Cardiac Amyloidosis Registry Study - A Multi-Center, Longitudinal, Observational Survey of Patients With Cardiac Amyloidosis
Conditions: Amyloidosis, Immunoglobulin Light-chain
Sponsor: Cedars-Sinai Medical Center

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Cardiac Amyloidosis Registry Study ("CARS") 
Version: Amendment 5  
 10Aug2023 
 
NCT05174338 
 
Jignesh Patel, MD PhD 
Cedars-Sinai Medical Center 

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Contents 
1.0 Summary of Changes 
2.0 Background, Rationale _____________________________________________________________ 3 
3.0 Study Objectives __________________________________________________________________ 6 
4.0 Study Design and Procedures ________________________________________________________ 6 
4.1 Study Type ________________________________________________________________ 6 
4.2 Date Range of Study ________________________________________________________ 7 
4.3 Total Number of Study Sites/Total Number of Subjects Projected _____________________ 7 
4.4 Record Review and Data/Specimen Sources ______________________________________ 7 
5.0 Eligibility/Subject Enrollment _______________________________________________________ 8 
5.1 Inclusion Criteria ___________________________________________________________ 8 
5.2 Exclusion Criteria __________________________________________________________ 8 
6.0 Data Collection and Management _____________________________________________________ 8 
6.1 Data/Specimen Storage ______________________________________________________ 8 
6.2 Confidentiality of Data ______________________________________________________ 9 
6.3 Security __________________________________________________________________ 9 
7.0 Data/Specimen Analysis and Statistical Plan (optional) ____________________________________ 9 
7.1 Statistical Plan _____________________________________________________________ 9 
7.2 Primary and Secondary Endpoints ______________________________________________ 9 
7.3 Statistical Methods __________________________________________________________ 9 
7.4 Sample Size and Power ______________________________________________________ 9 
Appendix 1  
 
 
 
 
 
 
 
 
 
 
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References _________________________________________________________________________ 10 
 
 

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1.0 Summary of Changes 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 4.3 
Total Number 
of Study 
Sites/Total 
Number of 
Subjects 
Projected 
Number of collaborating sites has increased.  
The total number of participating sites is yet 
to be determined.   
List of participating sites have been 
updated in appendix 1.  
Appendix 1 
Addition of participating sites to appendix 1. 
Updated appendix 1 to include 
additional sites that have joined the 
registry.  
 
Protocol Amendment 4 Changes 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 4.3 
Total Number 
of Study 
Sites/Total 
Number of 
Subjects 
Projected 
Added number of collaborating sites. The 
total number of participating sites is yet to be 
determined.   
List of participating sites have been 
entered in appendix 1.  
Section 5.2 
Exclusion 
Criteria 
For external sites, records that indicate No 
Research Flag or are noted as “Break the 
Glass” may be included based on institutional 
policies and appropriate approvals, as 
applicable. 
Sites to follow local institutional 
policies based on “Break the Glass” 
records.  
Appendix 1 
Addition of participating sites to appendix 1. 
Updated appendix 1 to include 
additional sites that have joined the 
registry.  
 
Protocol Amendment 3 Changes 

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Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 4.3 
Total Number 
of Study 
Sites/Total 
Number of 
Subjects 
Projected 
Added number of collaborating sites. The 
total number of participating sites is yet to be 
determined.   
List of participating sites have been 
entered in appendix 1.  
Section 6.2 
Confidentiality 
of Data 
Registration of study in ClinicalTrials.gov  
Registration of this observational 
study in ClinicalTrials.gov for 
publication purposes.  
Throughout 
Protocol 
Changing de-identified to limited data set 
Edits made to clarify that the data 
captured and entered in redcap will 
include identifiers.  
Appendix 1 
Addition of appendix 1. 
Appendix 1 added to list all 
participating sites as this is a multi-
center registry.  
 
2.0 Background, Rationale 
   Amyloidosis is a rare, multisystem disorder in which normally soluble protein is 
deposited in tissues, leading to organ dysfunction.  Several proteins have been identified 
to potentially lead to amyloid cardiomyopathy (AC). The most commonly encountered 
abnormal proteins are due to excess immunoglobulin light chain (AL) resulting from 
plasma cell dyscrasia in the bone marrow and transthyretin, a transport protein produced 
by the liver. Amyloidosis due to transthyretin typically occurs either as wild type 
(normal) transthyretin (ATTRwt) or mutant transthyretin (ATTRm) protein sequence. 
More than 120 mutations have been reported that lead to ATTRm with certain mutations 
having a propensity to lead to a predominant clinical phenotype of AC and others causing 
a predominantly neuropathic phenotype. ATTRwt (previously known as senile systemic 
amyloidosis) typically affects older male patients. ATTRm generally presents at an 
earlier age and is inherited in an autosomal dominant trait. Transthyretin is a 127 amino 
acid protein which circulates as a tetramer and carries the thyroid hormone thyroxine and 
retinol-binding protein bound to retinol. The pathogenicity of ATTR is related to the 
instability of the tetramers which exist in equilibrium with its constituent monomers. The 
monomers misfold to form prefibrillar proteins which then aggregate to form amyloid 
fibrils which deposit in various organs with a particular predilection for but not limited 
to, the heart and nervous system. The mechanisms of injury are not entirely understood. 
There are data to suggest that the pre-fibrillar protein aggregates may also directly 
contribute to organ toxicity. Light chain proteins seem to provoke direct oxidative stress 

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as well as apoptosis in cardiomyocytes. The deposition of misfolded proteins leads to 
stiff, non-compliant, myocardium and the extracellular space is expanded by deposits, 
causing myocardial hypertrophy and restrictive cardiomyopathy with diastolic 
abnormalities observed on echocardiography.  Beyond diastolic abnormalities, atrial 
arrhythmias, pericardial and pleural effusions are frequently observed. In systemic 
amyloidosis, findings can include neuropathy, nephrotic syndrome, macroglossia, carpal 
tunnel syndrome, and bleeding, can be seen due to fibril deposition in various tissue beds.  
 
    The prognosis of patients with either AL or ATTR cardiomyopathy depends on the 
extent and severity of organ involvement although overall, untreated AL has a much 
more rapidly progressive course. Kumar et al reported on an updated prognostic staging 
system for patients with cardiac AL amyloidosis identifying three independent predictors 
of mortality: (1) the difference between involved and uninvolved light chains (2) cardiac 
troponin T, and (3) NT-proBNP. Overall survival significantly decreased for each 
additional biomarker above the cutoff values.  This scoring system predates the use of 
proteasome inhibitors such as bortezomib and therefore limits its contemporary 
applicability. Beyond the use of biomarkers, the degree of late gadolinium enhancement 
seen on cardiac magnetic resonance has prognostic utility for long-term mortality in both 
AL and ATTR.  
    
   Median survival in a single-center study of patients with ATTRwt was 3.6 years with 
outcomes remaining static over the last 30-40 years. The authors report on three stages of 
disease based on whether cardiac biomarker values were above or below an NT-proBNP 
and/or troponin T cutoff. Four-year overall survival worsened with increasing stage. For 
ATTRm, untreated survival ranges between 2 and 15 years and dependent upon mutation 
sub-type. The V122I or valine to isoleucine mutation is the most common sub-type in the 
US and carries an 80% survival at 1 year and 28% at 5 years, respectively. Updated 
scoring systems and prognostication models will be necessary for AL and ATTR as novel 
therapies bend survival curves. 
    
   Rapezzi et al. reported that, of patients diagnosed with systemic amyloidosis, 51% of 
patients with AL and 34% of patients with TTR amyloid demonstrated evidence of 
cardiac amyloidosis, often with rapid progression to heart failure. Therefore, detailed 
characterization of AL and TTR cardiac amyloidosis and the development of effective 
treatment plans offering long-term survival for both diseases are of vital importance.    
    
    The recent availability of tafamidis for ATTR cardiomyopathy and patisiran and 
inotersen for hereditary ATTR neuropathy will affect outcomes in patients and the impact 
of these therapies will need to be assessed. Similarly, for AL amyloidosis, significant 
advances in chemotherapy and autologous stem cell transplantation have led to improved 
survival.   
    

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 Patients with end-stage cardiac disease may however need to be considered for advanced 
therapies including mechanical circulatory support and heart transplantation. 
   
   Given the rare nature of these diseases, a large, multi-center effort to describe the 
characteristics of these patients and their outcomes with these novel treatment modalities 
has not been established.  This multi-center effort will represent the largest collection of 
AL and TTR cardiac amyloidosis to date. (TBD) academic medical centers from the US 
will compile demographic, hemodynamic and organ-involvement data, as well as 
treatment strategies for AL and TTR amyloidosis. 
 
3.0 Study Objectives 
• Increase understanding of disease presentation, progression, and various treatment 
plans for AL and TTR cardiac amyloid through study of a large cohort of patients 
with AL and TTR amyloidosis. 
• Identify demographic, hemodynamic, and organ-involvement data that are predictors 
of long-term survival. 
• Compare the disease presentation, treatment strategies, and relative survival of AL 
and TTR amyloidosis patients, including patients listed for heart transplant. 
• Compare the use of therapeutic treatment modalities and their effect on long-term 
survival. 
• Compare the presentation and relative survival corresponding to different TTR 
mutations. 
• Analysis of diagnostic procedures 
 
Note: as the study develops and the transfer of data shows to be successful, additional 
data points will be identified to support the objectives. Only data points consistent 
with the research objectives will be obtained.  
 
4.0 Study Design and Procedures 
 
 
4.1 Study Type 
 
At all sites 
This registry is an observational, multi-center study designed to collect data and analyze 
it retrospectively on patients with AL or TTR cardiac amyloidosis who have been 
evaluated and treated at major amyloid centers across the US and internationally between 
1997 and 2025. Patients will be identified by the investigator and/or study team using 
established IRB-approved local databases. Where this is not available, subjects under the 
care of the local investigator will be identified and consented. No patient visits or patient 
procedures will be required for the purpose of this study. Data will be abstracted from the 
patients’ medical records from the time of presentation through most recent follow-up.   
 
At all sites (excluding Cedars-Sinai Medical Center) appropriate consent will be sought 
or justification for a waiver must be provided for the collection of data for purposes of 

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this registry. Sites are to obtain IRB approval through Western Institutional Review 
Board® (WIRB®) or through their local Institutional Review Board.    
 
 
At Cedars-Sinai Medical Center (CSMC) 
Cedars-Sinai data will include data that has been or will be collected under the Advanced 
Heart Disease registry (Pro00022311). The research activities at CSMC for this study 
directly fall under the consent obtained from subjects for inclusion in the Advanced Heart 
Disease registry. Therefore, consent for this study was obtained under a separate protocol 
at CSMC and all CSMC subjects provided consent to be included in this registry. As 
such, Western Institutional Review Board® (WIRB®) will not require consent for 
CSMC. Data from deceased individuals treated at CSMC will be included if appropriate 
consent was already obtained under the Advanced Heart Disease registry before their 
death.  
 
Confidential REDCap data will be stored and transferred between the existing Advanced 
Heart Registry and the new Heart Amyloidosis Registry. Primary identifiers including 
dates (year of birth, gender, age at presentation) will be recorded; however, these 
identifying dates will be used only in analysis to report duration between events and will 
not be reported in raw form.  
 
 
4.2 Date Range of Study 
The study population will include all adults evaluated at CSMC and collaborating 
institutions between 1997 and 2025.  Cases will be included from 1997 to 2025. Follow-
up information through end of study will be included.  
 
Data will be obtained from 1997 through 2025, meaning that some patients may be seen 
on an ongoing basis. 
 
 
4.3 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at multiple sites in the United States and internationally. 
Currently there are 25 additional sites participating in the United States. The total number 
of collaborating sites is yet to be determined. The participating sites are listed in appendix 
1. It is expected that the total patient population will be approximately 5,000 patients. 
 
4.4 Record Review and Data/ Sources 
Data that will be abstracted from the patients’ medical records are listed on the attached 
document: Data Chart Extraction Variables. Patients will be identified by the investigator 
and/or study team using established IRB-approved local databases. Where this is not 
available, subjects under the care of the local investigator will be identified and 
consented. Access to local electronic medical records may be required and where 
necessary, local IRB approval will be obtained. 
 
 

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5.0 Eligibility/Subject Enrollment 
 
 
5.1 Inclusion Criteria 
• Males and Females ages 18+  
• Established diagnosis of AL or TTR cardiomyopathy identified or treated within 
the timeframe 
• Specific to CSMC: If the individual provided consent while they were alive for 
the Advanced Heart Disease registry (Pro00022311), and if sufficient information 
exists in their chart, their data will be included. 
•  Information on deceased individuals may be included, but only with the 
appropriate approval from the external site IRB and/or according to the federal 
regulations for the protection of human subjects. 
 
 
5.2 Exclusion Criteria  
• 
At Cedars-Sinai, records that specifically state not to be used in research will not 
be accessed. Patients who have enacted a No Research Flag or are noted as 
“Break the Glass” will not be included.  For external sites, records that indicate 
No Research Flag or are noted as “Break the Glass” may be included based on 
institutional policies and appropriate approvals, as applicable.  
 
 
6.0 Data Collection and Management 
 
 
6.1 Data/ Storage 
Following chart abstraction of patient data at each clinical center, a limited data set 
will be shared with Cedars-Sinai Medical Center, the project administrator, through 
secure data entry in the CSMC REDCap database built for the registry which has 
secure web authentication and Secure Sockets Layer (SSL) encryption. No identifiers 
will be included in data transferred from one institution to another. Lists linking 
identifiers to data will be maintained for each institution and will not be shared with 
external institutions or sites. Each institution will gain access to the approved 
REDCap project, hosted by Cedars-Sinai, after the collaboration agreement is fully 
executed and WIRB or local IRB approval is obtained. 
Cedars-Sinai, acting as the project administrator, will maintain overall responsibility 
for database integrity.  Each participating academic center will designate which 
members of their study team need access the Redcap study database for data entry  
purposes.  Each participating center will submit their research proposals involving the 
registry data from all participating sites using the online proposal form provided by 
Cedars Sinai. All such research proposals will have to be reviewed and approved 
during scheduled or ad-hoc Investigator meetings. Prior to release of any publications 

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and or presentations, the manuscript or presentation would be distributed to the 
consortium for comments and or edits. 
All compiled data (limited data set) will be kept in the REDCap database to allow for 
institution-specific updates to patient data and for the addition of new patients 
evaluated and or listed for transplant at each institution. Data will be collected and 
kept for 10 years following the establishment of the database. Upon study completion, 
the secured database will be digitally locked to new additions and will remain 
encrypted.  
 
6.2 Confidentiality of Data  
To ensure the safety and integrity of the data collected in the study, all data will be 
stored securely in a REDCap database to which only the principal investigator, co-
investigators and study coordinators will have access. Data will be collected as a 
limited data set prior to entry into the RedCap database by local IRB approved study 
team. A separate local spreadsheet will be created by data extractors including only 
those identifiers needed to abstract the medical record. Identifier data elements will 
only be recorded on this spreadsheet as necessary to achieve the research purpose. 
This spreadsheet must be maintained securely, and access will be limited to the local 
co-investigator and study team. If any physical research records exist, they will be 
maintained in a secure location where access will also be limited to approved 
personnel at the local participating institution or site. 
 
A description of this registry is available on www.ClinicalTrials.gov, for publication 
purposes.  
 
 
6.3 Security   
All REDCap data will be stored on Cedars-Sinai’s servers and is 21 CFR part 11 
compliant.    
 
7.0 Data/Specimen Analysis and Statistical Plan (N/A FOR THIS REGISTRY) 
 
 
7.1 Statistical Plan 
 
 
7.2 Primary and Secondary Endpoints 
 
 
7.3 Statistical Methods 
 
 
7.4 Sample Size and Power 
 
 
 
 
 
 

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Appendix 1: List of Collaborating Sites  
Additional sites to be added. 
 
Columbia University 
New York, NY 
University of California, Davis  
Davis, CA 
Duke University  
Durham, NC 
University of California, San Francisco 
San Francisco, CA 
St. Luke Health System 
Kansas City, MO 
UT Health Science Center at Houston 
Houston, TX 
University of Arizona 
Tucson, AZ 
UT Southwestern Medical Center  
Dallas, TX 
Boston Medical Center  
Boston, MA 
Mount Sinai Medical Center  
New York, NY  
Johns Hopkins University 
Baltimore, MD  
Medical University of South Carolina  
Charleston, SC 
NYU 
New York, NY 
Scripps Health  
San Diego, CA 
Washington University  
St. Louis, MO 
Tufts Medical Center  
Boston, MA 
University of San Diego  
San Diego, CA 
University of Pennsylvania  
Philadelphia, PA 
Massachusetts General Hospital 
Boston, MA 
University of Utah  
Salt Lake City, UT 
MedStar Health and Vascular 
Institute/Georgetown University 
School of Medicine 
Washington, D.C. 
Cornell University 
Ithaca, New York 
Thomas Jefferson University  
Philadelphia, Pennsylvania 
University of Calgary 
Calgary, Alberta 
University of Washington 
Seattle, Washington 
 
 
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Zamagni E, Fonte ML, Palladini G, Salinaro F, Musca F, Obici L, Branzi A, Perlini S.  
Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 maintypes.  
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