
to the subjects’ clinic and hospital records when so requested as per the Subject 
Informed Consent/Patient Data Release Consent, and CTA. 
 
 
Monitoring Visits 
14.1.
Frequency of monitoring visits will occur based on subject enrollment, duration of the 
study, study compliance, findings from previous monitoring visits and any suspected 
inconsistency in data that requires investigation. Regulatory documents (e.g., 
IRB/MEC approval letters and CTAs, etc.) will be reviewed at a representative 
number of study centers. The number of centers and amount of subject data 
monitored against source documentation is determined by type of study and timing of 
data cutoff for study deadlines. 
Monitoring visits will be conducted periodically to assess site study progress, the 
investigator’s adherence to the CIP, regulatory compliance including but not limited 
to IRB/MEC approval and review of the study, maintenance of records and reports, 
and review of source documents against subject CRFs. Monitors facilitate 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. Communication with the site 
personnel occurs during the visit and following the visit via a written follow-up letter. 
Monitors may work with study personnel to determine appropriate corrective action 
recommendations and to identify trends within the study or at a particular center. 
 

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 Required Records and Reports  
15.
The investigator is responsible for the preparation and retention of the records cited 
below. It is recommended that measures be taken to prevent accidental or early 
destruction of study related materials. 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 may be maintained and signed electronically within the electronic data capture 
system during the trial. The following records are subject to inspection and must be 
retained for a period of two years (or longer as local law or hospital administration 
requires) after the date on which the investigation is terminated. 
 All correspondence between the IRB/MEC, sponsor, monitor, 
 Subject’s case history records, including: 
o Signed and dated informed consent form/patient data release 
o Medical history 
o Baseline, diagnostic assessment(s), implant data, and scheduled follow-
up 
o Documentation of the dates and rationale for any deviation from the 
protocol 
 Signed and dated CRFs. 
 All approved versions of the Clinical Investigation Plan, Patient Informed 
 Consents/Patient Data Releases 
 Lists of sites, investigators and IRB/MECs 
 Signed and dated Clinical Trial Agreement 
 Investigators current curriculum vitae (signed and dated, if required). 
 Delegated task list. 
 IRB/MEC approval documentation or a written waiver. Written information that 
the investigator or other study staff, when member of the IRB/MEC did not 
participate in the approval process (where applicable); IRB/MEC 
 Roster of MEC members (when applicable). 
 Study training records for site staff. 
 Regulatory Authority Approval (if applicable) 
 Insurance certificates (where applicable). 
 Any other records that local regulatory agencies require to be maintained. 
 Final Study Report including the statistical analysis. 
 
 
 
 
 
 

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Sponsor Records 
15.1.
Medtronic shall maintain the following accurate, complete, and current records: 
 All essential correspondence which pertains to the investigation 
 Signed Investigator Trial Agreements, and current investigator curriculum 
vitae (signed and dated, if required) , and delegated task list 
 All signed and dated case report forms submitted by investigator, 
      samples of informed consents, and other information provided to the 
subjects 
 Copies of all IRB/MEC approval letters, IRB/MEC rosters and relevant 
 IRB/MEC correspondence 
 Names of the institutions, investigators and IRB/MEC’s in which the 
clinical investigation will be conducted 
 Correspondence with authorities as required by national legislation 
 Insurance certificates, if applicable 
 Names/contact addresses of monitors 
 Statistical analyses and underlying supporting data 
 Final report of the clinical investigation 
 All approved versions of the Clinical Investigation Plan, PIC/PDR and 
study related reports 
 Study training records for site personnel and Medtronic personnel 
involved in the study 
 Any other records that local regulatory agencies require to be maintained. 
 
 
 
 
 
 
 
 
 
 
 

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Appendix A:  Patient Informed Consent and Patient Data 
Release 
 
At the time of Brady MX Clinical Investigation Plan Version 1 completion, the Patient 
Informed Consent and Patient Data Release form, that comply with local laws and 
regulations of Mexico were still being developed.  A Patient Informed Consent and 
Patient Data Release Form will be distributed under separate cover.  

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Appendix B:  Case Report Forms 
 
At the time of Brady MX Clinical Investigation Plan Version 1 completion, case report 
forms were still being developed.  Case Report Forms will be distributed under separate 
cover when available. 
 
 

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

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Authors, including Medtronic personnel, must at a minimum meet all of the conditions 
below: 
 
Substantial contribution to conception and design, or acquisition of data, 
or analysis and interpretation of data 
 
Drafting the article or revising it critically for important intellectual 
content 
 
Final approval of the version to be published 
Decisions regarding authorship and contributor-ship will be made by the committee. The 
selected authors will be responsible for drafting the publication. All selected authors must 
fulfill the authorship conditions stated above to be listed as authors, and all contributors 
who fulfill the conditions must be listed as authors. 
All investigators not listed as co-authors will be acknowledged as the “Medtronic  Brady 
MX  Clinical Study Investigators” and will be individually listed according to the guidelines 
of the applicable scientific journal.  Any other contributors will be acknowledged by name 
and their specific contribution indicated. 
Transparency 
Transparency of study results will be maintained by the following means: 
 
A final report, describing the results of all objectives and analysis, will be 
distributed to all investigators, MECs in Mexico when required by local law 
 
Submitting for publication the primary study results after the trial ends  
 
Disclosing financial interests of the co-authors of publications according to 
the policies set forth by the corresponding journals and conferences  
 
Making an individual centers study data accessible to the corresponding 
investigator after the completion of the trial, if requested 
 

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Appendix D:  Participating Investigators and Institutions 
 
At the time of Brady MX Clinical Investigation Plan Version 1 completion, center 
confirmation was not finalized.  A complete list of participating investigators and institutions 
where study activities will be conducted will be distributed under a separate cover when 
available. 

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Appendix E:  IRB/MEC List 
 
At the time of Brady MX Clinical Investigation Plan Version 1 completion, center 
information was not finalized. Therefore a complete list of participating IRB/MECs and the 
Chairperson(s) will be distributed under separate cover when available. 

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Appendix F:  Bibliography 
 
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Cardiac Defibrilators: Calendar Year 2009 A World Society of Arrhythmia’s Project. Pacing 
Clin Electrophysiol 20011 Aug;34:1013-1027 
2.  Mangrum JM. The Evaluation oand Management of Bradycardia. New England Journal 
of Medicine 2010 May;342(10):703-709 
3.  Epstein et al.  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac 
Rhythm Abnormalities. Heart Rhythm 2008;5:e1-e62. 
4.  Vardas PE. Guidelines for cardiac pacing and cardiac resynchronization therapy. 
European Heart Journal 2007 Sep;28(18):2256-95. 
5.  Nowak et al. Do gender differences exist in pacemaker implantation?. Europace 2010 
Feb;12(2):210-5) 
6.  Levander-Lindgren et al. Bradyarrhythmia profile and associated disease in 1265 
patients with cardiac pacing. Pacing Clin Electrophysiol 1988 Dec;11(12):2207-15 
7.  Sutton et atl. Electrophysiological and haemodynamic basis for application of new 
pacemaker technology in sick sinus syndrome and AV block. Br Heart J 1979 
May;41(5):600-12 
8.  Coma et al. Spanish Pacemaker Registry. Fifth Official Report of the Spanish Society of 
Cardiology Working Group on Cardiac Pacing. Rev Esp Cardiol 2008 Dec;61(12):1315-28 
9.  Hartel G. Treatment of sinoatrial syndrome with permanent cardiac pacing in 90 
patients. Acta med Scand. 1975 Nov;198(5):341-7 
10.  Yancy CW, Fonarow GC, Albert NM, et al. Improving evidence-based care for heart 
failure in outpatient cardiology practices: Primary results of IMPROVE HF [abstract]. 
Circulation 2010 Aug 10; 122(6):585-96 
11.  Fonarow GC et al. Am Heart J, 2007;154:12-38. 
12.  Nallamothu, et al.  Beyond the Randomized Clinical Trial: The Role of Effectiveness 
Studies in Evaluating Cardiovascular Therapies. Circ 2008;118;1294-1303. 
 
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