Long-term Monitoring of Patients With Cardiac Amyloidosis With Implantable Event Monitors
Phase: NA
Conditions: TTR Cardiac Amyloidosis
Sponsor: Mayo Clinic

 
Long-term monitoring of 
patients with cardiac 
amyloidosis with implantable 
event monitors 
 
NCT# 04421040 
 
August 22, 2023 

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CONFIDENTIAL 
 
 
Long term monitoring of patients with cardiac amyloidosis with 
implantable event monitors 
 
 
 
 
Principal Investigator 
 
Co-Investigators 
Omar Abou Ezzeddine, 
M.D., M.S. 
Department of Cardiology 
200 1st St SW. 
Rochester, MN 55902 
(77)4-8846 
 
Grace Lin, MD 
Rosalyn Adigun, MD, PharmD  
Peter Brady, MB, ChB, MD 
Yong-Mei Cha, MD 
Abhishek Deshmukh, MBBS 
Angela Dispenzieri, MD 
Martha Grogan, MD 
Dawn Pedrotty, MD, PhD 
Funding Sponsor: 
Pfizer 
235 East 42nd Street 
New York, NY 10017 
Mayo Clinic 
200 First St SW 
Rochester, MN 55905 
Biotronik 
6024 Jean Road 
Lake Oswego, OR 97035-557, USA 
Study Product: 
Biomonitor 3 (This device is being used in the study but is 
already FDA approved for this indication. The device is 
NOT under investigation.) 
Protocol Number: (IRBe) 
17-006298     IDE Number: Not Applicable 
Initial version: 4/10/2018 Version 1 
Revised: 
3/26/2019 Version 2 
Revised: 
10/16/2019 Version 3 
Revised: 
1/6/2020 Version 4 
Revised: 
1/30/2020 Version 5 
Revised: 
 4/30/2021 Version 6 
Revised: 
6/1/2022 Version 7 
          Revised:           1/5/2023 Version 8 

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CONFIDENTIAL 
 
         Revised:           3/21/2023 Version 9 
         Revised:            08/22/2023 Version 10 

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Table of Contents 
STUDY SUMMARY ............................................................................................................................................ 5 
1 
INTRODUCTION ....................................................................................................................................... 6 
1.1 
BACKGROUND ...................................................................................................................................................................... 6 
1.2 
DEVICE ................................................................................................................................................................................... 7 
1.3 
CLINICAL DATA TO DATE ................................................................................................................................................. 7 
1.4 
STUDY RATIONALE AND RISK/BENEFITS ..................................................................................................................... 8 
1.4.1 
Study Rationale ...............................................................................................................................8 
1.4.2 
Anticipated Risks .......................................................................................................................... 10 
1.4.3 
Potential Benefits ......................................................................................................................... 10 
2 
STUDY OBJECTIVES ............................................................................................................................. 10 
3 
STUDY DESIGN ....................................................................................................................................... 11 
3.1 
GENERAL DESIGN ............................................................................................................................................................ 11 
3.2 
PRIMARY STUDY ENDPOINTS........................................................................................................................................ 11 
3.3 
SECONDARY STUDY ENDPOINTS ................................................................................................................................. 12 
4 
SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL .................................................... 12 
4.1 
INCLUSION CRITERIA ....................................................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ..................................................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ................................................................................... 13 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ........................................................................................................................... 13 
4.4.1 
When and How to Withdraw Subjects .......................................................................................... 13 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 14 
4.5 
DESCRIPTION ..................................................................................................................................................................... 14 
4.6 
PREPARATION AND ADMINISTRATION/IMPLANTATION AND EXPLANTATION OF DEVICE .......................... 16 
4.7 
SUBJECT COMPLIANCE MONITORING ......................................................................................................................... 20 
4.8 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................................ 20 
4.9 
PACKAGING AND LABELING .......................................................................................................................................... 23 
4.10 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN ............................................................................................ 24 
4.10.1 
Receipt of Devices ................................................................................................................... 24 
4.10.2 
Storage .................................................................................................................................... 24 
4.10.3 
Distribution of Study Device ................................................................................................... 24 
4.10.4 
Return or Destruction of Device .............................................................................................. 24 
5 
STUDY PROCEDURES ........................................................................................................................... 25 
6 
STATISTICAL PLAN .............................................................................................................................. 26 
6.1 
SAMPLE SIZE DETERMINATION .................................................................................................................................... 26 
6.2 
STATISTICAL METHODS .................................................................................................................................................. 27 
6.3 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................................................. 27 
7 
SAFETY AND ADVERSE EVENTS....................................................................................................... 27 
7.1 
DEFINITIONS ...................................................................................................................................................................... 28 
7.2 
RECORDING OF ADVERSE EVENTS .............................................................................................................................. 30 
7.3 
SPONSOR-INVESTIGATOR REPORTING OF UNANTICIPATED ADVERSE DEVICE  EFFECTS  AND 
UNANTICIPATED PROBLEMS ........................................................................................................................................................... 31 
7.3.1 
Sponsor-Investigator Reporting, Notifying Mayo IRB .................................................................. 31 
7.4 
STOPPING RULES .............................................................................................................................................................. 31 
7.5 
MEDICAL MONITORING .................................................................................................................................................. 31 
8 
DATA HANDLING AND RECORD KEEPING .................................................................................... 32 
8.1 
CONFIDENTIALITY ............................................................................................................................................................ 32 
8.2 
SOURCE DOCUMENTS ..................................................................................................................................................... 32 

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8.3 
CASE REPORT FORMS .......................................................................................................................................................32 
8.4 
RECORDS RETENTION ......................................................................................................................................................33 
9 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 33 
9.1 
STUDY MONITORING PLAN ............................................................................................................................................33 
9.2 
AUDITING AND INSPECTING ...........................................................................................................................................34 
10 
ETHICAL CONSIDERATIONS ............................................................................................................ 34 
11 
STUDY FINANCES ................................................................................................................................. 34 
11.1 
FUNDING SOURCE .............................................................................................................................................................34 
12 
PUBLICATION PLAN ............................................................................................................................ 34 
13 
REFERENCES ......................................................................................................................................... 36 

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CONFIDENTIAL 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 

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CONFIDENTIAL 
 
Study Summary 
 
Title 
Long term monitoring of patients with cardiac amyloidosis with 
implantable event monitors 
Running Title 
Long term implantable monitors for cardiac amyloidosis. 
IRB Protocol 
Number 
17-006298 
Phase 
Pilot 
Overall Study 
Duration 
3 years 
Subject Participation 
Duration 
Approximately six months +31 days if removal 
Objectives 
There are four specific aims. We seek to determine in wild type 
transthyretin amyloidosis (ATTRwt): 
Specific Aim 1: Burden of conduction system disease and arrhythmias, 
specifically sinus node dysfunction, high grade heart block, and AF and 
VA, which will identify those who might benefit from a PPM or ICD 
Specific Aim 2: Mechanism of SCD (asystole, pulseless electrical 
activity, or sustained VA) and whether this is different in early vs. late 
stage amyloidosis. 
Specific Aim 3: Risk factors for SCA and more specifically whether 
bradycardia or VA predict SCD, or whether there are imaging or 
clinical characteristics that predict SCA 
Specific Aim 4: Utility of long term ECG monitoring in TTR-wt 
cardiomyopathy 
Number of Subjects 
50 
Diagnosis and Main 
Inclusion Criteria 
Patients with ATTRwt cardiac amyloidosis are included in this study. 
Device 
Biomonitor 3 (Utilized not investigational) 
Duration of 
Exposure 
Intended to remain in the body for 6 months pending clinical 
indications 
Reference therapy 
No change in standard of care treatment. 
Statistical 
Methodology 
Pilot Study 

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CONFIDENTIAL 
 
1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures. 
 
1.1 
Background 
Amyloid cardiomyopathy (AC) results from myocardial deposition of amyloid fibrils. The 
most common forms of amyloidosis associated with cardiac involvement include (1) AL 
amyloidosis, an immunoglobulin light chain plasma cell dyscrasia; (2) Transthyretin (TTR- 
m) an autosomal familial amyloidosis resulting from mutant transthyretin and (3) 
Transthyretin wild type (TTR-wt) amyloidosis, arising from a wild type transthyretin 
primarily in older individuals (1,2). The onset of a restrictive cardiomyopathy and 
progressive heart failure is the primary concern in cardiac amyloidosis, but another 
problematic aspect is infiltration of the conduction system, causing bradycardia, atrial 
arrhythmias (AF), and sudden cardiac death (SCD) (1,2). 
 
Conduction disease in AC manifests as high-grade atrioventricular (AV) block and sinus 
node dysfunction (bradycardia, heart rate <35bpm) and standard clinical indications for 
pacemaker implantation have been applied (1,3); however, many clinicians hesitate to treat 
with pacemakers (PPM) due to a perceived higher complication rate. Atrial fibrillation also 
presents several management dilemmas as AV nodal blocking agents typically utilized for 
rate control may be poorly tolerated, and data on anti-arrhythmic drug therapy and ablation 
are limited (4,5). A major limitation of ablation is high rates of AF recurrence in amyloidosis 
(4), hypothesized to occur because the arrhythmia is believed to arise from diffuse amyloid 
infiltration in the atrial tissue rather than from the pulmonary veins, rendering targeted 
ablation to isolate the pulmonary veins less effective. Although ventricular arrhythmias are 
also prevalent, their role in SCD in amyloidosis is also controversial (4,6-9). A longer term 
monitoring study with implantable loop recorders in a small number of patients with AL 
amyloidosis has suggested that bradycardia leading to asystole is the more likely culprit, at 
least in advanced amyloid cardiomyopathy, but it is not clear if this is also true earlier in the 
disease process or if it applies to TTR-wt (8). 
 
A particular challenge with TTR-wt is the paucity of data pertaining to arrhythmia risk. 
Much of the published literature, although also limited in scope and sample size, addresses 
arrhythmia risk only in AL amyloidosis. TTR-wt cardiomyopathy is characterized by a more 
indolent course compared to AL, and individuals may present with heart block or atrial 
arrhythmias prior to the onset of advanced heart failure symptoms and often before the 
diagnosis of TTR-wt cardiomyopathy (1,2). Advancements in imaging techniques such as 
cardiac magnetic resonance imaging and technetium pyrophosphate scintigraphy that permit 
earlier and non-biopsy diagnosis of TTR-wt diagnosis have enhanced the diagnosis of TTR- 
wt cardiomyopathy (10,11). As a result, it appears TTR-wt may be more prevalent than 
previously known; there is a significant overlap between TTR-wt cardiomyopathy and an 
ageing population of patients with heart failure with preserved ejection fraction, hypertrophic 
cardiomyopathy, and those with aortic stenosis undergoing transcatheter valve replacement 

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CONFIDENTIAL 
 
(12-14). Therefore arrhythmia risk and management in TTR-wt cardiomyopathy will impact 
an increasingly growing population of patients, with unique risk factors and management 
challenges that differ from those with other cardiovascular disease. 
 
One reason that arrhythmia management in amyloidosis has been focused on AL amyloidosis 
was due to the lack of disease modifying therapies for TTR-wt. The recent availability of 
disease modifying therapies for TTR amyloidosis that improve both symptoms and mortality 
also presents an opportunity to impact arrhythmia risk and management (15-17). Previous 
experiences of implantable cardiac device therapy in amyloid cardiomyopathy for arrhythmia 
management have suggested that earlier implantation may be associated with superior results 
(7,18). Whether the current therapies targeted towards stabilization and knockdown of 
circulating TTR will impact existing conduction disease is less clear, but these therapies may 
halt, delay or prevent onset of more severe disease that would not be amenable to treatment 
and could influence mortality. The main objective of this study is to identify TTR-wt 
cardiomyopathy patients at risk for bradycardia or SCD who may benefit from PPM or 
implantable cardioverter defibrillators (ICD), and to determine whether monitoring of TTR- 
wt patients undergoing treatment with disease modifying therapies will identify the subgroup 
of patients who will benefit most from PPM or ICD. 
 
1.2 
Device 
 
The device used in this protocol is NOT investigational. Biomonitor 3 is FDA and available 
on all markets for monitoring of arrhythmias. This protocol will use the device as FDA 
approved. 
 
Briefly, The Biomonitor 3 is indicated to detect the following cardiac arrhythmias: 
• atrial fibrillation 
• bradycardia, 
• sudden rate drop, 
• high ventricular rate (HVR), 
• asystole 
 
The Biomonitor 3 is indicated for use in: 
• Patients with clinical syndromes or situations at increased risk of cardiac arrhythmias 
• Patients who experience transient symptoms that may suggest a cardiac arrhythmia 
• The device has not been tested for and it is not intended for pediatric use 
 
1.3 
Clinical Data to Date 
 
Pilot Study Data submitted to FDA resulting in FDA approval of the Biomonitor implantable 
loop recorder (ILR) device 
The objective of this pilot study was to provide clinical data of the insertion procedure and 
the sensing quality of BIOTRONIK’s second generation of ILR, the BioMonitor 2, a device 
which is inserted subcutaneously. Data of 30 patients from 5 Australian clinical sites from 
December 18, 2014 through July 06, 2015 were included. The most common indications for 

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CONFIDENTIAL 
 
insertion of the BioMonitor 2 were syncope and symptomatic or asymptomatic atrial 
fibrillation. The published results demonstrate safety and efficacy of the insertion procedure 
and the study device. 
The next generation device, the Biomonitor 3 device was FDA approved in 2019 and 
represents an advancement from its predecessor. It is 60% smaller than the Biomonitor 2 
device and is preloaded into a single piece injection tool to permit less invasive and easier 
insertion, including office settings. Injectable implantable loop recorders which can be 
inserted subcutaneously are the industry standard. Device recordings offer increased signal 
quality over its predecessor, the Biomonitor 2. 
 
1.4 
Study Rationale and Risk/Benefits 
 
1.4.1 Study Rationale 
 
TTR-wt cardiomyopathy has been considered a life limiting, if indolent, and untreatable 
cause of heart failure in older individuals. For this reason, clinicians have hesitated to treat 
potentially life threatening arrhythmias, or to consider implantation of cardiac devices (PPM 
or ICD) which may improve symptoms and impact mortality. The recent availability of 
disease modifying therapies ushers in a new era of treatment strategies which improve both 
mortality and morbidity. The goal of the study is to identify patients who would also benefit 
from treatment of arrhythmias, and who might otherwise have succumbed to complications 
from arrhythmias, including stroke, sudden cardiac death, or injury from syncope due to 
bradycardia. 
 
Implantable loop recorders have been used successfully to monitor for arrhythmia burden and 
to identify causes of cryptogenic syncope and stroke in patients with cardiovascular disease 
(19,20). The devices can be implanted at low risk and with local anaesthesia and can be 
inserted in an office setting, and remaining in situ for up to 3 years to permit long term 
monitoring (21). The device are explanted at the time of battery expiration. Miniaturized 
implantable loop recorders have been used to document mechanisms of sudden death in late 
stage AL amyloidosis but have not been routinely utilized especially in TTR-wt (8). Given 
the perceived high risk for arrhythmias and the lack of robust data on arrhythmia burden, 
amyloid cardiomyopathy would seem an ideal population to monitor with implantable long- 
term loop recorders. 
 
An observation from the recently published Transthyretin Amyloidosis Cardiomyopathy 
Clinical Trial (ATTR-ACT) was the subgroup analysis suggesting greater benefit in less 
severe heart failure (17,22). Arrhythmia risk (AF, heart block, and cardiac arrest) might be 
different in patients with earlier stages of the disease, and if treatment with tafamidis might 
prevent further progression of conduction system disease and arrhythmia burden. The 
current study proposed is a pilot study and will not be powered to ascertain the effects of 
tafamidis on arrhythmia burden in different stages of disease, but observations from the study 
will provide preliminary data for future and necessary prospective monitoring studies. 
 
Despite high risk of SCD, appropriate risk stratification in amyloid cardiomyopathy is 
lacking. Traditional risk stratification with decreased ejection fraction (<35%) commonly 

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CONFIDENTIAL 
 
applied to ischemic cardiomyopathy is not useful in amyloid cardiomyopathy where decreased 
ejection fraction is a late finding and indicative of advanced disease and increased mortality 
due to low output and pump failure. Recent studies have cast increasing doubt on the wisdom 
of generalizing decreased ejection fraction as a risk stratifier for SCD in patients with heart 
failure due to other causes, specifically those with non-ischemic cardiomyopathies(23) and 
heart failure with preserved ejection fraction (24). At this time, patients with amyloid 
cardiomyopathy are without appropriate risk stratification metrics and are at risk for inadequate 
treatment and at increased risk for SCD. 
 
The prognostic value of non-sustained VA, another traditional risk factor for SCD in ischemic 
cardiomyopathy, is also controversial in amyloid cardiomyopathy. Long term outpatient 
monitoring of both supraventricular and ventricular arrhythmias for prognostic implications in 
relation to other diagnostic modalities is instrumental in understanding the disease process and 
providing appropriate therapy. 
 
Currently, the balance of data does not support ICD implantation in amyloid cardiomyopathy 
(7). However, some studies have demonstrated that ventricular arrhythmias resulting in SCD 
can be successfully treated with defibrillation, hypothesizing that this treatment may be more 
successful in earlier stage disease (8,26,27). SCD in late stage disease has been hypothesized 
to be due to electromechanical dissociation or bradycardia mediated asystole for which an ICD 
would not be beneficial (25)(8,18). The Mayo clinic staging system based on cardiac 
biomarkers has been validated and is used to stratify severity of disease (early vs late stage) in 
TTR-wt cardiomyopathy. The reported 4 year survival estimates of patients with Mayo stage I 
(TnT <0.05ng/ml and NT BNP <3000 pg/mL), II (either TnT >0.05 ng/ml or NT BNP 
>3000 pg/mL), and III (TnT >0.05 ng/ml and NT BNP >3000 pg/mL) TTRwt amyloidosis was 
57%, 42%, and 18%, respectively (28). Those patients with advanced amyloid cardiomyopathy 
may have estimated survival less than a year due to heart failure and should be excluded from 
ICD whereas those with earlier stage may still have added survival benefit. We hypothesize 
that the occurrence and treatibility of ventricular arrhythmias is dependent on disease 
progression and may be a phenomena of earlier stage disease. Monitoring at all stages of CA 
disease to understand arrhythmia risk at each stage is instrumental in understanding the true 
prevalence and treatment of arrhythmias. 
 
Patients with CA and conduction disease undergo pacemaker implantation for standard 
guideline criteria. However, bradycardia has been implicated as a mechanism for SCD. 
Bradycardia leading to asystole has been postulated to be a pre-terminal event reflecting an 
irreversible sick myocardium (8). A second hypothesis is that the reduced cardiac output 
associated with bradycardia might be sufficient to induce global ischemic stunning of the 
heavily infiltrated ventricular myocardium resulting in decompensation and pulseless electrical 
activity (PEA) arrest(8). In a study of AL amyloidosis patients monitored with ILR, one patient 
with severe bradycardia who underwent early pacemaker implantation survived. Therefore, it 
is possible that prophylactic pacemaker implantation into healthier myocardium may prevent 
SCD due to bradycardia, and treatment with disease modifying therapies can prevent further 
disease progression. Furthermore, a recent study of prophylactic pacemaker insertion in 
patients with TTR patients with a genetic variant associated with increased risk of conduction 
disorders showed a reduction in major cardiac 

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events over a 45 month follow up (29). The proposed study would permit improved 
understanding of the initiation of bradycardia, correlating to stage of disease and clinical 
imaging; helping to further elucidate the pathophysiology of bradycardia and heart block in 
CA. 
 
1.4.2 Anticipated Risks 
 
Biomonitor 3 is an FDA approved device and will be used in accordance with approved FDA 
usage. Risks have already been assessed for this device and deemed acceptable for this 
medical application. 
 
Risks for the BioMonitor 3 are minimal but include risk of bleeding and discomfort on 
insertion, infection, and malfunction. The BioMonitor 3 demonstrated excellent sensitivity 
for all types of arrhythmias, combined with a low false detection rate. 
 
List of Anticipated Risks: 
• Discomfort at time of insertion 
• Infection 
• Bleeding 
 
False detection is a minimal risk. The BioMonitor 3 has demonstrated excellent sensitivity 
for all types of arrhythmias, combined with a low false detection rate. 
 
1.4.3 Potential Benefits 
 
We hypothesize that arrhythmogenesis and SCD risk in this population is influenced by CA 
stage rather than reduced left ventricular ejection fraction, which is a marker of late disease 
and increased mortality due to heart failure, bradycardia, or asystole, rather than SCD due to 
VA. The purpose of this study is to identify TTR-wt cardiac amyloidosis patients at risk for 
bradycardia or SCD due to VA who may benefit from PPM or ICD, and to determine whether 
monitoring may be appropriate as standard of care to identify the subgroup of patients who 
will benefit from PPM or ICD. 
 
2 Study Objectives 
Listed below are the specific aims/objectives for this study. 
 
Specific Aim 1: Burden of conduction system disease and arrhythmias, specifically sinus node 
dysfunction, high grade heart block, and AF and VA, which will identify those who might 
benefit from a PPM or ICD 
Specific Aim 2: Mechanism of SCD (asystole, pulseless electrical activity, or sustained VA) 
and whether this is different in early vs. late stage amyloidosis. 
Specific Aim 3: Risk factors for SCA and more specifically whether bradycardia or VA 
predict SCD, or whether there are imaging or clinical characteristics that predict SCA 
Specific Aim 4: Utility of long term ECG monitoring in TTR-wt cardiomyopathy 

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CONFIDENTIAL 
 
 
2.1 Primary Objective 
 
This is a Pilot Study designed to support future expanded Pivotal Studies of the device. 
The study is designed to assess arrhythmic events using the implantable cardiac monitor, 
Biomonitor 3, in subjects presenting to the clinic with TTR-wt cardiac amyloidosis. 
 
2.2 Secondary Objective 
 
The secondary goal is to assess arrhythmogenesis in relation to stage of cardiac amyloidosis 
 
3 Study Design 
3.1 
General Design 
This is a pilot study of 50 patients to monitor arrhythmogensis for six months with +31 days 
post implantation in patients TTR-wt cardiac amyloidosis proven by endomyocardial biopsy 
or technetium pyrophosphate scintigraphy. Study staff will provide continuous monitoring of 
the ILR.  
 
The general design is outlined below: 
 
3.2 
Primary Study Endpoints 
 
1. Sudden cardiac death (including resuscitated cardiac arrest). 
RV Biopsy or PYP 
study proven TTR 
-wt amyloidosis 
25 patients with 
stage I or II 
25 patients with 
stage III 
Biomonitor 3 
implantation 
Biomonitor 3 
implantation 
6 months of 
monitoring 
6 months of 
monitoring 
Biomonitor 3 
explantation 
Biomonitor 3 
explantation 

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2. Syncope due to heart block or sinus node dysfunction requiring pacemaker 
 
3.3 
Secondary Study Endpoints 
 
1. All-cause mortality: with a focus on HF deaths and bradycardia/PEA 
2. PPM implantation and indication, frequent of pacing required, and if BIV pacing is 
needed 
3. ICD implantation and indication, frequency of shocks and if appropriate vs 
inappropriate and if successful defibrillation occurred 
4. Frequency of NSVT and predictability with other ventricular arrhythmias and sudden 
cardiac death 
5. Frequency of atrial flutter or fibrillation and predictability with other arrhythmias 
including predictability of ventricular arrhythmias and sudden cardiac death 
 
4 Subject Selection, Enrollment and Withdrawal 
The target population is patients with TTR-wt cardiac amyloidosis. We plan to enroll 50 
patients in this pilot study. Specifically, we will enroll 25 patients diagnosed with stage I 
or stage II disease and 25 with stage III disease. 
 
Patients will be screened and recruited from the Amyloidosis Clinics, heart failure clinics 
and respective hospital services. 
 
 
4.1 
Inclusion Criteria 
 
1. Cardiac biopsy or technetium pyrophosphate scintigraphy confirmed patients 
2. Stage I, II, and early and late stage III in numbers as described, irrespective of EF or 
NYHA functional class 
3. Patients aged 18 -85, both genders and of all races and ethnicities. 
4. Patients must be competent to give informed consent. 
5. Patients must be able to have the Biomonitor 3 implanted. 
6. Amyloid stages I-III patients with existing implantable cardiac devices such as pacemakers or 
defibrillators  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONFIDENTIAL 
 
 
 
4.2 
Exclusion Criteria 
 
1. Significant coronary artery disease > 75% luminal stenosis in at least 1 epicardial 
vessel (by cardiac catheterization or coronary computed tomography), or history of 
myocardial infarction or coronary revascularization. 
2. Congenital heart disease. 
3. Pregnant patients 
4. Patients whose heart failure is felt to be secondary to primary valvular disease (≥ 
moderate/severe mitral regurgitation), uncorrected thyroid disease, obstructive or 
hypertrophic cardiomyopathy, pericardial disease or a systemic illness. 
5. Absolute contraindications to cardiac MRI (such as renal failure with GFR<30%). 
6. Unwilling or unable to provide informed consent. 
7. Patients with other life threatening diseases that would likely decrease their life 
expectancy over the next four years. 
8. Patients who are post cardiac transplant. 
9. Difficulty to attend the follow-up schedule due to a history of medical 
noncompliance, difficulty, or unwillingness to return to the study center for follow 
up. 
10. Evidence of ongoing bacteremia or sepsis preventing implantation of a device. 
11. Unwilling or able to have the Biomonitor 3 interrogated 
 
 
 
 

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4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be screened and recruited from the from the Amyloidosis Clinics, heart failure 
clinics and respective hospital services. Patients will receive standard of care therapy including 
staging with cardiac biomarkers. We will recruit 25 patients with stage I or II and 25 patients 
with stage III. Prior to time of recruitment, inclusion and exclusion criteria will be reviewed 
for each patient. 
 
There are no known contraindications for the insertion of the BioMonitor 3. However, the 
patient’s particular medical condition may dictate whether or not a subcutaneous, chronically 
inserted device can be tolerated. 
 
Patients will have the option to leave the device in situ for the lifetime of the device . If opting 
for the full battery lifetime, the patient/insurance company would be responsible for the 
continued monitoring after the 6 month study period and the explantation of the device at 
battery end of life. 
 
4.4 
Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
 
Patients may withdraw at any time from the study. Reason for withdraw may include but are 
not limited to adverse events, progression of disease requiring withdrawal or simply the 
patient’s decision to withdraw. 
 
If a subject does withdraw, that subject will be replaced according to the originally assigned 
group to permit enrollment of 50 patients complete the study. 
 
Patients may be withdrawn from the study by the investigators if an insertable monitor 
requires emergent removal. Reasons for removal include, but are not limited to: patient 
death; loss of sensing; inability to program/interrogate the inserted monitor; infection, battery 
end of life (normal or premature); system upgrade; physician preference for another 
insertable monitor model; and/or other reason(s) which may or may not be known to the 
insertable monitor manufacturer. Complications related to other portions of the insertable 
monitor system (i.e., patient) may also result in insertable monitor removal. The table below 
summarizes some of the more common reasons for insertable monitor removal. 

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Source 
Cause 
Possible Effect 
Battery 
Premature depletion or other 
cause(s) resulting in excessive 
battery current drain. 
Inability to program/interrogate; sensing difficulty. 
Circuitry 
Electrical parameter changes 
due to shorts, opens, or 
component parametric drift 
Electromagnetic Interference 
(EMI) from large power 
tools, industrial equipment, 
electrocautery, defibrillation, 
radiation therapy, RF ablation 
therapy, etc. 
Reversion to “Elective Replacement” or electrical 
reset parameters; inability to program/ interrogate; 
other damage to circuit components resulting in 
permanent or temporary parameter changes. 
Patient 
Normal medical complication 
Infection 
Body rejection phenomena 
Fluid accumulation; migration; erosion. 
Physician preference 
Upgrade to an implantable cardiac pacemaker or 
implantable cardioverter defibrillator. 
 
If the device is removed due to need for a pacemaker or implantable cardioverter defibrillator 
the patient will continue to be monitored via the pacemaker or defibrillator as per clinically 
indicated standard of care monitoring protocol and intervals. 
 
If a subject chooses to withdraw from the study, and requests the monitor to be explanted 
prior to the end of the 6 month study monitoring period, there will be no further follow up. 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though a subject has withdrawn from the study, follow-up and survival data on such 
subjects throughout the protocol defined follow-up period will still need to be collected if 
possible. Such data is important to the integrity of the final study analysis since early 
withdrawal could be related to the safety profile of the study device. If a subject withdraws 
consent to participate in the study, for subject safety reasons, attempts will be made to obtain 
permission to collect follow up information whenever possible. 
 
4.5 
Description 
 
Biomonitor 3 is a programmable, subcutaneous insertable monitor able to record 
subcutaneous ECGs (sECGs) and other physiological parameters. 
 
The Biomonitor 3 is designed to automatically record the occurrence of arrhythmias in a 
patient. Arrhythmia may be classified as atrial fibrillation (AF), bradyarrhythmia, asystole, 
sudden rate drop, or high ventricular rate. In addition, the Biomonitor 3 can be activated by 
the patient to record cardiac rhythm during symptomatic episodes. 

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The Biomonitor 3 system consists of three main components: 
1. Biomonitor 3 insertable cardiac monitor - The Biomonitor 3 is a small, leadless 
device that is typically inserted under the skin, in the chest. The device uses two 
electrodes on the body of the device to continuously monitor the patient’s 
subcutaneous ECG. The device memory can store up to 30 min of subcutaneous ECG 
(sECG) recordings from automatically detected arrhythmias and up to 30 min of 
sECG recordings from patient-triggered episodes. When a patient experiences 
symptoms, the sECG recordings can be manually triggered by placing the Remote 
Assistant III over the Biomonitor 3. The insertable monitor is provided preloaded in 
an insertion tool. An incision tool is also provided. 
 
Note - The Biomonitor 3 subcutaneous ECG may differ from a surface ECG due to 
differences in electrode separation and device placement in the body. Biomonitor 3 
detects a subcutaneous ECG from a pair of electrodes. These signals are filtered in 
two different ways. For detection of QRS complexes, the signals are filtered with a 
passband of 10-40 Hz in order to suppress T-waves, artifacts, and baseline drift at low 
frequencies, and myoptentials and EMI at high frequencies. The resulting signal is 
appropriate for QRS detection as other components of the signal have been 
suppressed. This signal naturally does not have a typical ECG morphology due to the 
bandpass. For waveform display (real-time streaming sECG with the physician’s 
programmer and snapshots for review by the physician), a different passband is 
utilized to retain signal features that may have diagnostic value. This passband is 0.5 
– 40 Hz, which is designed to retain morphological features of a typical ECG while 
still rejecting large low frequency artifacts and baseline drift. 
 
2. BIOTRONIK Renamic / ICS 3000 Programmer – The programmer is used to set up 
the Biomonitor 3 to detect arrhythmias. It also allows you to view, save, or print the 
stored information. 
 
3. BIOTRONIK CardioMessenger® Smart is a telemetry patient device that forwards 
the data from the Biomonitor 3 to BIOTRONIK’s Home Monitoring Service Center. 
 
Biomonitor 3 may be used with BIOTRONIK Home Monitoring® technology, which is an 
automatic, wireless, remote monitoring system for management of patients with insertable 
cardiac monitors. When active, Home Monitoring enables the exchange of information about 
a patient’s cardiac status from the implant. The information is transmitted to the Home 
Monitoring Service Center (HMSC), where the physician may log in to review. The HMSC 
can be used to provide the physician with advanced reports from the implanted device and 
process them into a graphical and tabular format. This information may help the physician 
optimize the therapy process, possibly providing earlier notification of clinically relevant 
events to help guide future therapy. 
 
• BIOTRONIK conducted the TRUST study to evaluate the safety and effectiveness of 
Home Monitoring. With the TRUST study, BIOTRONIK was able to show the 
following with regards to Home Monitoring: 

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• BIOTRONIK Home Monitoring information may be used as a replacement for device 
interrogation during in-office follow-up visits. 
• A strategy of care using BIOTRONIK Home Monitoring with office visits when 
needed has been shown to extend the time between routine, scheduled in-office 
follow-ups of BIOTRONIK implantable devices in many patients. Home Monitoring 
data is helpful in determining the need for additional in-office follow-up. 
• BIOTRONIK Home Monitoring provides early detection of arrhythmias. 
• BIOTRONIK Home Monitoring provides early detection of silent, asymptomatic 
arrhythmias. 
• Automatic early detection of arrhythmias and device system anomalies by 
BIOTRONIK Home Monitoring allows for earlier intervention than conventional 
in-office follow-ups. 
• BIOTRONIK Home Monitoring allows for improved access to patient device data 
compared to conventional in-office follow-ups since device data is automatically 
collected and reported on a daily basis. 
• The implanted device’s Home Monitoring function can be used for the entire 
operational life of the implanted device (prior to ERI). 
• NOTE: When ERI mode is reached, this status is transmitted and Home Monitoring® 
will be discontinued after two weeks. 
 
Electromagnetic Interference (EMI) - Precautions for EMI interference with the 
Biomonitor 3 insertable cardiac monitors including cellular telephones, electronic article 
surveillance systems, and others. 
Use in Cellular Phone Restricted Areas - The mobile patient device (transmitter/receiver) 
should not be utilized in areas where cellular phones are restricted or prohibited (i.e., 
commercial aircraft). 
Elective Replacement Indicator (ERI) - When ERI mode is reached, this status is 
transmitted. Home Monitoring data transmissions will continue for another 2 weeks. After 2 
weeks, data will no longer be transmitted to the Service Center. 
Communication Loss - A system alert appears in the physician’s queue on the Home 
Monitoring website if no data transmissions occur for a period of time programmed by the 
user. You may configure alerts so that an SMS, fax and/or e-mail message is sent to the 
physician regarding the communication loss. If no data transmissions have been received by 
HMSC after 90 days, the patient will be deactivated. In the event of sustained communication 
loss, an in-office follow-up visit is recommended. 
 
4.6 
Preparation and Administration/Implantation and Explantation of Device 
 
Preparation of Device 
The Biomonitor 3 is preloaded in the insertion tool and is packaged with an incision tool in a 
single container sterilized with ethylene oxide. The device can be implanted in an office 
setting and all implantations for the study will be performed in the Clinical Research Trials 
Unit (CRTU). The implantation procedure is performed with injection of a local anesthetic 
(lidocaine). Conscious sedation is not required. 

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Peel off the sealing paper of the outer container 
as indicated by the arrow. 
 
 
 
 
 
 
 
 
 
 
 
 
Insertion 
The FIT OneStep Tool allows an “injection-like” insertion of the implant using a single tool. 
It is used for forming the device tunnel and subsequent subcutaneous delivery of the 
Biomonitor 3 implant. The Biomonitor 3 implant is provided preloaded into the blue 
tunneling end of FIT OneStep tool, 
which has a rigid clam-shell design. There is a small window over the BIOMONITOR III 
implant to allow the physician to see the implant in the FIT OneStep tool. The incision tool 
and FIT OneStep tool are intended for single use. 
 
Incision and FIT OneStep tools 
 
Biomonitor 3has been developed to be inserted in a close-fitting subcutaneous tunnel, 
preferably in or around the left side of the chest. Recommended locations are those areas 
close to the heart where the implant will be exposed to minimal movement from body 
positional changes or from arm movement. Suitable implant locations are shown below. In 
position A, a location between the suprasternal notch and the left nipple is shown. Position B 
shows an implant location of approximately 45° with respect to the midline. The choice of 
placement location is to be decided by the physician, on the basis of individual patient 
anatomy and comfort, as well as cosmetic considerations. The insertion process consists of 
four (4) intuitive steps: Incision, Tunneling, Unlocking and Retraction 

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Two recommended positions for the placement for Biomonitor 3 

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Biomonitor 3 insertion procedure 
 

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Explantation  
 
Explantation will be performed in the CRTU or the HRS Lab. Local anesthetic is injected 
into the previous incision site. Gentle traction is applied to the device and the device is 
removed. 
 
4.7 
Subject Compliance Monitoring 
 
All patients will undergo Home Monitoring of their device. By default, the Biomonitor 3 
will transmit all data and a daily trend report between 1:00 A.M. and 2:00 A.M. daily. 
BIOTRONIK’s Home Monitoring system is also designed to notify clinicians in less than 24 
hours of changes to the patient’s condition or status of the inserted device. Updated data may 
not be available if: 
• The patient’s CardioMessenger is off or damaged and is not able to connect to the 
Home Monitoring Service Center. 
• The CardioMessenger cannot establish a connection to the inserted device. 
• The telephone and/or Internet connection do not operate properly 
• The Home Monitoring Service Center is off-line (upgrades are typically completed in 
less than 24 hours) 
 
These updates will help to assist the subject to make the necessary changes so that data can 
be transmitted and they are not lost to follow up. 
 
4.8 
Prior and Concomitant Therapy 
 
Patients may continue on standard of care medical therapy for amyloidosis and any other 
medical therapy needed. 
 
Patients enrolled in the study with an implanted Biomonitor 3 need careful assessment prior 
to undergoing one of the following procedures. A detailed analysis of the advantages and 
risks should be made. Cardiac activity during one of these procedures should be confirmed 
by continuous monitoring of peripheral pulse or blood pressure. Following the procedures, 
insertable cardiac monitor function must be checked. 
Therapeutic Diathermy Equipment - Use of therapeutic diathermy equipment is to be 
avoided for insertable cardiac monitor patients due to possible heating effects of the 
insertable cardiac monitor and at the implant site. If diathermy therapy must be used, it 
should not be applied in the immediate vicinity of the insertable cardiac monitor. The 
patient’s peripheral pulse should be monitored continuously during the treatment. 
Transcutaneous Electrical Nerve Stimulation (TENS) - Transcutaneous electrical nerve 
stimulation may interfere with insertable cardiac monitor function. If necessary, the 
following measures may reduce the possibility of interference: 
Place the TENS electrodes as close to each other as possible. 
Place the TENS electrodes as far from the insertable cardiac monitor as possible. 
Monitor cardiac activity during TENS use. 

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Defibrillation - The following precautions are recommended to minimize the inherent risk of 
insertable cardiac monitor operation being adversely affected by defibrillation: 

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The paddles should be placed anterior-posterior or along a line perpendicular to the 
axis formed by the insertable cardiac monitor 
The energy setting should not be higher than required to achieve defibrillation. 
 
Radiation - Insertable cardiac monitor electronics may be damaged by exposure to radiation 
during radiotherapy. To minimize this risk when using such therapy, the insertable cardiac 
monitor should be protected with local radiation shielding. 
Lithotripsy - Lithotripsy treatment should be avoided for insertable cardiac monitor patients 
since electrical and/or mechanical interference with the insertable cardiac monitor is possible. 
If this procedure must be used, the greatest possible distance from the point of electrical and 
mechanical strain should be chosen in order to minimize a potential interference with the 
insertable cardiac monitor. 
Electrocautery - Electrocautery should never be performed within 15 cm (6 inches) of an 
insertable cardiac monitor because of the danger of damaging the insertable cardiac monitor. 
When possible, a bipolar electrocautery system should be used. 
Transurethral resection of the prostate - It is recommended that the cautery ground plate 
be placed under the buttocks or around the thigh, but not in the thoracic area where the 
current pathway could pass through or near the cardiac monitor. 
Importantly, the device is MR Conditional - The cardiac monitor is labeled and certified 
MR conditional. 
 
The following requirements must always be fulfilled in order to perform an MR scan using 
BIOTRONIK’s BioMonitor 3: 
1. There are no other active or abandoned cardiac implants (e.g., lead extensions, lead 
adapters or abandoned leads) in the patient’s body. 
2. Other active or passive implants are permitted if they are identified as MR conditional 
by the manufacturer. NOTE: An MRI scan is permitted only if the product-specific 
conditions are met for all implants and if no metal insertable device longer than 5 cm 
is in the vicinity of the BIOTRONIK cardiac monitor within a distance of less than 4 
cm. 
3. The device is located in the patient’s chest area. 
The MRI scanner has to meet the following conditions: 
1. Use of a clinical MRI system with a cylindrical bore and a static magnetic field 
strength of: 
a. 1.5 Tesla (for BioMonitor and BioMonitor 3) or 3.0 Tesla quadrature transmit 
coils 
b. only (for BioMonitor 2). 
 
2. The slew rate of the MRI scanner’s gradient fields should not exceed 200 T/m/s per 
axis. 
3. For the head and the extremities, local transmitter and receiver coils are approved for 
use in addition to the local receiver coils. 
4. Only local receiver coils may be used for the thorax. 

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5. Maximum spatial gradient of the static magnetic field specification must be ≤ 100T/m 
(10,000 gauss/cm). 
6. Under worst case conditions, the BioMonitor 3 is expected to produce a maximum 
temperature rise of <4.5° C after 30 minutes of continuous scanning. 
7. Image artifact and distortion can result from the presence of the BioMonitor 3 device 
within the field of view. Image artifact and distortion resulting from the presence of 
the device within the field of view must be considered when selecting the field of 
view and imaging parameters. These factors must also be considered when 
interpreting the MRI images. 
 
The following conditions must be met during the MR scan: 
1. The MR scan should be performed with the patient in supine position. 
2. The mean specific absorption rate (SAR) for the whole body as displayed by the MRI 
scanner must not exceed 4.0W/kg. 
3. The head absorption rate displayed by the MR scanner must not exceed 3.2 W/kg. 
 
Environmental factors 
The operation of any insertable cardiac monitor can be affected by certain environmental 
sources generating signals that resemble cardiac activity. In some cases the disturbance 
sources can couple sufficient energy to damage the insertable cardiac monitor. 
BIOTRONIK insertable cardiac monitors have been designed to significantly reduce 
susceptibility to disturbance sources. However, due to the variety and complexity of sources 
creating interference, there is no absolute protection against disturbance sources. Generally, it 
is assumed that disturbance sources produce only minor effects, if any, in insertable cardiac 
monitor patients. If the patient presumably will be exposed to one of the following 
environmental conditions, then the patient should be given the appropriate warnings. 
 
The following equipment (and similar devices) may affect normal insertable cardiac monitor 
operation: electric arc welders, electric melting furnaces, radio/television and radar 
transmitters, power generating facilities, high voltage transmission lines, electrical ignition 
systems (also of gasoline powered devices) if protective hoods, shrouds, etc., are removed, 
electrical tools, anti-theft devices of shopping centers and electrical appliances, if not in 
proper condition or not correctly grounded and encased. 
Patients should exercise reasonable caution in avoidance of devices which generate a strong 
electric or magnetic field. Some potential EMI sources include: 
High Voltage Power Transmission Lines - High voltage power transmission lines 
may generate enough EMI to interfere with insertable cardiac monitor operation if 
approached too closely. 
Home Appliances - Home appliances normally do not affect insertable cardiac 
monitor operation if the appliances are in proper condition and correctly grounded and 
encased. There are reports of insertable cardiac monitor disturbances caused by electrical 
tools and by electric razors that have touched the skin directly over the insertable cardiac 
monitor. 

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Communication Equipment - Communication equipment such as microwave 
transmitters, linear power amplifiers, or high-power amateur transmitters may generate 
enough EMI to interfere with insertable cardiac monitor operation if approached too closely. 
Commercial Electrical Equipment - Commercial electrical equipment such as arc 
welders, induction furnaces, or resistance welders may generate enough EMI to interfere with 
insertable cardiac monitor operation if approached too closely. 
Electrical Appliances - Electric hand-tools and electric razors (used directly over the 
skin of the insertable cardiac monitor) have been reported to cause insertable cardiac monitor 
disturbances. Home appliances that are in good working order and properly grounded do not 
usually produce enough EMI to interfere with the insertable cardiac monitor operation. 
Electronic Article Surveillance (EAS) - Equipment such as retail theft prevention 
systems may interact with the insertable cardiac monitor devices. Patients should be advised 
to walk directly through and not to remain near an EAS system longer than necessary. 
Cell Phones - Recent studies have indicated there may be a potential interaction between 
cellular phones and insertable cardiac monitor operation. Potential effects may be due to the 
radio frequency signal when the phone is within close proximity (within 6 inches [15 
centimeters]) to the insertable cardiac monitor. Based on testing to date, effects resulting 
from an interaction between cellular phones and the insertable cardiac monitors have been 
temporary. Simply moving the phone away from the inserted device will return it to its 
previous state of operation. 
To minimize such interactions, patients having an inserted cardiac monitor who operate a 
cellular phone should: 
• Maintain a minimum separation of 6 inches (15 centimeters) between a hand-held 
personal cellular phone and the inserted device. Portable and mobile cellular phones 
generally transmit at higher power levels compared to hand held models. For phones 
transmitting above 3 watts, maintain a minimum separation of 12 inches (30 
centimeters) between the antenna and the inserted device. 
• Patients should hold the phone to the ear opposite the side of the inserted device. 
Patients should not carry the phone in a breast pocket or on a belt over or within 6 
inches (15 centimeters) of the inserted device as some phones emit signals when they 
are turned ON but not in use (i.e., in the listen or standby mode). Store the phone in a 
location opposite the side of the cardiac monitor. 
 
4.9 
Packaging and Labeling 
 
The insertable monitor is shipped in a cardboard box, equipped with a quality control seal, 
and product information label. The label contains the model specifications, technical data, 
serial number, expiration date, and sterilization and storage information of the insertable 
monitor. The box contains a double container with the insertable monitor and product 
documentation. 
The insertable monitor and its accessories have been sealed in a container and gas sterilized 
with ethylene oxide. To assure sterility, the container should be checked for integrity prior to 
opening. If a breach of sterility is suspected, return the insertable monitor to BIOTRONIK. 

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The insertable monitor is packaged in two plastic containers, one within the other. Each is 
individually sealed and then sterilized with ethylene oxide. Due to the double packing, the 
outside of the inner container is sterile and can be removed using standard aseptic technique 
and placed on the sterile field. 
 
4.10 Receiving, Storage, Distribution and Return 
 
4.10.1 Receipt of Devices 
 
The Biomonitor 3 devices will be delivered directly to the study staff where they will be 
stored and inventoried. Biotronik will ship the devices directly to the study staff.  The 
devices will be stored in the study staff offices. Study staff will record receipt in the 
device accountability log. 
 
The designated study staff will count and verify that the shipment contains all the items noted 
in the shipping invoice. Any discrepancies, damaged or unusable devices in a given shipment 
will be documented in the study files. The sponsor-investigator will notify the supplier 
immediately of any discrepancies, damaged or unusable products. 
 
4.10.2 Storage 
 
Storage (temperature) - Recommended storage temperature range is -10° to 45°C (14°- 
113°F). Exposure to temperatures outside this range may result in insertable cardiac monitor 
malfunction. 
Temperature Stabilization - Allow the device to reach room temperature before 
programming or implanting the device. Temperature extremes may affect the initial device 
function. 
Storage - Store the device in a clean area, away from sources of disturbance to avoid damage 
to the device. 
 
4.10.3 Distribution of Study Device 
 
Biotronik will be providing the devices for implantation and no less than 5 devices will be 
stored for this specifical study protocol. Regular device inventory audits will be performed. 
This is done to ensure a sufficient supply for the study as well as ensure proper tracking of 
devices received and used. 
 
4.10.4 Return or Destruction of Device 
 
The device will not be used if the packaging is wet, punctured, opened or damaged because 
the integrity of the sterile packaging may be compromised. The device will not be used if an 
unpackaged insertable cardiac monitor is dropped onto a hard surface, The device will not be 
used if there noted damage on opening the package, or if the device is expired. All devices 
will be returned to Biotronik in exchange for a functional device. All device serial numbers 
will be recorded on implanation. 

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At routine intervals and at the completion of the study, there will be a reconciliation of 
devices shipped, devices utilized, and devices remaining. This reconciliation will be logged 
on the Device Accountability form, signed and dated. Any discrepancies noted will be 
documented, the sponsor-investigator will be notified and an investigation will be conducted 
to determine the cause of the discrepancy. Devices destroyed on site will be documented in 
the study files. 
 
5 Study Procedures 
Arrhythmias will be assessed via home monitoring through the Biomonitor 3 device. 
Superventricular tachycardia (SVT), ventricular arrhythmias (VA), bradycardia (<35bpm), 
heart block and atrial arrhythmias are considered of interest. 
 
Home Monitoring for arrythmias 
 
Telemetry tracings from the implantable monitor will be reviewed monthly or whenever an 
event occurs and/or a patient transmits data due to symptoms via remote assistance. 
 
Default transmission is data sent daily between 1:00AM and 2:00AM regardless of events. If 
there is a problem with transmission the device will alert the physician within 24 hours and 
this will help to maintain compliance of transmission. 
 
If no events occur the device will be interrogated prior to explantation at the end of the 6 
month monitoring period. 
 
The study investigators will be responsible for telemetry review. The patient’s treating 
cardiologist will be notified of events of clinical significance. Treatment of the arrhythmias 
will be based on current clinical guideline recommendations for bradycardia and VA. 
Clinical follow up will occur via standard of care clinical visits. 
 
SCD is defined as sudden and unexpected death within 1 hour of cardiac symptoms in the 
absence of progressive cardiac deterioration, unexpected death during sleep, or unexpected 
death within 24 hours after last being seen alive. Study participants who experience SCD while 
monitored and are successfully resuscitated after life-threatening VA will receive an 
implantable cardioverter defibrillator based on current clinical guidelines. These and other 
arrhythmic events recorded by the implantable monitor, or SCD that cannot be successfully 
resuscitated, will be considered events of interest and NOT adverse events, as these are not a 
consequence of monitoring via the implantable device. 
 
At the end of the 6 month monitoring period, the device will be explanted. Participants will 
be offered the choice to retain the device until battery end of life if clinically indicated. 
However, patients who opt to continue monitoring will be informed that their insurance 

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company will be billed for clinically indicated monitoring and explantation outside the study 
time frame.  
 
For any patients who expire during the study monitoring period, the terminal rhythm of 
participants who die will be reviewed remotely via the Biotronik website irrespective of 
whether the monitor can be retrieved. Patients will be informed of this possibility during the 
consent process. 
 
For stage III patients with existing ICD or pacemakers, rhythm monitoring will be obtained 
from the device over a 6 month timeframe and may be retrospective if applicable. 
 
Patients with existing implantable cardiac devices will undergo a device interrogation at enrollment and at the 
end of the 6 month monitoring period.   If available, records from interim routine and unscheduled clinical device 
interrogations during the 6 month monitoring period be requested for review by the investigators.  
 
 
Routine clinical follow up will be continued including clinically indicated ECHOs,ECGs, 
and blood work. 
 
Timeline for testing: 
An insertable monitor may be removed emergently at the investigator’s discretion at any time 
subsequent to an implant procedure. Reasons for removal include, but are not limited to: 
patient death; loss of sensing; inability to program/interrogate the inserted monitor; infection, 
EOS (normal or premature); or other reason(s). Complications related to other portions of the 
insertable monitor system may also result in insertable monitor removal. 
 
6 Statistical Plan 
Tests 
ECHO- TTE 
At baseline (clinical echo within 6 months of 
enrollment date) and scheduled as clinically 
indicated 
Biopsy or technetium 
pyrophosphate scintigraphy 
As clinically indicated, inclusion criteria for the 
study 
EKG 
Clinically indicated at baseline (within 6 months of 
enrollment) and when clinically indicated 
MRI with T1 
When clinically indicated 
Cardiopulmonary 
exercise 
test 
When clinically indicated 
Biomonitor 3 
Monitored with a clinically significant event 
NT proBNP 
When clinically indicated, inclusion criteria for the 
study based on clinically indicated testing 
Troponin T 
When clinically indicated, inclusion criteria for the 
study based on clinically indicated testing 
Labs: CBC, Basic Metabolic 
Panel, Mg 
When clinically indicated 
Urine pregnancy 
At baseline for women of child bearing potential 

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6.1 
Sample Size Determination 
This study is a pilot study, to assess the true arrhythmic burden seen in the TTR-wt 
population. This is a novel study design and no research exists. This study will provide the 
basis for future, larger scale trials. 

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6.2 
Statistical Methods 
Descriptive Statistics 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate 
for all variables. Baseline values for demographic, clinical, and outcome variables (primary 
and secondary) will be tabulated for the two groups. These analyses will help identify 
baseline clinical characteristics that may be associated with risk of sudden cardiac arrest or 
bradycardia requiring pacemaker implantation. 
 
Handling of Missing Data 
 
This is a prospective pilot study and all patients will be treated and monitored at Mayo Clinic 
in Rochester, MN. All clinically relevant data will stored in the Mayo Clinic electronic 
medical record (Epic). Data queries will be performed at the conclusion of the study to 
recover any missing data. 
 
Primary Hypothesis: 
 
The primary hypothesis that arrhythmogenesis and SCD risk in this population is influenced 
by amyloid cardiomyopathy stage rather than reduced left ventricular ejection fraction, which 
is often a marker of late disease and increased mortality due to heart failure, and that SCD due 
to asystole, rather than VA which could be treated with ICD. Conduction system disease 
causing heart block, atrial arrhythmias and VA leading to SCD may occur earlier in the disease 
process and treatment of AF, VA, and heart block could improve both morbidity and mortality. 
 
A Student’s t-test will be used to compare differences in arrhythmia burden between the 
patients in the two groups (early stage I-II vs stage III either with any implanted cardiac 
device). 
 
6.3 
Subject Population(s) for Analysis 
 
All-implanted population: Any subject enrolled into the study and had a device implanted. 
 
7 Safety and Adverse Events 
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form. Records of these events will be maintained and reports submitted to the 
appropriate regulatory committees per their requirements. Expected clinical adverse events 
and nonsignificant (not serious) clinical adverse events for the Biomonitor 3 will not be 
reported. Expected clinical adverse events and anticipated adverse device effects are those 
listed in Section 1.4.2 Anticipated Risks. 
 
We will gather information from the subject as soon after the occurrence as possible to 
decrease recall bias or omission. Use of a combination of both closed-ended questions as 

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well as open-ended responses may provide better information rather than only one or the 
other. 
 
The investigator and team will use lay language in the informed consent process to assure 
reliable information is being captured. Additionally subjects will be instructed to contact the 
investigator or study coordinator if the subject feels that they may possibly have experienced 
any adverse events between scheduled study visits or contacts. 
 
In addition, sponsors are required to report analyses of unexpected adverse device 
experiences to IRBs. FDA encourages efforts by investigators and sponsors to ensure that 
IRBs receive meaningful AE information. The ultimate goal is to provide more meaningful 
information to IRBs, particularly when sponsor analysis (including an analysis of the 
significance of the adverse event, with a discussion of previous similar events where 
appropriate) is made available to IRBs. 
 
7.1 
Definitions 
The only definition of an adverse event in the device regulations (21 CFR 812) is for an 
“Unanticipated Adverse Device Effect.” The regulations reference “Adverse Effects” and 
“Adverse Device Effects” may be either anticipated or unanticipated. Investigators will 
maintain records of all relevant observations including records concerning adverse device 
effects (whether anticipated or unanticipated), information and data on the condition of each 
subject upon entering and during the course of the investigation, including information about 
relevant previous medical history and the results of all diagnostic tests. 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, implantation of the device, or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
Adverse Effect (Event) 
Any infection at the site of the implantable device, excessive unstoppable bleeding or 
development of a hematoma requiring evacuation, or malfunction of the FDA approved 
device in a subject involved in this clinical trial. Malfunction of the device includes but is 
not limited loss of sensing; inability to program/interrogate the inserted monitor; or 
premature EOS. Complications related to other portions of the insertable monitor system 
may also result in insertable monitor removal. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 

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Any adverse event that results in hospitalization should be documented and reported as an 
unanticipated adverse device effect unless specifically instructed otherwise in this protocol. 
Any condition responsible for surgery should be documented as an adverse event if the 
condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances: 
 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful 
• 
Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study. 
 
Post-study Adverse Event 
 
All unresolved adverse events will be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the 
last scheduled visit, the investigator will instruct each subject to report any subsequent 
event(s) that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study. The investigator will notify the study regulatory 
sponsor of any death or adverse event occurring at any time after a subject has discontinued 
or terminated study participation that may reasonably be related to this study. The sponsor 
should also be notified if the investigator is aware of the development of problems, cancer or 
of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. 
 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: 
(1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, 
or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling 
change) that in the opinion of the local investigator may adversely affect the rights, 
safety, or welfare of the subjects or others, or substantially compromise the research 
data, AND 

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• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
Adverse Event Reporting Period 
 
 
1. Patients will be monitored for 6 months and all adverse events withing the 6 month time frame will be 
recorded.  If patients choose to retain the monitor, all subsequent monitoring will be clinically indicated.   
 
 
7.2 
Recording of Adverse Events 
Study subjects will be routinely questioned about adverse effects at study visits. Information 
on all adverse events will be recorded immediately in the source document, and also in the 
appropriate adverse event section of the case report form (CRF). All clearly related signs, 
symptoms, and abnormal physical exam of the implant site will be recorded in the source 
document. 
 
All adverse events occurring during the study period will be recorded. All observed or 
volunteered adverse effects (serious or non-serious) will be recorded in the subjects’ case 
history. For all adverse effects sufficient information will be pursued and or obtained as to 
permit; an adequate determination of the outcome, an assessment of the casual relationship 
between the adverse effect and the device. The clinical course of each event will be followed 
until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause. 
 
The only laboratory values that will prompt an investigation would be an elevated 
leukocytosis IN ADDITION to a physical inspection of the implanted site. If the implanted 
site is erythematous, hot, swollen, or there is drainage from the skin would further steps need 
to be taken to possibly extract the device. Positive blood cultures would indicate the 
necessity of a physical exam and inspection of the implant site. 
 
A form will be created for capturing information related to adverse events and submitted to 
the IRB. 
Adverse Event CRF: 
• Subject Study Number/Identifier 
• Device information (model and serial number) 
• Date of event onset 
• Description of the event 
• Indicate if device needed to be explanted 
• Subject current status, or if the event was resolved 
• Principal Investigator assessment of if the event was serious and justification for 

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determination 
• Principal Investigator assessment of causality and relationship to study treatment. 
 
7.3 
Sponsor-Investigator Reporting of Unanticipated Adverse Device Effects and 
Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log. The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required. 
 
The sponsor-investigator will promptly review documented Unanticipated Adverse Device 
Effects and as necessary shall report the results of such evaluation to FDA within 10 working 
days and Mayo IRB within 5 working days of initial notice of the effect. Thereafter the 
sponsor-investigator will submit such additional reports concerning the effect as requested. 
 
7.3.1 Sponsor-Investigator Reporting, Notifying Mayo IRB 
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
Deviations from the investigational plan. 
 
The sponsor-investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any 
deviation from the investigational plan to protect the life or physical well-being of a subject 
in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by 
the sponsor-investigator is required for changes in or deviations from a plan, and if these 
changes or deviations may affect the scientific soundness of the plan or the rights, safety, or 
welfare of human subjects, FDA and IRB notification in accordance with 21 CFR 812.35(a) 
also is required. 
 
7.4 
Stopping Rules 
The study involves implantation of an FDA approved monitoring device to monitor 
arrhythmias and does not provide any treatment. If frequent adverse events occur with 
implantation of the monitoring device that require early explantation (i.e. frequent infection), 
the study will be stopped. 
 
7.5 
Medical Monitoring 
 
The sponsor-investigator will oversee the safety of the study. This safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan. 

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8 Data Handling and Record Keeping 
8.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
(This information is contained within the Mayo IRB Informed Consent Template Section 12) 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term 
survival status that the subject is alive) at the end of their scheduled study period. 
 
8.2 
Source Documents 
 
Source data comprise all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. Our source documents include original 
documents, and data records including hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents. 
 
All data will be stored in the Mayo Clinic electronic medical record, and any data relevant to 
the study will be entered into the study database stored on secure Mayo Clinic servers which 
is compliant with the FDA’s electronic records and electronic signatures regulations at 21 
CFR Part 11. 
 
8.3 
Case Report Forms 
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study. The investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. 
 
The study case report form (CRF) is the primary data collection instrument for the study. All 
data requested on the CRF must be recorded. All missing data must be explained. If a space 

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on the CRF is left blank because the procedure was not done or the question was not asked, it 
will be recorded as “N/D”. If the item is not applicable to the individual case, write “N/A”. 
CRFs are electronic and are incorporated into the 
 
Data Management 
 
The data will be stored and managed as per protocol at the Mayo Clinic. 
 
Data Processing 
 
This is a single center study. All data will be entered monthly for all patients without 
arrhythmias and data will be entered within a week of a clinically relevant arrhythmic 
occurrence. 
 
Data Security and Confidentiality 
 
This is a single site study. The Mayo Clinic, Rochester, MN campus, is a major referral 
center for amyloidosis. Data security is of utmost concern at Mayo Clinic and data 
security and confidentiality will be maintained in accordance of Mayo Clinic standards. 
 
Data Quality Assurance 
 
Data will be entered into a RedCap secure database by the same person entering data on the 
CRFs. This data will be reviewed by one additional person on the protocol. 
 
Data Clarification Process 
 
Any questions about data will be address by the study coordinator or the person entering 
data. 
 
8.4 
Records Retention 
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study. These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for: 
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717, 
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
The investigator will allocate adequate time for such monitoring activities. The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit. 

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Data and safety monitoring provides a clinical investigation with a system for appropriate 
oversight and attention to the protection of human subjects by the investigator, research team, 
or an independent reviewer. A Data and Safety Monitoring Plan is a quality assurance plan 
for a research study. A written Data and Safety Monitoring Plan (DSMP) has been created. 
 
Clinical trial monitoring may include review of the study documents and data generated 
throughout the duration of the study to help ensure the validity and integrity of the data along 
with the protection of human research subjects. This will assist sponsor-investigators in 
complying with Food and Drug Administration regulations. 
 
9.2 
Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the monitor, and government regulatory agencies, of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.). The 
sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable compliance offices. 
 
10 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study. The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for review 
and approval by the IRB for the study. The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure. The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
 
11 Study Finances 
11.1 Funding Source 
The study is financed through Pfizer, Mayo Clinic and Biotronik. 
 
12 Publication Plan 
 
Study results will be published on completion of the study. 
 

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