Registry to Improve the Adoption of Consensus Treatment Guidelines (IMPROVE Brady)
Conditions: Sinus Node Dysfunction
Sponsor: Medtronic Cardiac Rhythm and Heart Failure



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CONTACT INFORMATION............................................................................................................. 5
ADVISORY COMMITTEE ............................................................................................................... 5
1
INTRODUCTION ................................................................................................................... 6
1.1
Study Purpose ......................................................................................................... 6
1.2
Study Scope ............................................................................................................ 6
2
BACKGROUND AND JUSTIFICATION................................................................................. 6
3
SYSTEM DESCRIPTION AND INTENDED USE.................................................................. 8
3.1
Device Description.................................................................................................. 8
3.2
Medtronic Programmers ......................................................................................... 8
4
METHODOLOGY................................................................................................................... 8
4.1
Study Objectives ..................................................................................................... 9
4.2
Subject Selection................................................................................................... 10
4.3
Study Design......................................................................................................... 11
4.4
Minimization of Bias ............................................................................................ 13
5
STUDY PROCEDURES ...................................................................................................... 13
5.1
Informed Consent/Patient Data Release Process.................................................. 14
5.2
Data Collection ..................................................................................................... 17
5.3
Enrollment/Baseline Procedures........................................................................... 18
5.4
Diagnostic Assessment Visit(s) ............................................................................ 18
5.5
Implant Visit ......................................................................................................... 19
5.6
Scheduled Follow-up Visit (Phase II only)........................................................... 19
5.7
Study Exit.............................................................................................................. 19
5.8
Lost to Follow-Up................................................................................................. 20
5.9
Subject Follow-up after Withdrawal..................................................................... 20
5.10 Medications........................................................................................................... 20
6
STUDY DEVIATIONS.......................................................................................................... 20
7
ADVERSE EVENTS ............................................................................................................ 21
7.1
Vigilance Reporting.............................................................................................. 21
8
SUBJECT DEATH ............................................................................................................... 22
8.1
Data Collection ..................................................................................................... 22
9
RISK ANALYSIS.................................................................................................................. 22
9.1
Potential Benefits.................................................................................................. 22
10
PLANNED STUDY CLOSURE, EARLY TERMINATION OF STUDY OR STUDY 
SUSPENSION ............................................................................................................................... 22
10.1 Planned Study Closure.......................................................................................... 22
10.2 Early Termination OR Suspension ....................................................................... 23
11
STATISTICAL METHODS AND DATA ANALYSIS............................................................. 24
11.1 Primary Objective(s)............................................................................................. 25
11.2 Secondary Objectives............................................................................................ 28
12
DATA AND QUALITY MANAGEMENT ............................................................................... 32
13
WARRANTY/ INSURANCE INFORMATION....................................................................... 32
13.1 Warranty ............................................................................................................... 32
13.2 Insurance (CEE).................................................................................................... 32

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13.3 Insurance (India)................................................................................................... 33
13.4 Insurance (Latin America).................................................................................... 33
13.5 Insurance (MEA) .................................................................................................. 33
13.6 Insurance (MEA) .................................................................................................. 33
14
MONITORING...................................................................................................................... 33
14.1 Monitoring Visits.................................................................................................. 33
15
REQUIRED RECORDS AND REPORTS............................................................................ 34
15.1 Investigator Records ............................................................................................. 34
15.2 Investigator Reports.............................................................................................. 35
15.3 Sponsor Records ................................................................................................... 36
15.4 Sponsor Reports.................................................................................................... 36
Appendix A:  Patient Informed Consent and Patient Data Release.............................................. 38
Appendix B:  Case Report Forms.................................................................................................. 39
Appendix C:  Preliminary Publication Plan .................................................................................... 40
Appendix D:  Participating Investigators and Institutions .............................................................. 42
Appendix E:  IRB/MEC List............................................................................................................ 43
Appendix F:  Study Overview ........................................................................................................ 44
Appendix G:  Bibliography............................................................................................................. 46

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1
INTRODUCTION
1.1
Study Purpose
Medtronic, Inc. is sponsoring a quality improvement study called the “Registry to 
Improve the Adoption of Consensus Treatment Guidelines” (IMPROVE Brady).
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 study is expected to provide evidence to support claim(s) that:

Education and process improvement initiatives can improve the diagnosis 
of and appropriate therapy application for SND

The quality improvement methods studied have general applicability and 
can be used by all centers 

Appropriate treatment minimizes caregiver burden

Appropriate treatment improves quality of life (QOL) and functional status
compared to pre-implant
1.2
Study Scope
The study may be conducted in countries located in Central and Eastern Europe 
(CEE), Greater China, India, Latin America, Asia, and Middle East and Africa 
(MEA).  Countries from other geographies may be added in the future.  The 
distribution of centers will be approximately 10 per geography or country and is 
determined by local evidence needs.  
Approximately 1,650 subjects per geography/country, or up to 14,850 subjects 
worldwide, will be enrolled in the study. An enrollment target of 6 subjects per 
center per month 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 
until 20% of the sample size for the geography/country has been reached for a 
maximum of 330 subjects per site.   
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 per 
geography/country, from first enrollment to last follow-up, is approximately 4.5
years per geography/country.  
2
BACKGROUND AND JUSTIFICATION
The World Health Survey of Cardiac Pacing and Cardioverter-Defibrillators
suggests that adoption of pacing therapy in emerging countries is lower than that 

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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.  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. 
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 
                                                     
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
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. Improving the use of evidence-based heart failure therapies in the outpatient setting : the 
IMPROVE HF performance improvement registry. Am Heart J, 2007;154:12-38.

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Cardiac Rhythm Abnormalities2 and the European Society of Cardiology (ESC) 
Guidelines for cardiac pacing and cardiac resynchronization therapy3.
The aim of IMPROVE Brady is to improve adoption of consensus treatment 
guidelines in the emerging countries 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.  
3
SYSTEM DESCRIPTION AND INTENDED USE
3.1
Device Description
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.
3.2
Medtronic Programmers
Medtronic programmers will need to be available at each implanting center to 
support study data collection requirements.  Programmers will be used to 
interrogate, program devices and save device data to a disk or USB.  All 
commercially released Medtronic programmers are available for use in this study.
4
METHODOLOGY
The IMPROVE Brady study is a prospective, interventional, sequential, post 
market study that may be conducted in CEE, Greater China, India Latin America, 
Asia and MEA.  Additional countries from other geographies may be added in the 
future.  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 
documentation tools that advocate and reinforce adherence to consensus 
                                                     
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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4.3
Study Design
There are two phases to IMPROVE Brady:
Sequential Design
Phase II:  Intervention Toolkit Implementation
Phase I: Control Period
Enrollment
Unscheduled 
Follow Up
Implant
Diagnosis 
And
Treatment 
Decision
Enrollment
Unscheduled 
Follow Up
Diagnosis 
And
Treatment 
Decision
Implant
Scheduled 
Follow Up
Exit
Exit
Exit
                                                   Site Intervention
Exit
Exit
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 12 months but will 
continue until 550 subjects have been enrolled for the geography/country.  For 
subjects enrolled during Phase I, collection of diagnostic assessment and implant 
data will be complete 6 months after the last enrollment for the geography/country.  
At that time, all Phase I subjects will be exited.
If a center becomes active after the geography/country enrollment goal for Phase I 
has been met or the center did not enroll at least 10 subjects before Phase I 
enrollment stopped then the center will enroll Phase I subjects until 10 subjects
have been enrolled at that center.  Once 10 subjects have been enrolled at the 
center, enrollment will stop and the subjects will be followed for a maximum of 6 
months and exited from the study.
Phase II:
The objective of the IMPROVE Brady 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 IMPROVE Brady 
toolkit.  In addition, the Principal Investigator and his/her colleagues are 
encouraged to adapt tools from the IMPROVE Brady 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 18 months per geography/country.  
The IMPROVE Brady 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.
During Phase II a patient survey assessing the subject’s quality of life and 
functional status, will be completed by subjects meeting an SND indication for 
pacing therapy and being implanted with a market released pacemaker from the 
Medtronic family of devices.  The patient survey must be completed before the 
implant procedure and again at 6 months post-implant.  
The caregiver of the subject being implanted with the market released pacemaker 
from the Medtronic family of devices will be asked to participate in a caregiver 
survey.  The purpose of the survey is to assess how providing care to the person 
receiving the pacemaker impacts the caregiver.  Prior to completing the survey an 
Informed Consent or Patient Data Release will need to be signed by the caregiver.  
The caregiver survey will be completed prior to the implant procedure and again at 
6 months post-implant.  The same caregiver must complete the pre and post 
implant surveys of the same patient.  
For subjects enrolled during Phase II collection of diagnostic assessment data will 
be complete 6 months after last enrollment for the geography/country.  At that 
time, any subjects without a diagnosis will be exited from the study.  Collection of 
implant data will be complete 6 months after the last Phase II diagnosis for the 
respective geography/country.  Any subjects not implanted by the end of the 6 
months will be exited from the study.  The Geography/country study timeline 
(Figure 2) depicts the geography/country timeline.

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Figure 2: Geography/country study timeline
4.4
Minimization of Bias
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 IMPROVE Brady

Study center characteristics will be collected at activation on possible 
differences that may effect the primary endpoints 

Centers will be used as their own control

Subjects will be screened to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment 

Subject demographics will be collected at baseline on possible differences
that may effect 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 10 subjects in each study Phase and 
enrollment at a site cannot exceed 20% of the sample size for the 
geography/country 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.
5
STUDY PROCEDURES
All local and regional regulatory 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), Institutional Review Board (IRB) or Head 
of the Medical Institution written approval of the current version of the 
Clinical Investigation Plan and Patient Informed consent/Patient Data 

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Release OR written documentation from the investigator stating approval is 
not required OR a written waiver from the MEC/IRB must be on file with the 
sponsor
o
When (MEC)/IRB 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

Competent Authority approval or notification (if required)

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 from the Medtronic family of devices.  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 Reveal

Ergometer or treadmill.
5.1
Informed Consent/Patient Data Release Process
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.

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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), Institutional Review Board (IRB) or Head of the Medical Institution must, if 
required by local laws and regulations, approve the Clinical Investigation Plan 
(CIP) and Patient Informed Consent/Patient Data Release (PIC/PDR).  If MEC/IRB 
approval is not required by local laws and regulations then written documentation 
from the investigator stating this or a waiver from the MEC/IRB must be sent to 
Medtronic.  Any changes to the PIC/PDR consent must be approved by Medtronic 
and the MEC/IRB 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/IRB 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 required)
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 

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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 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.  

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5.3
Enrollment/Baseline Procedures
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.  
Non-Implanting Physician/Site:  Enrollment is anticipated to occur prior to a final 
diagnosis of the patient being known, however, the patient may be enrolled at any 
time the IMPROVE Brady inclusion/exclusion criteria are met.
Implanting Physician/Site:  If the patient was enrolled in IMPROVE Brady by a 
referral physician/center and then referred to an implanting physician/center, also 
participating in the IMPROVE Brady study, an additional study consent does not 
need to be obtained.  If the patient was not previously enrolled in the study then 
the patient may be enrolled at any time the IMPROVE Brady 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, cardiovascular medication
use and referral information.  
5.4
Diagnostic Assessment Visit(s)
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.  Within each 
geography/country, collection of 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 and after the last Phase II enrollment for Phase II subjects.
The study protocol does not dictate when the Diagnostic Assessment(s) is/are to 
occur.
Any patient meeting an SND indication with a treatment plan that includes being 
implanted with an IPG device must have blood drawn to assess for untreated 
hypothyroidism (TSH & T4 exceeding normal limits) and anemia (HGB<10), if it 

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was not already done during the diagnostic assessment as part of the site’s 
standard of care.
5.5
Implant Visit
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.  
The implant will be performed according to the hospital’s standard implant 
practice.  IMPROVE Brady does not have device programming requirements.  
Information about the procedure, the device, and how the device was programmed 
will be collected.  A pre-discharge save-to-disk with a final interrogation will also be 
collected and submitted to Medtronic, if available.
(Phase II only)
At the implant visit the study subjects being implanted with a market released 
pacemaker from the Medtronic family of devices will complete a patient survey 
prior to implant to assess their quality of life and functional status.  During this visit 
the subject’s caregiver will be asked to complete a Caregiver survey after signing a 
PIC/PDR.  The purpose of the caregiver survey is to assess how providing care to
the patient impacts the caregiver.
5.6
Scheduled Follow-up Visit (Phase II only)
The scheduled 6 months post-implant follow up visit is required for subjects that 
received a market released pacemaker from the Medtronic family of devices and 
their participating caregiver.  During this visit the subject with the IPG will complete 
the patient survey and the caregiver will complete a caregiver survey.  The 
caregiver completing the survey must be the same caregiver that completed the 
pre-implant caregiver survey. 
5.7
Study Exit
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

Subject has met a SND indication for pacing therapy and did not receive a 
market released pacemaker from the Medtronic family of devices

Subject has met a SND indication for pacing therapy but will not be 
receiving pacing therapy

Subject has completed the final scheduled follow-up visit.

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
Geography/country completion of Phase I follow-up

Study Closure

Subject lost to follow-up

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)
5.8
Lost to Follow-Up
In the case that the subject is determined to be lost to follow-up, regulations set 
forth by the governing IRB/MEC (where applicable) will be followed.
5.9
Subject Follow-up after Withdrawal
Upon withdrawal from the study, no further study data will be collected or study 
visits will occur for the subject.
5.10 Medications 
There are no medications that are required for this study.  All cardiovascular 
medications and cardiovascular herbal treatments will be collected.  The only 
medications that are excluded from use during this study are investigational
medications.
6
STUDY DEVIATIONS
A study deviation is defined as an event within a study that did not occur according 
to the Clinical Investigation Plan or the Clinical Trial Agreement.
Prior approval by 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 

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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).  
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.  Refer to Investigator Reports (Table 2) for 
geography/country-specific deviation reporting requirements and timeframes for 
reporting to Medtronic and/or regulatory bodies.
Medtronic is responsible for analyzing deviations, assessing their significance, and 
identifying any additional corrective and/or preventive actions (e.g. amend the 
Clinical Investigation Plan, conduct additional training, terminate the 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.  
7
ADVERSE EVENTS
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.
7.1
Vigilance Reporting 
It is the responsibility of the investigator to report all product complaints and 
malfunctions immediately via the regular channels for CE marked products. 

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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.
8
SUBJECT DEATH
8.1
Data Collection 
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 Investigational 
Review Board (IRB) or Medical Ethics Committee (MEC). 
User (Investigator) reporting of deaths to regulatory authorities related to market 
approved products may be required.
9
RISK ANALYSIS
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.
The blood draw procedure that is performed as a protocol requirement is not 
associated with significant risk, and the procedure is carried out in many clinics as 
standard practice.
9.1
Potential Benefits
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.
10 PLANNED STUDY CLOSURE, EARLY TERMINATION 
OF STUDY OR STUDY SUSPENSION
10.1 Planned Study Closure
Study Closure is a process initiated by distribution of 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 

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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.
10.2 Early Termination OR Suspension
Early Termination of the Study is the closure of a clinical study that occurs prior to 
meeting defined endpoints.  This is possible for the whole study, a 
geography/country or a single center.
Study Suspension is a temporary postponement of study activities related to 
enrollment.  This is possible for the whole study, a geography/country 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 in the geography/country have been implanted 
with an indicated IPG at the completion of Phase I

SND indicated subjects are ≤ 5% of subjects enrolled in the 
geography/country and/or implanted subjects is ≤ 5% of indicated 
subjects in the geography/country by the end of Phase I

Enrollment is slower than anticipated

Observed/suspected performance of the market released pacemaker
from the Medtronic family of devices used in the study is different from the 
product’s design intent.

Decision by Medtronic or regulatory body (where the study is operating 
under regulatory body authority)
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 IRB/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.)

IRB/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)

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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 IRB/MEC approval lapse, the investigator will promptly inform the 
IRB/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 IRB/MEC (where applicable).
If the IRB/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 IRB/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.
11 STATISTICAL METHODS AND DATA ANALYSIS 
Medtronic statisticians 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 

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with SND and whether SND indicated subjects receive IPG therapy.  In current 
practice, both of these proportions are unknown for a set of patients meeting the 
study inclusion criteria.  Three principles will guide the statistical analysis outlined 
below.  The first principle is that the sample size calculations will use exact 
confidence intervals and tests to compare rates and binomial proportions.  The 
second principle of the analysis is that sample size calculations for Phase II 
(intervention phase) of the study design will depend on the outcomes observed in 
Phase I (control phase) of the study design.  Due to this, the Phase II sample size 
calculations provided herein are preliminary calculations that will be amended 
once Phase I data collection is completed. In general the study will start with a 1:2 
collection ratio for Phase I and Phase II sample sizes.  Twice as many subjects are 
enrolled in Phase II of the study design so that the study may also examine any 
temporal drift in the outcomes of interest or subject demographics.  The 1:2 
collection ratio will also allow for more information to contribute to secondary 
objectives 3 and 4. The third principle of the analysis is that both the statistical 
methods and the Phase II sample size calculations will be geography/country 
specific because the study outcomes are expected to vary by geography/country.
11.1 Primary Objective(s)
Primary Objective #1
Evaluate the impact of the intervention on the diagnosis of SND.
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 
where t= 6, 12, and 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 chi-square 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 geography.  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 geography/country as well as overall.  
B.  Determination of Patients/Data for Analysis

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All subjects that are enrolled in the study 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, 12 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= 6, 12, etc., 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 bradycardia subjects is currently unknown 
within the study geographies.  The PANARM HF study of 2000 subjects found that 
146 out of 331 bradycardia subjects (44%) had SND and that 15 (10%) of SND 
subjects opted for IPG therapy.  The power calculations conservatively assume
that the SND diagnosis will be 20% at six months of follow-up, or equivalently an 
SND incidence of 0.4 diagnoses per person-year.  Thus, the margin of error will be 
±4% in a sample of 500 subjects per geography/country, based on a 95% 
confidence interval.  If 500 subjects are collected in Phase I and 1000 subjects are 
collected in Phase II, assuming a type I error of 0.05 and power of 0.90, a chi-
square test will detect an increase in SND diagnosis of at least 8%.  For example, 
the study will find a statistically significant difference between a Phase I SND 
percentage of 20% at 6 months and a Phase II SND percentage of 28% at 6 
months. The Poisson regression for the same scenario has a power of 0.95 to 
compare SND incidence of 0.4 versus 0.56 diagnoses per person-year. If the 
proportion of SND diagnoses is smaller than 20%, there will be more power to 
detect significant differences in the diagnosis proportion.  Thus, the Phase II 
sample size will be recalculated within geography/country once Phase I data 
collection is complete.  It is expected that the study attrition rate may be 10-15% of 
the study population.  To account for attrition, the sample size for Phase I will be 
550 subjects per geography/country and for Phase II may be 1100 subjects per 
geography/country.  
Primary Objective #2
Evaluate the impact of the intervention on SND subjects receiving an indicated 
IPG device.
Endpoint Definition
The absolute change in the proportion of 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.
Analysis Methods
A. Statistical Methodology 

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To compare the proportion of subjects that receive indicated therapy pre-
intervention (Phase I) to the proportion post-intervention (Phase II), a Fisher’s 
Exact test will determine statistical significance.  A Fisher’s exact test is 
recommended for smaller sample sizes.  The proportion of subjects diagnosed will 
be evaluated at multiple time points because the time from diagnosis to implant is 
expected to vary by geography.  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 Fisher’s 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.
Sample Size Methods and Assumptions
The proportion of IPG therapy in SND subjects is currently unknown within the 
study geographies.  The PANARM HF study of 2000 subjects found that 146 out of 
331 bradycardia subjects (44%) had SND and that 15 (10%) of SND subjects
opted for IPG therapy.  PANARM HF included symptomatic HF which is different 
than the IMPROVE Brady population.  Thus, the percentages expected in
IMPROVE Brady may differ from those observed in PANARM HF.  Assuming that 
20% of subjects will be diagnosed with SND, this suggests that there will be 100
SND subjects in Phase I and 200 in Phase II per geography/country.  Further 
assuming that IPG therapy will be adopted by 10% of SND subjects at three 
months after diagnosis, or equivalently an IPG incidence of 0.25 diagnoses per 
person-year, this means that the margin of error will be ±8.0% in a sample of 100
subjects per geography/country, based on a 95% confidence interval.  If there are 
100 SND subjects in Phase I and 200 SND subjects in Phase II, assuming a type I 
error of 0.05 and power of 0.90, a Fisher’s Exact test will detect an increase in IPG 
therapy of at least 16% at three months after diagnosis.  This means that the 
objective will obtain statistical significance if 52 of 200 SND subjects in Phase II 

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opt for IPG therapy.  The Poisson regression for the same scenario has a power of 
0.95 to compare IPG incidence of 0.25 versus 0.625 implants per person-year.  
The power of this objective will improve if the percentage of SND diagnoses is 
larger than 20%. In order to better account for the proportion of SND diagnosis and 
IPG adoption per geography/country, the Phase II sample size will be recalculated 
within the geography/country once Phase I data collection is complete.
Stopping Guidelines for Futility
If Phase I of the study suggests that only 5% of enrolled subjects meet an SND 
indication and that only 5% of those indicated opt for IPG therapy, the study may 
close for futility at the end of Phase I within that geography/country.  Suppose that 
the percent of SND diagnosis is 5% and that 5% of those indicated will opt for
therapy.  Assuming 500 subjects in Phase I, 5,440 subjects will be needed in 
Phase II to see an increase in the implant rate from 5% to 30%.  This suggests a 
scenario with insufficient power to continue into Phase II.
11.2 Secondary Objectives
Secondary Objective #1
Describe the diagnosis and treatment of phase I subjects.
Endpoint Definition
The proportion of subjects receiving an SND diagnosis and the number of 
diagnosis that result in indicated therapy at pre-specified time points and the 
number of subjects diagnosed and implanted per person-year
Analysis Methods
A.  Statistical Methodology
An exact 95% confidence interval of a binomial proportion at each pre-determined 
time point will be used to calculate the margin of error for the SND and IPG 
proportions in Phase I of the study.  
B.  Determination of Patients/Data for Analysis
All subjects that are enrolled in the study will be included in the determination of 
the proportion estimates of SND.  The proportion estimates will be calculated 
based on information from fixed time points at 6 months of follow-up, 12 months, 
and any additional 6-month interval thereafter for which there is follow-up data 
available.  The number of subjects that obtain a SND diagnosis by pre-specified 
time point t= 6, 12, etc., is included in the numerator and the number of subjects 
enrolled is included in the denominator. The number of subjects that meet 
inclusion criteria and obtain a SND diagnosis shall be included in the determination 
of the proportion estimates of IPG therapy. The proportion estimates will be 
calculated based on information from fixed time points at 3 months of follow-up, 6 
months, and any additional 3-month interval thereafter for which there is follow-up 

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data available. 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.
Secondary Objective #2
Evaluate the change in the time to diagnosis of SND before and after intervention.
Endpoint Definition
Time to diagnosis in days (date of diagnosis – date of enrollment); number of visits 
to diagnosis
Secondary Objective #3
Evaluate the change in the time to receiving an indicated IPG device for SND 
subjects before and after intervention.
Endpoint Definition
Time to treatment in days (date of implant – date of diagnosis); number of visits to 
treatment
Analysis Methods
A.  Statistical Methodology
For Secondary Objectives 2 and 3 above, the following statistical analysis is 
proposed.  A stratified log-rank test of two Kaplan-Meier curves will determine if 
there is a significant difference in the time to endpoint before and after 
intervention.  The stratification will occur by geography/country and also by site.  
Stratified Cox models may also be fit to examine independent variables of interest 
that may affect SND diagnosis, such as gender and age.  Descriptive statistics will 
be used to characterize the number of visits that occur before an SND diagnosis 
and between the diagnosis and implant and further will examine number of visits 
separated by Phase, geography/country, type of enrolling physician, and possibly 
other baseline characteristics.
B.  Determination of Patients/Data for Analysis
The subjects to include in the analysis of secondary objectives 2 and 3 are the 
same as specified for primary objectives 1 and 2 respectively.
Secondary Objective #4
Evaluate the Caregiver burden between pre-implant and 6 months post-implant
Endpoint Definition
Compare the difference in caregiver burden from pre-implant to 6 months post-
implant

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Analysis Methods
A.  Statistical Methodology
Descriptive statistics will be used to summarize the difference in caregiver burden
between pre-implant and 6 months post-implant.  
B.  Determination of Patients/Data for Analysis
Subjects in Phase II who opt to receive an indicated therapy and are implanted 
with a market released pacemaker from the Medtronic family of devices will be 
followed from implant to 6 months post-implant.  The primary caregiver of these 
subjects will be asked to complete a questionnaire that assesses caregiver burden 
at the time of implant and 6 months post-implant.
Secondary Objective #5
Evaluate change in Quality of Life (QOL) and functional status between pre-
implant and 6 months post-implant.
Endpoint Definition
Compare the difference in QOL and functional status between pre-implant and 6 
months post-implant.
Analysis Methods
A.  Statistical Methodology
Descriptive statistics will be used to summarize the difference in QOL and 
functional status between pre-implant and 6 months post-implant.  
B.  Determination of Patients/Data for Analysis
Subjects in Phase II who opt to receive an indicated therapy and are implanted 
with a market released pacemaker from the Medtronic Family of devices will be 
followed from implant to 6 months post-implant.  These subjects will be asked to 
complete a questionnaire that assesses their QOL at the time of implant and 6 
months post-implant.

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13.3 Insurance (India)
Medtronic India Pvt., 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.
13.4 Insurance (Latin America)
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.
13.5 Insurance (MEA)
The Medtronic Mediterranean SAL is a wholly owned subsidiary of Medtronic Inc., 
which as the parent company of such entity maintains appropriate clinical study 
liability insurance coverage as required under applicable laws and regulations and 
will comply with applicable law and custom concerning specific insurance 
coverage. If required, a Clinical Trial Insurance statement/certificate will be 
provided to the MEC/IRB.
13.6 Insurance (MEA)
The Medtronic Africa (Pty) Ltd.is a wholly owned subsidiary of Medtronic Inc., 
which as the parent company of such entity maintains appropriate clinical study 
liability insurance coverage as required under applicable laws and regulations and 
will comply with applicable law and custom concerning specific insurance 
coverage. If required, a Clinical Trial Insurance statement/certificate will be 
provided to the MEC/IRB.
14 MONITORING
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.
14.1 Monitoring Visits
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 

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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. 
15 REQUIRED RECORDS AND REPORTS
15.1 Investigator Records
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.

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Appendix A: Patient Informed Consent and Patient Data 
Release
At the time of IMPROVE Brady Clinical Investigation Plan Version 1 completion, 
the Patient Informed Consent and Patient Data Release form, that comply with 
local laws and regulations of the participating geographies/countries 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 IMPROVE Brady 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 IMPROVE Brady data will be handled according to 
Cardiac Rhythm Disease Management Standard Operating Procedures and as 
indicated in the Clinical Trial Agreement.  
Publication Committee
The IMPROVE Brady 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 
IMPROVE Brady  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 and Competent Authorities of 
participating countries when required by local law

registering and posting the study results on ClinicalTrials.gov based on the 
posting rules stipulated

submitting for publication the primary study results after the 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 IMPROVE Brady 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 IMPROVE Brady 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: Study Overview
Study purpose
The purpose of this global, prospective, multi-center, post-market study is to characterize the 
current management of patients presenting with possible sinus node dysfunction (SND) and to 
assess practice-specific process improvement intervention consisting of education, critical care 
pathways and documentation tools that advocate and reinforce the use of evidence-based 
therapies intended to improve adherence to consensus treatment guidelines and the quality of 
care for SND patients.
Study scope and design
The study may be conducted in 9 geographies/countries; with approximately 10 study centers per 
geography or country.  Approximately 1,650 subjects per geography/country, or up to 14,850 
subjects worldwide, will be enrolled in the study.  There are two phase to the study.  Enrollment 
for Phase I is anticipated to occur for approximately 12 months but will continue until 550 patients 
have been enrolled for the geography/country.  Enrollment during Phase II is anticipated to occur 
for approximately 18 months or until approximately 1100 patients per geography/country have 
been enrolled. Centers that enroll faster than others will be allowed to enroll up to 20% of the 
sample size, maximum of 330 subjects per site, for each geography/country.
Phase I of the study serves as the control period, during which physicians will assess and treat 
subjects per their site’s standard care practice.  For subjects enrolled during Phase I, information 
will be collected regarding what was done to diagnose a patient and, if applicable, information 
regarding the device that was implanted.  All Phase I patients will be exited from the study and 
not allowed to partake in Phase II of the study.
At the completion of Phase I, the Principal Investigator and co-investigators will complete an 
educational workshop and provided access to the IMPROVE Brady toolkit. 
The Principal 
Investigator and his/her colleagues are encouraged to use the toolkit to create a practice specific 
process improvement intervention regarding the diagnosis and treatment plan for patients.  The 
educational workshop and toolkit is the intervention being examined, in the study. The IMPROVE 
Brady toolkit may include, but not limited to, diagnostic algorithm(s), patient video and tools for
investigators to educate their patients about their disease state, available therapy options, and 
benefits and risks associated with the therapy options.  Information collected in Phase II will be 
identical to Phase I regarding what was done to diagnose a patient and, if applicable, information 
regarding the device that was implanted.  
CLINICAL STUDY OBJECTIVES 
Primary objectives 
1.
Evaluate the impact of the intervention on the diagnosis of SND
2.
Evaluate the impact of the intervention on SND subjects that receive an indicated IPG 
device
Secondary objectives
1.
The key secondary objectives with pre-specified hypotheses to be tested include:
2.
Describe the diagnosis and treatment of Phase I subjects

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3.
Evaluate the change in time to diagnosis of SND before and after intervention
4.
Evaluate the change in the time to receiving an indicated IPG device for SND subjects 
before and after intervention
5.
Evaluate the caregiver burden between pre-implant and 6 months post-implant
6.
Evaluate change in Quality of Life (QOL) and functional status between pre-implant
7.
and 6 months post-implant
Main Inclusion / exclusion criteria (not an exhaustive list)
Inclusion Criteria: 

Patient is at least 18 years of age 

Patient's heart rate meets at least one of the following: 
o
Patient has a sinus rate ≤50 OR a junctional escape rhythm no faster than 50 
o
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). 
Exclusion Criteria: 

Patient has type II 2nd degree AV block, High degree AV block (2:1, 3:1, 4:1 etc.) or 3rd 
degree AV block 

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 
Study Duration
The expected study duration per geography/country, from first enrollment in Phase I to last follow-
up in Phase II, is approximately 4.5 years per geography/country.
Study Devices
Any market released pacemaker from the Medtronic family of devices and any market released 
lead may be used in this study
Study Sponsor and Management
The study is being sponsored and managed by Medtronic, Inc.

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Appendix G: Bibliography
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
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.
.