Conditions: Transthyretin Amyloid Polyneuropathy (ATTR-PN)
Keywords: tafamidis meglumine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
This is a single-arm, open-label, multicenter study designed to evaluate the efficacy, safety, tolerability as well as pharmacodynamics of tafamidis meglumine in ATTR-PN participants in China.

Approximately 10-15 participants are planned to be enrolled. All enrolled participants will receive oral tafamidis meglumine 20 mg soft capsules once daily for 72 weeks (18 months).

Detailed description:
This is a single-arm, open-label, multicenter study designed to evaluate the efficacy, safety, tolerability as well as pharmacodynamics of tafamidis meglumine in ATTR-PN participants in China.

All enrolled participants will receive oral tafamidis meglumine 20 mg soft capsules once daily starting on Day 1. Clinical visits will be scheduled at Baseline (Day 1) and at Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 60 and Week 72. At Week 36 and Week 60 site visit, assessment of adverse events, safety related lab testings, concomitant medications and investigational product compliance will be scheduled. Every 6 weeks (do not exceed 7 weeks since last confirmation) telephone contacts will be made during visits in which no investigative site visits are scheduled for assessment of adverse events, concomitant medications and investigational product compliance (between Week 12 and 24, between Week 24 and 36, between Week 36 and 48, between Week 48 and 60, and between Week 60 and 72).

Arms:
arm 1: Chinese patients diagnosed with ATTR-PN treated with tafamidis 20mg once daily oral administration for 72 weeks (18 months).

Interventions: intervention 1: tafamidis meglumine
Intervention descriptions: intervention 1: Tafamidis meglumine 20 mg, once daily, oral administration, for 72 weeks (18 months).

Protocol document:
Prot_000.pdf: 
Tafamidis meglumine 
Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
Page 1 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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. 
 
 
 
 
 
 
A SINGLE ARM, MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE 
EFFICACY, SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF 
ORALLY ADMINISTERED TAFAMIDIS MEGLUMINE IN TRANSTHYRETIN 
AMYLOID POLYNEUROPATHY PARTICIPANTS IN CHINA 
 
 
Investigational Product Number: 
PF-06291826 
Investigational Product Name: 
Tafamidis meglumine 
United States (US) Investigational New 
Drug (IND) Number: 
European Clinical Trials Database 
(EudraCT) Number: 
N/A 
N/A 
Protocol Number: 
B3461078 
Phase: 
4 
Short Title: The Effect of Tafamidis Meglumine in Transthyretin Amyloid 
Polyneuropathy Participants 
 
 
 
 


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Protocol B3461078 
 Final Protocol Amendment 3, 2 September 2021 
 
PFIZER CONFIDENTIAL 
Page2 
 
 
Protocol Amendment Summary of Changes Table 
 
Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment3 
2 September 
2021 
The study intervention duration was changed 
from 48 weeks (Month 12 to 72 weeks Month 
18 
The primaiy 
esbman en pomt was changed from "NIS-LL 
change from baseline at Week 48 (Month 12)" to 
"NIS-LL change from baseline at Week 72 
(Month 18)". Secondaiy endpoints were changed 
from ''NIS-LL at other visits than Week 48" to 
"NIS-LL at other visits than Week 72" and 
"Phaimacodynamics: TTR stabilization and TTR 
concentration at Day 1 (baseline), Week 8, Week 
12, Week 24 and Week 48" to 
"Pha1macodynamics: TTR stabilization and TTR 
concenti·ation at Day 1 (baseline), Week 8, Week 
12, Week 24, Week 48 and Week 72". The similar 
change was made in the following sections: 
• 
Section 1.1 Synopsis 
• 
Section 1.3. Schedule of Activities (SoA) 
• 
Section 3 OBJECTIVES, ESTIMANDS, 
AND ENDPOINTS 
• 
Section 4 STUDY DESIGN 
• 
Section 8.6 Pharmacodynamics 
• 
Section 9.1.1.1 Primary Estimand 
• 
Section 10.9 Appendix 9: Alternative 
Measures During Public Emergencies 
Section 1.1 Synopsis: 
• 
Clinical visits will be scheduled at 
Baseline (Da 1 and at Week 4, Week 8, 


Tafamidis meglumine 
Protocol B3461078 
 Final Protocol Amendment 3, 2 September 2021 
 
PFIZER CONFIDENTIAL 
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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
Week 12, Week 24 and Week 48. was 
changed to Clinical visits will be 
scheduled at Baseline (Day 1) and at 
Week 4, Week 8, Week 12, Week 24, Week 
48, Week 60 and Week 72. due to the 
extension of study duration. 
• 
 At Week 36 site visit, assessment of 
adverse events, was changed to At Week 
36 and Week 60 site visit, assessment of 
adverse events, due to the extension of 
study duration. 
• 
 between Week 48 and 60, and between 
Week 60 and 72 was added at the end of 
the last sentence in Overall Design in this 
section, due to the extension of study 
duration. 
• 
 During the treatment period, each 
partidpant will receive 20 mg tafamidis 
meglumine once daily for 48 weeks was 
changed to During the treatment period, 
each participant will receive 20 mg 
tafamidis meglumine once dai y for 72 
weeks due to the extension of study 
duration. 
Section 1.3 Schedule of Activities (SoA): 
• 
Two columns of Week 60 and Week 72 (or 
Early Study Discontinuation) were added 
to the SoA to meet CDE's 
 
assessments were also added to evaluate 
the efficacy, safety, tolerability and 
pha1macodynamics of tafamidis 
meglumine. 


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Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
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Document History 
Document 
Version Date 
Summary of Changes and Rationale 
• A new column of End of Treatment was 
added, because this visit is clinical 
important and the data is clinically 
valuable if participants withdraw the 
investigational treatment earlier. 
• (or Early Study Discontinuation) was 
deleted from column Week 48, because 
Early Study Discontinuation visit should 
be the same as Week 72. 
• Echocardiography was added in 
Screening, and Echocardiography at 
Baseline was added with a note d. 
Because Echocardiography 30 days prior 
to the baseline will be more feasible for 
the sites. 
• d. All laboratory tests do not need to be 
repeated if acceptable screening 
assessment is performed within 30 days 
prior Day 1 was changed to d. All the 
tests do not need to be repeated if 
acceptable screening assessment is 
performed within 30 days prior Day 1. 
Because echocardiography is not a 
laboratory test. 
• Between Week 12 to Week 24, Week 24 
and 36, and between Week 36 and 48 was 
changed to Between Week 12 to Week 24, 
Week 24 to Week 36, Week 36 to Week 48, 
Week 48 to Week 60, and between Week 
60 to Week 72 in note ‘i’ due to the study 
duration extension. 
Section 2.2.4 Clinical Overview: the 
development program for Tafamidis was updated 


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Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
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per the latest Investigator Brochure of Tafamidis 
as of March 2021. 
Section 4.1 Overall Design: all the clinical visits 
in this section were updated according to the new 
SOA, because the clinical visits increased due to 
the extension of study duration. 
Section 5.2 Exclusion Criteria: eg, was added 
before Val122Ile, Leu111Met, Ile68Leu in item 
11, because there may be other cardiomyopathy 
specific TTR mutations newly detected. 
Section 8. Study Assessments And Procedures: 
changed amount of total blood sampling from 
approximately 150-200 ml to 200-250 ml, 
provided the total volume taken during the study 
does not exceed 250 ml was changed to provided 
the total volume taken during the study does not 
exceed 300 ml, due to study visit increase. 
Section 8.1 Neuropathy Impairment Score- 
Lower Limb (NIS-LL): the item numbers were 
deleted for NIS scale, and the item numbers were 
updated for NIS-LL, because NIS-LL instead of 
the full NIS scale is now appended in the 
protocol. The same change was also made in 
section 9.4.1.1 Neuropathy Impairment Score- 
Lower Limb (NIS-LL). 
Section 8.2.6.4 Echocardiograms: The 
assessment of end-diastolic interventricular septal 
thickness for study entry will be based on the 
echocardiogram performed at the Baseline visit. 
If the Baseline echocardiographic recording is 
not clear enough to accurately determine the end- 
diastolic interventricular septal wall thickness, it 
must be repeated. was deleted from this section, 


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Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
Page 6 
 
 
 
Document History 
Document 
Version Date 
Summary of Changes and Rationale 
because an Echocardiograms is not relevant to the 
study entry. 
Section 10.2 Appendix 2: Clinical Laboratory 
Tests: Serum pregnancy testing was moved from 
column Chemistry to column Other in Table 1. 
Protocol-Required Safety Laboratory Assessments 
per protocol template. 
Section 10.9.3.1 Laboratory Testing: Serum 
pregnancy testing was moved from column 
Chemistry to column Other in Table 2. Protocol 
Required Safety Laboratory Assessments 
Permitted at a Local Laboratory per protocol 
template. 
Original protocol 
01 June 2019 
N/A 
Please refer to Protocol Amendment History in Section 10.10 Appendix 10. 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 


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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 12 
1. PROTOCOL SUMMARY ................................................................................................... 13 
1.1. Synopsis ................................................................................................................... 13 
1.2. Schema ..................................................................................................................... 15 
1.3. Schedule of Activities (SoA) ................................................................................... 16 
2. INTRODUCTION ................................................................................................................ 22 
2.1. Study Rationale ........................................................................................................ 22 
2.2. Background .............................................................................................................. 22 
2.2.1. Disease Introduction .................................................................................... 22 
2.2.2. Treatment of ATTR-PN .............................................................................. 23 
2.2.3. ATTR-PN in China ..................................................................................... 23 
2.2.4. Clinical Overview ....................................................................................... 24 
2.3. Benefit/Risk Assessment ......................................................................................... 24 
2.3.1. Benefit ......................................................................................................... 24 
2.3.2. Risks ............................................................................................................ 26 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ............................................................ 28 
4. STUDY DESIGN ................................................................................................................. 29 
4.1. Overall Design ......................................................................................................... 29 
4.2. Scientific Rationale for Study Design ..................................................................... 30 
4.3. Justification for Dose ............................................................................................... 30 
4.4. End of Study Definition ........................................................................................... 32 
5. STUDY POPULATION ...................................................................................................... 32 
5.1. Inclusion Criteria ..................................................................................................... 33 
5.2. Exclusion Criteria .................................................................................................... 33 
5.3. Lifestyle Considerations .......................................................................................... 35 
5.3.1. Activity ....................................................................................................... 35 
5.3.2. Contraception .............................................................................................. 35 
5.4. Screen Failures ........................................................................................................ 36 
6. STUDY INTERVENTION .................................................................................................. 36 
6.1. Study Intervention(s) Administered ......................................................................... 36 


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6.1.1. Administration ............................................................................................ 37 
6.2. Preparation/Handling/Storage/Accountability ......................................................... 37 
6.2.1. Preparation and Dispensing ........................................................................ 38 
6.3. Measures to Minimize Bias: Randomization and Blinding .................................... 39 
6.3.1. Allocation to Investigational Product ........................................................ 39 
6.4. Study Intervention Compliance .............................................................................. 39 
6.5. Concomitant Therapy ............................................................................................. 39 
6.5.1. Permitted Medicine .................................................................................... 39 
6.5.2. Excluded Medicine, Treatment and Substances ......................................... 39 
6.5.3. Rescue Medicine ........................................................................................ 40 
6.6. Dose Modification .................................................................................................. 40 
6.7. Intervention After the End of the Study ................................................................. 40 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 41 
7.1. Discontinuation of Study Intervention .................................................................... 41 
7.2. Participant Discontinuation/Withdrawal From the Study ...................................... 41 
7.2.1. Withdrawal of Consent .............................................................................. 42 
7.3. Lost to Followup ..................................................................................................... 42 
8. STUDY ASSESSMENTS AND PROCEDURES .............................................................. 43 
8.1. Efficacy Assessments ............................................................................................. 44 
8.1.1. Neuropathy Impairment Score-Lower Limb (NIS-LL) ............................. 44 
8.1.2. Norfolk QOL-DN ....................................................................................... 45 
8.2. Safety Assessments ................................................................................................. 46 
8.2.1. Physical Examinations ............................................................................... 46 
8.2.2. Vital Signs .................................................................................................. 46 
8.2.3. Electrocardiograms ..................................................................................... 47 
8.2.4. Clinical Safety Laboratory Assessments .................................................... 47 
8.2.5. Pregnancy Testing ...................................................................................... 48 
8.2.6. Other Assessment ....................................................................................... 48 
8.2.6.1. Medical History ........................................................................ 48 
8.2.6.2. Biopsy Documentation of Amyloid .......................................... 48 
8.2.6.3. TTR Genotyping ....................................................................... 48 


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8.2.6.4. Echocardiograms ....................................................................... 49 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 49 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information ....... 50 
8.3.1.1. Reporting SAEs to Pfizer Safety ............................................... 50 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 51 
8.3.2. Method of Detecting AEs and SAEs ........................................................... 51 
8.3.3. Followup of AEs and SAEs ........................................................................ 51 
8.3.4. Regulatory Reporting Requirements for SAEs ........................................... 51 
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 52 
8.3.5.1. Exposure During Pregnancy ...................................................... 52 
8.3.5.2. Exposure During Breastfeeding ................................................. 54 
8.3.5.3. Occupational Exposure .............................................................. 54 
8.3.6. Cardiovascular and Death Events ................................................................ 54 
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 55 
8.3.8. Adverse Events of Special Interest ............................................................. 56 
8.3.8.1. Lack of Efficacy ........................................................................ 56 
8.3.9. Medical Device Deficiencies ...................................................................... 56 
8.3.10. Medication Errors ...................................................................................... 56 
8.4. Treatment of Overdose ............................................................................................ 57 
8.5. Pharmacokinetics ..................................................................................................... 58 
8.6. Pharmacodynamics .................................................................................................. 58 
8.7. Immunogenicity Assessments ................................................................................. 58 
8.8. Genetics ................................................................................................................... 58 
8.8.1. Specified Genetics ....................................................................................... 58 
8.9. Biomarkers ............................................................................................................... 58 
8.10. Health Economics .................................................................................................. 58 
8.10.1. 36-Item Short Form Survey (SF-36) ......................................................... 59 
8.10.2. EQ-5D-5L ................................................................................................. 59 
9. STATISTICAL CONSIDERATIONS ................................................................................. 59 
9.1. Estimands and Statistical Hypotheses ..................................................................... 59 


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9.1.1. Estimands ................................................................................................... 59 
9.1.1.1. Primary Estimand ..................................................................... 59 
9.1.1.2. Secondary Estimands ................................................................ 59 
9.2. Sample Size Determination .................................................................................... 60 
9.3. Populations for Analysis ......................................................................................... 60 
9.4. Statistical Analyses ................................................................................................. 60 
9.4.1. Efficacy Analyses ...................................................................................... 60 
9.4.1.1. Neuropathy Impairment Score-Lower Limb (NIS-LL) ............ 60 
9.4.1.2. Modified BMI(body mass index) ............................................. 60 
9.4.1.3. Norfolk QOL-DN ..................................................................... 61 
9.4.2. Safety Analyses .......................................................................................... 61 
9.4.3. Quality of Life Analyses ............................................................................ 61 
9.4.3.1. 36-item-Short Form (SF-36) Score .......................................... 61 
9.4.3.2. EQ-5D-5L Index Score ............................................................. 62 
9.4.4. Pharmacodynamics: TTR Concentration and TTR Stabilization ............... 62 
9.5. Interim Analyses ..................................................................................................... 63 
9.5.1. Data Monitoring Committee ...................................................................... 63 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 64 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 64 
10.1.1. Regulatory and Ethical Considerations .................................................... 64 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 64 
10.1.2. Financial Disclosure ................................................................................. 65 
10.1.3. Informed Consent Process ....................................................................... 65 
10.1.4. Data Protection ......................................................................................... 66 
10.1.5. Dissemination of Clinical Study Data ...................................................... 66 
10.1.6. Data Quality Assurance ............................................................................ 68 
10.1.7. Source Documents ................................................................................... 69 
10.1.8. Study and Site Closure ............................................................................. 69 
10.1.9. Publication Policy .................................................................................... 70 
10.1.10. Sponsor’s Qualified Medical Personnel ................................................. 70 


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10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 72 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Followup, and Reporting ....................................................................... 73 
10.3.1. Definition of AE ....................................................................................... 73 
10.3.2. Definition of an SAE ................................................................................ 74 
10.3.3. Recording/Reporting and Followup of AEs and/or SAEs ....................... 75 
10.3.4. Reporting of SAEs ................................................................................... 79 
10.4. Appendix 4: Contraception Methods .................................................................... 80 
10.4.1. Male Participant Reproductive Inclusion Criteria ................................... 80 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 80 
10.4.3. Woman of Childbearing Potential (WOCBP) .......................................... 80 
10.4.4. Contraception Methods ............................................................................ 81 
CCI 
 
10.6. Appendix 6: Liver Safety: Suggested Actions and Followup Assessments ......... 84 
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ................................... 86 
CCI 
 
10.9. Appendix 9: Alternative Measures During Public Emergencies .......................... 90 
10.9.1. Eligibility ................................................................................................. 90 
10.9.2. Telehealth Visits ....................................................................................... 90 
10.9.3. Alternative Facilities for Safety Assessments .......................................... 91 
10.9.3.1. Laboratory Testing ................................................................. 91 
10.9.3.2. Imaging ................................................................................... 93 
10.9.3.3. Electrocardiograms ................................................................. 93 
10.9.4. Study Intervention .................................................................................... 93 
10.9.5. Home Health Visits .................................................................................. 93 
10.9.6. Adverse Events and Serious Adverse Events........................................... 93 
10.9.7. Efficacy Assessments ............................................................................... 94 
10.9.8. Independent Oversight Committees ......................................................... 94 
10.10. Appendix 10: Protocol Amendment History ...................................................... 95 
10.11. Abbreviations .................................................................................................... 116 
11. REFERENCES ................................................................................................................ 120 


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Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
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LIST OF TABLES 
Table 1. 
Protocol-Required Safety Laboratory Assessments ................................. 72 
Table 2. 
Protocol Required Safety Laboratory Assessments Permitted at a 
Local Laboratory ...................................................................................... 92 


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Protocol B3461078 
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: The Effect of Tafamidis Meglumine in Transthyretin Amyloid Polyneuropathy 
Participants 
Rationale 
Transthyretin amyloidosis is a protein misfolding disease with a broad spectrum of 
manifestations. When the peripheral nerves are affected predominately, the disease is termed 
transthyretin amyloid polyneuropathy (ATTR-PN). When the heart is primarily affected, the 
disease is called transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-PN is a fatal 
illness resulting from autosomal dominantly inherited single-point mutations on the 
transthyretin gene. 
Tafamidis is a specific stabilizer of both variant and wild-type TTR. Tafamidis binds to TTR 
at the thyroxine binding sites and inhibits TTR tetramer dissociation, the rate limiting step in 
the amyloidogenic process. The result disrupts the amyloid cascade and fibril formation and 
interrupts disease progression. 
In China, ATTR-PN is rare, estimated to affect approximately 1997 persons (with range from 
435 to 10,134). In recent years, about 30-40 case reports have been published and several 
families impacted by ATTR-PN, with different TTR gene mutations from those observed in 
Europe were reported. Delay in the time to diagnosis is a major obstacle to the optimal 
management of ATTR-PN in China, where typically patients are correctly diagnosed several 
years after the emergence of first clinical sign of the disease. Given the significant unmet 
medical need, it is critical to raise disease awareness, to facilitate earlier diagnosis and 
urgently enable access to treatment of this potentially fatal disease. 
Objectives, Estimands, and Endpoints 
 
Objectives 
Estimands 
Endpoints 
Primary: 
To evaluate the effect 
Descriptive statistics of 
Change from baseline NIS-LL at 
of tafamidis 
the NIS-LL change from 
Week 72 (Month 18) 
meglumine on 
baseline at Week 72 
clinical efficacy in 
(Month 18), regardless of 
ATTR-PN 
whether or not 
participants. 
participant continues 
with/adheres to treatment 


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Objectives 
Estimands 
Endpoints 
Secondary: 
To evaluate the 
efficacy, safety, 
tolerability, and 
pharmacodynamics 
of tafamidis 
meglumine in 
ATTR-PN 
participants. 
Descriptive statistics of 
the secondary endpoints 
in ATTR-PN 
participants, regardless of 
whether or not 
participant continues 
with/adheres to 
treatment. 
Efficacy: Change from baseline at 
follow-up visit on the following 
scales: 
• NIS-LL at other visits than 
Week 72 
• TQOL score and 5 domains as 
measured by the Norfolk 
QOL – Diabetic Neuropathy 
(Norfolk QOL-DN); 
• Modified Body Mass Index 
(mBMI); 
• 36-item short form (SF-36); 
• EQ-5D-5L Index Score. 
Safety: Adverse events, vital signs 
(temperature, blood pressure, pulse 
rate, and respiratory rate), ECGs, 
ECHO, clinical laboratory 
evaluations. 
Pharmacodynamics: TTR 
stabilization and TTR concentration 
at Day 1 (baseline), Week 8, 
Week 12, Week 24, Week 48 and 
Week 72. 
Overall Design 
This is a single-arm, open-label, multicenter study designed to evaluate the efficacy, safety, 
tolerability as well as pharmacodynamics of tafamidis meglumine in ATTR-PN participants 
in China. 
All enrolled participants will receive oral tafamidis meglumine 20 mg soft capsules once 
daily starting on Day 1. Clinical visits will be scheduled at Baseline (Day 1) and at Week 4, 
Week 8, Week 12, Week 24, Week 48, Week 60 and Week 72. At Week 36 and Week 60 site 
visit, assessment of adverse events, safety related lab testings, concomitant medications and 
investigational product compliance will be scheduled. Every 6 weeks (do not exceed 7 weeks 
since last confirmation) telephone contacts will be made during visits in which no 


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 Final Protocol Amendment 3, 2 September 2021 
 
 
investigative site visits are scheduled for assessment of adverse events, concomitant 
medications and investigational product compliance (between Week 12 and 24, between 
Week 24 and 36, between Week 36 and 48, between Week 48 and 60, and between Week 60 
and 72). 
Number of Participants 
 
Intervention Groups and Duration 
The study starts with the signing of the infonned consent document, and is divided into 
3 periods, including: screening period (Day-30 to Day 0), treatment period (72 weeks), and 
follow-up period (28 days after last dose). 
During the treatment period, each participant will receive 20 mg tafamidis meglumine once 
daily for 72 weeks. 
Data Monitoring Committee: No 
This study will not use a data monitoring committee (DMC). 
 
Statistical Methods 
Descriptive statistics summaiy will be done for all the study endpoints. The analysis will be 
done at the end of the study with no interim analysis planned. 
1.2. Schema 
Not applicable. 


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1.3. Schedule of Activities (SoA) 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
 
Activity 
Scree 
ning 
Day 
1 
Base 
line 
Week 
4 
(Day 
28) 
Wee 
k 8 
(Day 
56) 
Week 
12 
(Day 
84) 
Week 
24 
(Day 
168) 
Week 36 
(Day 252) 
Week 48 
(Month 
12/Day 
336) 
Week 60 
(Month 
15/Day 
420) 
End of 
treatment 
Week 72 
(Month 
18/Day 504) 
(or Early 
Study 
Discontinuati 
on) 
Post-study 
follow-up (28 
days after last 
dose) 
Allowable 
window 
Day - 
30-0 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
±14 days 
±14 days 
±14 days 
+14 days 
±14 days 
+7 days 
Informed 
consent 
X 
Medical 
history/ 
demographi 
cs 
X 
Review of 
entrance 
criteria 
X 
X 
Registration 
X 
X 
Biopsy to 
confirm 
amyloid 
Xa 
Confirmatio 
n of 
Val30Met or 
non-Val30 
X 


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Activity 
Scree 
ning 
Day 
1 
Base 
line 
Week 
4 
(Day 
28) 
Wee 
k 8 
(Day 
56) 
Week 
12 
(Day 
84) 
Week 
24 
(Day 
168) 
Week 36 
(Day 252) 
Week 48 
(Month 
12/Day 
336) 
Week 60 
(Month 
15/Day 
420) 
End of 
treatment 
Week 72 
(Month 
18/Day 504) 
(or Early 
Study 
Discontinuati 
on) 
Post-study 
follow-up (28 
days after last 
dose) 
Allowable 
window 
Day - 
30-0 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
±14 days 
±14 days 
±14 days 
+14 days 
±14 days 
+7 days 
Met 
genotype 
Serology 
(HBsAg, 
HIV 
antibodies, 
HCV 
antibodies) 
X 
Complete 
physical 
examination 
(PE) 
X 
X 
X 
X 
Abbreviated 
PE 
X 
X 
X 
X 
X 
X 
X 
Body height 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
sample for 
TTR 
stabilization 
assay, TTR 
concentratio 
n 
Xb 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 


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Activity 
Scree 
ning 
Day 
1 
Base 
line 
Week 
4 
(Day 
28) 
Wee 
k 8 
(Day 
56) 
Week 
12 
(Day 
84) 
Week 
24 
(Day 
168) 
Week 36 
(Day 252) 
Week 48 
(Month 
12/Day 
336) 
Week 60 
(Month 
15/Day 
420) 
End of 
treatment 
Week 72 
(Month 
18/Day 504) 
(or Early 
Study 
Discontinuati 
on) 
Post-study 
follow-up (28 
days after last 
dose) 
Allowable 
window 
Day - 
30-0 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
±14 days 
±14 days 
±14 days 
+14 days 
±14 days 
+7 days 
Laboratory 
tests 
(hematology 
, serum 
chemistry, 
TSH, total 
T4, free T4, 
RBP, and 
urinalysis) 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
NT-pro- 
BNP, 
Troponin 
I/T, 
coagulation 
panel 
X 
Xd 
X 
X 
X 
X 
X 
Contracepti 
on check: 
serum 
pregnancy 
test (females 
of 
child-bearin 
g potential 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol B3461078 
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Page 19 
 
 
 
Activity 
Scree 
ning 
Day 
1 
Base 
line 
Week 
4 
(Day 
28) 
Wee 
k 8 
(Day 
56) 
Week 
12 
(Day 
84) 
Week 
24 
(Day 
168) 
Week 36 
(Day 252) 
Week 48 
(Month 
12/Day 
336) 
Week 60 
(Month 
15/Day 
420) 
End of 
treatment 
Week 72 
(Month 
18/Day 504) 
(or Early 
Study 
Discontinuati 
on) 
Post-study 
follow-up (28 
days after last 
dose) 
Allowable 
window 
Day - 
30-0 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
±14 days 
±14 days 
±14 days 
+14 days 
±14 days 
+7 days 
Contracepti 
on check: 
urine 
pregnancy 
test (females 
of 
child-bearin 
g potential 
only) 
X 
X 
Serum FSHe 
X 
12-Lead 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiog 
raphy 
X 
Xd 
X 
X 
X 
Karnofsky 
Performance 
Status Scale 
X 
NIS-LLf 
Xg 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
SF-36 
X 
X 
X 
X 
Norfolk 
QOL-DN 
X 
X 
X 
X 
Dispense 
investigatio 
nal product 
Xh 
X 
X 
X 
X 
X 
X 
Collect all 
dispensed 
investigatio 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
Page 20 
 
 
 
Activity 
Scree 
ning 
Day 
1 
Base 
line 
Week 
4 
(Day 
28) 
Wee 
k 8 
(Day 
56) 
Week 
12 
(Day 
84) 
Week 
24 
(Day 
168) 
Week 36 
(Day 252) 
Week 48 
(Month 
12/Day 
336) 
Week 60 
(Month 
15/Day 
420) 
End of 
treatment 
Week 72 
(Month 
18/Day 504) 
(or Early 
Study 
Discontinuati 
on) 
Post-study 
follow-up (28 
days after last 
dose) 
Allowable 
window 
Day - 
30-0 
±7 
days 
±7 
days 
±7 
days 
±14 
days 
±14 days 
±14 days 
±14 days 
+14 days 
±14 days 
+7 days 
nal product 
bottle 
Concomitan 
t 
treatment(s)i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study 
medication 
compliancei 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious and 
non-serious 
adverse 
events 
monitoringi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
 
Abbreviations: Val30Met=substitution of methionine for valine at position 30; PE: physical examination; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency 
virus; HCV=Hepatitis C virus; TTR: transthyretin; TSH = thyroid-stimulating hormone; T4 = thyroxine; RBP = Retinol-binding protein; NT-pro-BNP = N-terminal B-type 
natriuretic peptide; FSH=follicle stimulating hormone; ECG= electrocardiogram; NIS-LL=Neuropathy Impairment Score-Lower Limb; EQ-5D-5L: EuroQoL 5 Dimensions 5 
Levels; Norfolk QOL-DN=Norfolk Quality of Life Diabetic Neuropathy; SF-36: 36-Item Survey 
a. 
Biopsy must have been performed within 5 years of enrollment. If greater than 5 years, biopsy must be repeated at the investigative site. 
b. 
Baseline (Day 1) sample: collect pre-dose during the clinic visit. The actual pre-dose blood sampling time and the time of first dose taken will be recorded. 
c. 
Collect samples during site visit. Refer to the chronology of events in Section 8. At site visit, the time of last dose taken prior to blood collection for TTR stabilization assay 
and TTR concentration will be checked and recorded. The actual blood sampling time will be recorded. 
d. 
All the tests do not need to be repeated if acceptable screening assessment is performed within 30 days prior Day 1. 
e. 
Performing only on 45-60 year old females who have been amenorrhea for at least 2 years. 
f. 
NIS-LL testing is performed 2 times at least 24 hours apart within a 1-week period by the same neurologist. 
g. 
Baseline evaluations maybe performed during the screening period only in cases where scheduling did not permit the examinations at baseline. 


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h. 
All the assessments and procedures at Day 1 (baseline) visit in the SoA should be completed prior to the investigational product administration on Day 1. Only on Day 1, the 
investigational product will be administered at site during clinic visit. 
i. 
Between Week 12 to Week 24, Week 24 to Week 36, Week 36 to Week 48, Week 48 to Week 60, and between Week 60 to Week 72, every 6 weeks telephone contact (with a 
window of ±7 days) to monitor for adverse events, study medication compliance and concurrent medications (refer to Section 8.3). 
j. 
Telephone contact can be used to monitor for adverse events. 


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2. INTRODUCTION 
Tafamidis binds with negative cooperativity to the 2 transthyretin (TTR) thyroxine binding 
sites and has been developed as an oral specific stabilizer of TTR tetramer that is cmTently 
used for the treatment of patients with stage 1 symptomatic polynemopathy to delay 
nemologic impaitment. 
In August 2018, the Notice on Soliciting Opinions on List of New Drngs with Urgent 
Clinical Need Marketed Overseas announced that tafamidis for ATTR-PN was included in 
the NMPA (National Medical Products Administration) List of 48 products for which there 
was an mgent clinical need in China. 
 
d to 
 
 
 
 
2.1. Study Rationale 
and is 
designed to evaluate the efficacy, safety, tolerability and pha1macodynamics of tafamidis 
meglmnine in ATTR-PN participantsin China. The treatment dose and regimen requit·ed in 
protocol are aligned with the approved label in China. 
Complete info1mation for this compound may be found in the single reference safety 
document, which for this study is the Investigator Brochure (IB). 
 
2.2. Background 
2.2.1. Disease Introduction 
Transthyretin amyloidosis is a protein misfolding disease with a broad spectrnm of 
manifestations. When the peripheral nerves are affected predominately, the disease is te1med 
transthyretin amyloid polynemopathy (ATTR-PN). ATTR-PN is a fatal illness resulting 
from autosomal dominantly inherited single-point mutations on the transthyretin gene. 
The main feature of ATTR-PN, regardless of genetic mutation, ethnic background, or 
geographic location, is a progressive, length-dependent degenerative sensorimotor and 
autonomic neuropathy.1-7 Symptoms of ATTR-PN often start as non-specific numbness or 
pain in the extremities, which progresses to include more severe senso1y distmbances, motor 
weakness and autonomic dysfunction. Time-to-diagnosis in non-endemic regions, such as 
the US (United States), has been estimated at 4 years.8 
This constellation of sympto111Shas a devastating impact on adults stricken with ATTR-PN in 
the prime of then·lives. Paiiicipant typically die from progressive and relentless worsening 
of nemopathy, seconda1y infections, cachexia, or sudden death.9,10 
 
 


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Final Protocol Amendment 3, 2 September 2021 
This disease typically strikes people in their 30s to 50s. A person affected by this disease 
will develop a slow, steady, and devastating neurologic decline leading ultimately to death. 
Rates of disease progression can vary somewhat by mutation, with mean survival of 10 to 
15 years following symptom onset for participants with Val30Met mutation and 3 to 13 years 
for participantswith non-Val30Met mutations.10 
2.2.2. Treatment of ATTR-PN 
Tafamidis is a specific stabilizer of both variant and wild-type TTR. Tafamidis binds to TTR 
(also referred to as pre-albumin) at the thyroxine binding sites and inhibits TTR tetramer 
dissociation, the rate limiting step in the amyloidogenic process. The result disrupts the 
amyloid cascade and fibril formation and interrupts disease progression. It has been 
developed as an oral specific stabilizer of TTR tetramer. 
In 2011 tafamidis became the first pharmacotherapy available for ATTR-PN when it was 
approved in the EU (European Union) under Exceptional Circumstances and it was approved 
to treat ATTR-PN in Japan on 20 September 2013 and on 05 February 2020 in China. 
Tafamidis is also approved in the following countries: Argentina, Brazil, Colombia, Hong 
Kong, Israel, Macau, Macedonia, Mexico, Russia, Serbia and South Korea and it remains the 
only orally administered small molecule that has been approved to treat ATTR-PN. 
2.2.3. ATTR-PN in China 
In China, ATTR-PN is rare, estimated to effect approximately 1997 persons (with range from 
435 to 10,134).11 In the 1990s, the first ATTR-PN kindred was diagnosed in Peking Union 
Medical College Hospital.12 In recent years, about 30-40 case reports have been published 
and several families impacted by ATTR-PN with different TTR gene mutations from those 
observed in Europe were reported.13-17 
Several factors, including the rarity of the disease in the general population, a lack of 
awareness among physicians of variable clinical features, and limited access to diagnostic 
tools (ie, histopathological and genetic screening) contribute to high rates of misdiagnosis 
and poorer patient outcomes. Common initial misdiagnoses of ATTR-PN include idiopathic 
axonal polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and lumbar 
spinal stenosis. Diabetes or chronic alcoholism may induce polyneuropathies similar to 
ATTR-PN. Further potential misdiagnoses include Charcot–Marie–Tooth neuropathy or 
motor neuron disease. 
Delay in the time to diagnosis is a major obstacle to the optimal management of ATTR-PN in 
China, where typically patients are correctly diagnosed several years after the emergence of 
first clinical sign of the disease. Given the significant unmet medical need, it is critical to 
raise disease awareness, to facilitate earlier diagnosis and urgently enable access to treatment 
of this potentially fatal disease. 
In August 2018, the Notice on Soliciting Opinions on List of New Drugs with Urgent 
Clinical Need Marketed Overseas announced that tafamidis for ATTR-PN was included in 
the NMPA List of 48 products for which there was an urgent clinical need in China. 


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 Final Protocol Amendment 3, 2 September 2021 
 
 
2.2.4. Clinical Overview 
As of March 2021, the development program for tafamidis includes 20 Phase 1 studies, in 
healthy paiticipants (19 studies) and hepatically impaired paiticipants (1 study), 1 controlled 
and 4 uncontrolled studies in paiticipants with ATTR-PN, 1 controlled and 3 uncontrolled 
studies in paiticipants with ATTRCM, and 6 noninterventional studies in ATTR paiticipants. 
Cumulatively, it is estimated that 2356 pa1ticipants have paiticipated in the tafamidis clinical 
development program: 2146 paiticipants were exposed to tafainidis. 
Data demonstrating the efficacy oftafamidis for the treatment of ATTR-PN are derived from 
1 pivotal Phase 3, randomized placebo-controlled, efficacy and safety study (Study Fx-005) in 
which a total of 65 paiticipants (with the Val30Met mutation) were randomized to tafainidis 
for 18 months, as well as data from the extension to Study Fx-005, ie, Study Fx-006, in which 
data from paiticipants originally treated with placebo and then switched to tafamidis 
treatment provide fmther evidence of efficacy in a more severely affected pa1ticipants 
population and the sustainability of the treatment effect in paiticipants who were on 
tafamidis for a full 30 months. 
A suppo1tive Phase II study (uncontrolled Study FxlA-201) enrolled 21 ATTR-PN 
paiticipants (with mutations other than Val30Met) who were treated with tafamidis for up to 
12 months. Each clinical study has been followed by a single treatment aim extension study 
designed to provide long-te1m data (safety and efficacy) of treatment with tafamidis 
meglumine 20 mg QD (Once daily) (Study FxlA-303). All efficacy studies were perfo1med 
using the -soft capsule fo1mulation at the dose of 20 mg daily; therefore, no in vitro - in vivo 
conelation studies were waiTanted. 
2.3. Benefit/Risk Assessment 
More detailed infonnation about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of tafainidis may be found in the investigator's brochure, 
which is the single reference safety document (SRSD) for this study. 
2.3.1. Benefit 
The benefits of treatment with tafamidis include: 
 
• 
 Tafamidis was well-tolerated and demonstrated an acceptable safety profile in healthy 
volunteer studies, the pivotal study of patients with ATTR-PN, and the suppo1tive 
patient studies conducted. There were few serious adverse events, with no change in 
the safety profile following longer te1m treatment. 
• 
Study Fx-005 
Progression 
rates for the pa1ticipants treated with tafamidis were statistically significantly less 
than those for placebo-treated paiticipants for key efficacy pai·ameters. The slower 
progression rate translated to preserved neurologic function in tafainidis paiticipants 
compai·ed with untreated participants. 


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• In the Efficacy Evaluable population in Study Fx-005, 60% percent of ATTR-PN 
participants administered tafamidis had no progression of neurological impairment(as 
demonstrated by the NIS-LL(Neuropathy Impairment Score - Lower Limb)), 
compared with 38% of participants on placebo. Similar rates of response were 
observed after 30 months of treatment (and therefore demonstrating durability of 
effect to the medication over time). 
• Evidence of treatment effect was observed as early as Week 24 for certain outcomes 
(eg, neurophysiological tests), with persistence of effect across all outcome measures 
demonstrated through 30 months of treatment. 
• The rate of deterioration of neurologic function was decreased by 52%, and that for 
neurophysiological function by 84% for small fiber and 54% for large fiber, and was 
maintained over 30 months of follow-up. These results are clinically relevant, and 
represent better neurologic status in those on tafamidis at the end of 18 months 
compared with placebo. Importantly, the observed decrease in rate of progression 
would be expected to translate to maintained functional status longer term. 
• Improvement in nutritional status and long-term maintenance of mBMI(modified 
body mass index) and maintenance of effect through 30 months of follow-up. This is 
a critical effect, as low mBMI is clearly associated with worse outcomes in 
participants with ATTR-PN. 
• In the most relevant population in Study Fx-005, participant reported quality of life 
was maintained, with persistence of effect over 30 months of follow-up in Study 
Fx-006. 
• Earlier treatment with tafamidis resulted in better neurologic outcome for those 
participants receiving treatment for the entire 30 month follow-up period, compared 
with those participants receiving tafamidis for only the last 12 months of this period. 
This highlights the importance of early diagnosis and initiation of treatment as soon as 
possible. 
• TTR amyloid polyneuropathy is an ultra-orphan disease with estimated world-wide 
patient population of <10,000. There is a serious unmet medical need for an effective 
pharmacologic therapy, as the only currently available treatment is liver 
transplantation. However, liver transplantation is insufficient given the shortage of 
available organs, first-year mortality rates of approximately 10%, long-term 
morbidity due to chronic immunosuppression and progression of cardiomyopathy 
post-transplantation. In addition, for those patients who are not liver transplant 
candidates, or unable to find a suitable match, there are no available treatments. 
Thus, tafamidis offers ATTR-PN patients a viable pharmacologic treatment that 
preserves neurologic function, nutritional status and quality of life. The effects on 
overall survival will be determined in the post-marketing setting. 


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2.3.2. Risks 
Safety issues that have been identified as risks or considered as potential risks associated 
with tafamidis treatment are discussed below: 
• Identified Adverse Drug Reactions (ADRs): participants in the tafamidis treatment 
arm of the placebo-controlled study Fx-005 experienced certain adverse events at a 
higher rate than placebo-treated participants. Based on review and all available AE 
data for ATTR-PN participants receiving 20 mg of tafamidis meglumine administered 
daily for an average of 538 days (n = 127), and taking into account other factors such 
as the mechanism of action of tafamidis, the known symptoms of underlying TTR 
amyloidosis disease, and the temporality of the adverse event to the administration of 
tafamidis, adverse drug reactions (ie, adverse events for which there is a reason to 
conclude that tafamidis caused the event) were determined to be: urinary tract 
infection, diarrhea, upper abdominal pain, and vaginal infection. 
• Theoretical/Potential Risks: 
• Liver enzyme elevations: A participant in Study Fx-005 (01-062) was observed to 
have an increase in liver enzymes (AST(aspartate aminotransferase), 
ALT(alanine aminotransferase), GGT(gamma-glutamyl transferase)) following 
18 months of treatment with tafamidis meglumine 20 mg daily. The liver 
function abnormalities improved despite continuation of tafamidis. Review of the 
case, including liver biopsy findings, by an independent expert determined that 
drug-induced liver injury was unlikely. 
However, given the importance of this potential safety risk, liver function in 
participants taking tafamidis will continue to be assessed and monitored in 
clinical trials. Spontaneous reports consistent with possible drug induced liver 
injury will be identified for specific data collection using a hepatotoxicity data 
capture aid questionnaire(refer to Appendix 6 for liver safety: Suggested Actions 
and Follow-up Assessments). 
• Hypersensitivity: A hypersensitivity reaction and a case of urticaria occurred in 
the clinical trials with tafamidis - neither case provided definitive evidence of 
tafamidis hypersensitivity. However, due to the uncertainty around causality from 
these reports and the potential putative role of the acyl glucuronide metabolite of 
tafamidis in hypersensitivity reactions, spontaneous reports consistent with 
hypersensitivity and/or skin reactions will be identified for specific data collection 
using an Allergic reactions, Hypersensitivity, Skin reaction data capture aid 
questionnaire. 
• Reproductive toxicity: Due to preclinical rabbit developmental toxicity findings, 
the relative lack of data on pregnant women exposed to tafamidis, and information 
on human reproductive toxicity, all women of childbearing potential should use 
appropriate contraception when taking tafamidis. To collect information about 


Tafamidis meglumine 
Protocol B3461078 
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PFIZER CONFIDENTIAL 
Page 27 
 
 
women who inadvertently become pregnant while taking tafamidis, the TESPO 
(Tafamidis Enhanced Surveillance of Pregnancy Outcomes) program will be in 
place to extend collection of routine post-natal safety information collection to 
12 months post birth with questions regarding developmental progression. 
• Changes in thyroid function, particularly in pregnant women. Due to the 
theoretical risk of thyroid function abnormalities related to displacement of 
thyroxine from the thyroxine binding site on the transthyretin tetramer, and given 
the increased risk of thyroid dysfunction during pregnancy and potential negative 
impact to the fetus, a thyroid dysfunction data capture aid will be incorporated 
into routine pharmacovigilance activities for adverse event reports consistent with 
thyroid dysfunction. In addition, information about thyroid function will be 
requested in cases of exposure during pregnancy. 
• Participants enrolled in the clinical studies were intended to represent the general 
population of patients with the disease. As ATTR-PN is endemic to certain locales 
(eg, Portugal), enrollment of participants from these centers of high disease prevalence 
was performed. The inclusion/exclusion criteria were generally unrestrictive; 
however, criteria did preclude participants with more advanced stage of disease from 
enrollment. Outcomes from the development program can be extrapolated to the 
general population with ATTR-PN with early to mid-stage disease. The effect of 
tafamidis in patients with severe disease is not known. 


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PFIZER CONFIDENTIAL 
Page 28 
 
 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
 
Objectives 
Estimands 
Endpoints 
Primary: 
To evaluate the effect of 
tafamidis meglumine on 
clinical efficacy in 
ATTR-PN participants. 
Descriptive statistics of the 
NIS-LL change from 
baseline at Week 72 
(Month 18), regardless of 
whether or not participant 
continues with/adheres to 
treatment 
Change from baseline NIS-LL at 
Week 72 (Month 18) 
Secondary: 
To evaluate the 
efficacy, safety, 
tolerability, and 
pharmacodynamics of 
tafamidis meglumine in 
ATTR-PN participants. 
Descriptive statistics of the 
secondary endpoints in 
ATTR-PN participants, 
regardless of whether or not 
participant continues 
with/adheres to treatment. 
Efficacy: Change from baseline at 
follow-up visit on the following 
scales: 
• NIS-LL at other visits than 
Week 72 
• TQOL score and 5 
domains as measured by 
the Norfolk 
QOL - Diabetic 
Neuropathy (Norfolk 
QOL-DN); 
• Modified Body Mass Index 
(mBMI); 
• 36-item short form 
(SF-36); 
• EQ-5D-5L Index Score. 
Safety: Adverse events, vital signs 
(temperature, blood pressure, pulse 
rate, and respiratory rate), ECGs, 
ECHO, clinical laboratory 
evaluations. 
Pharmacodynamics: TTR 
stabilization and TTR 
concentration at Day 1 (baseline), 


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 Final Protocol Amendment 3, 2 September 2021 
 
PFIZER CONFIDENTIAL 
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All emolled pruticipants will 
 
Week 8, Week 12, Week 24, Week 
48 and Week 72. 
However, when the investigator has judged the SAE (serious adverse event) to have a causal 
relationship with the investigational product, the investigator must additionally repo1t the 
event to Pfizer Safety as described in the Adverse Event Repo1ting section, even if that event 
is a component of the endpoint. 
4. STUDY DESIGN 
4.1. Overall Design 
This is a single-rum, open-label, multicenter study designed to evaluate the efficacy, safety, 
tolerability and phrumacodynamics oftafamiclis meglumine in ATTR-PN pruticipants in 
China. 
 
receive oral tafamidis meglumine 20 mg soft capsules once daily struting on Day 1. At 
Day 1, Week 24, Week 48 and Week 72 (or Early Study Discontinuation), NIS-LL testing 
will be perfo1med for each pruticipant to dete1mine the change from baseline. At Day 1 
(Baseline), Week 8, Week 12, Week 24, Week 48 and Week 72 (or Eru·ly Study 
Discontinuation), blood samples will be collected from each pruticipant to dete1mine TTR 
stabilization and TTR concentration. 
Before engaging in any study procedme, each pruticipant must sign and date an info1med 
consent fo1m. Paiticipants will be evaluated for study eligibility dming the screening period 
between Days -30 and Day 0. Screening laborato1y evaluations must be completed within 
3 days before Baseline (Day 1) in order for results to be available and reviewed before study 
emollment. 
Paiticipants who are dete1mined to be eligible, based on screening assessments, will be 
emolled in the study. After completion of Screening and Baseline assessments, participants 
will sta1t study medication on Day 1. 
Interventional product should be taken at the same time each day throughout the treatment 
period. 
Clinical visits will be scheduled at Baseline (Day 1) and at Week 4, Week 8, Week 12, 
Week 24, Week 48, Week 60 and Week 72 (or Eru·ly Study Discontinuation). At Week 36 
and Week 60 site visit, assessment of adverse events, safety related lab testings, concomitant 
medications and investigational product compliance will be scheduled. Eve1y 6 weeks (with 
a window of ±7 days) telephone contacts will be made dming visits in which no investigative 
site visits are scheduled for assessment of adverse events, concomitant medications and 
investigational product compliance (between Week 12 and 24, Week 24 and 36, Week 36 
and 48, Week 48 and 60, and between Week 60 and 72). 


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Efficacy assessments to be perfonned during the study include NIS-LL (Neuropathy 
Impai.J.ment Score-Lower Limb), Norfolk QOL-DN (Norfolk Quality of Life - Diabetic 
Neuropathy), mBMI, SF-36 (36-Item Survey) and EQ-5D-5L (EuroQoL-5 Dimensions 5 
Levels). NIS-LL testing is perfo1med 2 times at least 24 hours apart within a I-week period 
by the same neurologist before and/or at the baseline visit. Both evaluations are completed 
prior to study medication administration at baseline visit. 
Safety assessments to be perfonned during the study includemeasurement of vital signs, 
clinical laborat01y evaluations, including hematology, coagulation panel, and sernm 
chemistiy, ECG (electi·ocardiogram), ECHO (Echogram) and monitoring of adverse events. 
4.2. Scientific Rationale for Study Design 
In August 2018, the Notice on Soliciting Opinions on List of New Drngs with Urgent 
Clinical Need Marketed Overseas announced that tafamidis for ATTR-PN was included in 
the NMPA List of 48 products for which there was an urgent clinical need in China. 
 
Considering the exti-emely low revalence of ATTR-PN in China as a rai·e disease, the 
proposed sample size for the 
study may already be ve1y 
challenging for recrnitment. T 1e estnnahon to recrn1t approximatelyl0-15 patiicipants is 
based on the practical li.J.nitation of patients in China. The original proposed 6 months 
ti·eatlnent duration is based on the previous experience on license renewal timeline- 
and 6 months is enouoh for collectin  TTR stabilization data safet and 
 
t e ti·eatlnent an 
to 18 months (Week 72) in protocol amendment 3. 
4.3. Justification for Dose 
The proposed dosing regimen and administi·ation in this study is 20 mg soft tafainidis 
meglumine capsule (containing 12.2 mg oftafamidis free-acid) administered orally once 
daily, with or without food, consistent with the approved label in China. 
The approved therapeutic indication for tafamidis meglumine in China is same as is cmTently 
approved in the EU: "Treatment of ti·ansthyretin amyloidosis in adult patients with stage 1 
symptomatic polyneuropathy to delay peripheral neurologic impairment." Tafamidis 
meglumine soft capsule is also approved in Japan i.J.12013 for "delay of peripheral neurologic 
impai1ment in patients with ti·ansthyretin familial amyloid polyneuropathy 
(TTR-FAP(Transthyretin Familial Amyloid Pol euro ath 
"with the same dosing 
recommendation 20 m 
orall 
dail . 


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CCI 
18 The conclusion of the 
report is “Study of adverse reactions and infections etc. during the survey unit period 
revealed no particular problematic characteristic issues in terms of the safety of 
VYNDAQEL. Therefore, it was concluded that no further safety assurance measures need 
be adopted at this time.” 
The efficacy and safety of once daily 20 mg tafamidis meglumine for the treatment of 
ATTR-PN was demonstrated in participants with a documented Val30Met TTR variant in the 
randomized placebo-controlled clinical trial B3461020 (Fx-005) and in the subsequent long 
term extension study B3461023. Additional supportive data were provided by an ongoing, 
non-interventional study (Transthyretin-Associated Amyloidosis Outcomes Survey 
[THAOS]) (Study B3461001), independent analysis of data collected in Portuguese 
specialized centers, and analyses of data from participants with non-Val30Met mutation 
participating in study B3461023 or B3461022 (Fx1A-201). 
This approved dosing regimen in China (the one in this study), is the same as the one 
approved in EU and Japan, is also supported by following data from Asian participant, 
primarily from Japanese, when comparing to data from Western participants as appropriate. 
• Study B3461009 is a Phase 1, single center, double-blinded (sponsor-open), placebo 
controlled parallel study in healthy Japanese and Western volunteers. Each 
participant was randomly assigned to a single treatment of either tafamidis 
meglumine 20 mg Phase 2/3 capsule, tafamidis meglumine 40 mg (2 x 20 mg) Phase 
2/3 capsules, or placebo capsule in a 3:3:1 fashion, in the fasted state. Serial plasma 
samples were collected for 168 hours post dose. Mean PK parameters were similar 
between Japanese and Western participants (please see Table 14.4.3.1 of the 
B3461009 Report Body). Percent stabilization at Tmax (time of maximum observed 
concentration) and 24 hours post-dose of tafamidis meglumine 20 mg or 40 mg was 
similar between Japanese and Western participants (Figure 4 of B3461009 Report 
Body). 
• Study B3461010 is an uncontrolled, open-label Phase 3 study with the primary 
objective of determining TTR stabilization at steady-state, as measured in Japanese 
participants with ATTR-PN following oral tafamidis meglumine 20 mg soft capsules 
once daily. The study enrolled 10 participants; 7 completed study treatment and 
3 discontinued. All participants were treated with 20 mg tafamidis meglumine 
(orally, once daily). The TTR genotypes were Val30Met in 9 participants and 
non-Val30Met (Ser77Tyr) in 1 participant. All participantsachieved TTR 
stabilization (the percent stabilization was equal to or greater than 32%) at Week 8, 
Week 26, and 9 of 10 participants (90.0%) at Week 52 and 8 of 10 participants 
(80.0%) at Week 78 achieved TTR stabilization. Data from this study contributed to 
the population PK (pharmacokinetic(s)) analyses and the TTR stabilization analyses 
summarized following this. 


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• In order to examine the effect of certain intrinsic factors including age, gender, race, 
health status, and renal function on the PK of tafamidis, a population PK analysis was 
conducted with analysis dataset consisted of 13,123 observations from 760 
participants (333 healthy participants, 292 ATTR-CM participants, and 135 ATTR- 
PN participants). Of those observations, a total of 11,472 were used in the population 
PK analysis after consideration of exclusions due to data exclusion criteria and 
observations below the limit of quantification. The study population consisted of 
639 males and 121 females with a median age of 49.5 years (range 18 88 years) and 
a median weight of 76 kg (range 32 – 133.8 kg). There were 584 White, 61 Black, 
69 Asian, 45 Other, and 1 of unknown race. The median value for creatinine 
clearance was 93.7 mL/min (range 17.4 – 220.6 mL/min). Nine moderate and 9 mild 
hepatic impaired participants from the Phase 1 hepatic impairment study B3461016 
(Fx1A-105) were included in the hepatically impaired group. Results from this 
analysis showed that no dosage adjustment is necessary with tafamidis for intrinsic or 
extrinsic factors, including gender, race, age, nor for participants with renal 
impairment or mild and moderate hepatic impairment. No data are available in 
participants with severe hepatic impairment. The results support tafamidis 
meglumine 20 mg once-daily oral dosing. 
• Population pharmacodynamics analyses (% TTR stabilization relative to tafamidis: 
TTR stoichiometry) were conducted using pooled data from 11 different clinical 
studies in which TTR stabilization was measured. In this analysis there were 5.5% 
(36/660) Japanese participants. No clinically meaningful impact of ethnicity 
(Japanese vs non-Japanese) was noted on the exposure-response relationship. 
4.4. End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Male or female participants between the ages of 18 and 80 years. 
• Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Type of Participant and Disease Characteristics: 
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations and other study procedures. 
3. Participants have amyloid documented by biopsy in accordance with institutional site 
standard of care (Biopsy must have been performed within 5 years of enrollment). 
4. Participants must have a TTR mutation that is associated with ATTR-PN. (See 
Section 8.2.6.3 for further details). 
5. Participants have peripheral and/or autonomic neuropathy with a Karnofsky 
Performance Status ≥50 (refer to Appendix 5). 
6. Stages of disease according to symptom severity-stage I. 
Informed Consent: 
7. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the informed consent 
document (ICD) and in this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study. 


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Prior/Concomitant Therapy: 
2. Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 3-4 times/month. The following NSAID are 
allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac. 
3. Use of diflunisal, tauroursodeoxycholate, doxycycline, inotersen, patisiran or any 
other TTR stabilizing agent, or experimental interventions for familial amyloidosis 
within 30 days prior to the study entry and/or during study participation. Participants 
who are taking or who have previously taken tafamidis. 
Prior/Concurrent Clinical Study Experience: 
4. Previous administration with an investigational drug within 30 days or 5 half-lives 
preceding the first dose of investigational product used in this study (whichever is 
longer). 
Diagnostic Assessments: 
5. Participant has primary (light chain) or secondary amyloidosis. 
6. If female, participant is pregnant or breast feeding, or plans to be pregnant or breast 
feeding in the next 18 months. 
7. Participant has received prior liver or any other organ except cornea transplantation. 
8. Participant requires significant assistance with ambulation or is wheel chair bound. 
9. Participants with positive results for hepatitis B surface antigen (HBsAg), 
anti-hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV). 
10. Participant has liver function test abnormalities: alanine transaminases (ALT) and/or 
aspartate transaminases (AST) >2 times upper limit of normal (ULN) that in the 
medical judgment of the investigator are due to reduced liver function or active liver 
disease. 
11. Participants with cardiomyopathy specific TTR mutations (eg, Val122Ile, 
Leu111Met, Ile68Leu). 
12. Participant has a co-morbidity anticipated to limit survival to less than 18 months. 
13. Participant has other causes of sensorimotor neuropathy (B12 deficiency, Diabetes 
Mellitus, HIV treated with retroviral medications, thyroid disorders, alcohol abuse, 
Fabry disease, Lyme disease, sarcoidosis, Sjogren’s Syndrome, Systemic Lupus 
Erythematosus, alcohol dependency, celiac disease, Chronic Inflammatory 
Demyelinating Polyneuropathy, and chronic inflammatory diseases). 


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Other Exclusions: 
14. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
5.3. Lifestyle Considerations 
5.3.1. Activity 
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, and aerobics) for 48 hours prior to each blood collection for clinical laboratory 
tests. Walking at a normal pace will be permitted. 
5.3.2. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception). In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner. 
Participants need to affirm that they meet the criteria for correct use of at least 2 of the 
selected methods of contraception. In this study, female participants who are of childbearing 
potential may receive tafamidis, which has been associated with teratogenic risk. All female 
participants who are of childbearing potential and, in the opinion of the investigator, are 
sexually active and at risk for pregnancy must agree to use with their partner(s) 2 methods of 
highly effective contraception must be used throughout the study and continued for 28 days 
after the last dose. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following: 
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception are allowed provided the participant plans to remain on the 
same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness. 


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2. Correctly placed intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate. 
4. Male sterilization with absence of sperm in the postvasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label). 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who recover from acute medical conditions may, according to the best medical 
judgment of the investigator, be appropriate for rescreening. If individuals recovered within 
30 days, the individual inclusion/exclusion criteria may need repeating according to the 
nature of the medical event and clinical judgement of the investigator. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. For individuals whose eligibility assessment has been impacted due to 
public emergencies (including COVID-19), please refer to Section 10.9.1. 
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention. 
6.1. Study Intervention(s) Administered 
 
Intervention Name 
Tafamidis meglumine 
PF-06291826 
ARM Name 
N/A 
Type 
Drug 
Dose Formulation 
Tafamidis meglumine soft capsule 20 mg. 
Unit Dose Strength(s) 
Tafamidis meglumine soft capsule 20 mg. 
Dosage Level(s) 
20 mg once daily. 


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Route of 
Administration 
Oral 
Investigational 
Medicinal Product 
(IMP) and 
Noninvestigational 
Medicinal Product 
(NIMP) 
IMP 
Sourcing 
Provided centrally by the sponsor as soft capsules containing tafamidis 
meglumine 20 mg. 
Refer to the IP manual. 
Packaging and 
Labeling 
Study intervention will be provided in packs of 30 x 1 soft capsules. Each pack 
will be labeled as per country requirement. 
The product will be provided as open label. 
 
6.1.1. Administration 
All enrolled participants will receive a once-daily oral dose of tafamidis meglumine 20 mg in 
a soft capsule formulation. Each participant will receive the first dose of study medication on 
Day 1 at site during clinic visit. 
Participants will self-administer investigational product at home except Day 1 (baseline). 
Investigational product is to be taken by mouth, with water. Participants will be instructed to 
take investigational product at the same time each day throughout the treatment period. 
Participants will swallow the investigational product whole, and will not manipulate or chew 
the investigational product prior to swallowing. 
6.2. Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 


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interventions will be accounted for using an investigational product accountability 
form/record. All empty containers (as appropriate) and unused products must be 
taken to the investigator by the participant at every visit and at the end of the study. 
4. Further guidance and information for the final disposition of unused study 
interventions are provided in the Investigational product (IP) manual. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual. 
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site). If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented. 
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual. 
6.2.1. Preparation and Dispensing 
The investigational product will be dispensed by pharmacist/site staff manually at each visit 
from Day 1 onwards until end of trial (EOT) according to the IP manual. A qualified staff 
member will dispense the investigational product, in quantities appropriate for the study visit 
schedule. The participant/caregiver should be instructed to maintain the product in the 
container(s) provided throughout the course of dosing and take the container(s) to the site at 
the next study visit. 


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6.3. Measures to Minimize Bias: Randomization and Blinding 
6.3.1. Allocation to Investigational Product 
This is an open-label, single arm study; potential bias will be reduced by the following steps: 
data review committee to evaluate all the data collected. The investigator’s knowledge of the 
treatment should not influence the decision to enroll a particular participant or affect the 
order in which participants are enrolled. 
Investigational product will be dispensed at the study visits summarized in the SoA. 
6.4. Study Intervention Compliance 
All investigational product will be self-administered by the study participants at home except 
taking it at site during clinic visit on Day 1 (baseline). Treatment compliance will be 
determined through capsule counting procedures at followup visits and participants-physician 
interviews during the scheduled study visits. Compliance will be monitored and recorded in 
Drug Accountability Form and each participant’s CRF(case report form). Additionally, 
interventional product accountability audits will be performed by the study monitor during 
routine monitoring visits. 
6.5. Concomitant Therapy 
6.5.1. Permitted Medicine 
Over-the-counter (OTC) medications may be taken after study medication administration for 
the management of a self-limiting indication (eg, acetaminophen for headache) at the 
investigator’s discretion. The use of concomitant OTC medications must be approved by the 
investigator before administration. All prescription medications must be approved by the 
investigator throughout the treatment period of the study. All participants will be instructed 
regarding the importance of consulting with the investigator before taking any medication 
during the study. Use of concomitant drugs with a narrow therapeutic window, eg, warfarin 
and digoxin, should be done with caution. Monitoring of adverse effects will be performed. 
All medication taken by the participant during the study must be recorded in the participant’s 
eCRF. If a participant is offered, in accordance with the prevailing local guidelines, a 
COVID-19 vaccine, it should be permitted. This would be recorded as a concomitant 
medication and standard AE collection and reporting processes would be followed. 
6.5.2. Excluded Medicine, Treatment and Substances 
The following medications and substances are prohibited during the study, as specified 
below: 
• Any investigational intervention within 30 days before Day 1 (Baseline) and during 
the study participation. 
• Chronic use of non-protocol approved non-steroidal anti-inflammatory drugs 
(NSAIDs), defined as greater than 4 times/month. The following NSAID are 


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allowed: acetylsalicylic acid, etodolac, ibuprofen, indomethacin, ketoprofen, 
nabumetone, naproxen, nimesulide, piroxicam, and sulindac. Topical ophthalmic 
NSAIDs administered while the participant’s nasal punctum is occluded are also 
permitted. All other NSAIDs are prohibited.Use of diflunisal, tauroursodeoxycholate, 
doxycycline, inotersen or patisiran or any other TTR stabilizing agent within 30 days 
prior to the study entry and/or during study participation is prohibited. 
• Liver or any other organ except cornea transplantation is prohibited during study 
participation. Participants undergoing liver or any other organ except cornea 
transplantation will be withdrawn from the study. 
• Drugs known to affect autonomic function and impact orthostatic blood pressure 
measurements. 
• Anticholinergics (eg, tricyclic antidepressants, antispasmodics, antihistamines, 
over-the counter cold remedies): 
• Participants who are stable on anticholinergics at study start should try to 
maintain the dose and frequency throughout the study. 
• Sympathomimetics, diuretics and alpha blockers (including those for benign prostate 
hyperplasia): 
• Participants who are stable on sympathomimetics, diuretics and alpha blockers at 
study start should try to maintain the dose and frequency throughout the study; 
• Any sympathomimetics, diuretics and alpha blockers started after the screening 
assessments must be discontinued for 72 hours prior to conducting any clinical 
assessments of orthostatic blood pressure, provided there is no safety risk to the 
participant. A list of prohibited medications as examples will be provided in the 
Study manual. 
• Nicotine, caffeine and alcohol are not permitted for 3 hours prior to orthostatic blood 
pressure measurements. 
6.5.3. Rescue Medicine 
There is no rescue therapy to reverse the adverse events (AEs) observed with investigational 
product; standard medical supportive care must be provided to manage the AEs. 
6.6. Dose Modification 
No dose modification is required based on age and gender. 
6.7. Intervention After the End of the Study 
No intervention will be provided to study participants at the end of the study. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: 
• Withdrawal of consent; 
• Pregnancy; 
• Protocol noncompliance; 
• Liver or other organ except cornea transplantation; 
• Unexpected allergic reaction; 
• Serious disease; 
• Serious and/or intolerable adverse events; 
• Others, which investigators decide not to continue study. 
Note that discontinuation of investigational product does not represent withdrawal from the 
study. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated. See the SoA for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following: 
• Refused further study procedures; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor. 


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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
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. 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol specified follow up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future followup, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 
and/or posttreatment study followup, and entered on the appropriate CRF page. In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law. 
7.3. Lost to Followup 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study; 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record; 


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• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
Where multiple procedures are scheduled at the same nominal time point(s) relative to 
dosing, the following chronology of events is suggested: 
1. ECG 
2. Vitals: Blood pressure/pulse rate. 
3. Blood sample collection. 
4. Blood specimens for TTR stabilization and TTR concentrationshould be obtained 
within the specified time windows if applicable. 
5. All the assessments and procedures at baseline visit in the SoA should be completed 
prior to the investigational product administration on Day 1. 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
At the discretion of the investigator, isolated abnormal tests can be repeated for confirmation. 
However, the entire panel should not be repeated. In the event the repeated test confirms an 
abnormal value, no further testing is necessary. The abnormal test value from the 
confirmatory test will be entered into the database and the participant will be considered a 
screen failure. If the repeat test does not confirm the abnormal value (ie, it is within the 
normal range), the investigator is required to again repeat the specific laboratory test. If this 
further repeat test confirms a value within the normal range, the last repeated normal value is 
entered into the database. If the further repeat test value is abnormal, this value will be 
entered into the database, and the participant will be considered a screening failure. 


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Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
The total blood sampling volume for individual participants in this study is approximately 
200-250 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 300 mL, and the total volume taken during 
the study does not exceed 550 mL during any period of 56 consecutive days. In exceptional 
circumstances, such as medical emergencies, this volume may be exceeded and will not 
constitute a protocol deviation in such circumstances. 
8.1. Efficacy Assessments 
8.1.1. Neuropathy Impairment Score-Lower Limb (NIS-LL) 
The neurologic functioning will be evaluated using the Neuropathy Impairment Score (NIS) 
scale. NIS scale will provide a single score of total body neuropathic deficits and total body 
subset scores for cranial nerves, muscle weakness, reflexes, and sensation. The NIS scoring 
categories are cranial nerves, muscle weakness, reflexes, and sensation. Each item is scored 
separately for left and right. 
Only a subset of the NIS scale focusing on the lower limbs (NIS-LL) will be performed to 
provide a single score of lower limb neuropathic deficits and lower limb subset scores for 
muscle weakness, reflexes, and sensation in great toe. The subset for the lower limbs (NIS- 
LL) includes muscle weakness (sum of Items 1-8), reflexes (sum of Items 9 and 10), 
sensation in great toe (sum of Items 11-14). The total NIS-LL score will be calculated as the 
sum of the subset scores. During this study, NIS-LL assessments will be performed 2 times 
at least 24 hours apart within a 1-week period at times specified in the NIS-LL assessments 
at baseline are completed prior to study medication administration. The average of the 2 
NIS-LL scores will be used for analysis. Each participant’s NIS-LL testing is to be 
performed by the same neurologist throughout the course of the study. 


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Components of cranial nerves, muscle weakness are scored to eight levels: 
0 = Normal 
1 = 25% Weak 
2 = 50% Weak 
3 = 75% Weak 
3.25 = Move against gravity 
3.5 = Movement, gravity eliminated 
3.75 = Muscle flicker, no movement 
4 = Paralysis 
Components of reflexes and sensation (touch pressure, pin-prick, vibration, and joint 
position) in index finger and great toe are scored 0 = normal, 1= decreased, or 2 = absent. 
The neurologists involved in NIS scoring must undergo training sessions that will illustrate 
the method to normalize the data generated by the physician examination. In addition, all 
neurologists will receive a NIS training video prepared specifically for this study(refer to 
Appendix 8 for details). 
8.1.2. Norfolk QOL-DN 
Quality of Life (QOL) will be assessed using the Norfolk QOL-DN, a tool which was 
developed to capture participant-reported aspects of neuropathy, particularly when the 
participant base is comprised of participants with polyneuropathy and somatic and autonomic 
symptoms. The Norfolk QOL-DN has been used to evaluate several diabetic neuropathy 
drugs in clinical trials. The developers showed in a study population in Germany with 
5 stages of neuropathy severity according to the criteria of Dyck19 that Norfolk QOL-DN was 
able to discriminate the presence of neuropathy and distinguish the stages within the 
population.20 
The Norfolk QOL-DN is a self-administered questionnaire, designed to capture and quantify 
the impact of neuropathy on the quality of life of individual participants with neuropathy. 
The 35 scored questions are numbered items that comprise the entire scale, and they are 
arranged thematically so that the wording of the questions and the type of response is 
grouped together. However, the content and topic of each individual question concerns 
particular functions or symptoms that are related to the following themes: 
• Total Quality of Life Score; 
• Physical Functioning/Large Fiber Neuropathy; 
• Activities of Daily Living (ADLs); 
• Symptoms; 
• Small Fiber Neuropathy; 


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• Autonomic Neuropathy. 
Quality of Life (QOL) will be assessed using the Norfolk QOL-DN at times specified in 
theSoA. 
Additional details on the content of the Norfolk QOL-DN and how it is scored are contained 
in a stand alone document. 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be at any time during the study to assess any perceived safety 
concerns. 
8.2.1. Physical Examinations 
A complete physical examination will include assessments of the general appearance, head 
and neck, eyes, ears, nose, throat, genitourinary, endocrine, skin, musculoskeletal, 
immunologic/allergies, hematologic/lymphatic, cardiovascular, respiratory, gastrointestinal, 
and neurological systems. Height and weight will also be measured and recorded. 
An abbreviated physical examination will include assessments of the general appearance, 
cardiovascular, respiratory and gastrointestinal system. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.3.1 to 8.3.3. 
8.2.2. Vital Signs 
Vital signs will be recorded at times specified in the SoA. 
Supine and standing blood pressure will be measured with the participant’s arm supported at 
the level of the heart, and recorded to the nearest mm Hg. The same arm (preferably the 
dominant arm) will be used throughout the trial. The participant should be supine for at least 
3 minutes before the supine blood pressure is obtained. Standing blood pressure should then 
be measured approximately 2 minutes after the participant assumes the standing position. 
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time point. The use of automated devices for measuring BP 
and pulse rate are acceptable, although, when done manually, pulse rate will be measured in 
the brachial/radial artery for at least 30 seconds. When the timing of these measurements 
coincides with a blood collection, blood pressure and pulse rate should be obtained prior to 
the nominal time of the blood collection. 


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8.2.3. Electrocardiograms 
12-Lead ECGs should be collected at times specified in the SoA section of this protocol 
using an ECG machine that automatically calculates the heart rate and measures PR, QT, and 
QTc intervals and QRS complex. All scheduled ECGs should be performed after the 
participant has rested quietly for at least 10 minutes in a supine position. 
If a postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or b) an 
absolute QT or QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged (generally QTcB), as defined above, repeat measurements may not be 
necessary if a qualified medical provider’s interpretation determines that the QTcF values are 
in the acceptable range. 
ECG values of potential clinical concern are listed in Appendix 7. 
8.2.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. 
The values of laboratory tests obtained on Day 1 will be considered as baseline assessment. 
All blood samples for laboratory safety tests will be collected in the morning prior to 
administration of study medication. All values obtained during the study are to be recorded 
in the eCRF. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 


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All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF. 
8.2.5. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP (woman of childbearing 
potential)at the times listed in the SoA. Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and a second negative pregnancy 
test result will be required at the baseline visit prior the participant’s receiving the 
investigational product. Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded if the 
serum pregnancy result is positive. 
8.2.6. Other Assessment 
8.2.6.1. Medical History 
A complete medical history is to be documented for all participants during the screening 
period. 
8.2.6.2. Biopsy Documentation of Amyloid 
Nerve, rectal, fat pad, skin tissue, salivary gland samples or other acceptable tissue must be 
tested by the investigational site as per the site’s standard of care for amyloid biopsy using 
Congo red staining to confirm the presence of amyloid. Stained tissue will be viewed under 
polarized light used to demonstrate amyloid characteristic ‘apple-green’ birefringence or 
other analysis can be utilized to confirm the deposit of amyloid. It is possible that the 
participant’s amyloid biopsy may have been performed before the Screening visit outside the 
auspices of this study. 
For purposes of this study, an existing biopsy result will be considered valid if it is 
documented in writing and the biopsy was performed within 5 years of study enrollment. If 
the biopsy is not valid, it will be repeated as a screening procedure at the investigational site. 
8.2.6.3. TTR Genotyping 
At the time of Screening examination, a serum sample will be obtained to analyze complete 
TTR sequencing at the investigational site by institutional site standard of care. If TTR 


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genotyping showing Val30Met or non Val30Met has been performed within last 5 years, a 
participant can start to be dosed. 
8.2.6.4. Echocardiograms 
Echocardiography (2D Doppler) will be performed for all participants at timepoint on the 
SoA. Each echocardiogram will be recorded and reviewed locally by the clinical site, and 
the clinical significance of echocardiogram findings will be assessed by the Investigator. 
The following parameters will be included in the assessment: 
1. Interventricular septal wall thickness (mm); 
2. Left ventricle posterior wall thickness (mm); 
3. Left ventricular ejection fraction (%); 
4. Left ventricular stroke volume (mL); 
5. Fractional shortening (%); 
6. Left atrial diameter, anterior-posterior (mm); 
7. Left atrial diameter, medio-lateral (mm); 
8. Left atrial diameter, superior-inferior (mm); 
9. Left ventricular end systolic diameter (mm); 
10. Left ventricular end systolic volume (mL); 
11. Left ventricular end diastolic diameter (mm); 
12. Left ventricular end diastolic volume (mL); 
13. Left ventricular mass (g); 
14. E/A(E peak/A peak) Ratio. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the Investigator or 
other healthcare providers (clinical signs, test results, etc.). 


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study intervention (see Section 7.1). 
During the active collection period as described in Section 8.3.1, each participant/legally 
authorized representative will be questioned about the occurrence of AEs in a nonleading 
manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days after the last administration of the study intervention. 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form. 
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 


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Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
8.3.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. Followup of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3. 
8.3.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 


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Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.3.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure. 
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.3.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
• A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental EDP: 
o A female family member or healthcare provider reports that she is pregnant 
after having been exposed to the study intervention by ingestion, inhalation or 
skin contact. 
o A male family member or healthcare provider who has been exposed to the 
study intervention by ingestion, inhalation or skin contact, then exposes his 
female partner prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 


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• If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 calendar 
days after last administration of the study intervention. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow up to the initial EDP Supplemental Form. 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 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
• Spontaneous abortion including 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 the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. 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). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner. The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner. 


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The Tafamidis Enhanced Surveillance Pregnancy Outcomes (TESPO) program follows the 
progress and outcome of reported pregnancies in women exposed to tafamidis. Tafamidis 
exposure during pregnancy will be reported to TESPO program. 
8.3.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion, inhalation or skin contact. 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
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 SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
8.3.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form, regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file. 
8.3.6. Cardiovascular and Death Events 
Not applicable. 


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8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
The following disease-related event (DREs) is common in participants with ATTR-PN and 
can be serious/life threatening: 
• Death. 
Because these events are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the 
event may meet the definition of an SAE. These events will be recorded on the 
corresponding CRF page in the participant’s CRF within 24 hours. 
AEs reported from studies associated with hospitalization or prolongations of hospitalization 
are considered serious. Any initial admission (even if less than 24 hours) to a healthcare 
facility meets these criteria. 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). 
Hospitalization does not include the following: 
1. Rehabilitation facilities; 
2. Hospice facilities; 
3. Respite care (eg, caregiver relief); 
4. Skilled nursing facilities; 
5. Nursing homes; 
6. Routine emergency room admissions; 
7. Same day surgeries (as outpatient/same day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE. Examples include: 
1. Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality); 
2. Social admission (eg, participanthas no place to sleep); 
3. Administrative admission (eg, for yearly physical exam); 


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4. Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
5. Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
6. Hospitalization for observation without a medical AE; 
7. Pre-planned treatments or surgical procedures should be noted in the Baseline 
documentation for the entire protocol and/or for the individual participant. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE. 
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an SAE (instead of a DRE): 
• The event is, in the investigator’s opinion, of greater intensity, frequency, or duration 
than expected for the individual participant. 
OR 
• The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.3.8. Adverse Events of Special Interest 
Not applicable. 
8.3.8.1. Lack of Efficacy 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE. 
8.3.9. Medical Device Deficiencies 
Not applicable. 
8.3.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 


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Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.4. Treatment of Overdose 
For this study, any dose of tafamidis meglumine greater than 20 mg within a 24-hour time 
period will be considered an overdose. 
Pfizer does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor within 24 hours. 
Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of tafamidis meglumine 
(whichever is longer). 
2. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
3. Overdose is reportable to Safety only when associated with an SAE. 


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. Pharmacodynamics 
Pharmacodynamic parameters of TTR stabilization and TTR concentrations are evaluated as 
secondary endpoints in this study. 
One (1) dipotassium ethylenediaminetetraacetic acid (K2 EDTA) blood sample of 
approximately 10 mL (with exception of an additional 10 mL of K2 EDTA blood sample 
taken at the pre-dose blood sample only on Day 1 (Baseline) for method development and 
validation) will be collected for measurement of TTR stabilization and TTR concentrations 
pre-dose during the clinic visit on Day 1 (Baseline), and during the clinic visits at Week 8, 
Week 12, Week 24, Week 48, and Week 72 (or End of Treatment/Early Study 
Discontinuation), please refer to SoA for details. Instructions for the collection and handling 
of biological samples will be provided in the laboratory manual or by the sponsor. The actual 
date and time (24 hour clock time) of each sample will be recorded. Samples will be 
analyzed using a validated analytical method in compliance with Pfizer standard operating 
procedures. 
The samples must be processed and shipped as indicated in the instructions provided to the 
investigator site to maintain sample integrity. Any deviations from the sample handling 
procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 
8.7. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
8.8. Genetics 
8.8.1. Specified Genetics 
Genetics (specified analyses) are not evaluated in this study. 
8.9. Biomarkers 
Biomarkers are not evaluated in this study. 
8.10. Health Economics 
SF-36 and EQ-5D-5L will be measured in this study. 


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8.10.1. 36-Item Short Form Survey (SF-36) 
The SF-36 includes 36 items covering 8 domains: physical function (PF, 10 items), 
role-physical (RP, 4 items), bodily pain (2 items), general health (GH, 5 items), vitality (VT, 
4 items), social function (SF, 2 items), role-emotional (RE, 3 items), and mental health (MH, 
5 items). 
The health-related quality of life will be evaluated with Chinese version of 36 Item Short 
Form Survey (SF-36), which is regarded as a measurement tool by which to evaluate quality 
of life, and has a wide range of applications. See the SoA for time points when this will be 
performed (refer to a stand alone document for details). 
8.10.2. EQ-5D-5L 
The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS). The health-related quality of life will be evaluated with a 
standardized instrument EQ-5D-5L (Chinese version) that can be used in a wide range of 
health conditions and treatments. See the SoA for time points when this will be performed 
(refer to a stand alone document for details). 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. 
9.1. Estimands and Statistical Hypotheses 
This is an estimation study with no statistical hypothesis to test. 
9.1.1. Estimands 
9.1.1.1. Primary Estimand 
The primary estimand will be the descriptive statistics of the primary endpoint, change from 
baseline NIS-LL at Week 72 (Month 18), regardless of whether or not participant continues 
with/adheres to treatment. This includes all observations collected after treatment 
discontinuation or non-adherence to treatment. 
9.1.1.2. Secondary Estimands 
The secondary estimands will be the descriptive statistics of the corresponding secondary 
endpoints in ATTR-PN participants, regardless of whether or not participant continues 
with/adheres to treatment. 


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9.2. Sample Size Determination 
Due to the practical limitation of eligible patients, around 10-15 participants will be enrolled 
in this study. 
9.3. Populations for Analysis 
For purposes of analysis, the following populations are defined: 
 
Population 
Description 
Enrolled 
All participants who sign the ICD. 
Efficacy 
All participants who take at least 1 dose of tafamidis 
meglumine soft capsule 20 mg. 
Safety 
The same as above efficacy population. 
Pharmacodynamic 
All participants who have at least 1 assessment of the TTR 
stabilization. 
9.4. Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
9.4.1. Efficacy Analyses 
All efficacy analyses will be performed on the efficacy population. Both baseline and 
change from baseline efficacy measures will be summarized descriptively by visit. Baseline 
for any endpoints is defined as the last measurement prior to dosing on Day 1 of the study, 
unless otherwise specified. Change from baseline value is calculated by subtracting the 
baseline value from follow up visit value. 
9.4.1.1. Neuropathy Impairment Score-Lower Limb (NIS-LL) 
NIS-LL testing is performed 2 times at each visit as per the SoA. The average value of the 
2 scores will be used for the analysis. 
NIS-LL will be utilized to calculate a total neuropathic deficit score for the lower limbs. In 
addition, subset scores for the lower limbs: muscle weakness (sum of Items 1-8), reflexes 
(sum of Items 9 and 10), sensation in great toe (sum of Items 11-14) will be calculated. The 
total NIS-LL will be calculated as the sum of the subset scores. 
9.4.1.2. Modified BMI(body mass index) 
The mBMI, calculated by multiplying the BMI (kg/height in m2) by serum albumin level 
(g/L), will be evaluated. 


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9.4.1.3. Norfolk QOL-DN 
The 35 individual questions are grouped into total score and 5 domains and will be calculated 
as follows: 
1 Total QOL; sum of items 1-35 
1 Physical Functioning/Large Fiber; sum of items 8, 11, 13-15, 24, 27-35 
1 Activities of Daily Living (ADLs); sum of items 12, 22, 23, 25, 26 
1 Symptoms; sum of items 1-7, 9 
1 Small Fiber; sum of items 10, 16, 17, 18 
1 Autonomic; sum of items 19, 20, 21 
If missing questions occurs, the missing score will be imputed as the mean of the 
non-missing questions within the domain for that visit as long as at least 60% of the items 
within the domain have a non-missing response. The domain score will then be the sum of 
the non-missing and imputed questions. If all 35 questions are non-missing or imputed as 
defined above, then the total QOL will be calculated as the sum of the non-missing items and 
the imputed values. If questions could not be imputed as defined above due to less than 
60% of responses in a domain; however, at least 60% of the total questions are either 
non-missing or imputed, then the total QOL will be calculated as the mean of the 
non-missing and imputed questions times 35. If greater than 40% of the items in a domain or 
Total QOL are missing, then the domain is deemed missing. 
9.4.2. Safety Analyses 
All safety analyses will be performed on the safety population. Safety and tolerability data 
will be summarized descriptively in tabular or graphical format. 
• The incidence of all adverse event and all laboratory test abnormalities will be 
tabulated. 
• Effects of tafamidis on temperature, blood pressure, pulse rate, respiratory rate, 
QT/QTc will be evaluated for baseline and change from baseline values at each visit. 
9.4.3. Quality of Life Analyses 
Quality of life analyses will be performed on the efficacy population. Both baseline and 
change from baseline measures will be summarized descriptively by visit. 
9.4.3.1. 36-item-Short Form (SF-36) Score 
The SF-36 includes 36 items covering 8 domains: physical function (PF, 10 items), 
rolephysical (RP, 4 items), bodily pain (2 items), general health (GH, 5 items), vitality 
(VT, 4 items), social function (SF, 2 items), role-emotional (RE, 3 items), and mental health 


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(MH, 5 items). Scoring method: According to the different weights attributed to each item, 
the SF36 scoring method calculates the sum of the integrals of each item in each dimension, 
obtains the integrals of eight dimensions. The Physical Component Summary (PCS) is 
assessed by grouping all physical components (PF, RP, BP, and GH) together; similarly, the 
Mental Component Summary (MCS) encompasses mental components (VT, SF, RE, and 
MH), and then converts the integrals into the final score ranging from 0 to 100. High scores 
in each dimension and high overall scores indicate a better quality of life. 
9.4.3.2. EQ-5D-5L Index Score 
The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ 
visual analogue scale (EQ VAS). 
The descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems and extreme problems. The participant is 
asked to indicate his/her health state by ticking the box next to the most appropriate 
statement in each of the 5 dimensions. This decision results in a 1-digit number that 
expresses the level selected for that dimension. The digits for the 5 dimensions can be 
combined into a 5-digit number that describes the participant’s health state. The EQ-5D 
utility scores were calculated based on the available Chinese value set for the EQ-5D-5L 
instrument. The score ranges from -0.391 to 1, where 1 represents full health, 0 represents 
death, and a score less than 0 represents a health status worse than death. 
The EQ VAS records the participant’s self-rated health on a vertical visual analogue scale, 
where the endpoints are labelled ‘The best health you can imagine’ and ‘The worst health 
you can imagine’. The VAS scores can be used as a quantitative measure of overall 
self-rated health status that ranged from 0 (worst health) to 100 (best health). 
9.4.4. Pharmacodynamics: TTR Concentration and TTR Stabilization 
The TTR concentration and percent TTR stabilization will be determined. 
Declaring a participant to have been “stabilized” is defined as percent stabilization equal to 
or greater than 32%. 
All pharmacodynamic analyses will be performed on the pharmacodynamic population. TTR 
concentration and percent stabilization will be summarized descriptively, as continuous 
measures, by visit, regardless of whether or not participant continues with/adhere to 
treatment. The proportion of participants who achieve TTR stabilization (ie, who has been 
stabilized) and its 95% confidence interval will be calculated and summarized, as categorical 
measure, by visit, regardless of whether or not participant continues with/adhere to treatment. 


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9.5. Interim Analyses 
No formal interim analysis will be conducted for this study. As this is an open label study, 
the sponsor may conduct reviews of the data during the course of the study for the purpose of 
safety assessment or supporting clinical development decisions. 
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC). 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines; 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 
10.1.2. Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center. 
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
The investigator further must ensure that each study participant or his or her legally 
authorized 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. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICD. 
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study. 


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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative. 
A participant who is rescreened is not required to sign another ICD if the rescreening does 
not exceed 30 days from the previous ICD signature date. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected 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, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
10.1.5. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs). 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted. US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 


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(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations. 
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated. 
EudraCT 
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations. 
www.pfizer.com 
Pfizer posts public disclosure synopses (CSR(clinical study report) synopses in which any 
data that could be used to identify individual participants have been removed) on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov. 
Documents within marketing authorization packages/submissions 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website. Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data. Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015. 
Data Sharing 
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 


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10.1.6. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties. 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 


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investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
10.1.7. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Definition of what constitutes source data can be found in source document agreement. 
10.1.8. Study and Site Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or ICH GCP guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
• If the study is prematurely terminated or suspended, the sponsor shall promptly 
inform the investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) 


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used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.9. Publication Policy 
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results. 
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors. 
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply. 
10.1.10. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECCcontains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 


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phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number.The 
ECC is intended to augment, but not replace, the established communication pathways 
between the investigator site and the study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number 
is not intended for use by the participant directly, if a participant calls that number, he or she 
will be directed back to the investigator site. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns. 
 
Table 2. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN/Urea and 
creatinine 
Glucose (fasting) 
Ca++ 
Na+, K+, Cl- 
Total CO2 
(bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Gamma glutamyl 
transferase (GGT) 
Uric acid 
Albumin 
Total protein 
Total Cholesterol 
Inorganic Phosphorous 
Globulin 
Thyroid-stimulating 
hormone (TSH) 
Total thyroxine (T4) 
Free T4 
NT-pro-BNP 
Troponin I/Troponin T 
Protein 
Nitrites 
Leukocytes 
(qualitative) 
Occult blood 
Microscopy and 
culturea 
FSHb 
Urine pregnancy testing 
Serum pregnancy testing 
Coagulation Panel (PT, PTT, 
and INR) 
Retinol-binding protein 
HBsAg,c HIV antibody,c HCV 
antibodiesc 
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; Ca = Calcium; Cl = Chlorine; CO2 = carbon dioxide; FSH = 
follicle-stimulating hormone; GGT: Gamma glutamyl transferase; Hb = Hemoglobin; HBsAg = Hepatitis 
B surface antigen; HCV = Hepatitis C antibody; HIV = human immunodeficiency virus; INR = 
international normalized ratio; K = potassium; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; Na = sodium; NT-pro-BNP = 
N-terminal B-type natriuretic peptide; PT = prothrombin time; PTT = Partial Thromboplastin Time; qual = 
qualitative; RBC = red blood cell; T4: Total thyroxine; TSH: Thyroid-stimulating hormone; WBC = white 
blood cell. 
a. Performing only when urine dipstick analysis is positive. 
b. Performing only on 45-60 year-old females who have been amenorrhea for at least 2 years. 
c. Screening only. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Followup, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• 
An AE is any untoward medical occunence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abno1mal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
Any abno1mal laborato1y test results (hematology, clinical chemistiy, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abno1mal laborato1y test results that meet any of the conditions below must be 
recorded as an AE. 
• 
Is associated with accompanying symptoms. 
• 
Requires additional diagnostic testing or medical/surgical intervention. 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant dtug treatment, or other therapy. 
• 
 Exacerbation of a chronic or inte1mittent preexisting condition including either 
an increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the stmt of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected dtug-dt·ug interaction. 
• 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be rep01ted 
as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-hmming intent. Such overdoses should be repo1ted regm·dless of 
sequelae. 


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Events 
Meeting the AE Definition 
• 
 Any clinically significant abno1mal laborato1y findings or other abno1mal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the paiticipant's condition. 
• 
 The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
paiticipant's condition. 
• 
 Medical or smgical procedme (eg, endoscopy, appendectomy): the condition that 
leads to the procedme is the AE. 
• 
 Situations in which an untoward medical occU1Tence did not occm (social and/or 
convenience admission to a hospital). 
• 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the stait of the study that do not worsen. 
10.3.2. Definition of an SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below: 
a. 
Results in death 
b.  Is life-threatening 
The te1m "life-threatening" in the definition of "serious" refers to an event in which the 
paiticipant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
C. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the pa1ticipant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician's office or 
outpatient setting. Complications that occm dming hospitalization ai·e AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether "hospitalization" occurred or was necessaiy, the 
AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 


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• The te1m disability means a substantial disrnption of a person's ability to conduct 
n01mal life functions. 
•  This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, dianhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent eve1yday life functions but do not constitute a substantial disrnption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a 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 laborato1y findings 
indicating an infection in a paiticipant exposed to a Pfizer product. The te1ms 
"suspected transmission" and "transmission" ai·e considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
phannacovigilance personnel. Such cases ai·e also considered for rep01ting as 
product defects, if appropriate. 
g. Other situations: 
•  Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations, such as significant medical events that 
may jeopai·dize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
•  Examples of such events include invasive or malignant cancers, 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 
drng dependency or drng abuse. 
 
 
10.3.3. Recording/Reporting and Followup of AEs and/or SAEs 
 
AE and SAE Recording/Reporting 
The table below summai·izes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Fo1m to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (I) SAEs; (2) 
nonserious adverse events (AEs); and (3) exposure to the study intervention under study 
during pregnancy or breastfeeding, and occupational exposure. 


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It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must 
be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE 
Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form which would also 
include details of any SAE that might be associated with the EDB. 
*** Environmental or Occupational exposure: AEs or SAEs associated with occupational 
exposure are reported to Pfizer Safety using the CT SAE Report Form. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, 
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF. 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE).** 
Environmental or 
occupational exposure 
to the product under 
study to a non- 
None. Exposure to a study 
non-participant is not 
collected on the CRF. 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported.*** 
participant (not 
involving EDP or EDB) 


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• 
It is not acceptable for the investigator to send photocopies of the pruiicipant's 
medical records to Pfizer Safety in lieu of completion of the CT SAE Repo1i 
Fonn/AE/SAE CRF page. 
• 
 There may be instances when copies of medical records for ce1iain cases are 
requested by Pfizer Safety. In this case, all pa1ticipant identifiers, with the 
exception of the pruticipant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical info1mation. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE repo1ted 
during the study and assign it to 1 of the following categories: 
• 
 Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Moderate: Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instnnnental ADL. Instrnmental ADL refers to prepru·ing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• 
Severe: Severe or medically significant but not immediately life-threatening 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self case ADL. Self care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden. 
• 
An event is defined as "serious" when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occmTence of each AE/SAE. The investigator will use clinical 
judgement to dete1mine the relationship. 
• 
 A "reasonable possibility" of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be rnled out. 


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• 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or product info1mation, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality. 
• 
 There may be situations in which an SAE has occmTed and the investigator has 
minimal info1mation to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
info1mation and send an SAE follow-up report with the updated causality 
assessment. 
• 
 The causality assessment is one of the criteria used when dete1mining regulat01y 
reporting requirements. 
• 
 If the investigator does not know whether or not the study intervention caused 
the event, then the event will be handled as "related to study intervention" for 
reporting pmposes, as defined by the sponsor. In addition, if the investigator 
dete1mines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and repo1i 
such an assessment in the dedicated section of the CT SAE Report Fo1m and in 
accordance with the SAE rep01iing requirements. 
 
 
Follow up of AEs and SAEs 
• 
 The investigator is obligated to perfo1m or anange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laborato1y tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers. 
• 
 If a pa1iicipant dies during pa1iicipation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmo1iem findings, including histopathology. 


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• 
New or updated info1mation will be recorded in the originally submitted 
documents. 
• 
The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the info1mation. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool 
• 
The primaiy mechanism for repo11ing an SAE to Pfizer Safety will be the 
electronic data collection tool. 
• 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to repo11 the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as the data 
become available. 
• 
 After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the enhy of new data or changes to existing data. 
• 
If a site receives a repo11 of a new SAE from a study paiiicipant or receives 
updated data on a previously repo1ied SAE after the electi·onic data collection 
tool has been taken off-line, then the site can report this infonnation on a paper 
SAE fo1m (see next section) or to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via CT SAE Report Form 
• 
Facsimile transmission of the CT SAE Repo11 Fo1m is the prefened method to 
transmit this info1mation to Pfizer Safety. 
• 
 In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Fo1m sent by overnight mail or 
com .er 
. 
-i se1v1ce. 
• 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Repo11 Fo1m pages within the designated 
repo11ing time frames. 


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10.4. Appendix 4: Contraception Methods 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate study intervention(s): 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
• Is not a WOCBP (see definitions below in Section 10.4.3). 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any study 
intervention(s). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 


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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study. 
2. Postmenopausal female: 
• A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 
• Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.4. Contraception Methods 
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
Intrauterine device (IUD). 


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2. Intrauterine hormone-releasing system (IUS). 
3. Bilateral tubal occlusion. 
4. Vasectomized partner. 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
5. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral; 
• Intravaginal; 
• Transdermal. 
6. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral; 
• Injectable. 
7. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Followup Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI). Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.” 
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks. The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory 
sample). In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased. This occurrence is still regarded as a potential DILI. Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase. Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology. A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found. Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as Adverse Events (AEs) 
• 
Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• 
New PR inte1val prolongation >280 msec. 
• 
New prolongation of QTcF to >480 msec (absolute) or by 60 msec from 
baseline. 
• 
New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie, rate <120 bpm. 
• 
New-onset type I second-degree (Wenckebach) AV(atrioventricular) block of 
>30 seconds' duration. 
• 
Frequent premature ventricular complexes (PVCs), triplets, or short inte1vals 
(<30 seconds) of consecutive ventricular complexes. 
ECG Findings That May Qualify as Serious Adverse Events (SAEs) 
• 
QTcF prolongation >500 msec. 
• 
New ST-T changes suggestive of myocardial ischemia. 
• 
New-onset left bundle branch block (QRS >120 msec). 
• 
New-onset right bundle branch block (QRS >120 msec). 
• 
Symptomatic bradycardia. 
• 
Asystole: 
• 
 In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 
• 
In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer; 
• 
Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120bpm. 


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•  Sustained supraventricular tachycardia (rate>120 bpm) ("sustained"= sho1i 
duration with relevant symptoms or lasting >1 minute). 
•  Ventricular rhythms >30 seconds' duration, including idioventricular rhythm 
(rate <40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymo1phic ventricular tachycardia>100 bpm (such as torsades de 
pointes). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heaii block. 
ECG Findings That Qualify as Serious Adverse Events 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyaIThythmias (>30 seconds' duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
•  Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion. 
• Ventriculai·fibrillation/flutter. 
• At the discretion of the investigator, any aiThythmia classified as an adverse 
expenence. 
The enumerated list of major events of potential clinical concern are recommended as "ale1ts" or 
notifications from the core ECG laboratoty to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 


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Touch-pressure, pin-prick and vibration sensation are tested on the dorsal surface, at the 
base of the nail, of the tenninal phalanx of the great toe. Touch-pressure is assessed with 


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10.9. Appendix 9: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
Investigators should continue to follow the protocol and data entry timelines. Any deviations 
to the protocol due to public emergencies, including the COVID-19, should be documented 
and recorded as deviations as requested by Health Authorities. When the situation permits, 
eg, quarantines or travel bans/advisories ceased, it is expected that participants go will return 
to their original study sites to complete an in-clinic visit indicated in SoA for the nearest 
missing visit (especially the visit of Week 72 or early study discontinuation), even if the date 
is out of the scheduled visit window and some of the study measures have already been 
performed at an alternative facility. 
10.9.1. Eligibility 
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A participant should be excluded if he/she has a positive test 
result for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Participants with active infections are excluded from study 
participation as per Exclusion Criteria 1 (medical conditions). When the infection 
resolves, the participant should not be considered for re-screening. Individuals who has 
signed the ICD for participation in this study and are out of the screening window due to 
assessment of the eligibility due to public emergencies, including COVID-19, can be 
rescreened. All the screening, rescreening and baseline procedures should be done at the 
study sites, according to SoA. 
10.9.2. Telehealth Visits 
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the SoA or unscheduled 
visits. Telehealth visits may be used to continue to assess participant safety and collect data 
points. Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit: 
• Review and record study intervention(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.3. 


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• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4 and Section 10.9.3.1 of this appendix regarding 
pregnancy tests. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 
10.9.3. Alternative Facilities for Safety Assessments 
Safety assessment, including complete physical examination (PE)/abbreviated PE, vital signs, 
laboratory tests, imaging, and ECGs can be performed at a local alternative facility if the 
investigator considered it as necessary and the study participant is unable to visit the study 
site, where allowable by law or local guidance. The specific alternative facility for each 
participant should be recommended by the investigator who has already had an alignment 
with the sponsor in a case by case basis. 
All the results of safety assessments performed at a local alternative facility should be well 
documented and provided to the site staff as indicated in Sections 10.9.3.1, 10.9.3.2 and 
10.9.3.3 below. 
10.9.3.1. Laboratory Testing 
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations. 
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory: 


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Table 3. 
Protocol Required Safety Laboratory Assessments Permitted at a Local 
Laboratory 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN/Urea and 
creatinine 
Glucose (fasting) 
Ca++ 
Na+, K+, Cl- 
TotalCO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Gamma glutamyl 
transferase (GGT) 
Uric acid 
Albumin 
Total protein 
Total Cholesterol 
Serum pregnancy 
testing 
Inorganic Phosphorous 
Globulin 
Thyroid-stimulating 
hormone (TSH) 
Total thyroxine (T4) 
Free T4 
NT-pro-BNP 
Troponin I/Troponin T 
Protein 
Nitrites 
Leukocytes 
(qualitative) 
Occult blood 
Microscopy and 
culturea 
Coagulation Panel (PT, PTT, 
and INR) 
Retinol-binding protein 
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CO2 = carbon dioxide; Ca = Calcium; Cl = Chlorine; GGT: Gamma glutamyl 
transferase; Hb = Hemoglobin; INR = international normalized ratio; K = potassium; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; Na = sodium; NT-pro-BNP = N-terminal B-type natriuretic peptide; PT = 
prothrombin time; PTT = Partial Thromboplastin Time; qual = qualitative; RBC = red blood cell; TSH: 
Thyroid-stimulating hormone; T4: Total thyroxine; WBC = white blood cell. 
a. Performing only when urine dipstick analysis is positive. 
 
It is expected that all participants should have protocol-specified safety laboratory tests 
performed per protocol SoA. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible. The local laboratory reports should be filed in the 
participant’s source documents/medical records. Relevant data from the local laboratory 
report should be recorded on the CRF. 
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 


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requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. 
10.9.3.2. Imaging 
If the participant is unable to visit the study site for Echocardiography, the participant may 
visit an alternative facility to have the Echocardiography performed. Qualified study site 
personnel must order, receive, and review results. 
10.9.3.3. Electrocardiograms 
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. 
10.9.4. Study Intervention 
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered. 
Tafamidis meglumine may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the tafamidis 
meglumine. Pfizer does not permit the shipment of tafamidis meglumine by mail. The 
tracking record of shipments and the chain of custody of tafamidis meglumine must be kept 
in the participant’s source documents/medical records. 
The study drug should only be permitted to be shipped to the participants after the 
assessments by the investigators. And the dispensed investigational product bottle should be 
collected at the next onsite visit. 
10.9.5. Home Health Visits 
A home health care service will not be utilized in this study. 
10.9.6. Adverse Events and Serious Adverse Events 
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. Study 
treatment should continue unless the investigator/treating physician is concerned about the 
safety of the participant, in which case temporary or permanent discontinuation may be 
required. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 


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10.9.7. Efficacy Assessments 
Efficacy assessment, including body weight, serum albumin level, Neuropathy Impairment 
Score-Lower Limb (NIS-LL) can be performed at a local alternative facility if the 
investigator considered it as necessary and the study participant is unable to visit the study 
site, where allowable by law or local guidance. The study investigator can give instructions 
to the health care provider at a local alternative facility to keep the consistency of the 
assessment. The results of these assessments performed at a local alternative facility should 
be well documented and provided to the site investigators. 
For participant report outcomes, including Norfolk QOL-DN, SF-36 and EQ-5D-5L, paper 
scales will be mailed to the participant at the corresponding visit window, if the study 
participant is unable to visit the study site. The results will be reported by the participant in 
the scheduled visit window and mailed back to the investigator in a timely manner. 
For TTR stabilization and TTR concentration assay, blood sample will not be collected at the 
alternative facility due to the complexity of sample management. 
10.9.8. Independent Oversight Committees 
This study will not use an Independent Oversight Committee. 


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10.10. Appendix 10: Protocol Amendment History 
The Protocol Amendment Summa1y of Changes Table for the cmrent amendment is located 
directly before the TOC. The protocol amendment summaiy of changes tables for past 
amendment(s) can be found below: 
Amendment 2 (20 April 2021) 
 
Section# and Name 
Description of Change 
Brief Rationale 
Protocol Title 
 
 
 
 
 
 
 
 
Section 1.1 Synopsis 
Section 2 
INTRODUCTION 
Section 4 STUDY 
DESIGN 
 
 
 
 
 
 
 
Section 1.1 Synopsis 
Section 1.3. Schedule 
of Activities (SoA) 
 
Section 4 STUDY 
DESIGN 
• 
The protocol title was revised 
to A single arm, multicenter, 
open-label study to evaluate 
the efficacy, safety, tolerability, 
and phannacodynamics of 
orally administered tafamidis 
meglumine on in transthyretin 
amyloid po yneuropathy 
participants in china. 
• 
The study design was changed 
from This study is designed to 
determine the effect of 
tafamidis meglumine on TTR 
stabilization as well as 
tafamidis meglumine safety, 
tolerability and efficacy in 
ATTR-PN patients in China to 
This study is designed to 
evaluate the efficacy, safety, 
tolerability as well as 
pharmacodynamics of 
tafamidis meglumine in ATTR- 
PN participants in China. 
• 
 The study intervention duration 
was changed from 24 weeks to 
48 weeks. 
For better description of 
the study characteristic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.9 
Appendix 9: 
Alternative Measures 
During Public 
Emergencies 
 


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Tafamidis meglumine 
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Section # and Name 
Descri tion of Chan e 
Brief Rationale 
Section 1.1 Synopsis 
Section 3 
OBJECTIVES, 
ESTIMANDS, AND 
ENDPOINTS 
Section 9.1.1.1 
Primruy Estimands 
• 
The prima1y objective changed 
from To determine the 
tafamidis meglumine on 
transthyretin (TTR) 
stabilization at steady-state in 
ATTR-PN patients to To 
evaluate the effect of tafamidis 
meglumine on clinical efficacy 
in ATTR-PN participants. 
 
• 
 The secondruy objective 
changed from To evaluate the 
safety, tolerability and efficacy 
of tafamidis meglumine in 
ATTR-PN participants to To 
evaluate the efficacy, safety, 
tolerability, and 
pharmacodynamics of 
tafamidis meglumine in 
ATTR-PN participants. 
• 
The prima1y endpoint changed 
from TTR stabilization at 
Week 8 compared with 
Baseline, as measured by a 
validated immunoturbidimetric 
assay to Change from baseline 
NIS-LL at Week 48 (Month 12). 
 
 
 
 
 
 
 
 
- 
c ange from 
baseline is proposed 
as the new primruy 
endpoint. 
• 
 Neuropathy Impairment Score; 
NIS-LL (lower limb) was 
changed to NIS-LL at other 
visits than Week 48 in the 
secondruy endpoints. 
 
• 
 In seconda1y endpoint, TTR 
stabilization at each follow up 
visit aft.er Week 8 and TTR 
concentration at Day 1 
(baseline), Week 8, Week 12 
and Week 24 was changed to 
Pharmacodvnamic: TTR 
stabilization and TTR 
 
concentration at Day 1 
 


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Section # and Name 
Description of Change 
Brief Rationale 
(baseline), Week 8, Week 12, 
Week 24 and Week 48. 
Physical examination 
deleted from the seconda1y 
Safety endpoints, because 
physical examination findings 
collected dming the study will 
be considered somce data and 
will not be required to be 
repo1ted as safety endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1.3. Schedule 
of Activities (SoA) 
• 
The prima1y estimands 
changed from Estimated 
proportion of patients 
achieving TTR stabilization at 
Week 8 in ATTR-PN patients, 
regardless of whether or not 
patient continues with/adheres 
to treatment to Descriptive 
statistics of the NIS-LL change 
fi-orn baseline at Week 48 
(Month 12), regardless of 
whether or not partidpant 
continues with/adheres to 
treatment. 
 
• 
Two columns of Week 36 and 
Week 48 (or Early Study 
Discontinuation) were added 
to the SoA. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
related assessments were 
also added to evaluate 
the efficacy, safety, 
tolerability and 
phaimacodynamics of 
tafamidis meglumine. 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3. Schedule 
of Activities (SoA) 
 
Section 1.3. Schedule 
of Activities (SoA) 
 
 
 
 
 
 
 
 
Section 1.3. Schedule 
of Activities (SoA) 
 
 
 
 
 
 
 
 
 
 
 
Section 1.3. Schedule 
of Activities (SoA) 
• The days in the SoA for 
week 4, week 8, week 12, 
week 24 was updated. 
• A column of Post-study follow- 
up (28 days after last dose) 
was added to the SoA, the 
allowable window is +7 days. 
The only activity required for 
this visit is Serious and 
nonserious adverse events 
monitoring, with note j. 
Telephone contact can be used 
to monitor for adverse events. 
• Note c was changed from At 
site visit, the time of last dose 
taken will be checked and 
recorded together with the 
actual blood sampling time to 
Collect samples during site 
visit. At site visit, the time of 
last dose taken prior to blood 
collection for TTR stabilization 
assay and TTR concentration 
will be checked and recorded. 
The actual blood sampling time 
will be recorded for clarity. 
• TSH, total T4, free T4, RBP 
was added into Laboratory 
tests to be consistent with 
Table 1. NT-pro-BNP, 
Troponin I/Troponin T, 
coagulation panel were listed 
as a separate activity as they 
will not be tested in some 
visits. Note d. All Laboratory 
tests do not need to be repeated 
if acceptable screening 
assessment is performed within 
30 days prior to Day 1 was 
The calculation was 
wrong in the former 
protocol. 
To meet the adverse 
event collection 
requirement in 
section 8.3.1. 
 
 
 
 
 
 
Refer to the chronology 
of events in Section 8. 
 
 
 
 
 
 
 
 
 
 
 
To avoid unnecessary 
repeating lab tests within 
a short period of time. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
added for Laboratory tests on 
Day 1. 
 
Section 1.3. Schedule 
of Activities (SoA) 
Section 4.1 Overall 
Design 
Section 10.9.7 
Efficacy Assessments 
 
Section 1.3. Schedule 
of Activities (SoA) 
 
 
 
Section 1.3. Schedule 
of Activities (SoA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1.3. Schedule 
of Activities (SoA) 
 
 
Section 4.1 Overall 
Design 
• NIS was updated as NIS-LL in 
the activity because only lower 
limbs are assessed. The 
abbreviations NIS was updated 
as NIS-LL: Neuropathy 
Impairment Score-Lower Limb 
accordingly below the SoA 
table. 
• Note f was simplified as 
NIS-LL testing is performed 2 
times at least 24 hours apart 
within a 1-week period by the 
same neurologist. 
• Note h. All the assessments and 
procedures at Day 1 (baseline) 
visit in the SoA should be 
completed prior to the 
investigational product 
administration on Day 1. Only 
on Day 1, the investigational 
product will be administered at 
site during clinic visit was 
added to Dispense 
investigational product on 
Day 1 to make sure that all the 
baseline values are obtained 
before investigation product 
administration. 
• Note i. After Week 12 was 
changed to Between Week 12 
to Week 24, Week 24 and 36, 
and between Week 36 and 48. 
• The enrollment will be 
competitive and the enrollment 
duration is approximately 16 
months was deleted. 
Only lower limbs are 
assessed. 
 
 
 
 
 
 
For protocol internal 
consistency. 
 
 
 
To make sure that all the 
baseline values are 
obtained before 
investigation product 
administration. 
 
 
 
 
 
 
 
 
 
 
The follow-up is 
prolonged due to study 
extension. 
 
The limitation of 
recruitment was removed 
upon team’s decision. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.4 Screen 
Failures 
 
 
 
 
 
 
 
 
 
 
 
Section 6.5.1 
Permitted Medicine 
 
 
 
 
 
 
 
Section 6.5.2 
Excluded Medicine, 
Treatment and 
Substances 
 
 
 
 
Section 6.5.2 
Excluded Medicine, 
Treatment and 
Substances 
• Individuals who recover from 
acute medical conditions may, 
according to the best medical 
judgment of the investigator, be 
appropriate for rescreening. If 
individuals recovered within 30 
days, the individual 
inclusion/exclusion criteria 
may need repeating according 
to the nature of the medical 
event and clinical judgement of 
the investigator was added as 
paragraph 2 in this section. 
• If a participant is offered, in 
accordance with the prevailing 
local guidelines, a COVID-19 
vaccine, it should be permitted. 
This would be recorded as a 
concomitant medication and 
standard AE collection and 
reporting processes would be 
followed was added. 
• Any investigational drug within 
30 days before Day 1 
(Baseline) through 8 weeks of 
study participation was 
changed to Any investigational 
intervention within 30 days 
before Day 1 (Baseline) and 
during the study participation. 
• Chronic use of non-protocol 
approved non-steroidal anti- 
inflammatory drugs (NSAIDs), 
defined as greater than 3-4 
times/month was changed to 
Chronic use of non-protocol 
approved non-steroidal anti- 
inflammatory drugs (NSAIDs), 
defined as greater than 4 
times/month. 
For better clarification. 
 
 
 
 
 
 
 
 
 
 
 
 
For better clarification. 
 
 
 
 
 
 
 
 
Because any 
investigational 
intervention (drug or 
non-drug) should be 
excluded during the 
whole study 
participation. 
 
Because 3-4 times/month 
is a confusing criterion. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.2 
Excluded Medicine, 
Treatment and 
Substances 
 
Section 6.5.2 
Excluded Medicine, 
Treatment and 
Substances 
 
 
 
 
 
Section 7.1 
Discontinuation of 
Study Intervention 
 
 
 
 
 
 
 
Section 7.1 
Discontinuation of 
Study Intervention 
 
 
 
 
 
 
 
Section 7.1 
Discontinuation of 
Study Intervention 
• Topical ophthalmic NSAIDs 
administered while the 
participant’s nasal punctum is 
occluded are also permitted 
was added. 
• Use of diflunisal, 
tauroursodeoxycholate, 
doxycycline, inotersen or 
patisiran or any other TTR 
stabilizing agent within 
30 days prior to the study entry 
and/or during study 
participation is prohibited was 
added. 
• A participant may be 
withdrawn from the study for 
any of the following reasons 
was updated as It may be 
necessary for a participant to 
permanently discontinue study 
intervention. Reasons for 
permanent discontinuation of 
study intervention include the 
following. 
• In rare instances, it may be 
necessary for a participant to 
permanently discontinue 
investigational product. Per 
the study estimands, if 
investigational product is 
permanently discontinued, the 
participant will remain in the 
study to be evaluated for 
adverse events was deleted. 
• If study intervention is 
permanently discontinued, the 
participant will remain in the 
study to be evaluated per SoA 
was added. 
To add some flexibility 
with concomitant 
therapies. 
 
 
because diflunisal, 
tauroursodeoxycholate, 
doxycycline, inotersen or 
patisiran or any other 
TTR stabilizing agent 
can affect TTR stability. 
 
 
 
Per the updated protocol 
template released on 
01 March 2021. 
 
 
 
 
 
 
 
Per the updated protocol 
template released on 
01 March 2021. 
 
 
 
 
 
 
 
Per the updated protocol 
template released on 
01 March 2021. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1 
Discontinuation of 
Study Intervention 
 
 
 
 
 
 
 
 
 
Section 7.2 
Participant 
Discontinuation/With 
drawal From the 
Study 
 
 
 
 
Section 7.3 Lost to 
Follow-up 
 
 
Section 8. STUDY 
ASSESSMENTS 
AND 
PROCEDURES 
 
 
Section 8. STUDY 
ASSESSMENTS 
AND 
PROCEDURES 
• In the event of discontinuation 
of study intervention, it must be 
documented on the appropriate 
CRF/in the medical records 
whether the participant is 
discontinuing further receipt of 
study intervention or also from 
study procedures, 
posttreatment study follow-up, 
and/or future collection of 
additional information was 
added. 
• The criteria for withdrawal 
from the study and the data 
management for these 
participants was changed per 
updated template. 
• A new section title 
Section 7.2.1 was added 
before Withdrawal of consent. 
• Discontinuation of specific 
sites or of the study as a whole 
is handled as part of 
Appendix 1 was deleted. 
• All the assessments and 
procedures at baseline visit in 
the SoA should be completed 
prior to the investigational 
product administration on 
Day 1 was added. 
• At the discretion of the 
investigator, isolated abnormal 
tests can be repeated for 
confirmation. However, the 
entire panel should not be 
repeated. In the event the 
repeated test confirms an 
abnormal value, no further 
testing is necessary. The 
Per the updated protocol 
template released on 
01 March 2021. 
 
 
 
 
 
 
 
 
 
Per the updated protocol 
template released on 
01 March 2021. 
 
 
 
 
 
 
Per the updated protocol 
template released on 
01 March 2021. 
 
To clarify and emphasize 
this common practice in 
all clinical trials which is 
to avoid any effect of the 
investigational product 
on baseline assessments. 
To provide instructions 
under the situation when 
isolated abnormal tests 
are detected in screening 
period. 


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Section # and Name 
Description of Change 
Brief Rationale 
abnormal test value from the 
confirmatory test will be 
entered into the database and 
the participant will be 
considered a screen failure. If 
the repeat test does not confirm 
the abnormal value (i.e., it is 
within the normal range), the 
investigator is required to 
again repeat the specific 
laborat01y test. If this further 
repeat test confirms a value 
within the normal range, the 
last repeated normal value is 
entered into the database. If 
the further repeat test value is 
abnormal, this value will be 
entered into the database and 
the participant will be 
considered a screen failure 
was added as paragraph 7 after 
"as applicable". 
 
Section 8. STUDY 
ASSESSMENTS 
AND 
PROCEDURES 
 
 
 
 
 
 
 
 
Section 8.1 Efficacy 
Assessment 
• 
 The total volume tak,en during 
the study does not exceed 
550 ml during any period of 
56 consecutive days. In 
exceptional circumstances, 
such as medical emergencies, 
this volume may be exceeded 
and will not constitute a 
protocol deviation in such 
circumstances was added in 
the last pru:agraph. 
• 
 TTR Stabilization and TTR 
concentration Measurement 
was moved from Section 8.1.1 
to Section 8.6. 
For more details about 
the blood volume 
collected. 
 
Section 8.1.1 
Nemopathy 
• 
The section title was modified 
Updated endpoint. 
to Neuropathy Impairment 
Score-Lower Limb (NIS-LL) to 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Impairment Score 
(NIS) 
be consistent with the updated 
endpoint. 
 
Section 8.1.1 
Neuropathy 
Impairment Score 
(NIS) 
Section 8.2.1 
Physical 
Examinations 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.6.2 
Biopsy 
Documentation of 
Amyloid 
 
 
Section 8.3 Adverse 
Events, Serious 
Adverse Events, and 
Other Safety 
Reporting 
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE 
and SAE Information 
• The wording of paragraph 1, 2 
and 3 was revised accordingly. 
 
 
• Physical examination findings 
collected during the study will 
be considered source data and 
will not be required to be 
reported, unless otherwise 
noted. Any untoward physical 
examination findings that are 
identified during the active 
collection period and meet the 
definition of an AE or SAE 
(Appendix 3) must be reported 
according to the processes in 
Sections 8.3.1 to 8.3.3 was 
added. 
• Or other analysis can be 
utilized to confirm the deposit 
of amyloid was added behind 
‘apple-green’ birefringence, 
 
• The whole section was 
updated. 
 
 
 
• In paragraph 3, and Pfizer 
concurs with that assessment 
was deleted. 
Only NIS-LL is to be 
tested in the study. 
 
 
Per the updated protocol 
template released on 
01 March 2021. 
 
 
 
 
 
 
 
 
 
 
 
To add some flexibility 
for the acceptable biopsy 
analysis methods for the 
confirmation of amyloid 
deposition. 
 
Per the new protocol 
template with more 
specific requirements of 
reporting and collecting 
AEs. 
Per updated template. 
 
Section 8.3.1.1 
Reporting SAEs to 
Pfizer Safety 
• The section was updated 
Per the new protocol 
template with more 
specific requirement to 
 


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Section # and Name 
Description of Change 
Brief Rationale 
report SAEs to Pfizer 
Safety. 
 
Section 8.3.1.2 
Recording 
Nonserious AEs and 
SAEs on the CRF 
 
 
 
 
 
Section 8.3.4 
Regulatory Reporting 
Requirements for 
SAEs 
• During the active collection 
period, both nonserious AEs 
and SAEs are recorded on the 
CRF was changed to The 
investigator is to record on the 
CRF all directly observed and 
all spontaneously reported AEs 
and SAEs reported by the 
participant. 
• an investigator safety report 
was changed to SUSARs. 
• investigator’s brochure was 
changed to SRSD(s). 
Per updated template. 
 
 
 
 
 
 
 
 
Per updated template. 
 
Section 8.3.5 
Environmental 
Exposure, Exposure 
During Pregnancy or 
Breastfeeding, and 
Occupational 
Exposure 
 
Section 8.3.5.1 
Exposure During 
Pregnancy 
 
 
Section 8.3.5.2 
Exposure During 
Breastfeeding 
• The whole section was 
updated. 
 
 
 
 
 
• The whole section was 
updated. 
 
 
 
• The whole section was 
updated. 
Per the new protocol 
template with more 
specific instruction to 
define EDP, 
breastfeeding and 
occupational exposure 
for investigators. 
 
Per the new protocol 
template with more 
specific requirement to 
report and manage an 
EDP for investigators. 
Per the new protocol 
template with very 
specific requirement to 
report and manage an 
exposure during 
breastfeeding for 
investigators. 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.5.3 
Occupational 
Exposure 
 
 
 
Section 8.3.6. 
Cardiovascular and 
Death Events 
Section 8.3.7. 
Disease-Related 
Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs or 
SAEs 
 
Section 8.3.9.1 Lack 
of Efficacy 
• The whole section was 
updated. 
 
 
 
 
• This new section was added 
per updated template. 
• all the content in the previous 
section of Hospitalization was 
removed to this section. 
 
 
 
 
 
• Lack of efficacy in an approved 
indication should be reported 
as an SAE to Pfizer Safety was 
changed to The investigator 
must report signs, symptoms, 
and/or clinical sequelae 
resulting from lack of efficacy. 
Lack of efficacy or failure of 
expected pharmacological 
action is reportable to Pfizer 
Safety only if associated with 
an SAE. 
Per the new protocol 
template with more 
specific requirement to 
report and manage an 
occupational exposure 
for investigators. 
Per updated template. 
 
 
The content in section 
Hospitalization fits the 
definition of Disease- 
Related Events and/or 
Disease-Related 
Outcomes Not 
Qualifying as AEs or 
SAEs. 
Per updated template. 
A new section Section 8.3.10. Medical Device Deficiencies was added per updated 
template. 
A new section Section 8.7 Immunogenicity Assessment was added per updated template. 
Section 9.2 Sample 
Size Determination: 
 
 
 
 
Section 9.4 Statistical 
Analyses: Section 
• The whole section was 
simplified as Due to the 
practical limitation of eligible 
patients, around 10-15 
participants will be enrolled in 
this study. 
• The content in Section 9.4.4 is 
simplified as Declaring a 
For better clarification. 
 
 
 
 
 
For better clarification as 
TTR Stabilization is not 
 


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Section # and Name 
Description of Change 
Brief Rationale 
TTR Stabilization 
was moved to 
Section 9.4.4 TTR 
Stabilization and 
TTR concentration in 
Pharmacodynamics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.4.1.1 
Neuropathy 
Impairment Score 
(NIS) 
participant to have been 
“stabilized” is defined as 
percent stabilization equal to 
or greater than 32%. All 
pharmacodynamic analyses 
will be performed on the 
pharmacodynamic population. 
TTR concentration and percent 
stabilization will be 
summarized descriptively, as 
continuous measures, by visit, 
regardless of whether or not 
participant continues 
with/adhere to treatment. The 
proportion of participants who 
achieve TTR stabilization (ie, 
who has been stabilized) and 
its 95% confidence interval 
will be calculated and 
summarized, as categorical 
measure, by visit, regardless of 
whether or not participant 
continues with/adhere to 
treatment. 
• The section title was modified 
to Neuropathy Impairment 
Score-Lower Limb (NIS-LL) to 
be consistent with the 
secondary endpoint. 
• NIS in this section was 
modified as NIS-LL. 
• The NIS will provide a total 
body single score of 
neuropathic deficits and subset 
scores for cranial nerves (sum 
of Items 1-5), muscle weakness 
(sum of Items 6-24), reflexes 
(sum of Items 25-29), and 
sensation (sum of Items 30-37). 
considered as efficacy 
endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only NIS-LL score, not 
total NIS score, is 
calculated in this study. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
The total score is the sum of all 
items was deleted. 
 
Section 10.1.3 
Informed Consent 
Process 
 
 
 
Section 10.1.8 Study 
and Site Closure 
. 
• A participant who is 
rescreened is not required to 
sign another ICD if the 
rescreening does not exceed 30 
days from the previous ICD 
signature date was added. 
• The study start date is the date 
on which the clinical study will 
be open for recruitment of 
participants. The first act of 
recruitment is the date of the 
first participant’s first visit and 
will be the study start date was 
added as the 1st and 2nd 
paragraph. 
• If the study is prematurely 
terminated or suspended, the 
sponsor shall promptly inform 
the investigators, the 
ECs/IRBs, the regulatory 
authorities, and any CRO(s) 
used in the study of the reason 
for termination or suspension, 
as specified by the applicable 
regulatory requirements. The 
investigator shall promptly 
inform the participant and 
should assure appropriate 
participant therapy and/or 
follow-up was added after 
Reasons for the early closure 
of a study site by the sponsor 
may include but are not limited 
to:. 
To add some flexibility 
for some participants 
who recover from acute 
medical conditions. 
 
 
Per the updated protocol 
template. 
Section 10.1.10 Sponsor’s Qualified Medical Personnel: 
The whole section was updated per the protocol template released on 01 March 2021. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Table 1 
Protocol-Required 
Safety Laboratory 
Assessments 
 
Table 2 Protocol- 
Required Safety 
Laboratory 
Assessments 
permitted at a local 
laboratory 
• Inorganic Phosphorous, 
Globulin, Thyroid-stimulating 
hormone (TSH), Total 
thyroxine (T4), Free T4, NT- 
pro-BNP, Troponin I were 
moved from Other to 
Chemistry as they are 
chemistry parameters. 
• Troponin I was revised as 
Troponin I/Troponin T, and 
BUN was revised as BUN/Urea 
for site feasibility reasons. 
• Pre-albumin (transthyretin) 
was deleted from Other in this 
table, because it is presented as 
TTR concentrations 
(pharmacodynamics 
assessment) and is not a safety 
laboratory assessment. 
For better clarification 
and for site feasibility 
reasons. 
Section 10.3.1 Definition of AE: 
The whole section was updated per the new protocol template with more specific 
conditions to record as AEs for investigators. 
 
Section 10.3.2 Definition of SAE: 
The whole section was updated per the new protocol template with more specific 
conditions to record as SAEs for investigators. 
Section 10.3.3 Recording/Reporting and Follow up of AEs and/or SAEs: 
The whole section was updated per the new protocol template with more specific 
requirements to record and manage events as AE/SAEs, more specific instruction of 
assessment of intensity for each AE/SAE, and more instructions for follow-up AEs and 
SAEs for investigators. 
 
Section 10.4 
Appendix 4: 
Contraception 
Methods 
• The section title was changed 
from Contraceptive Guidance 
and Collection of Pregnancy 
Information to Contraception 
Methods. 
• All the content under 
Collection of Pregnancy 
Per the updated protocol 
template. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Information was deleted 
because it was duplicated in 
section 8.3.5. 
 
Section 10.8 
Appendix 8: 
Neuropathy 
Impairment Score 
• (NIS): the section title was 
changed to Appendix 8: 
Neuropathy Impairment Score- 
Lower Limb (NIS-LL), and the 
scale was simplified to NIS- 
LL related content only. 
Only lower limbs will be 
assessed in the study 
now, NIS scale was 
simplified as NIS-LL 
scale in this amendment. 
Patient(s) or subject(s) was changed to participant(s) throughout the protocol per the 
latest protocol template. 
Editorial, grammatical, formatting, and administrative changes were made 
throughout the document. 
 
 
Amendment 1 (20 August 2020) 
 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
TABLE OF 
CONTENTS 
Schedule of 
Activities 
(Section 1.3) 
 
Objectives, 
Estimands, and 
Endpoints 
(Section 1.1 Synopsis 
and Section 3) 
 
Overall Design 
(Section 4.1) 
 
Excluded Medicine, 
Treatment and 
Substances 
(Section 6.5.2) 
• “Σ7 NTs NDS” as measured by 
nerve conduction studies 
(NCS), vibration detection 
threshold (VDT) and heart rate 
response to deep breathing 
(HRDB) was deleted from 
secondary endpoint and all 
related components. 
There is no China 
regulatory agency 
certified equipment that 
would allow 
Investigators to perform 
quantitative sensory 
testing (QST), nerve 
conduction studies 
(NCS), vibration 
detection threshold 
(VDT) and heart rate 
response to deep 
breathing assessment) 
(HRDB). 


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PFIZER CONFIDENTIAL 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Study 
ASSESSMENTS 
AND 
PROCEDURES 
(Section 8) 
 
Statistical 
Considerations 
(Section 9) 
 
Appendix 10: 
Abbreviations 
(Section 10.10). 
 
REFERENCE 
(Section 11). 
 
Protocol Title 
 
 
 
 
 
 
 
 
 
 
 
Section 1.1 Synopsis 
 
Section 4.1 Overall 
Design 
 
Section 4.2 Scientific 
Rationale for Study 
Design 
 
Section 9.2 Sample 
Size Determination 
Section 1.1 Synopsis 
• 
The protocol title was revised 
to A single arm, multicenter, 
open-label study to determine 
the effect of orally 
administered tafamidis 
meglumine on transthyretin 
stabilization, safety, 
tolerability and efficacy in 
transthyretin amyloid 
polyneuropathy patients in 
china. 
• 
Number of Participants was 
changed from Approximately 
10 to Approximately 10-15. 
 
 
 
 
 
 
 
 
• 
 The enrollment will be 
competitive and the enrollment 
duration is approximately 
For better description of 
the study characteristic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PFIZER CONFIDENTIAL 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Section 1.1 Synopsis: The sho1i title was updated to be in line with the sho1i title on 
page 1. 
 
Synopsis 
(Section 1.1) 
 
Introduction (Section 
2) 
Objectives, 
Estimands, and 
Endpoints (Section 3) 
Overall Design 
(Section 4.1) 
Scientific Rationale 
for Study Design 
(Section 4.2) 
Synopsis 
(Section 1.1) 
 
Objectives, 
Estimands, Endpoints 
(Section 3) 
 
Safety Analyses 
(Section 9.4.2) 
Section 1.3 Schedule 
of Activities (SoA) 
 
Section 1.3 Schedule 
of Activities (SoA) 
• 
 The primaiy objective of the 
study was changed from To 
determine transthyretin (TTR) 
stabilization to To detennine 
the effect of tafamidis 
meglumine on transthyretin 
(TTR) stabilization. 
 
 
 
 
 
 
 
 
 
• 
 Heart rate was changed to 
pulse rate in secondaiy 
endpoints. 
 
 
 
 
 
 
• 
HIV-I and -2 antibodies test 
was changed to to HIV 
antibody. 
• 
 Karnofsky Performance Status 
assessment was added to 
screening assessments. 
To be consistent with 
protocol title. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To be consistent with 
the rest of protocol. 
 
 
 
 
 
 
 
For better clai·ification. 
 
 
 
This was missing in 
original protocol. 


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Brief Rationale 
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Section 1.3 Schedule 
of Activities (SoA) 
 
 
 
 
Section 1.3 Schedule 
of Activities (SoA) 
 
 
Section 1.3 Schedule 
of Activities (SoA) 
 
 
 
 
 
Section 1.3 Schedule 
of Activities (SoA) 
 
 
 
 
 
 
Section 2.2.4 Clinical 
Overview 
 
Section 5.2 Exclusion 
Criteria: 
 
 
 
 
Section 5.2 Exclusion 
Criteria: 
Prior/Concomitant 
Therapy 
• QST for vibration perception 
in the feet utilizing CASE IV 
was removed from screening 
assessments. 
 
 
• QST (CASE IV), HRDB, and 
NCS assessments were 
removed from Schedule of 
Activities (SoA) table. 
• ECG was deleted at Week 4 
and Week 12. 
 
 
 
 
 
• SoA Footnote b.sampling 3 
hours after dosing tafamidis 
was changed to b. At site 
visit, the time of last dose 
taken will be checked and 
recorded on the relevant CRF 
page, together with the actual 
blood sampling time. 
• Update the clinical 
development programs 
 
• Text “Participant has no 
recordable sensory threshold 
for vibration perception in 
both feet, as measured by 
CASE IV” was removed from 
exclusion criteria 8. 
• Inotersen and patisiran were 
added. 
Certified CASE IV 
equipment is not 
available in China. 
certified CASE IV 
equipment is not 
available in China. 
Certified equipment is 
not available in China. 
 
 
There are no potential or 
identified risks of acute 
or subacute ECG 
changes nor for that 
matter cardiac risks in 
the previous clinical 
data. 
For better clarification. 
 
 
 
 
 
 
 
According to the latest 
clinical development 
plan. 
Due to unavailability of 
certificated CASE IV 
equipment in China 
necessary to perform 
QST. 
 
As they are TTR 
stabilizing agents. 


Tafamidis meglumine 
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Description of Change 
Brief Rationale 
PFIZER CONFIDENTIAL 
Page 114 
 
 
 
 
 
 
 
Section 6.5.2 
Excluded Medicine, 
Treatment and 
Substances 
Section 6.1 Study 
Intervention(s) 
Administered 
 
Section 8 STUDY 
ASSESSMENTS 
AND 
PROCEDURES 
Section 8.1.1 TTR 
Stabilization and 
TTR Concentration 
Measurement 
 
 
 
 
• The package used in China 
was updated. 
 
 
• The total blood sampling 
volume and maximum total 
volume for individual 
participants was updated. 
• At 3 hours after dosing at 
Week 8, and at Week 12 and 
24 (or Early Study 
Discontinuation) was changed 
to and after ECG, blood 
pressure/pulse rate collection 
and blood sample collection 
for clinical laboratory tests 
during the study visit at 
Week 8, Week 12 and 24 (or 
Early Study Discontinuation). 
 
 
 
 
According to the local 
label from in bottles of 
40 capsules to in packs 
of 30 x 1 soft capsules. 
Re-calculation. 
 
 
 
The TTR stabilization 
and TTR concentration 
will be quite stable at 
Week 8, so the limit of 3 
hours after dosing at 
Week 8 will not be 
necessary. 
 
Section 8.2.3 
Electrocardiograms 
 
Section 8.6 
Pharmacodynamics 
(PD) 
 
 
 
 
Section 9.4.1 
Efficacy Analysis 
• QTc was changed to QTcF 
wherever applicable 
 
• PD parameters of TTR 
stabilization and TTR 
concentrations were changed 
from primary endpoint to 
efficacy endpoint (both 
primary and secondary 
endpoint). 
• The paragraph of all efficacy 
analyses was moved from 
To make the description 
more scientific and 
accurate. 
For protocol internal 
consistency. 
 
 
 
 
 
For better clarification. 


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Description of Change 
Brief Rationale 
PFIZER CONFIDENTIAL 
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Section 10.2 
Appendix 2: Clinical 
Laboratory Tests, 
Table 1 
 
Section 10.2 
Appendix 2: Clinical 
Laboratory Tests, 
Table 1 
 
 
 
Section 10.2 
Appendix 2: Clinical 
Laboratory Tests, 
Table 1 
Section 
10.8/10.9/10.11 
Appendix 8/9/11: 
Section 9.4.1.1 to 
Section 9.4.1. 
• HIV-1 and -2 antibodies test 
was changed to HIV antibody. 
• Troponin 1 was corrected to 
Troponin I. 
• PH, glucose, ketones, 
bilirubin, urobilinogen, 
specific gravity were deleted, 
and leukocytes (qualitative), 
microscopy and culture was 
added in urinalysis. 
 
• Blood (free Hb) was changed 
to Occult blood. 
 
• All 3 patient report scales were 
deleted. 
 
 
For better clarification. 
 
 
 
 
Some are unnecessary 
parameters since there is 
a lab chemistry, and 
leukocytes, microscopy 
and culture are essential 
to detect urinary tract 
infection. 
To meet the clinical 
practice in China. 
 
 
Due to copyright 
reasons, and will be 
provided as separate 
documents. 
A new Section 10.9 Appendix 9: Alternative Measures During Public Emergencies 
was added due to the requirement of new protocol template. 
Delete gelatin and add meglumine in the investigational drug throughout the document 
wherever applicable to be consistent with the local label. 
Editorial, grammatical, formatting, and administrative changes were made 
throughout the document. 
 


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10.11. Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
Abs 
Absolute 
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATTR 
transthyretin amyloid 
ATTR-CM 
transthyretin amyloid cardiomyopathy 
ATTR-PN 
transthyretin amyloid polyneuropathy 
AUC 
area under the curve 
AV 
atrioventricular 
BA 
bioavailability 
BE 
bioequivalence 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
Ca 
calcium 
CCI 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
Cl 
chloride 
Cmax 
maximum observed concentration 
CO2 
carbon dioxide (bicarbonate) 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease-2019 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
clinical study report 
CT 
clinical trial 
CTMS 
clinical trial management system 
CV 
cardiovascular 
DCT 
data collection tool 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DRE 
disease-related event 
DU 
dispensable unit 


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Abbreviation 
Term 
E/A 
E peak/A peak 
EC 
ethics committee 
ECC 
Emergency Contact Card 
ECG 
electrocardiogram 
ECHO 
Echocardiography 
eCRF 
electronic case report form 
E-DMC 
external data monitoring committee 
EDP 
exposure during pregnancy 
EDR 
extemporaneous dispensing record 
EMA 
European Medicines Agency 
EOT 
end of trial 
EQ-5D-5L 
EuroQoL 5 Dimensions 5 Levels 
EQ VAS 
EuroQoL visual analogue scale 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FSH 
follicle-stimulating hormone 
FOI 
fraction of initial tetramer concentration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GH 
general health 
HbA1c 
hemoglobin A1c 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HCVAb 
hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IB 
investigator’s brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation 
ID 
identification 
IMP 
investigational medicinal product 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP manual 
investigational product manual 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IWR 
interactive Web-based response 


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Abbreviation 
Term 
K 
potassium 
K2 EDTA 
dipotassium ethylenediaminetetraacetic acid 
LBBB 
left bundle branch block 
LFT 
liver function test 
mBMI 
modified body mass index 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MSC 
Mental Component Summary 
MCV 
mean corpuscular volume 
MH 
mental health 
N/A 
not applicable 
Na 
sodium 
NSAID 
non-steroidal anti-inflammatory drug 
NAb 
neutralizing antibodies 
NIMP 
noninvestigational medicinal product 
NIS 
Neuropathy Impairment Score 
NIS-LL 
Neuropathy Impairment Score-lower limb 
NMPA 
National Medical Products Administration 
Norfolk QOL-DN 
Norfolk Quality of Life - Diabetic Neuropathy 
NT-pro-BNP 
N terminal pro B-type natriuretic peptide 
PCD 
primary completion date 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 
PE 
Physical examination 
PF 
physical function 
PI 
principal investigator 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PTT 
Partial Thromboplastin Time 
PVC 
premature ventricular complexe 
QD 
Once daily 
QOL 
Quality of Life 
OTC 
Over-the-counter 
QTc 
corrected QT 
QTcB 
corrected QT (Bazetts method) 
QTcF 
corrected QT (Fridericia method) 
qual 
qualitative 
RBC 
red blood cell 
RBP 
Retinol-binding protein 
RE 
role-emotional 
RP 
role-physical 
SARS-CoV2 
Severe Acute Respiratory Syndrome-Coronavirus 2002 


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Abbreviation 
Term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF 
social function 
SF-36 
36-Item Short Form Survey 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SToD 
study team on demand 
SUSAR 
suspected unexpected serious adverse reaction 
T4 
Thyroxine 
TESPO 
Tafamidis Enhanced Surveillance of Pregnancy Outcomes 
THAOS 
Transthyretin-Associated Amyloidosis Outcomes Surve 
Tmax 
time of maximum observed concentration 
TBili 
total bilirubin 
TQOL 
Total Quality of Life 
TSH 
Thyroid-stimulating hormone 
TTR 
transthyretin 
TTR-FAP 
Transthyretin Familial Amyloid Polyneuropathy 
TOC 
table of contents 
ULN 
upper limit of normal 
US 
United States 
Val30Met 
substitution of methionine for valine at position 30 
VT 
vitality 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 


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Page 120 
 
 
11. REFERENCES 
1. 
Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic 
polyneuropathy. Arch Neurol 2005;62:1057-62. 
2. 
Benson MD, Wallace MR. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, et al, 
editors. The metabolic basis of inherited disease, 6 ed. New York: McGraw-Hill; 
1989:2439-60. 
3. 
Benson MD. Amyloidosis. In: Scriver CR, Beudet AL, Sly WS, et al, editors. The 
metabolic and molecular bases of inherited diseases. 8 ed. New York: McGraw- 
Hill;2001:5345-78. 
4. 
Costa PP, Figueira AS, Bravo FR. Amyloid fibril protein related to prealbumin in 
familial amyloidotic polyneuropathy. Proc Natl Acad Sci USA 1978;75(9):4499-503. 
5. 
Herlenius G, Wilczek HE, Larsson M, et al. Ten years of international experience with 
liver transplantation for familial amyloidotic polyneuropathy: results from the Familial 
Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 
2004;77(1):64-71. 
6. 
Saraiva MJ, Costa PP, Goodman DS. Studies on plasma transthyretin (prealbumin) in 
familial amyloidotic polyneuropathy, Portuguese type. J Lab Clin Med 
1983;102(4):590-603. 
7. 
Saraiva MJ, Costa PP, Goodman DS. Transthyretin (prealbumin) in familial 
amyloidotic polyneuropathy: genetic and functional aspects. Adv Neurol 1988;48:189- 
200. 
8. 
Kim DH, Zeldenrust SR, Low PA, et al. Quantitative sensation and autonomic test 
abnormalities in transthyretin amyloidosis polyneuropathy. Muscle Nerve 
2009;40:363-70. 
9. 
Coutinho P, Martins da Silva A, Lopes Lima J, et al. Forty years of experience with 
type I amyloid neuropathy. Review of 483 cases. In: Glenner GG, Pinho e Costa P, 
Falcao de Freitas A, editors. Amyloid and Amyloidosis. Amsterdam: 1980. p.88-98. 
10. Rapezzi C, Quarta CC, Riva L, et al. Transthyretin-related amyloidoses and the heart: a 
clinical overview. Nat Rev Cardiol 2010;7:398-408. 
11. Schmidt HH, Waddington-Cruz M, et al. Estimating the global prevalence of 
transthyretin familial amyloid polyneuropathy. Muscle Nerve 57: 829–837, 2018. 
12. Guan HZ, Liu Q, et al. The clinical, pathological and genetic studies of transthyretin 
familial amyloid polyneuropathy. Chin J Neurol 2015; 48(1):7-12. 


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Protocol B3461078 
Final Protocol Amendment 3, 2 September 2021 
PFIZER CONFIDENTIAL 
Page 121 
 
 
13. Liu G, Ni W, Wang H, et al. Clinical features of familial amyloid polyneuropathy 
carrying transthyretin mutations in four Chinese kindreds. J Peripher Nerv Syst 2017; 
22(1):19-26. 
14. Liu JY, Guo YJ, Zhou CK, et al. Clinical and histopathological features of familial 
amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family. J Neurol 
Sci 2011; 304(1-2):83-6. 
15. Li H, Zhang Y, Cao L, et al. Curcumin could reduce the monomer of TTR with 
Tyr114Cys mutation via autophagy in cell model of familial amyloid polyneuropathy. 
Drug Des Devel Ther 2014; 8:2121-8. 
16. Meng LC, Lyu H, Zhang W, et al. Hereditary transthyretin amyloidosis in eight Chinese 
families. Chin Med J 2015; 128(21):2902-5. 
17. Chen H, Zhou XY, Wang J, et al. Exome sequencing and gene prioritization correct 
misdiagnosis in a Chinese kindred with familial amyloid polyneuropathy. Sci Rep 2016; 
6:26362. 
18. Japan Annual Safety Report (August 2018). 
19. Dyck, P. J., K. M. Kratz, J. L. Karnes, et al. The prevalence by staged severity of 
various types of diabetic neuropathy, retinopathy, and nephropathy in a population- 
based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993. 43:817-824. 
20. Vinik, A. I. Advances in diabetes for the millennium: new treatments for diabetic 
neuropathies. MedGenMed 2004. 6:13. 

SAP_001.pdf: 
Protocol B3461078 (Tafamidis Meglumine) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol B3461078
A SINGLE ARM, MULTICENTER, OPEN-LABEL STUDY TO EVALUATE THE  
EFFICACY, SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF 
ORALLY ADMINISTERED TAFAMIDIS MEGLUMINE IN TRANSTHYRETIN 
AMYLOID POLYNEUROPATHY PARTICIPANTS  IN CHINA
Statistical Analysis Plan 
(SAP)
Version:
3
Date:
21 Feb 2023


Protocol B3461078 (Tafamidis Meglumine) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.1.1. Primary Estimand(s).....................................................................................5
2.1.2. Secondary Estimand(s).................................................................................6
2.1.3. Supplementary Estimand(s)..........................................................................6
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint ......................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................8
3.2.1. Efficacy Endpoints........................................................................................8
3.2.2. Quality of Life Endpoints.............................................................................8
3.2.3. Safety Endpoints...........................................................................................8
3.2.4. Pharmacodynamics Endpoints......................................................................8
3.3. Baseline Variables.....................................................................................................8
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................9
5.1. Hypotheses and Decision Rules ................................................................................9
5.2. General Methods .......................................................................................................9
5.2.1. Analyses for Continuous Endpoints .............................................................9
5.2.2. Analyses for Categorical Endpoints .............................................................9
5.3. Methods to Manage Missing Data ............................................................................9
6. ANALYSES AND SUMMARIES ......................................................................................10
6.1. Primary Endpoint(s) ................................................................................................10
6.1.1. Change from Baseline NIS-LL at Week 72 (Month 18) ............................10
6.1.1.1. Main Analysis ...........................................................................10
6.1.1.2. Supplementary Analyses...........................................................10
6.2. Secondary Endpoint(s) ............................................................................................10


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6.2.1. All other Efficacy (3.2.1) and Quality of Life Endpoints (3.2.2) ...............11
6.2.2. TTR Concentration and TTR Stabilization.................................................11
6.3. Other Endpoint(s)....................................................................................................11
6.4. Subset Analyses.......................................................................................................11
6.5. Baseline and Other Summaries and Analyses.........................................................11
6.5.1. Baseline Summaries....................................................................................11
6.5.2. Study Conduct and Participant Disposition................................................12
6.5.3. Study Treatment Exposure .........................................................................12
6.5.4. Concomitant Medications and Nondrug Treatments..................................12
6.6. Safety Summaries and Analyses .............................................................................12
6.6.1. Adverse Events ...........................................................................................12
6.6.2. Vital Signs ..................................................................................................12
6.6.3. Electrocardiograms (ECG) .........................................................................12
6.6.4. Laboratory Data..........................................................................................12
6.6.5. Echocardiography.......................................................................................13
6.7. Additional Analyses Depicting COVID-19 Pandemic Impact................................13
7. INTERIM ANALYSES.......................................................................................................13
7.1. Introduction .............................................................................................................13
7.2. Interim Analyses and Summaries............................................................................13
8. APPENDICES .....................................................................................................................13
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
APPENDICES
Appendix 1. Data Derivation Details.......................................................................................13
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................13


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
01 June 2019
Original 
05 Jun 2019
N/A
N/A
2
28 Mar 2022
3
02 Sep 2021
Per protocol 
amendment 3
Update whole document per Protocol 
Amendment 3 changes.
3
20 Jan 2023
3
02 Sep 2021
Add in 
analysis 
related to 
COVID-19 
impact
Section 2.1.2 was added back due to mistaken 
deletion in version 2.
More details about the primary endpoint were 
added in Section 3.1.
Add in references for some endpoints in 
Section 3.2
Due to COVID-19 pandemic, some patients 
were unable to come back for site visit.  
Instead, their assessments were done using 
alternative approach, eg, at local facility
following protocol amendment 3 Appendix 9 
“Alternative Measures During Public 
Emergencies” guidances. Thus, alternative 
data assessment approach is added as an 
additional intercurrent event.  The 
corresponding Estimands and Analyses 
contents are updated.
Add in Covid-19 impact analyses in Section 
6.7.
Add in analysis window for endpoints 
assessed less frequently in Appendix 1.1.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B3461078.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.


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2.1. Study Objectives, Endpoints, and Estimands
Objectives
Estimands
Endpoints
Primary: 
To evaluate the effect 
of tafamidis 
meglumine on 
clinical efficacy in 
ATTR-PN 
participants.
Descriptive statistics of 
the NIS-LL change from 
baseline at Week 72  
(Month 18), regardless of 
whether or not participant
continues with/adheres to 
treatment
Change from baseline NIS-LL at 
Week 72 (Month 18)
Secondary:
To evaluate the 
efficacy, safety, 
tolerability, and 
pharmacodynamics of 
tafamidis meglumine 
in ATTR-PN 
participants.
Descriptive statistics of 
the secondary endpoints 
in ATTR-PN participants, 
regardless of whether or 
not participant continues 
with/adheres to treatment.
Efficacy: Change from baseline at 
follow-up visit on the following 
scales:

NIS-LL at other visits than 
Week 72 

TQOL score and 5 domains as 
measured by the Norfolk QOL 
– Diabetic Neuropathy 
(Norfolk QOL-DN);

Modified Body Mass Index 
(mBMI);

36-item short form (SF-36);

EQ-5D-5L Index Score.
Safety: Adverse events, vital signs 
(temperature, blood pressure, pulse 
rate, and respiratory rate), ECGs, 
ECHO, clinical laboratory 
evaluations.
Pharmacodynamics: TTR stabilization 
and TTR concentration at Day 1 
(baseline), Week 8, Week 12, Week 
24, Week 48 and Week 72.
2.1.1. Primary Estimand(s)
The primary estimand of this study will use the treatment policy strategy and estimate the 
change from baseline NIS-LL at week 72 (month 18) in the ATTR-PN patients, regardless of 
whether an intercurrent event occurs. The estimand is defined according to the primary 


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objective and is in alignment with the primary endpoint.  It includes the following 5
attributes: 

Population: ATTR-PN patients, as defined by the inclusion and exclusion criteria to 
reflect the targeted patient population

Treatment: Oral tafamidis meglumine 20 mg soft capsules once daily;

Variable: Change from baseline NIS-LL at week 72 (month 18);

Intercurrent event(s): Treatment discontinuation, non-adherence to treatment, or 
alternative assessment approach is not considered. All data collected after treatment 
discontinuation or non-adherence to treatment (defined as treatment compliance of 
<80% before the assessment), or collected by alternative assessment approach are 
included. 

Population-level summary: Descriptive statistics of change from baseline NIS-LL at 
week 72 (month 18).
2.1.2. Secondary Estimand(s)
The secondary estimands of this study will also use the treatment policy strategy and evaluate
the efficacy, safety, tolerability, and pharmacodynamics of tafamidis in China ATTR-PN 
patients, regardless of whether an intercurrent event occurs. The estimand is defined 
according to the secondary objectives and is in alignment with the secondary endpoints.  It 
includes the following 5 attributes: 

Population: ATTR-PN patients, as defined by the inclusion and exclusion criteria, and 
who received the study treatment; 

Treatment: Oral tafamidis meglumine 20 mg soft capsules once daily;

Variable: The corresponding secondary endpoint;

Intercurrent event(s): Treatment discontinuation, non-adherence to treatment, or 
alternative assessment approach is not considered. All data collected after treatment 
discontinuation or non-adherence to treatment (defined as treatment compliance of 
<80% before the assessment), or collected by alternative assessment approach are 
included.

Population-level summary:  Descriptive statistics of variable. 
2.1.3. Supplementary Estimand(s)
A supplementary estimand for the primary endpoint will use the hypothetical strategy, which
differs from the primary estimand (Section 2.1.1) in the following attribute: 


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
Intercurrent event(s): Data after the intercurrent event, treatment discontinuation or 
non-adherence to treatment, if collected; or data collected by alternative assessment 
approach, if done, will be excluded. 
2.2. Study Design
This is a post approval commitment study conducted in China.  It is a single-arm, open-label, 
multicenter study designed to evaluate the efficacy, safety, tolerability as well as 
pharmacodynamics of tafamidis meglumine in ATTR-PN participants in China.  
Participants will be evaluated for study eligibility during the screening period between Days -
30 and Day 0.  Approximately 10 - 15 participants will be enrolled.  All enrolled participants
will receive oral tafamidis meglumine 20 mg soft gelatin capsules once daily starting on Day 
1 for 72 weeks (18 months).  Site visits will be scheduled at Baseline (Day 1) and at Week 4, 
Week 8, Week 12, Week 24, Week 36, Week 48, Week 60, end of treatment, and Week 72
(or Early Study Discontinuation). Every 6 weeks (do not exceed 7 weeks since last 
confirmation) telephone contacts will be made during visits in which no investigative site 
visits are scheduled for assessment of adverse events, concomitant medications and 
investigational product compliance (between Week 12 and 24, between Week 24 and 36, 
between Week 36 and 48, between Week 48 and 60, and between Week 60 and 72).
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Baseline for below endpoints is defined as the last measurement prior to dosing on Day 1 of 
the study.  Change from baseline value is calculated by subtracting the baseline value from 
follow up visit value.
3.1. Primary Endpoint

Change from baseline NIS-LL at Week 72 (Month 18)
NIS-LL will be utilized to calculate a total neuropathic deficit score for the lower limbs.  In 
addition, subset scores for the lower limbs: muscle weakness (sum of Items 1-8), reflexes 
(sum of Items 9 and 10), sensation in great toe (sum of Items 11-14) will be calculated.  The 
total NIS-LL will be calculated as the sum of the subset scores.
NIS-LL testing is performed 2 times at each visit.  The average value of the 2 scores will be 
used for the analysis.  The composite NIS-LL will be calculated by first taking the average 
over the two individual subset scores for muscle weakness, reflexes and sensation in great 
toe, for both left and right limbs, taken at least 24 hours apart within one week of each other.  
If one of the two individual subset scores is missing, the non-missing value is used to impute 
the missing value.  The averages of each subset score then will be summed to obtain the 
composite NIS-LL score for that visit’s assessment.  If both individual subset scores are 
missing within the month assessment, the average will be missing and thus the composite 
NIS-LL will be missing for that visit. 


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3.2. Secondary Endpoint(s)
3.2.1. Efficacy Endpoints

Change from Baseline in NIS-LL (lower limb) score at other visits than week 72;

Change from baseline in the total quality of life (TQOL) score and 5 domains as 
measured by the Norfolk QOL – Diabetic Neuropathy (Norfolk QOL-DN); Refer to 
protocol section 9.4.1.3 for detailed calculation

Change from baseline in modified Body Mass Index (mBMI); mBMI is calculated by 
multiplying the BMI (kg/height in m2) by serum albumin level (g/L).
3.2.2. Quality of Life Endpoints

Change from baseline in Short-Form 36 (SF-36, version 2, Acute) score; Refer to 
protocol section 9.4.3.1 for detailed calculation

Change from baseline in EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) index score.
Refer to protocol section 9.4.3.2 for detailed calculation.
3.2.3. Safety Endpoints

Incidence and severity of adverse events;

Incidence of vital sign (temperature, blood pressure, heart rate and respiratory rate) 
abnormalities and changes from baseline in vital sign measurements;

Change from baseline in ECG measurements and incidence of electrocardiogram 
(ECG) abnormalities;

Incidence of clinically significant changes on Echocardiography

Change from baseline in clinical laboratory values and incidence of abnormalities;
3.2.4. Pharmacodynamics Endpoints

TTR stabilization at Day 1 (baseline), Week 8, Week 12, Week 24, Week 48 and 
Week 72;

TTR concentration at Day 1 (baseline), Week 8, Week 12, Week 24, Week 48 and 
Week 72.
Declaring a participant to have been “stabilized” is defined as percent stabilization equal to 
or greater than 32%.  Refer to the separate Bioanalytical Plan as Appendix of Bioanalytical 
Report for calculation of percent stabilization. 
3.3. Baseline Variables

Demographic characteristics;


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
Basic disease diagnosis;

Medical history.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Population
Description
Enrolled 
All participants who sign the ICD.
Efficacy
All participants who take at least 1 dose of tafamidis meglumine 
soft gelatin capsule 20 mg.
Safety
The same as above efficacy population.
Pharmacodynamic 
(PD)
All participants who take at least 1 dose of tafamidis meglumine 
soft gelatin capsule 20 mg and who have at least 1 TTR 
concentration/stabilization value.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
This is an estimation study with no statistical hypothesis nor decision rules.
5.2. General Methods
5.2.1. Analyses for Continuous Endpoints
The data for all continuous endpoints will be summarized by time point in tables containing 
descriptive statistics (N, mean, standard deviation, standard error of the mean, minimum, 1st, 
2nd (median) and 3rd quartiles and maximum) for baseline and change from baseline for those 
endpoints measured at baseline.  
5.2.2. Analyses for Categorical Endpoints
The data for categorical endpoints (including binary) will be summarized by contingency 
tables that show the counts/frequency and percentage in the various categories at each time
point.  For some categorical endpoints, such as the presence or severity of adverse events, 
contingency or frequency tables will consider the data over the entire duration of the study 
and will not be constructed at each time point.  
The 2-sided 95% confidence interval for the proportion estimate will be calculated with 
Clopper-Pearson exact method.
5.3. Methods to Manage Missing Data
For the NIS-LL, Norfolk QOL-DN, SF-36 and EQ-5D-5L instruments, rules suggested by 
the developers of these will be followed in calculating scores when individual question/items 
may be missing.  If these rules are not enough for calculating a score, then the endpoint will 
be considered to have a missing value.  Missing values in any of the endpoints will not be 
imputed when summarizing these endpoints using descriptive statistics due to small sample 
size.


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For safety data, missing dates and severity of adverse events will be imputed following Pfizer 
Reporting Standards.  No imputation will be done for missing vital signs, ECG, 
Echocardiography, and laboratory measurements.
No imputation will be done for missing TTR concentration and modified BMI.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Change from Baseline NIS-LL at Week 72 (Month 18)
6.1.1.1. Main Analysis

Estimand strategy: Treatment Policy (Section 2.1.1).

Analysis set: Efficacy (Section 4). All participants who took at least 1 dose of tafamidis 
meglumine soft gelatin capsule 20 mg.

Analysis methodology: Descriptive Summmary stated in Section 5.2.1 will be followed.

Intercurrent events and missing data: All data collected after treatment discontinuation or
non-adherence to treatment (defined as treatment compliance of <80% before the 
assessment), or collected by alternative assessment approach are included; No imputation 
will be done to missing data due to small sample size of the study.  

The basic summary statistics will be calculated.  The 95% confidence interval will be 
presented for change from baseline NIS-LL at week 72 (month 18).
6.1.1.2. Supplementary Analyses
An analysis that assesses the primary endpoint using a hypothetical estimand strategy 
(Section 2.1.3) will be performed.  It will use the same methodology and summary as the 
main analysis but will exclude data collected after the intercurrent events of treatment
discontinuation or non-adherence to treatment (defined as treatment compliance <80% before 
the assessment), or by alternative assessment approach.  
This study is conducted after the COVID-19 pandemic anchor date (09 January 2020 for 
China).  The pandemic affected some patients’ week 72 on-site visit around the end of 2022.  
Those subjects were unable to visit on site due to quarantine and travel restriction.  Their 
week 72 visit assessments were done at local alternative facility per protocol amendment 3 
Appendix 9 “Alternative Measures During Public Emergencies”.  In order to assess this 
impact, those subjects with week 72 NIS-LL data collected by local alternative facility will 
be excluded from the main analysis.
6.2. Secondary Endpoint(s)
No sensitivity or supplementary analysis will be done for any secondary endpoint.  The main 
analyses are as following.


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6.2.1. All other Efficacy (3.2.1) and Quality of Life Endpoints (3.2.2)

Estimand strategy: Treatment Policy (Section 2.1.2).

Analysis set: Efficacy (Section 4).  All participants who take at least 1 dose of tafamidis 
meglumine soft gelatin capsule 20 mg.

Analysis methodology: Descriptive Summmary stated in Section 5.2.1 will be followed.  

Intercurrent events and missing data: All data collected after treatment discontinuation or 
non-adherence to treatment, or collected by alternative assessment approach are included; 
Missing data will not be imputed.

The basic summary statistics will be calculated by visit.  The change from baseline over 
time in NIS-LL, mBMI and TQOL of Norfolk QOL-DN will be plotted graphically.
6.2.2. TTR Concentration and TTR Stabilization

Estimand strategy: Treatment Policy (Section 2.1.2).

Analysis set: Pharmacodynamic (Section 4).  Participants must have a TTR 
concentration/stabilization assessment to be included.

Analysis methodology: Descriptive Summmary stated in Section 5.2.2 will be followed.  

Intercurrent events and missing data: All data collected after treatment discontinuation or 
non-adherence to treatment, or collected by alternative assessment approach are included; 
missing data will not be imputed.

The counts and proportion of participants who achieve TTR stabilization (ie, who has 
been stabilized) at the post baseline visits per SOA and its 2-sided 95% confidence 
interval will be presented in both table and graphically.
6.3. Other Endpoint(s)
Not applicable.  There are no exploratory endpoints for this study.
6.4. Subset Analyses
No subset analysis is planned for this study. 
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Baseline variables will be summarized descriptively.  Continuous variables will follow 
methods in Section 5.2.1.  Categorical variables will follow methods in Section 5.2.2.  
Medical history will be listed by participant.


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6.5.2. Study Conduct and Participant Disposition
The end of study subject disposition will be shown by subject evaluation groups. 
Frequency/counts will be provided for subject discontinuation(s) and study completion.
6.5.3. Study Treatment Exposure
The duration of treatment will be calculated as: date of the last dose – date of the first dose 
+ 1.  Any missed doses/off drug period will be ignored in the duration calculation.  The 
treatment exposure will be defined as the number of days that participants took the study 
drug.  Both will be summarized in following categories (days): 1, 2-28 (4 weeks), 29-56 (4-8 
weeks), 57-84 (8-12 weeks), 85-168 (12 weeks-6 months), 169-252 (6-9 months), 253-336 
(9-12 months), 337-420 (12-15 months), ≥421 (15-18 months).
Since study treatment should be taken once daily, study drug compliance will be calculated 
for each patient as: treatment exposure / treatment duration × 100.  Compliance will be listed 
as both a continuous and categorical (<80%, ≥80%) endpoint.
6.5.4. Concomitant Medications and Nondrug Treatments
Concomitant medication usage by medication type will be tabulated using the WHO-Drug 
dictionary and listed following Pfizer Data Standard.  Nondrug treatment will be listed as 
well.
6.6. Safety Summaries and Analyses
6.6.1. Adverse Events
Treatment emergent adverse event is defined as any adverse event started after the first dose.  
TEAEs will be summarized according to Pfizer Reporting Standards.  The summary tables of
TEAE and TEAE by System Organ Class (SOC) will be provided. The incidence and 
severity of TEAE will be presented by SOC and MeDRA Preferred Term (PT).
6.6.2. Vital Signs
Summary statistics for changes from baseline in vital sign parameters will be provided by 
visit following Pfizer Reporting Standards. Participants with abnormalities will be 
summarized by each vital sign parameter. Individual values for actual value will be listed.
6.6.3. Electrocardiograms (ECG)
ECG parameters (QT interval, QRS etc) in actual and change from baseline will be
summarized descriptively following Pfizer Reporting Standards. In addition, the incidence 
of ECG abnormalities will also be summarized descriptively following Pfizer Reporting 
Standards. 
6.6.4. Laboratory Data
The incidence of laboratory abnormalities observed at any time during the study will be 
tabulated following Pfizer Reporting Standards and summary statistics for changes from 
baseline will be provided by visit.


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6.6.5. Echocardiography
The number (%) of subjects with normal, abnormal not clinically significant, abnormal
clinically significant and unevaluable was summarized at each visit. 
6.7. Additional Analyses Depicting COVID-19 Pandemic Impact
In order to report the impact of COVID-19 on clinical trial populations and study data, the
following listings and summaries will be produced, in addition to the supplementary analysis  
for the primary endpoint as in Section 6.1.1.2:

Listing of subjects with alternative facility or telehealth visits replacing site visits due 
to COVID-19 pandemic

Listing of subjects with missing or non-site collected NIS-LL assessments due to 
COVID-19 pandemic

A separate summary table solely for subject discontinuations from investigational
product and withdrawal from study related to COVID-19 pandemic, if any, will be
provided

Protocol deviations related to COVID-19 pandemic will be summarized and listed
separately. Both important and non-important PDs related to COVID-19 pandemic
will be reported

COVID-19 related AEs, if any, will be reported separately
7. INTERIM ANALYSES
No interim analysis will be conducted for this study. As this is an open label study, the 
sponsor may conduct reviews of the data during the course of the study for the purpose of 
safety assessment.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.
8. APPENDICES
Appendix 1. Data Derivation Details
Appendix 1.1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy, PD variables, and for any safety displays that 
display by visit. The study day will be calculated as: date of assessment/collection – date of 
the first dose + 1.  If two or more visits/observations fall into the same window, the 


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visit/observation closest to the target day should be used in the analyses.  If there is a tie, the 
later visit should be used. All observations will, however, be included in the listings.
For assessments scheduled at baseline, week 24, 48 and 72 visits, below analysis window are 
used:
Visit Label
Target Day
Definition [Day Window] –
Lower
Definition [Day Window]  
Upper
Baseline
1
Day 1 = date of first dose of study treatment taken in the study
Prior to first dose of study treatment taken in the study
Week 24
168
2
252
Week 48 
336
253
420
Week 72
504
421
553
For all the other assessments, below analysis windows are applied:
Visit Label
Target Day
Definition [Day Window] –
Lower
Definition [Day Window]  
Upper
Baseline
1
Day 1 = date of first dose of study treatment taken in the study
Prior to first dose of study treatment taken in the study
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
126
Week 24
168
127
210
Week 36
252
211
294
Week 48 
336
295
378
Week 60
420
379
462
Week 72
504
463
553