Transthyretin Amyloidosis Outcomes Survey (THAOS): A Global, Multi-Center, Longitudinal, Observational Survey of Patients With Documented Transthyretin Gene Mutations or Wild-Type Transthyretin Amyloidosis.
Conditions: Transthyretin Gene Mutations, Transthyretin Amyloidosis
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL 
PASS Information 
 
Title 
Transthyretin Amyloidosis Outcomes 
Survey (THAOS): A Global, Multi-Center, 
Longitudinal, Observational Survey of 
Patients With Documented Transthyretin 
Gene Mutations or Wild-Type Transthyretin 
Amyloidosis 
Protocol number 
B3461001 
Protocol version identifier 
Protocol Amendment 5, 13 July 2020 
Date of last version of protocol 
07 July 2015 
Active substance 
N07XX08 tafamidis 
Medicinal product 
tafamidis 
Product reference 
EU/1/11/717/001-004 
Procedure number 
EMEA/H/C/002294/XX 
Marketing Authorization Holder (MAH) 
Pfizer Europe MA EEIG 
Joint Post-Authorization Safety Study 
(PASS) 
No 
Research question and objectives 
The Transthyretin Amyloidosis Outcomes 
Survey (THAOS) is a longitudinal, 
observational survey open to all patients 
with transthyretin- amyloidosis and 
participants with transthyretin (TTR) gene 
mutations without a diagnosis of 
transthyretin amyloidosis (ATTR 
amyloidosis). To date, limited data are 
available on the natural history of the 
hereditary and wild-type forms of the 
disease, including the regional differences in 
disease expression by TTR variants and non- 

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This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
mutated TTR, and the genotypic-phenotypic 
relationship in ATTR amyloidosis. 
The principal aims of the outcome survey 
are to better understand and characterize the 
natural history of the disease by studying a 
large and heterogeneous patient population. 
Country(ies /Regions of study 
Argentina, Australia, Austria, Belgium, 
Brazil, Bulgaria, Canada, Cyprus, Denmark, 
France, Germany, Greece, Israel, Italy, 
Japan, Korea, Luxembourg, Macedonia, 
Malaysia, Mexico, Netherlands, People’s 
Republic of China, Portugal, Republic of 
China, Taiwan, Romania, Spain, Sweden, 
Switzerland, Turkey, United States 
Author 
PPD 
Marketing Authorisation Holder(s) 
 
Marketing Authorisation Holder(s) 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
MAH contact person 
PPD 
Work Telephone: PPD 
Mobile Telephone: PPD 
Email: PPD 
 
 

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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS ...................................................................................................... 3 
2. LIST OF ABBREVIATIONS ............................................................................................... 6 
3. RESPONSIBLE PARTIES ................................................................................................... 8 
4. ABSTRACT .......................................................................................................................... 9 
5. AMENDMENTS AND UPDATES .................................................................................... 11 
6. MILESTONES .................................................................................................................... 18 
7. RATIONALE AND BACKGROUND ............................................................................... 18 
7.1. Disease Background ............................................................................................... 18 
7.2. Rationale for the Survey ......................................................................................... 20 
7.3. Role of THAOS in the Tafamidis European Union Post-Marketing 
Commitment ............................................................................................................. 21 
8. RESEARCH QUESTION AND OBJECTIVES ................................................................. 21 
9. RESEARCH METHODS .................................................................................................... 22 
9.1. Study Design ........................................................................................................... 22 
9.1.1. Study Treatment and Duration ................................................................... 23 
9.2. Setting ..................................................................................................................... 23 
9.2.1. Inclusion Criteria ........................................................................................ 23 
9.2.2. Exclusion Criteria ...................................................................................... 24 
9.2.3. Genotyping ................................................................................................. 24 
9.3. Variables ................................................................................................................. 24 
9.3.1. Study Assessments ..................................................................................... 24 
9.3.2. Safety Assessments .................................................................................... 25 
9.3.3. Eligibility/Baseline Visit ............................................................................ 26 
9.3.4. Return Visit ................................................................................................ 26 
9.3.5. Retrospective Visit ..................................................................................... 27 
9.3.6. Final Visit ................................................................................................... 27 
9.4. Data Sources ........................................................................................................... 27 
9.5. Study Size ............................................................................................................... 27 
9.6. Data Management ................................................................................................... 27 
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic 
Data Record ..................................................................................................... 27 

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9.6.2. Record Retention ........................................................................................ 28 
9.7. Data Analysis .......................................................................................................... 29 
9.7.1. Statistical Methods ..................................................................................... 29 
9.7.2. Data Summaries ......................................................................................... 29 
9.7.3. Scientific Board .......................................................................................... 29 
9.7.4. Interim Analyses ........................................................................................ 30 
9.8. Quality Control ....................................................................................................... 30 
9.8.1. Data Editing ............................................................................................... 30 
9.8.2. Audits ......................................................................................................... 30 
9.8.3. THAOS Electronic Clinical Database ........................................................ 30 
9.9. Limitations of the Research Methods ..................................................................... 30 
9.10. Other Aspects ........................................................................................................ 31 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................ 31 
10.1. Patient Information ............................................................................................... 31 
10.2. Patient Consent ..................................................................................................... 31 
10.2.1. Participation in Investigational Clinical Trials ........................................ 32 
10.3. Patient Withdrawal ............................................................................................... 33 
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............ 33 
10.5. Ethical Conduct of the Study ................................................................................ 33 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS FOR TAFAMIDIS-TREATED SUBJECTS ............................................... 34 
11.1. Requirements ........................................................................................................ 34 
11.2. Reporting Period ................................................................................................... 35 
11.3. Causality Assessment ........................................................................................... 36 
11.4. Definitions of Safety Events ................................................................................. 36 
11.4.1. Adverse Events ........................................................................................ 36 
11.4.2. Abnormal Test Findings ........................................................................... 37 
11.4.3. Serious Adverse Events ........................................................................... 37 
11.5. Hospitalization ...................................................................................................... 38 
11.6. Scenarios Necessitating Reporting to Pfizer Safety within 24 Hours .................. 39 
11.6.1. Exposure During Pregnancy .................................................................... 39 
11.6.2. Exposure During Breastfeeding ............................................................... 40 

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11.6.3. Medication Error ....................................................................................... 40 
11.6.4. Overdose, Misuse, Extravasation .............................................................. 41 
11.6.5. Lack of Efficacy ........................................................................................ 41 
11.6.6. Occupational Exposure ............................................................................. 41 
11.7. Single Reference Safety Document ....................................................................... 41 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ........ 41 
12.1. Communication and Publication of Study Results ................................................ 41 
13. REFERENCES ................................................................................................................... 43 
14. LIST OF TABLES ............................................................................................................. 46 
15. LIST OF FIGURES ............................................................................................................ 46 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ......................................................... 46 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .......................................... 46 
ANNEX 3. ADDITIONAL INFORMATION ......................................................................... 46 

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2. LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse event 
ATTR 
Amyloid fibril protein derived from misfolded TTR 
ATTR amyloidosis 
Disease resulting from deposition of ATTR 
ATTR-CM 
Transthyretin amyloid cardiomyopathy (formerly TTR-CM, or 
Senile Systemic Amyloidosis) 
ATTRm 
ATTR due to a hereditary mutation 
ATTR-PN 
Transthyretin amyloid polyneuropathy (formerly TTR-FAP) 
ATTRwt 
ATTR due to wild type mutation 
CHMP 
Committee for Medicinal Products for Human Use 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case Report Form 
CSR 
Clinical study agreement 
DCTs 
Data collection tools 
EDP 
Exposure During Pregnancy 
EMA 
European Medicines Agency 
EMEA 
European Medicines Evaluation Agency 
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
CCI 
 
EU 
European Union 
EU-CHMP 
European Union Committee for Medicinal Products for Human 
Use 
FAC 
Familial Amyloid Cardiomyopathy 
FAP 
Familial Amyloid Polyneuropathy 
FDA 
Food and Drug Administration 
GFR 
Glomerular Filtration Rate 
GPP 
Good Pharmacoepidemiology Practices 
ICH 
International Conference on Harmonization 

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Abbreviation 
Definition 
IRB/IEC 
Institutional Review Board /Independent Ethics Committee 
ISPE 
International Society for Pharmacoepidemiology 
ISPOR
International Society for Pharmacoeconomics and Outcomes 
Research 
CCI 
 
NI 
Non-interventional 
NIS AEM 
Non-Interventional Study Adverse Event Monitoring 
CCI 
 
 
 
PhRMA 
Pharmaceutical Research and Manufacturers Association 
PASS 
Post-Authorization Safety Study 
PI 
Principal Investigator 
QoL 
Quality of life 
RMP 
European Medicines Agency Risk Management Plan 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SSA 
Senile Systemic Amyloidosis 
TESPO 
Tafamidis Enhanced Surveillance for Pregnancy Outcomes 
THAOS 
Transthyretin Amyloidosis Outcomes Survey 
TTR 
Transthyretin 
TTR-CM 
Transthyretin cardiomyopathy (now ATTR-CM) 
TTR-FAP 
Transthyretin familial amyloid polyneuropathy (now ATTR-PN) 
US 
United States 
UTI 
Urinary Tract Infection 
Val30Met 
Substitution of methionine for valine at position 30 

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3. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
The contact details for the Principal Investigators in the Transthyretin Amyloidosis 
Outcomes Survey (THAOS) are available upon request. 
Country Coordinating Investigators 
The contact details for the Principal Investigators who serve as the Country Coordinating 
Investigators in the Transthyretin Amyloidosis Outcomes Survey (THAOS) are available 
upon request. 

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4. ABSTRACT 
Transthyretin Amyloidosis Outcomes Survey (THAOS): A Global, Multi-Center, 
Longitudinal, Observational Survey of Patients With Documented Transthyretin Gene 
Mutations or Wild-Type Transthyretin Amyloidosis (Amendment 5; 13 July 2020, 
PPD 
 ) 
RATIONALE AND BACKGROUND: Transthyretin (TTR) amyloidosis is a rare disease 
caused by dissociation of the transthyretin tetramer into monomers, which misfold, 
ultimately forming amyloid deposits in various organs. This structural instability of the TTR 
tetramer can occur due to genetic mutations of the gene encoding the TTR protein or can be 
associated with aging. There are over 120 known mutations of TTR gene, which result in 
variable phenotypic expressions of amyloidosis that commonly affect the peripheral nerves, 
heart, kidney or eye. 
The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a longitudinal, observational 
survey open to all patients with TTR gene mutations without a diagnosis of ATTR 
amyloidosis and to patients diagnosed with ATTR amyloidosis (inclusive of ATTR-PN and 
ATTR-CM). To date, limited data are available on the natural history of the hereditary 
(ATTRm) and wild-type (ATTRwt) forms of the disease, including the regional differences 
in disease expression by TTR variants and non-mutated TTR, and the genotypic-phenotypic 
relationship in ATTR amyloidosis. 
The principal aims of the outcome survey are to better understand and characterize the 
natural history of the disease by studying a large and heterogeneous patient population. 
Survey data may be used to develop new treatment guidelines and recommendations, and to 
inform and educate clinicians about the management of this disease. 
The survey can also generate descriptive safety summaries using adverse and serious adverse 
event (AE/SAE) data in tafamidis-treated participants. 
RESEARCH QUESTION AND OBJECTIVES: The objectives of THAOS are to describe 
the population of patients affected with ATTR amyloidosis and to enhance the understanding 
of the disease natural history, including the variability and progression of the hereditary and 
acquired forms of disease. 
STUDY DESIGN: THAOS is a non-interventional, global, multi-center, longitudinal 
observational survey open to all patients with ATTR amyloidosis, including both inherited 
and wild-type forms of disease, and participants with TTR gene mutations without disease 
diagnosis. There is no set number of patients who will be enrolled. The study has been open 
since 2007 and will continue until Pfizer declares the study complete (currently estimated to 
be the year 2023) or as long as patients are able to participate, or until they withdraw consent. 
THAOS does not involve the administration of an investigational agent or other intervention. 
Patients will continue to receive their current medications and all other standard care for their 
disease. It is recommended that patient assessments be conducted at least annually and be 
recorded in the THAOS electronic data record close to the time they are performed. 

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Treatment with tafamidis or with other disease modifying therapies will be according to the 
product label with commercially available product or according to protocol-specified 
requirements if a participant is enrolled in a tafamidis interventional study. 
In addition to routine procedures for standard of care, patients will be asked to complete 
patient outcome questionnaires at least annually; these are optional and do not affect a 
patient’s eligibility to participate in the survey. 
The survey will be conducted at sites worldwide. 
POPULATION: The study population includes patients with confirmed hereditary or 
wild-type ATTR amyloidosis and those with TTR gene mutation without a diagnosis of 
ATTR amyloidosis. 
VARIABLES: A series of assessments will be used to assess disease progression and the 
effects of tafamidis treatment including patient demographics, TTR genetic test results, 
family disease history, medical history, annual medical assessment, general examination, 
concomitant medications, hospitalizations, transplant history and complications, AE/SAE 
reporting for tafamidis-treated subjects, events of interest, clinical laboratory data, urinalysis, 
cardiovascular assessments, neurologic assessments, eye examination, body composition, 
 
DATA SOURCES: A computer-based application will be used for entering data into the 
THAOS electronic data record, allowing sites to enter data remotely through locally secured 
connections. The THAOS electronic data record allows for data to be recorded from an 
eligibility/baseline visit, at return visits, and in the form of status updates if the patient has 
not visited the site. In addition, THAOS physicians have the option of recording pre-baseline 
retrospective patient data. Final data entry (the entry of a status update indicating that the 
patient has been discontinued) will occur when the survey is completed, if the patient dies, or 
elects to discontinue the survey. 
STUDY SIZE: There is no pre-determined number of enrolled patients or participating sites 
in THAOS. 
DATA ANALYSIS: Analysis of clinical outcomes will be conducted on all enrolled patients 
with available data. Outcomes will be examined for the entire patient group, as well as 
through stratification of important variables that may affect outcomes (for example, but not 
limited to, TTR data, age, race, gender, country of origin). Outcomes will include results of 
the key clinical, functional and Patient Reported Outcome assessments used to define 
progression of disease. 
MILESTONES: Safety data required as part of the European Medicines Agency Risk 
Management Plan (RMP) for tafamidis will be analyzed annually for submission to the 
relevant regulatory authorities. 
and patient death. 
CCI 

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5. AMENDMENTS AND UPDATES 
 
Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
1 
31-Jul- 
2007 
Substantial 
All 
Update disease terms 
and abbreviation 
nomenclature. New 
term hereditary 
transthyretin 
amyloidoses ATTR. 
ATTR-PN, ATTR- 
CM. 
Update disease terms and 
abbreviation 
nomenclature. New term 
hereditary transthyretin 
amyloidoses ATTR. 
ATTR-PN, ATTR-CM. 
2 
20-Jan- 
2010 
Substantial 
All 
Clarify that a patient 
may participate in 
THAOS if enrolled in 
an open-label or 
double-blind clinical 
trial. 
Clarify that a patient may 
participate in THAOS if 
enrolled in an open-label 
or double-blind clinical 
trial. 
3 
30-Sep- 
2011 
Substantial 
All 
Addition of Pfizer 
safety language for 
adverse event and 
serious adverse event 
collection. Addition of 
safety data collection. 
Change of sponsor to 
Pfizer INC. 
Addition of Pfizer safety 
language for adverse event 
and serious adverse event 
collection. Addition of 
safety data collection. 
Change of sponsor to 
Pfizer INC. 
4 
07–Jul- 
Substantial 
All 
Significant protocol 
The proposed protocol has 
2015 
reformatting according 
been reformatted according 
to the requirements for 
to the requirements for 
non-interventional post- 
non-interventional 
authorization safety 
post-authorization safety 
study (PASS) protocols 
study (PASS) protocols as 
and alignment with 
specified in the European 
appropriate guidance 
Medicine Agency’s (EMA) 
documents. 
Guideline on Good 
Pharmacovigilance 
Practices: Module VIII 
– Post-Authorisation Safety 
Studies (PASS) and 
Guidance for the Format 
and Content of the Protocol 
of Non-Interventional Post- 
Authorisation Safety 
Studies. This has resulted 
in the addition of several 
sections including PASS 
information, MAH 
information, Responsible 
Parties, Abstract, and 
Milestones. Changes were 
made to the Research 
Methods section to adhere 
to this format. 
Section 6.0 
Section 6.0 Rationale 
Section updated to include 
Rationale and 
and Background 
information for marketing 
Background 
updated to include 
approval of tafamidis for 
information for 
treatment of ATTR in adult 
marketing approval of 
patients with Stage 1 
tafamidis for treatment 
symptomatic 
of ATTR in adult 
polyneuropathy to delay 

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Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
patients with Stage 1 
symptomatic 
polyneuropathy to delay 
peripheral neurologic 
impairment. 
peripheral neurologic 
impairment. 
Section 8.1 
Study Design; 
8.4 Data 
Sources 
Language revised to 
include the ability to 
record data in the form 
of status updates for 
those subjects that have 
not visited the site. 
Language revised to 
include the ability to record 
data in the form of status 
updates for those subjects 
that have not visited the 
site. 
Section 8.2.1 
Inclusion 
Criteria 
Inclusion Criteria 3 
modified to allow 
identification of cardiac 
involvement by 
echocardiogram. 
Inclusion Criteria 3 
modified to allow 
identification of cardiac 
involvement by 
echocardiogram. 
Inclusion Criteria #3: 
Confirmed genotyped TTR 
mutation with or without a 
diagnosis of ATTR, or 
wild-type TTR 
amyloidosis. Confirmation 
of wild-type TTR 
amyloidosis will be 
determined by genotyped 
confirmation that patient 
does not possess a known 
mutation in TTR gene 
(ie, is a carrier of wild-type 
allele only) via genetic 
testing and one of the 
following set of criteria: 
Evidence of cardiac 
involvement by 
echocardiogram as defined 
by mean left ventricle wall 
thickness of >12 mm, and 
presence of amyloid in 
cardiac biopsy tissue 
confirmed as TTR amyloid 
by mass spectrometry or; or 
evidence of cardiac 
involvement by 
echocardiogram as defined 
by mean left ventricle wall 
thickness of >12 mm, and 
presence of amyloid in non- 
cardiac tissue confirmed as 
TTR amyloid by mass 
spectrometry or 
immunohistochemistry or 
evidence of cardiac 
involvement by 
echocardiogram as defined 
by mean left ventricle wall 
thickness of >12 mm, no 

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Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
evidence of primary (light 
chain) amyloidosis, and 
presence of amyloid in 
cardiac tissue indirectly 
confirmed by scintigraphy 
with a ‘bone seeking tracer’ 
eg, 99mTC-DPD 
[99Mtc-3,3- 
diphosphono-1,2-propano- 
dicarboxylic acid], 
99mTC-PYP 
[Pyrophosphate], and 
99mTC-HMDP 
[hydroxymethylene 
diphosphonate] with 
Perugini grade ≥2. 
Section 
8.10.1.3 
Safety and 
efficacy in 
patients with 
TTR FAP 
mutations 
other than 
V30M 
Section 8.10.1.3 Safety 
and efficacy in patients 
with TTR FAP 
mutations other than 
V30M added. 
Section 8.10.1.3 Safety and 
efficacy in patients with 
TTR FAP mutations other 
than V30M added. 
Section 9.1.1 
Participation 
in 
Investigationa 
l Clinical 
Trials 
Section 9.1.1 
Participation in 
Investigational Clinical 
Trials language revised 
to specify that there will 
be no reconciliation 
between databases and 
to allow for data entry 
for clinical trial data 
that was collected 
during the clinical trial 
study. 
Section 9.1.1 Participation 
in Investigational Clinical 
Trials language revised to 
specify that there will be no 
reconciliation between 
databases and to allow for 
data entry for clinical trial 
data that was collected 
during the clinical trial 
study. Revision: Data 
collected during the course 
of the clinical trial may be 
entered retrospectively at 
the end of the trial if the 
THAOS principal 
investigator obtains and 
documents approval from 
the study sponsor who 
conducted the clinical trial. 
Retrospective data entry 
cannot occur until the study 
has been unblinded, which 
will permit identification of 
the treatment received 
during the trial. No 
reconciliation between 
databases will occur. For 
interventional clinical trials 
that include open-label 
tafamidis or other open- 
label investigational 
products, patients may 

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Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
continue in THAOS, with 
the approval of the 
Sponsor, but AE data 
collection will be addressed 
through the interventional 
clinical trial sponsor. The 
THAOS principal 
investigator is responsible 
for obtaining and 
documenting approval from 
the study sponsor for 
investigational agents other 
than tafamidis. 
Section 10 
Management 
and Reporting 
of Adverse 
Events/Adver 
se Reactions 
for 
Tafamidis-Tre 
ated Subjects 
Language regarding 
reporting of overdose, 
misuse, extravasation 
and occupational 
exposure within 
24 hours was added. 
Language regarding 
reporting of overdose, 
misuse, extravasation and 
occupational exposure 
within 24 hours was added 
to align with current safety 
reporting practices. This 
was previously included in 
Administrative Update 
dated 06June2014. 
Section 10.7 
Single 
Reference 
Safety 
Document 
Single Reference Safety 
Document identified. 
Single Reference Safety 
Document identified. 
Added, “The Product Label 
should continue to be used 
by the investigator for 
prescribing purposes and 
guidance.” This was 
previously included in 
Administrative Update 
dated 12December2013. 
5 
17 
January 
2020 and 
including 
updates 
to reflect 
EMA 
requests 
13July20 
20 
Substantial 
Throughout 
document 
The Table of Contents 
section has now been 
captured with a page 
number in the Table of 
Contents, thus causing 
each section to be 
numbered 1 digit higher 
in protocol amendment 
5 when compared to 
protocol amendment 4. 
To conform to the new 
Pfizer Non-Interventional 
Study protocol template. 

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Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
Throughout 
document 
Nomenclature updated: 
• 
from 
transthyretin-assoc 
iated amyloidosis 
to just transthyretin 
amyloidosis. 
• 
from Transthyretin 
(TTR) Mutations 
or Wild-Type TTR 
Amyloidosis to 
Transthyretin 
(TTR) Gene 
Mutations or 
Wild-Type ATTR 
Amyloidosis. 
• 
from amyloidoses 
to amyloidosis. 
• 
from familial 
amyloid 
polyneuropathy 
(TTR-FAP) to 
transthyretin 
amyloid 
polyneuropathy 
(ATTR-PN). 
• 
from familial 
amyloid 
cardiomyopathy 
(FAC) to 
transthyretin 
amyloid 
cardiomyopathy 
(ATTR-CM). 
As the understanding of 
ATTR amyloidosis 
advances, naming 
conventions are evolving to 
become more accurate in 
their description of the 
disease. 
Section 
formerly 
6.1/new 
7.1 Disease 
Background 
More information on 
ATTR-CM 
(cardiomyopathy) was 
added 
To provide further 
information about clinical 
features of the pathology. 
Section 
formerly 
8.2.1/new 
9.2.1 
Inclusion 
Criteria 
Evidence of cardiac 
involvement by 
echocardiogram as 
defined by mean left 
ventricle wall thickness 
of >12 mm was 
removed from the 
Inclusion Criteria for 
wild type patients with 
presence of TTR 
amyloid in cardiac 
tissue confirmed by a 
cardiac biopsy or 
scintigraphy. 
Positive endomyocardial 
biopsy or bone scintigraphy 
with Perugini grade ≥2 are 
sufficient for identification 
of cardiac ATTR 
involvement. 

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Amendment 
Number 
Date 
Substantial or 
Administrative 
Amendment 
Protocol 
Section(s) 
Changed 
Summary of 
Amendment(s) 
Reason 
Section 9.2 
A footnote was added to 
Table 1: 
The following 
important identified 
risks (Urinary tract 
infections, Diarrhea, 
Upper abdominal pain 
and Vaginal infections); 
important potential risks 
(Hypersensitivity 
reactions); and missing 
information (Safety and 
efficacy in elderly 
patients and Longer- 
term safety) have been 
removed from the list of 
ongoing safety concerns 
from the tafamidis EU 
RMP Update (v 9.3), 
approved on 
17 February 2020. 
To clarify the information 
in Table 1 was not aligned 
with the tafamidus EU 
RMP Update (v 9.3), 
approved on 17 February 
2020. 
Section 
formerly 
8.6/new 9.6 
Data 
Management 
The text has been 
updated with the latest 
Pfizer protocol template 
language. 
To conform to the new 
Pfizer Non-Interventional 
Study protocol template. 
Section 
formerly 
8.7/new 9.7. 
Data Analysis 
The text has been 
updated with the latest 
Pfizer protocol template 
language. 
To conform to the new 
Pfizer Non-Interventional 
Study protocol template. 
Section 
formerly 
8.8.1/new 
10 Data 
protection and 
patient 
identification. 
Moved to Section 10. 
To conform to the new 
Pfizer Non-Interventional 
Study protocol template. 
Section 
formerly 
9/new 
10 Protection 
of Human 
Subjects. 
Patient Information and 
Consent split into 
2 sub-sections. The text 
has been updated with 
the latest Pfizer 
protocol template 
language. 
To conform to the new 
Pfizer Non-Interventional 
Study protocol template. 
Section 
formerly 8.10/ 
new 9.10 
Other 
Aspects. 
Sub-category 
“Important Missing 
Data” removed and 
“Not Applicable” 
added. 
This was duplicative of the 
text captured in Table 1. 
Section 
formerly 
10/new 11 
Management 
and Reporting 
of Adverse 
events. 
Removed requirement 
to report Pregnancy of 
Partner. 
As tafamidis has been 
shown not to be present in 
seminal fluid and therefore 
male contraception is not 
required in the approved 
Product Information, 
collection of data regarding 
the pregnant partner of the 

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CCI 
Annex 
male recipient of tafamidis 
is not needed. 
Reason 
Summary of 
Amendment(s) 
Protocol 
Section(s) 
Changed 
Substantial or 
Administrative 
Amendment 
Date 
Amendment 
Number 

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6. MILESTONES 
 
Milestone 
Planned date 
Start of data collection (First Subject First Visit: FSFV) 
16 December 2007 
End of data collection (Last Subject Last Visit: LSLV) 
16 June 2023 
Study progress report 
Study progress reports are submitted to 
the EMA annually 
Final study report 
16 May 2024 
 
7. RATIONALE AND BACKGROUND 
7.1. Disease Background 
Transthyretin (TTR) a 127-amino acid, tetrameric protein, primarily synthesized in the liver, 
is a secreted protein present in the blood and cerebrospinal fluid and is a carrier of thyroxine 
and retinol-binding protein-retinol (vitamin A) complex. Transthyretin amyloidosis (ATTR 
amyloidosis) is a rare disease caused by destabilization and dissociation of the native TTR 
tetramer into monomers, which can result in misfolding and the formation of amyloid fibrils 
in various organs in amounts sufficient to impair normal functioning.1-5 
The 2 major phenotypes which form the spectrum of ATTR amyloidosis are transthyretin 
amyloid polyneuropathy (ATTR-PN), formerly referred to as transthyretin familial amyloid 
polyneuropathy (TTR-FAP), which primarily affects the peripheral and autonomic nerves, 
and transthyretin amyloid cardiomyopathy (ATTR-CM) which primarily affects the 
myocardium. These clinical manifestations may occur in isolation or together. Both result in 
progressively impaired function, and ultimately in death. 
There are over 130 known mutations of TTR gene,4 which result in variable phenotypic 
expressions of amyloidosis that commonly affect the peripheral nerves, heart, kidney or 
eye.6,7 
ATTR-PN 
The hereditary forms of ATTR amyloidosis are autosomal dominantly inherited diseases8,9 
with a variable penetrance that can affect multiple generations in a family and have a 
substantial impact on patients and their families. Val30Met (substitution of methionine for 
valine at position 30) is the most common mutation associated with ATTR-PN, with 
symptom onset usually in the third to fourth decade of life, depending on the mutation carried 
and the patient’s ethnic background.6-11 

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The main feature of ATTR-PN is progressive sensorimotor and autonomic neuropathy. 
Sensory neuropathy typically starts in the lower extremities followed by motor neuropathy 
within a few years.8,10,11 Autonomic neuropathy quite often accompanies the sensory and 
motor deficits.12 ATTR-PN is more frequently observed in certain areas of Portugal, 
Sweden, and Japan but has been identified throughout the world.11 Although penetrance 
varies greatly among geographic and ethnic foci, the outcome of the disease is invariably 
progressive and fatal. The lifespan for patients is severely shortened, with death occurring 
within a mean of 10-15 years from the first symptoms.14,1 
Disease-modifying therapies for ATTR-PN include TTR stabilizer tafamidis,30 orthotopic 
liver transplantation,13-15 RNA interference (RNAi)-based drugs, and transthyretin-directed 
antisense oligonucleotide drugs. Tafamidis meglumine was approved in the European Union 
(EU) on 16 November 2011 for the treatment of ATTR in adult patients with Stage 1 
symptomatic polyneuropathy to delay peripheral neurologic impairment. Currently, it is 
approved for ATTR-PN in over 40 countries worldwide. Subsequently, Tegsedi (inotersen) 
and Onpattro (patisiran) for the treatment of hereditary ATTR amyloidosis in patients with 
polyneuropathy (ATTR-PN) have also been approved in the EU and US.16-18 
Tafamidis is a novel specific stabilizer of both tetrameric wild-type (w-t) TTR and of 
amyloidogenic variants of TTR (ATTR). By binding to the native tetrameric form of TTR, 
tafamidis inhibits tetramer dissociation, the rate limiting step in the formation of TTR 
amyloid. By inhibiting TTR amyloid formation, this novel class of TTR stabilizer drug has 
the potential to disrupt the progression of ATTR. The specificity of the binding to TTR also 
limits tafamidis to the treatment of ATTR amyloidosis only, with no activity anticipated for 
other types of amyloidosis. Tafamidis slows the progression of disease and therefore 
represents a disease modifying therapy. 
ATTR-CM 
ATTR-CM occurs when the amyloid fibrils infiltrate the myocardium, leading to diastolic 
dysfunction progressing to, heart failure, restrictive cardiomyopathy, and death.19 
ATTR-CM, also known as familial amyloid cardiomyopathy (FAC), is a late-onset disease 
with symptoms typically occurring in patients over 60 years old.20 This disease can be 
inherited as an autosomal dominant trait caused by mutation in the TTR gene (commonly the 
Val122Ile mutation which occurs with high frequency [prevalence of 3.9%]22 in 
African-Americans); however, a mutation in TTR gene is not a pre-requisite for developing 
ATTR-CM. In the elderly, wild-type (normal) TTR may become structurally unstable 
resulting in deposition of amyloid fibrils primarily in heart tissue and leading to restrictive 
cardiomyopathy and heart failure.21 
Wild-type ATTR amyloidosis (previously known as senile systemic amyloidosis (SSA) or 
senile cardiac amyloidosis,23-27 is diagnosed based on positive bone scintigraphy21,29 
(Perugini grade ≥2)30 or confirmed ATTR amyloid by tissue biopsy and 
immunohistochemical staining, and characteristic echocardiographic abnormalities21,29 in the 
absence of a TTR gene mutation and a plasma cell dyscrasia. The clinical presentation of 

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wild-type ATTR amyloidosis is similar to variant ATTR-CM, with the disease primarily 
affecting elderly males.20 
Combined heart and liver transplantation is a treatment option for ATTR-CM, however is 
limited by organ availability and significant patient co-morbidity. 
Tafamidis is currently the only approved treatment for ATTR-CM with approvals in a 
growing number of countries worldwide including but not limited to: Japan (March 2019) for 
tafamidis meglumine 80 mg daily in patients with wild-type and variant forms of ATTR-CM; 
the US (May 2019) for tafamidis meglumine 80 mg daily and tafamidis 61mg daily for the 
treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated 
amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related 
hospitalization; and the EU (February 2020) as a line extension to tafamidis 61 mg daily for 
the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with 
cardiomyopathy. 
This non-interventional study (disease registry), designated as a post-authorization safety 
study (PASS) is open to all patients with transthyretin (TTR) gene mutations without a 
diagnosis of ATTR amyloidosis and to patients diagnosed with ATTR amyloidosis (inclusive 
of ATTR-PN and ATTR-CM) in agreement with the European Medicine Agency (EMA) 
until 16 June 2023. 
7.2. Rationale for the Survey 
The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a longitudinal, observational 
survey open to all patients with TTR gene mutations without a diagnosis of ATTR 
amyloidosis and to patients diagnosed with ATTR amyloidosis (inclusive of ATTR-PN and 
ATTR-CM). To date, limited data are available on the natural history of the hereditary 
(ATTRm) and wild-type (ATTRwt) forms of the disease, including the regional differences 
in disease expression by TTR variants and non-mutated TTR, and the genotypic-phenotypic 
relationship in ATTR amyloidosis. 
The principal aims of the outcome survey are to better understand and characterize the 
natural history of the disease by studying a large and heterogeneous patient population. 
Survey data may be used to develop new treatment guidelines and recommendations, and to 
inform and educate clinicians about the management of this disease. 
The survey can also generate descriptive safety summaries using adverse and serious adverse 
event (AE/SAE) data in tafamidis-treated participants. All AE/SAE data will be collected 
and summarized, including (but not limited to) the safety concerns detailed in Table 1, 
Summary of Safety Concerns to be Assessed in THAOS. 
AE/SAE data collection in THAOS will be utilized in the post-marketing setting to provide 
additional information on the safety of tafamidis over the long term as well as its effect on 
survival. 

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Limited data was collected in ATTR-CM studies with tafamidis in patients with New York 
Heart Association (NYHA) class IV, and it is expected that THAOS will provide additional 
information on the safety and efficacy of tafamidis in this population. Safety data will be 
collected through THAOS for all participants treated with tafamidis. 
Additional data corresponding to the events of interest detailed in Table 1 Summary of Safety 
Concerns to be Assessed in THAOS will also be collected for all THAOS participants 
(tafamidis-treated and participants not treated with tafamidis). The purpose of the additional 
data collection is to further characterize the natural history of disease amongst untreated 
participants and, as applicable, to gather data to provide context for safety events observed 
amongst tafamidis-treated participants. 
7.3. Role of THAOS in the Tafamidis European Union Post-Marketing Commitment 
On 21 July 2011 the European Union (EU) Committee for Medicinal Products for Human 
Use (CHMP) adopted a positive opinion, recommending the granting of a marketing 
authorization for the medicinal product tafamidis 20 mg capsule intended for the treatment of 
ATTR amyloidosis in adult patients with Stage 1 symptomatic polyneuropathy to delay 
peripheral neurologic impairment. Granting of marketing authorization for tafamidis was 
made under exceptional circumstances. The collection of safety data in THAOS will fulfill 
part of the post-marketing commitment to the CHMP for tafamidis. This non-interventional 
(NI) study is designated as a Post-Authorisation Safety Study (PASS) and is a commitment to 
the EMA. Additionally, data in ATTR-CM patients collected via this registry will further 
characterize important potential risks and missing information with tafamidis (see Section 8) 
as agreed with the EMA during the line extension procedure for ATTR-CM. 
8. RESEARCH QUESTION AND OBJECTIVES 
The objectives of THAOS are to: 
• Describe the population of patients affected with ATTR amyloidosis; 
• Enhance the understanding of disease natural history, including the variability and 
progression of the hereditary and acquired forms of the disease; 
• Better understand the genotype – phenotype relationship in ATTRm.; 
• Compare the progression of disease and overall survival in patients with ATTR with 
and without liver transplant; 
• Foster an international community of medical experts who will develop 
recommendations on the clinical management of ATTR amyloidosis; 
• Provide information to better understand the management and treatment of patients 
with ATTR amyloidosis through publication of the survey data; 

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• For tafamidis-treated participants, collect and summarize all AE/SAE data, including 
for the specific safety concerns outlined in Table 1 Summary of Safety Concerns to 
be Assessed in THAOS comprising important identified risks, important potential 
risks, and missing information that includes long-term safety in ATTR-CM patients 
with NYHA Class IV. For those not treated with tafamidis, collect and summarize 
additional data on the events of interest listed in Table 1. 
9. RESEARCH METHODS 
9.1. Study Design 
THAOS is a non-interventional, global, multi-center, longitudinal observational survey open 
to all patients with ATTR amyloidosis, including both inherited and wild-type forms of 
disease, and participants with TTR gene mutations without disease diagnosis. There is no set 
number of patients who will be enrolled. The study has been open since 2007 and will 
continue until Pfizer declares the study complete (currently estimated to be the year 2023). 
or as long as patients are able to participate, or until they withdraw consent. 
THAOS does not involve the administration of an investigational agent or other intervention. 
Patients will continue to receive their current medications and all other standard care for their 
disease. It is recommended that patient assessments be conducted at least annually and 
recorded in the THAOS electronic data record close to the time they are performed. 
Treatment with tafamidis or with other disease modifying therapies will be according to the 
product label with commercially available product or according to protocol-specified 
requirements if a participant is enrolled in a tafamidis interventional study. 
In addition to routine procedures for standard of care, patients will be asked to complete 
patient outcome questionnaires at least annually; these are optional and do not affect a 
patient’s eligibility to participate in the survey. 
The THAOS electronic data record allows for data to be recorded from an eligibility/baseline 
visit, at return visits, and in the form of status updates if the patient has not visited the site. 
In addition, THAOS physicians have the option of recording pre-baseline retrospective 
patient data. Final data entry (the entry of a status update indicating that the patient has been 
discontinued) will occur when the survey is completed, if the patient dies, or elects to 
discontinue the survey. 
Physicians at survey sites will evaluate patients to determine eligibility. Each patient must 
review and sign an informed consent document before any data are recorded in the THAOS 
electronic data record. The date the informed consent form is signed will be documented in 
the THAOS electronic data record. 
Data will be recorded from all patient visits and entered into the THAOS electronic data 
record as soon as possible after the visit is complete. Data will be entered into a secure, 
confidential computer-based application which allows for remote data entry through locally 
secured connections. A Scientific Board representing the THAOS physicians will meet at 
least annually and recommend statistical analyses. 

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Each survey site will be required to obtain local Institutional Review Board (IRB)/Ethics 
Committee (EC) approval to participate in THAOS and before enrolling patients. 
There is no pre-determined number of enrolled patients or participating sites in THAOS. The 
survey will be conducted at sites worldwide. 
9.1.1. Study Treatment and Duration 
THAOS has been open since 2007. There is no set number of patients who will be enrolled 
in the survey. Patients will be enrolled from different countries around the world. All 
patients who take part in this survey will be followed until the survey is declared complete by 
Pfizer (currently estimated to be the year 2023) or as long as they are able to participate, or 
until they withdraw consent to participate. For those patients receiving tafamidis, the dosage 
recommendations (including dosage strength and timing of the dosing) should be based on 
the prescribing physician’s clinical judgment and the approved product label or open-label 
study protocol (for those patients receiving tafamidis as part of their participation in a clinical 
study). 
9.2. Setting 
The study population includes patients with confirmed genotyped TTR mutation with or 
without a diagnosis of hereditary or wild-type ATTR amyloidosis. 
Assessments were proposed by a team of experts as components of standard clinical practice 
for patients with ATTR amyloidosis and are recommended but are not required; the 
assessments to be performed will be determined by the investigator according to the patient’s 
individual care plan. Additional information on assessments is included in a separate 
THAOS Case Report Form Completion Guidelines which will be provided to each survey 
site. 
9.2.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion into 
THAOS: 
1. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
2. Males and females ≥18 years of age. 
3. Confirmed genotyped TTR mutation with or without a diagnosis of hereditary or 
wild-type ATTR amyloidosis. Confirmation of ATTRwt amyloidosis will be 
determined by genotyped confirmation that patient does not possess a known 
mutation in TTR gene (ie, is a carrier of wild-type allele only) via genetic testing and 
one of the following set of criteria (a, b, or c): 
a. Presence of amyloid in cardiac biopsy tissue confirmed as TTR amyloid by mass 
spectrometry or immunohistochemistry; or 

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b. Evidence of cardiac involvement by echocardiogram as defined by left ventricle 
wall thickness of >12 mm, and presence of amyloid in non-cardiac tissue 
confirmed as TTR amyloid by mass spectrometry or immunohistochemistry; or 
c. No evidence of primary (light chain) amyloidosis, and presence of amyloid in 
cardiac tissue indirectly confirmed by scintigraphy with a “bone seeking tracer” 
eg, 99mTC-DPD [99mTC-3,3-diphosphono-1,2-propano-dicarboxylic acid], 
99mTC- PYP [Pyrophosphate], and 99mTC-HMDP [hydroxymethylene 
diphosphonate] with Perugini grade ≥2. 
9.2.2. Exclusion Criteria 
Patients meeting any of the following will not be included in the study: 
1. Patient has primary or secondary amyloidosis. 
9.2.3. Genotyping 
TTR genotyping is required to confirm patient eligibility and will be performed before the 
Eligibility/Baseline visit and outside of the auspices of the survey according to the site’s 
standard practices. For patients with a documented TTR gene mutation, the mutation(s) will 
be recorded in the patient’s medical record and in the electronic data record. 
9.3. Variables 
The objectives of THAOS are to describe the population of patients affected with ATTR 
amyloidosis and to enhance the understanding of the disease natural history, including the 
variability and progression of the hereditary and acquired forms of disease. 
All visits are intended to be outpatient visits. Assessments are recommended but not 
required and will be determined by the investigator. All assessments that occur will be 
recorded in the THAOS electronic data record. The THAOS Electronic Case Report Form 
Completion Guidelines detail how the data for these assessments should be entered into the 
electronic data record. Blank worksheets and QoL questionnaires (available in patient’s 
native language) are available to download from the THAOS electronic data record. 
9.3.1. Study Assessments 
• Written informed consent/assent. 
• Inclusion/exclusion criteria. 
• Patient demographics (year of birth, gender, ethnic origin, race (if allowed by local 
regulations). 
• TTR genetic test results. 
• Family disease history (previous family history of ATTR amyloidosis). 

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• Medical history (past and current signs, symptoms, and medical diagnoses). 
• Annual medical assessment (current signs and symptoms). 
• General examination (weight/height, vital signs, CCI 
 
• Concomitant medications (category, indication, start and stop dates). 
• Hospitalizations (admission and discharge dates, reason for hospitalization). 
• Transplant history and complications (date(s) of transplant(s), organ(s) transplanted, 
information on complications). 
• AE/SAE reporting for tafamidis-treated subjects. 
• Events of interest (as listed in Table 1, Summary of Safety Concerns to be Assessed 
in THAOS). 
• Clinical laboratory data (hematology, clinical chemistry, liver function tests, thyroid 
function tests). 
• Urinalysis (includes glomerular filtration rate [GFR]). 
• Cardiovascular assessments (electrocardiogram, echocardiogram, Holter monitoring, 
CCI 
 
• Neurologic assessments (deep tendon reflexes, sensation [pinprick, soft touch, 
vibration, and position sense], motor strength, nerve conduction studies). 
• Eye examination (intraocular pressure, vitreous, presence of opacities). 
• Body composition (total bone mineral density and content, total lean and fat mass). 
• 
 
 
• Patient death (data on patient death will be collected independently of the visit 
schedule). 
9.3.2. Safety Assessments 
AE/SAE data collected in THAOS will be used to further characterize the safety profile of 
tafamidis and as a result, to fulfill certain aspects of the EU post-marketing commitment for 
tafamidis. Based on the safety concerns detailed in Table 1, corresponding data for Events of 
Interest will be collected to characterize both the natural history of ATTR in participants not 
treated with tafamidis and safety concerns amongst tafamidis-treated patients. 
CCI 

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Table 1. 
*Summary of Safety Concerns to be Assessed in THAOS 
 
Important identified risks 
(Adverse Drug Reactions) 
Urinary tract infection 
Diarrhea 
Vaginal infections 
Upper abdominal pain 
Important potential risks 
Hepatotoxicity 
Hypersensitivity reactions 
Reproductive and developmental toxicity and lactation 
Changes in thyroid function, particularly in pregnant 
women 
Important missing 
information 
Safety and efficacy in elderly patients 
Longer term safety 
Safety and efficacy in patients with ATTR-PN mutations 
other than Val30Met 
Patients with NYHA Class IV 
Patients with severe hepatic impairment 
Note: *The following important identified risks (Urinary tract infections, Diarrhea, Upper abdominal pain 
and Vaginal infections); important potential risks (Hypersensitivity reactions); and missing information 
(Safety and efficacy in elderly patients and Longer-term safety) have been removed from the list of 
ongoing safety concerns from the tafamidis EU RMP Update (v 9.3), approved on 17 February 2020. 
 
 
All AE/SAE data will be collected for participants treated with commercially available 
tafamidis; participants receiving tafamidis as part of their participation in an open-label 
clinical study will have AE/SAE data collection through the open-label clinical study; 
reporting of other events in addition to the Events of Interest will be available for participants 
not treated with tafamidis. 
9.3.3. Eligibility/Baseline Visit 
This visit will be performed to determine a patient’s eligibility. It includes obtaining 
informed consent, chart review to determine eligibility, and recording results of study 
assessments as outlined in Section 9.3.1 Study Assessments. 
9.3.4. Return Visit 
Return visits will, on average, be conducted annually or more frequently at the discretion of 
the survey physician. The reporting window for collecting changes in signs, symptoms, AE 
information, and new diagnoses is from the last prior visit. 

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9.3.5. Retrospective Visit 
Any assessments listed in Section 9.3.1 Study Assessments and performed prior to the 
patient’s Eligibility/Baseline visit may be entered into the THAOS electronic data record as 
retrospective visit data. This data collection is optional. 
9.3.6. Final Visit 
Final visit data collection, including collection of AE/SAE information, will be performed at 
the completion of the survey, or at the time a patient dies or elects to discontinue from the 
survey, whichever occurs first. If a patient dies while enrolled in the survey, the site is asked 
to collect all available information about the patient’s death and complete the final visit 
assessment and patient death case report forms in the THAOS electronic data record. 
9.4. Data Sources 
The THAOS electronic data record allows for data to be recorded from an eligibility/baseline 
visit, at return visits, and in the form of status updates, if the patient has not visited the site. 
In addition, THAOS physicians have the option of recording pre-baseline retrospective 
patient data. Final data entry (the entry of a status update indicating that the patient has been 
discontinued) will occur when the survey is completed, if the patient dies, or elects to 
discontinue the survey (refer to Section 9.3.6 above). 
9.5. Study Size 
THAOS has been open since 2007. There is no set number of patients who will be enrolled 
in the survey. Patients will be enrolled from different countries around the world. All 
patients who take part in this survey will be followed until the survey is declared complete by 
Pfizer (currently estimated to be the year 2023) or as long as they are able to participate, or 
until they withdraw consent to participate. 
9.6. Data Management 
9.6.1. Case Report Forms (CRFs)/Data Collection Tools (DCTs)/Electronic Data Record 
As used in this protocol the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A computer-based application will be used for entering data into the THAOS electronic data 
record, allowing sites to enter data remotely through locally secured connections. The 
computer-based application and the data to be collected and entered are described in the 
THAOS Case Report Form Completion Guidelines which will be provided to each site. 
A CRF is required and should be completed for each included patient. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and will be password 
protected or secured in a locked room to prevent access by unauthorized third parties. 

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The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases the source documents are the hospital or the physician's chart. In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
Prior to initiating the survey, the Sponsor or its designee will train the THAOS physician and 
site staff to use the THAOS electronic data record and review the THAOS Case Report Form 
Completion Guidelines. Ongoing technical support will be provided to survey sites by a 
database development company. 
9.6.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms. source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should 
be retained by the investigator according to local regulations or as specified in the clinical 
study agreement (CSA), whichever is longer. The investigator must ensure that the records 
continue to be stored securely for so long as they are retained. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 

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9.7. Data Analysis 
9.7.1. Statistical Methods 
Detailed methodology for summary and statistical analyses of data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be dated, filed and maintained 
by the sponsor. The SAP may modify the plans outlined in the protocol; any major 
modifications of primary endpoint definitions or their analyses would be reflected in a 
protocol amendment. 
9.7.2. Data Summaries 
THAOS data will be available for analysis on 3 different levels: by patient, by individual 
survey site, and across survey sites. 
The primary objective of the survey is to better understand the natural history of ATTR 
(hereditary and wild-type forms) and the progression of disease in this patient population. 
Analysis of clinical outcomes will be conducted on all enrolled patients with available data. 
Outcomes will be examined for the entire patient group, as well as through stratification of 
important variables that may affect outcomes (for example, but not limited to, TTR variant, 
age, race, gender, country of origin). Outcomes will include results of the key clinical, 
functional and QoL assessments used to define progression of disease. 
Data will be summarized descriptively and modeled using appropriate statistical 
methodology. 
THAOS physicians may use the THAOS electronic clinical database to obtain ongoing 
longitudinal data on their individual patients to assist them in following and caring for their 
patients. A physician can extract their individual survey site data for an individual or all 
patients enrolled at the survey site to identify trends in the data and/or assist in patient care 
and monitoring at their survey site. 
THAOS physicians may request or share data across survey sites. A request may pertain to 
available information on patients with a newly identified TTR variant, or on a subset of 
patients to assist a THAOS physician with the clinical management of a patient (or patients), 
or to provide information pertinent to research interests across survey sites. Requests for 
data should be forwarded to the Sponsor for processing and will be promptly reviewed. 
9.7.3. Scientific Board 
The Scientific Board is comprised of a group of scientific and clinical experts in the field of 
amyloid disease who will provide scientific oversight and interpretation of the data 
originating from THAOS and its sub-studies. The role of the Board is to develop treatment 
recommendations and practice guidelines for patients with transthyretin amyloidosis based 
on findings from either the survey or external data. The roles and responsibilities of the 
Board are detailed in the THAOS Scientific Board Charter. 

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9.7.4. Interim Analyses 
There is no formal interim analysis planned. 
Safety data required as part of the European Medicines Agency RMP for tafamidis will be 
analyzed and submitted annually. 
One or more data extracts will be performed annually in order to support ad hoc analyses for 
publications and for pricing and reimbursement. 
9.8. Quality Control 
9.8.1. Data Editing 
Data entered into the THAOS electronic clinical database will be automatically checked 
according to the database specifications, focusing on data critical for analysis, using limits set 
within the programming. Error messages will appear notifying the sites of discrepancies as 
they are identified or at the point of data signature. Data clarification requests may be 
generated and sent electronically to the THAOS sites. Completed requests will be returned 
to the electronic clinical database. All changes to the THAOS electronic clinical database 
will be tracked via an audit trail. 
9.8.2. Audits 
Local or international regulatory authorities, the IRB/EC, the Sponsor, or its designee, may 
request access to all patient consent forms, source documents, THAOS electronic data 
records, and other survey documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all 
times for these activities. 
9.8.3. THAOS Electronic Clinical Database 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered in the THAOS electronic clinical database from source 
documents (eg, hospital or physician patient charts), physical examinations, and patient 
reports. The investigator must ensure that the information is accurate, authentic/original, 
attributable, complete, consistent, timely (contemporaneous), enduring, and available when 
required. 
9.9. Limitations of the Research Methods 
The observational nature of this study has the potential to introduce selection or 
ascertainment bias. The study population could be more heterogeneous. Confounding leads 
to biased estimates of associations of risk factors or treatment with outcome and thus impacts 
the validity of the conclusions from the study. Analytical methods (like matching, 
multivariate regression) would be used to control for confounding. 
Other potential limitations to the validity of the study include missing data and loss to 
follow-up or censoring. Appropriate statistical methods would be employed to account for 
missing data and described in the SAP. Sensitivity analysis to assess the impact of loss to 
follow-up will also be explored. 

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9.10. Other Aspects 
Not Applicable. 
10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient Information 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
Upon entry into THAOS, a patient will be assigned a unique patient number. This number is 
a combination of the site country identifier, the assigned site number, and the number given 
to a patient in order of enrollment at the site (eg, SE 01 005 is the fifth patient enrolled at the 
first participating site in Sweden). Each patient will be identified by this unique number. In 
order to maintain patient privacy, all databases, survey reports, and communications will 
identify the patient only by the unique patient number. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, patient-specific code. 
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity. In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patients’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
10.2. Patient Consent 
The informed consent/assent documents and any patient recruitment materials must be in 
compliance with local regulatory requirements and legal requirements, including applicable 
privacy laws. 
The informed consent/assent documents used during the informed consent process and any 
patient recruitment materials must be reviewed and approved by Pfizer, approved by the 
institutional review board (IRB)/independent ethics committee (IEC) before use, and 
available for inspection. 

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The investigator must ensure that each study patient, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study, the sharing of 
data relating to the study and possible risks associated with participation, including the risks 
associated with the processing of the patient’s personal data. The investigator further must 
ensure that each study patient, or his or her legally acceptable representative, is fully 
informed about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/IEC. If the investigator determines that 
a patient’s decisional capacity is so limited that he or she cannot reasonably be consulted, 
then, as permitted by the IRB/IEC and consistent with local regulatory and legal 
requirements, the patient’s assent may be waived with source documentation of the reason 
assent was not obtained. If the study patient does not provide his or her own consent, the 
source documents must record why the patient did not provide consent (eg, minor, 
decisionally impaired adult), how the investigator determined that the person signing the 
consent was the patient’s legally acceptable representative, the consent signer’s relationship 
to the study patient (eg, parent, spouse), and that the patient’s assent was obtained or waived. 
If assent is obtained verbally, it must be documented in the source documents. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient’s legally acceptable representative before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent/assent document. 
10.2.1. Participation in Investigational Clinical Trials 
If a patient in Spain elects to participate in a double-blind or open-label interventional trial, 
entry of data into THAOS will be prohibited from the date patient begins taking study drug 
(or device) until the end of the interventional trial. Data collected prior to a patient receiving 
treatment in a double-blind or open-label interventional trial (eg, baseline, pre-treatment 
assessments, or any historical data) can be entered into the THAOS electronic data 
record/database and data collection can resume after completion of the interventional trial. 
Data collected during the time of participation in an interventional trial may not be entered 
into THAOS 
For patients enrolled outside of Spain, if a patient elects to participate in a double-blind 
investigational clinical trial, collection of THAOS data will be temporarily suspended during 
the period that the patient is taking study drug (or device). 
Data collected prior to a patient receiving treatment in a double-blind investigational trial 
(eg, baseline, pre-treatment assessments, or any historical data), as well as data collected 
after the patient’s completion or withdrawal from a double-blind investigational trial, can be 
entered into the THAOS electronic data record/database. Data collected during the course of 
the clinical trial may be entered retrospectively at the end of the trial if the THAOS principal 
investigator obtains and documents approval from the study sponsor who conducted the 
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which will permit identification of the treatment received during the trial. No reconciliation 
between databases will occur. 
As the goal of the survey is to document the course (or natural history) of TTR amyloidosis, 
the use of known interventions, including open-label investigational agents or devices, will 
be permitted. For interventional clinical trials that include open-label tafamidis or other 
open-label investigational products, patients may continue in THAOS, with the approval of 
the Sponsor, but AE data collection will be addressed through the interventional clinical trial 
sponsor. The THAOS principal investigator is responsible for obtaining and documenting 
approval from the study sponsor for investigational agents other than tafamidis. 
10.3. Patient Withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons. In any circumstance, every effort should be made to document 
patient outcome, if applicable. The investigator would inquire about the reason for 
withdrawal and follow-up with the patient regarding any unresolved AEs. 
Whenever possible, the patient should return for a final visit and the reason for withdrawal 
recorded. If a patient does not return for further assessments and no longer wishes to 
participate in THAOS, the reason the patient provides for discontinuation from the survey 
will be recorded. In the event that a patient does not complete an annual visit, can no longer 
be contacted within one year of a scheduled annual visit, and the patient’s status is unknown, 
the patient will be considered lost to follow-up and the principal investigator (PI) will be 
required to change the patient status in that individual’s THAOS clinical database 
accordingly. 
If the patient withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
10.4. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(eg, recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with 
the IRB/IEC should be retained by the investigator. Copies of IRB/IEC approvals should be 
forwarded to Pfizer. 
10.5. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Practices for Outcomes 
Research issued by the International Society for Pharmacoeconomics and Outcomes 
Research (ISPOR), International Ethical Guidelines for Epidemiological Research issued by 
the Council for International Organizations of Medical Sciences (CIOMS), EMA European 

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Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) Guide on 
Methodological Standards in Pharmacoepidemiology, and Food and Drug Administration 
(FDA) Guidance for Industry: Good Pharmacovigilance and Pharmacoepidemiologic 
Assessment, FDA Guidance for Industry and FDA Staff: Best Practices for Conducting and 
Reporting of Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data, 
Guidance for Industry: Patient-Reported Outcome Measures: Use in Medical Product 
Development to Support Labeling Claims. 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS FOR TAFAMIDIS-TREATED SUBJECTS 
11.1. Requirements 
The table below summarizes the requirements for recording safety events in the THAOS 
electronic data record and for reporting safety events on the non-interventional study (NIS) 
adverse event monitoring (AEM) Report Form to Pfizer Safety. These requirements are 
delineated for 3 types of events: (1) serious adverse events (SAEs); (2) non-serious AEs (as 
applicable); and (3) scenarios involving drug exposure, including exposure during pregnancy 
(EDP), exposure during breast feeding, medication error, overdose, misuse, extravasation, 
and occupational exposure. These events are defined in the section “Definitions of Safety 
Events” 
 
Safety event 
Recorded in the THAOS 
electronic data record 
Reported on the NIS 
AEM Report Form to 
Pfizer Safety within 
24 hours of awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 
Scenarios involving exposure 
to a drug under study, 
including EDP, exposure 
during breastfeeding, 
medication error, overdose, 
misuse, extravasation; lack of 
efficacy; and occupational 
exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure 
All (regardless of 
whether associated with 
an AE) 
 
For each AE, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(see section "Serious Adverse Events” below). 
Safety events listed in the table above must be reported to Pfizer within 24 hours of 
awareness of the event by the investigator regardless of whether the event is determined 
by the investigator to be related to tafamidis. In particular if the SAE is fatal or 
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immediately, irrespective of the extent of available event information. This timeframe also 
applies to additional new (follow-up) information on previously forwarded safety event 
reports. In the rare situation that the investigator does not become immediately aware of the 
occurrence of a safety event, the investigator must report the event within 24 hours after 
learning of it and document the time of his/her first awareness of the events. 
For safety events that are considered serious, or that are identified in the far-right column of 
the table above, that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with 
this 24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain 
specific follow-up information in an expedited fashion. This information is more detailed 
than that recorded in the THAOS electronic clinical database. In general, this will include a 
description of the AE in sufficient detail to allow for a complete medical assessment of the 
case and independent determination of possible causality. Any information relevant to the 
event, such as concomitant medications and illnesses must be provided. In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer or its designated representative. 
11.2. Reporting Period 
For each patient, the safety event reporting period begins at the time of the patient’s first dose 
of tafamidis or the time of the patient’s informed consent if s/he is being treated with 
tafamidis at study start and lasts through the end of the observation period of the study, 
which must include at least 28 calendar days following the last administration of a drug 
under study; a report must be submitted to Pfizer Safety (or its designated representative) for 
any of the types of safety events listed in the table above occurring during this period. 
If a patient was administered a drug under study on the last day of the observation period, 
then the reporting period should be extended for 28 calendar days following the end of 
observation. 
Most often, the date of informed consent is the same as the date of enrollment. In some 
situations, there may be a lag between the dates of informed consent and enrollment. In these 
instances, if a patient provides informed consent but is never enrolled in the study (eg, patient 
changes his/her mind about participation), the reporting period ends on the date of the 
decision to not enroll the patient. 
If the investigator becomes aware of a SAE occurring at any time after completion of the 
study and s/he considers the SAE to be related to tafamidis, the SAE also must be reported to 
Pfizer Safety. 

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11.3. Causality Assessment 
The investigator is required to assess and record the causal relationship. 
For all AEs, sufficient information should be obtained by the investigator to determine the 
causality of each AE. For AEs with a causal relationship to tafamidis, follow-up by the 
investigator is required until the event and/or its sequelae resolve or stabilize at a level 
acceptable to the investigator, and Pfizer concurs with that assessment. 
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that tafamidis caused or contributed to an AE. If the investigator’s 
final determination of causality is “unknown” and the investigator cannot determine whether 
tafamidis caused the event, then the event will be handled as related to tafamidis for reporting 
purposes and the safety event must be reported within 24 hours. 
If the investigator cannot determine the etiology of the event but the investigator determines 
that tafamidis did not cause the event, this should be clearly documented in the THAOS 
electronic clinical database and the NIS AEM Report Form. 
11.4. Definitions of Safety Events 
11.4.1. Adverse Events 
An AE is any untoward medical occurrence in a patient administered a medicinal product. 
The event need not necessarily have a causal relationship with the product treatment or 
usage. Examples of AEs include but are not limited to: 
• Abnormal test findings (see below for circumstances in which an abnormal test 
finding constitutes an AE); 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease; 
• Lack of efficacy; 
• Drug abuse; 
• Drug dependency. 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 

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• Drug misuse; 
• Off-label use; 
• Drug interactions; 
• Extravasation; 
• EDP; 
• Exposure during breast feeding; 
• Medication error; 
• Occupational exposure. 
11.4.2. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
11.4.3. Serious Adverse Events 
A SAE is any untoward medical occurrence in a patient administered a medicinal or 
nutritional product (including pediatric formulas) at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute AEs); 

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• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes listed in the 
definition above, the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious. The event may be suspected from 
clinical symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product. The terms “suspected transmission” and “transmission” are considered 
synonymous. These cases are considered unexpected and handled as serious expedited cases 
by pharmacovigilance personnel. Such cases are also considered for reporting as product 
defects, if appropriate. 
11.5. Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, an event leading to an emergency room visit should be assessed for medical 
importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. 
For example, the following reports of hospitalization without a medical AE are not to be 
reported: 
• Social admission (eg, patient/subject has no place to sleep); 
• Administrative admission (eg, for yearly exam); 
• Optional admission not associated with a precipitating medical AE (eg, for elective 
cosmetic surgery); 
• Hospitalization for observation without a medical AE; 

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• Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (eg, for 
work-up of persistent pre-treatment lab abnormality); 
• Protocol-specified admission during clinical study (eg, for a procedure required by 
the study protocol). 
11.6. Scenarios Necessitating Reporting to Pfizer Safety within 24 Hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are 
described below. 
11.6.1. Exposure During Pregnancy 
1. An exposure during pregnancy (EDP) occurs if a female becomes, or is found to be, 
pregnant either while receiving or having been directly exposed to (eg, environmental 
exposure) tafamidis, or the female becomes, or is found to be, pregnant after 
discontinuing and/or being directly exposed to tafamidis (maternal exposure). 
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
As a general rule, prospective and retrospective EDP reports from any source are reportable 
irrespective of the presence of an associated AE and the procedures for SAE reporting should 
be followed. 
If a study participant becomes, or is found to be, pregnant during the study participant’s 
treatment with tafamidis, this information must be submitted to Pfizer, irrespective of 
whether an adverse event has occurred, using the NIS AEM Report Form and the EDP 
Supplemental Form, and through the Tafamidis Enhanced Surveillance for Pregnancy 
Outcomes (TESPO). Reporting to TESPO for women exposed to tafamidis will also include 
a 6-month and 12-month post-birth follow-up questionnaire regarding developmental 
milestones. 
In addition, the information regarding environmental exposure to tafamidis in a pregnant 
woman (eg, a patient reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage) must be submitted using the NIS AEM Report Form and the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred. 
Information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, 
follow-up is conducted to obtain information on EDP outcome for all EDP reports with 
pregnancy outcome unknown. A pregnancy is followed until completion or until pregnancy 
termination (eg, induced abortion) and Pfizer is notified of the outcome. This information is 
provided as a follow up to the initial EDP report. 

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In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth. In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly 
and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (eg, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
procedures for reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to investigational product. 
Additional information regarding the EDP may be requested. Further follow-up of birth 
outcomes will be handled on a case-by-case basis (eg, follow-up on preterm infants to 
identify developmental delays). 
11.6.2. Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an AE associated with such a 
drug’s administration, the AE is reported together with the exposure during breastfeeding. 
11.6.3. Medication Error 
A medication error is any unintentional error in the prescribing, dispensing or administration 
of a medicinal product that may cause or lead to inappropriate medication use or patient harm 
while in the control of the health care professional, patient, or consumer. Such events may 
be related to professional practice, health care products, procedures, and systems including: 
prescribing; order communication; product labeling, packaging, and nomenclature; 
compounding; dispensing; distribution; administration; education; monitoring; and use. 
Medication errors include: 
• Near misses, involving or not involving a patient directly (eg, inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or 
prescription on the part of the healthcare provider or the patient/consumer); 
• Confusion with regard to invented name (eg, trade name, brand name). 

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The investigator must submit the following medication errors to Pfizer within 24 hours of 
awareness, irrespective of the presence of an associated AE/SAE: 
• Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE. 
• Medication errors including potential medication errors or near misses that do not 
involve a patient directly. When a medication error does not involve patient exposure 
to the product the following minimum criteria constitute a medication error report: 
• An identifiable reporter; 
• A suspect product; 
• The event medication error. 
11.6.4. Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE. 
11.6.5. Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product. 
11.6.6. Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the 
investigator, irrespective of the presence of an associated AE/SAE. 
11.7. Single Reference Safety Document 
The Core Data Sheet will serve as the single reference safety document during the course of 
the study, which will be used by Pfizer safety to assess any safety events reported to Pfizer 
Safety by the investigator during the course of this study. 
The Product Label should continue to be used by the investigator for prescribing purposes 
and guidance. 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
12.1. Communication and Publication of Study Results 
In the event of any prohibition or restriction imposed (eg, All information in the protocol and 
other documents provided to the survey physician and survey team are privileged and 
confidential information. The physician will use this information to accomplish the survey 
and will not use it for publication without written consent from the Sponsor. It is understood 
that the survey physician has agreed to provide the Sponsor with data obtained during the 
survey. The information obtained from the survey may be disclosed to regulatory 
authority(ies), other investigators, or other parties identified by the Sponsor. 

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It is anticipated that the survey results will be presented at scientific meetings and/or 
published in peer-reviewed scientific or medical journals. The Scientific Board will oversee 
publication of pooled survey results, which will reflect the experience of all participating 
centers 
The Sponsor will retain legal ownership of all data collected from all sites that participate in 
the survey. Data from each participating site is the property of that participating site. Each 
participating physician is free to use and publish his or her own data in compliance with the 
agreement with the Sponsor. 

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13. References 
1. 
Connelly S, Choi S, Johnson SM, et al. Structure based design of kinetic stabilizers that 
ameliorate the transthyretin amyloidoses. Curr Opin Struct Biol 2010; 20(1):54-62. 
2. 
Klabunde T, Petrassi HM, Oza VB, et al. Rational design of potent human transthyretin 
amyloid disease inhibitors. Nat Struct Biol 2000; 7(4):312-21. 
3. 
Johnson SM, Wiseman RL, Sekijima Y, et al. Native state kinetic stabilization as a 
strategy to ameliorate protein misfolding diseases: A focus on the transthyretin 
amyloidoses. Acc Chem Res 2005; 38(12):911-21. 
4. 
Sekijima, Y., Ueda, M., Koike, H. et al. Diagnosis and management of transthyretin 
familial amyloid polyneuropathy in Japan: red-flag symptom clusters and treatment 
algorithm. Orphanet J Rare Dis 13, 6 (2018) doi:10.1186/s13023-017-0726-x. 
5. 
Gavrin LK, Denny A, Saiah E. Small Molecules that Target Protein Misfolding. J Med 
Chem. 2012;55(24):10823-43. 
6. 
Adams D, Suhr O, et al. First European consensus for diagnosis, management, and 
treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2016, 29 
(suppl 1):S14–S26. 
7. 
Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary 
amyloidosis for clinicians. Orphanet J Rare Dis 8, 31 (2013) doi:10.1186/1750-1172-8- 
31. 
8. 
Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic 
polyneuropathy. Arch Neurol. 2005; 62:1057-1062. 
9. 
Adams D. Hereditary and acquired amyloid neuropathies. J Neurol. 2001; 248:647-657. 
10. Lobato L. Portuguese-type amyloidosis (transthyretin amyloidosis, ATTR V30M). J. 
Nephrol. 2003; 16:438-442. 
11. Waddington Cruz M, Schmidt H, et al. Epidemiological and clinical characteristics of 
symptomatic hereditary transthyretin amyloid polyneuropathy: A global case series. 
Orphanet J Rare Dis. 2019;14(1):34. 
12. Conceicao I, Coelho T, et al. Assessment of patients with hereditary transthyretin 
amyloidosis – understanding the impact of management and disease progression. 
Amyloid. 2019;26(3):103-111. 
13. Sharma P, Perri RE, Sirven JE, et al. Outcome of liver transplantation for familial 
amyloidotic polyneuropathy. Liver Transpl. 2003; 9:1273-1280. 

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14. Tashima K, Ando Y, Terazaki H, et al. Outcome of liver transplantation for 
transthyretin amyloidosis: follow-up of Japanese familial amyloidotic polyneuropathy 
patients. J. Neurol. Sci. 1999; 171:19-23. 
15. Herlenius G, Wilczek HE, Larsson M, Ericzon BG. Ten years of international 
experience with liver transplantation for familial amyloidotic polyneuropathy: results 
from the Familial Amyloidotic Polyneuropathy World Transplant Registry. 
Transplantation. 2004; 77:64-71. 
16. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for 
hereditary transthyretin amyloidosis. N Engl J Med 2018;379:11-21. 
17. Buxbaum JN. Oligonucleotide drugs for transthyretin amyloidosis. N Engl J Med 
2018;379:82-85. 
18. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with 
hereditary transthyretin amyloidosis. N Engl J Med 2018;379:22-31. 
19. Hattori T, Takei Y, Koyama J, Nakazato M, Ikeda S. Clinical and pathological studies 
of cardiac amyloidosis in transthyretin type familial amyloid polyneuropathy. Amyloid. 
2003; 10: 229-239. 
20. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126: 
1286-300. 
21. Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a 
clinical overview. Nat Rev Cardiol 2010; 7: 398-408. 
22. Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant sequence transthyretin 
(isoleucine 122) in late onset cardiac amyloidosis in black Americans. NEJM 1997; 
336:466-73. 
23. Westermark P, Sletten K, Johansson B, Cornwell, III GG. Fibril in senile systemic 
amyloidosis is derived from normal transthyretin. Proc. Natl. Acad. Sci. 1993; 87:2843- 
2845. 
24. Pitkanen P, Westermark P, Cornwell, III GG. Senile systemic amyloidosis. Am J 
Pathol. 1984; 117:391-399. 
25. Westermark P, Bergstrom J, Solomon A, Murphy C, Sletten K. Transthyretin-derived 
senile systemic amyloidosis: clinicopathologic and structural considerations. Amyloid. 
2003; 10 Suppl 1:48-54. 
26. Saraiva MJ. Transthyretin mutations in health and disease. Hum Mutat 1995; 5(3):191 
6. 

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27. Kyle RA, Spittell PC, Gertz MA, et al. The premortem recognition of systemic senile 
amyloidosis with cardiac involvement. Am. J. Med. 1996; 101:395-400. 
28. Witteles R, Bokhari S, Damy T, et al. Screening for transthyretin amyloid 
cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709-716. 
29. Hutt D, Fontana M, Burniston, et al. Prognostic utility of the Perugini grading of 99m 
Tc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with 
skeletal muscle and soft tissue amyloid. Eur Heart J Cardiovasc Imaging. 2017 Dec 
1;18(12):1344-1350. Doi: 10.1093/ehjci/jew325. 
30. Maurer MS, Schwartz, JH, Gundapaneni B, et al. Tafamidis treatment for patients with 
transthyretin amyloid cardiomyopathy. N Engl J Med. 2018; 379;1007-1016. 

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14. LIST OF TABLES 
Table 1. 
Summary of Safety Concerns to be Assessed in THAOS ......................... 26 
15. LIST OF FIGURES 
None. 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
None. 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
This annex is not required. 
ANNEX 3. ADDITIONAL INFORMATION 
See Patient Reported Outcome Questionnaires below. 

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Date(GMT) 
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Document Approval Record 
 
 
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020 
 
B3461001 Non-lnterventional Protocol Amendment 5 (clean)_13 July 2 
020 
 
 
PPD 
 
PPD 
 
 
16-Jul-2020 12:39:30 
Business Line Approver 
 
16-Jul-2020 21:49:21 
EUQPPV Approval 
Document Name: 
Document Title: