Conditions: Healthy
Keywords: Tafamidis, B3461103
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 22
Healthy volunteers: yes

Brief summary:
The purpose of this clinical trial is to compare a tablet and a capsule form of tafamidis without food and to assess the amount of tafamidis in blood after taking the tablet form with food.

This study is seeking healthy participants over the age of 18.

All participants in the study will receive either one tablet or capsule of study medicine on the first day without food, then receive one dose of the other tablet or capsule form 16 days later without food. All participants will then receive one dose of the tablet form with food 16 days later.

We will evaluate the amounts in blood for 8 days after taking each dose of the study medicine.

Participants will take part in this study for about 96 days. The first visit is a screening visit to ensure that participants are appropriate for the study. Up to 28 days later, eligible participants will visit the study clinic three times (and stay overnight in the clinical research center for 8 nights each time). The study team will also call participants over the phone 28 to 35 days after the last dose of medicine.

Detailed description:

Arms:
arm 1: On Day 1 of each period, participants will receive a single dose of one of the tafamidis formulations under fasted or fed conditions. Each period is separated by a washout of at least 16 days between administration of study drug. arm 2: On Day 1 of each period, participants will receive a single dose of one of the tafamidis formulations under fasted or fed conditions. Each period is separated by a washout of at least 16 days between administration of study drug.

Interventions: intervention 1: Tafamidis free acid tablet (Test) intervention 2: Tafamidis meglumine capsule (Reference)
Intervention descriptions: intervention 1: 12.2 mg tafamidis free acid tablet (Test) intervention 2: Commercial 20 mg tafamidis meglumine capsule (Reference)

Protocol document:
Prot_000.pdf: 
PF-06291826 
Protocol B3461103 
Final Protocol, 19 May 2022 
 
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. 
 
 
 
Title Page 
 
A PHASE 1, OPEN-LABEL, RANDOMIZED, CROSSOVER, SINGLE DOSE STUDY 
TO DETERMINE THE BIOEQUIVALENCE OF 12.2 MG TAFAMIDIS FREE ACID 
TABLETS AND COMMERCIAL 20 MG TAFAMIDIS MEGLUMINE CAPSULES 
ADMINISTERED UNDER FASTED CONDITIONS AND THE EFFECT OF FOOD 
ON ORAL BIOAVAILABILITY OF 12.2 MG TAFAMIDIS FREE ACID TABLETS 
IN HEALTHY ADULT PARTICIPANTS 
 
 
Study Intervention Number: 
PF-06291826 
Study Intervention Name: 
Tafamidis 
US IND Number: 
CCI  
EudraCT Number: 
Not Applicable 
ClinicalTrials.gov ID: 
Not Available 
Pediatric Investigational Plan Number: 
Not Applicable 
Protocol Number: 
B3461103 
Phase: 
1 
Brief Title: Phase 1 Study to Determine Bioequivalence of 12.2 mg Tafamidis Free 
Acid Tablets and Commercial 20 mg Tafamidis Meglumine Capsules Administered 
Under Fasted Conditions and the Effect of Food on Oral Bioavailability of 12.2 mg 
Tafamidis Free Acid Tablets in Healthy Adult Participants 
 
 
 
 
 


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Document History 
 
Document 
Version Date 
Original protocol 
19 May 2022 
Protocol for Health Canada 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
Page 3 
 
 
TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 7 
1. PROTOCOL SUMMARY ..................................................................................................... 8 
1.1. Synopsis ..................................................................................................................... 8 
1.2. Schema..................................................................................................................... 13 
1.3. Schedule of Activities .............................................................................................. 14 
2. INTRODUCTION ................................................................................................................ 20 
2.1. Study Rationale ........................................................................................................ 20 
2.2. Background .............................................................................................................. 20 
2.3. Benefit/Risk Assessment ......................................................................................... 21 
2.3.1. Risk Assessment ......................................................................................... 22 
2.3.2. Overall Benefit/Risk Conclusion ................................................................ 23 
3. OBJECTIVES AND ENDPOINTS ..................................................................................... 23 
4. STUDY DESIGN ................................................................................................................. 23 
4.1. Overall Design ......................................................................................................... 23 
4.2. Scientific Rationale for Study Design ..................................................................... 24 
4.2.1. Choice of Contraception/Barrier Requirements .......................................... 24 
4.2.2. Collection of Retained Research Samples .................................................. 24 
4.3. Justification for Dose ............................................................................................... 24 
4.4. End of Study Definition ........................................................................................... 25 
5. STUDY POPULATION ...................................................................................................... 25 
5.1. Inclusion Criteria ..................................................................................................... 25 
5.2. Exclusion Criteria .................................................................................................... 25 
5.3. Lifestyle Considerations .......................................................................................... 28 
5.3.1. Meals and Dietary Restrictions ................................................................... 28 
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................. 29 
5.3.3. Activity ....................................................................................................... 29 
5.4. Screen Failures ......................................................................................................... 29 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .................................. 29 
6.1. Study Intervention(s) Administered ......................................................................... 29 
6.1.1. Administration ............................................................................................. 31 
6.2. Preparation, Handling, Storage, and Accountability ............................................... 31 


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6.2.1. Preparation and Dispensing .........................................................................32 
6.3. Assignment to Study Intervention ...........................................................................33 
6.4. Blinding ...................................................................................................................33 
6.4.1. Blinding of Participants ...............................................................................33 
6.4.2. Blinding of Site Personnel ...........................................................................33 
6.4.3. Blinding of the Sponsor ..............................................................................33 
6.5. Study Intervention Compliance ...............................................................................33 
6.6. Dose Modification ...................................................................................................33 
6.7. Continued Access to Study Intervention After the End of the Study ......................33 
6.8. Treatment of Overdose ............................................................................................34 
6.9. Prior and Concomitant Therapy ...............................................................................34 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................35 
7.1. Discontinuation of Study Intervention .....................................................................35 
7.1.1. ECG Changes ..............................................................................................35 
7.1.2. COVID-19 ...................................................................................................35 
7.2. Participant Discontinuation/Withdrawal From the Study .......................................35 
7.2.1. Withdrawal of Consent ...............................................................................36 
7.3. Lost to Follow-up ....................................................................................................36 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................36 
8.1. Administrative and Baseline Procedures .................................................................36 
8.2. Efficacy Assessments ..............................................................................................37 
8.3. Safety Assessments ..................................................................................................38 
8.3.1. Physical Examinations ................................................................................38 
8.3.2. Vital Signs ...................................................................................................38 
8.3.2.1. Blood Pressure and Pulse Rate ..................................................38 
8.3.2.2. Temperature ...............................................................................39 
8.3.3. Electrocardiograms ......................................................................................39 
8.3.4. Clinical Safety Laboratory Assessments .....................................................39 
8.3.5. COVID-19 Specific Assessments ...............................................................40 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting ..................40 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information .......41 


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8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 41 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 41 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 42 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 42 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 42 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 43 
8.4.5.1. Exposure During Pregnancy ...................................................... 43 
8.4.5.2. Exposure During Breastfeeding ................................................. 44 
8.4.5.3. Occupational Exposure .............................................................. 45 
8.4.6. Cardiovascular and Death Events ................................................................ 45 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 45 
8.4.8. Adverse Events of Special Interest ............................................................. 45 
8.4.8.1. Lack of Efficacy......................................................................... 45 
8.4.9. Medical Device Deficiencies ...................................................................... 45 
8.4.10. Medication Errors ...................................................................................... 45 
8.5. Pharmacokinetics ..................................................................................................... 46 
8.5.1. Plasma for Analysis of Tafamidis ............................................................... 46 
8.6. Genetics ................................................................................................................... 47 
8.6.1. Specified Genetics ....................................................................................... 47 
8.6.2. Retained Research Samples for Genetics .................................................... 47 
8.7. Biomarkers ............................................................................................................... 47 
8.7.1. Specified Gene Expression (RNA) Research ............................................. 47 
8.7.2. Specified Protein Research .......................................................................... 47 
8.7.3. Specified Metabolomic Research ................................................................ 47 
8.8. Immunogenicity Assessments ................................................................................. 47 
8.9. Health Economics .................................................................................................... 47 
9. STATISTICAL CONSIDERATIONS ................................................................................. 48 
9.1. Statistical Hypotheses .............................................................................................. 48 
9.2. Analysis Sets ............................................................................................................ 48 
9.3. Statistical Analyses .................................................................................................. 49 
9.3.1. Pharmacokinetic Analyses .......................................................................... 49 


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9.3.1.1. Derivation of Pharmacokinetic Parameters ...............................49 
9.3.2. Safety Analyses ...........................................................................................51 
9.3.3. Other Analyses ............................................................................................51 
9.4. Interim Analyses ......................................................................................................52 
9.5. Sample Size Determination .....................................................................................52 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...........................................................................................................53 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................53 
10.1.1. Regulatory and Ethical Considerations .....................................................53 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .........................................................................53 
10.1.2. Informed Consent Process ........................................................................54 
10.1.3. Data Protection ..........................................................................................55 
10.1.4. Committees Structure ................................................................................55 
10.1.4.1. Data Monitoring Committee ....................................................55 
10.1.5. Dissemination of Clinical Study Data .......................................................55 
10.1.6. Data Quality Assurance .............................................................................56 
10.1.7. Source Documents ....................................................................................58 
10.1.8. Study and Site Start and Closure ...............................................................58 
10.1.9. Publication Policy .....................................................................................59 
10.1.10. Sponsor’s Medically Qualified Individual ..............................................60 
10.2. Appendix 2: Clinical Laboratory Tests .................................................................61 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................................62 
10.3.1. Definition of AE ........................................................................................62 
10.3.2. Definition of an SAE .................................................................................63 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ............................................................................64 
10.3.4. Reporting of SAEs ....................................................................................68 
10.4. Appendix 4: Contraceptive and Barrier Guidance .................................................69 
10.4.1. Male Participant Reproductive Inclusion Criteria ....................................69 
10.4.2. Female Participant Reproductive Inclusion Criteria .................................69 
10.5. Appendix 5: Genetics ............................................................................................70 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ........71 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines .............................................73 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ..............................................................................73 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ................73 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................73 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities ...................................................................................................73 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ....................................74 
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI........76 
10.10. Appendix 10: Abbreviations ................................................................................77 
11. REFERENCES ...................................................................................................................80 
 
 
LIST OF TABLES 
Table 1. 
Study Schedule of Assessment..................................................................14 
Table 2. 
B3461103 Treatment Sequence Schema ..................................................24 
Table 3. 
Description of Tafamidis Treatment .........................................................24 
Table 4. 
Plasma Tafamidis Pharmacokinetic Parameters Definitions .................... 49 
Table 5. 
Protocol-Required Safety Laboratory Assessments .................................. 61 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Open-Label, Randomized, Crossover, Single Dose Study to 
Determine the Bioequivalence of 12.2 mg Tafamidis Free Acid Tablets and Commercial 
20 mg Tafamidis Meglumine Capsules Administered Under Fasted Conditions and the Effect 
of Food on Oral Bioavailability of 12.2 mg Tafamidis Free Acid Tablets in Healthy Adult 
Participants 
 
Brief Title: Phase 1 Study to Determine Bioequivalence of 12.2 mg Tafamidis Free acid 
Tablets and Commercial 20 mg Tafamidis Meglumine Capsules Administered Under Fasted 
Conditions and the Effect of Food on Oral Bioavailabilty in Healthy Adult Participants 
 
Regulatory Agency Identification Number(s): 
 
 
US IND Number: 
CCI  
EudraCT Number: 
Not Applicable 
ClinicalTrials.gov ID: 
Not Available 
Pediatric Investigational Plan Number: 
Not Applicable 
Protocol Number: 
B3461103 
Phase: 
1 
Rationale: 
This study will be conducted to determine if a 12.2 mg tafamidis free acid tablet (Test) is 
bioequivalent to the commercial 20 mg tafamidis meglumine soft gelatin capsule (Reference) 
and to estimate the effect of food on the bioavailability of the 12.2 mg tafamidis free acid 
tablet. 


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Objectives and Endpoints: 
Objectives 
Endpoints 
 
Primary: 
 
• To establish the bioequivalence of 12.2 mg 
tafamidis free acid tablet (Test) and commercial 
20 mg tafamidis meglumine soft gelatin 
capsules (Reference) in fasted healthy 
participants. 
Secondary: 
 
• To estimate the relative bioavailability of a 
single dose of the 12.2 mg tafamidis free acid 
tablet administered under fed conditions 
compared to a single dose of the 12.2 mg 
tafamidis free acid tablet administered under 
fasted conditions in healthy participants. 
CCI 
 
 
Primary: 
 
• AUCinf (if data permit, otherwise 
AUClast) and Cmax of tafamidis. 
 
 
 
Secondary: 
 
• Not Applicable 
 
 
 
 
 
 
 
 
 
 
Overall Design: 
 
This is a Phase 1, open-label, randomized, 3-way crossover, single dose study to determine 
the bioequivalence of PF-06291826 (tafamidis) 12.2 mg tafamidis free acid tablets versus 
commercial 20 mg tafamidis meglumine capsules administered under fasted conditions and 
to estimate the effect of food on the 12.2 mg tafamidis free acid tablet in healthy participants. 
 
Number of Participants: 
 
The sample size of 22 participants (11 participants per sequence in the fasted arms) to ensure 
a minimum of 18 PK evaluable participants for this 3-way crossover will provide 95% power 
that the 90% confidence interval for the ratio of Test to Reference for AUCinf will lie within 
the acceptance region of (80%, 125%) and 89% power that 90% confidence interval for the 
ratio of Test to Reference treatment for Cmax will lie within the acceptance region of (80%, 
125%). Consequently, this study has approximately 85% power overall to demonstrate 
bioequivalence of the Test treatment to the Reference treatment [ie, equivalence in both 
AUCinf and Cmax]. This estimate is based on the assumption that the true ratio between Test 
and Reference treatments for both AUCinf and Cmax is 0.9. 


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PFIZER CONFIDENTIAL 
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The power calculations assumed the estimates of within participant standard deviations of 
0.098 and 0.119 for loge AUCinf and loge Cmax, respectively, obtained as an average from 
studies B3461030, B3461044 and B3461095. 
 
Study Population: 
 
Inclusion and exclusion criteria are listed below: 
 
Inclusion Criteria 
 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study: 
 
1. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at screening. 
 
2. Healthy female participants of nonchildbearing potential and/or male participants 
who are overtly healthy as determined by medical evaluation including medical 
history, physical examination, and laboratory tests. 
 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
Exclusion Criteria 
 
Participants with any of the following characteristics/conditions will be excluded: 
 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 
 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 
 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. 
 
• Hypersensitivity to any component of the formulations 
2. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 


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PFIZER CONFIDENTIAL 
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3. Use of prescription or nonprescription drugs, dietary and herbal supplements within 
7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details). 
 
4. Current use of any prohibited concomitant medication(s) or participant 
unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.9 
Prior and Concomitant Therapy. 
 
5. Previous administration with an investigational product (drug or vaccine) within 6 
months (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
 
6. A positive urine drug test. 
 
7. Screening seated BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of seated rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility. 
 
8. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice 
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted- ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant. 
 
9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
 
• AST or ALT level ≥ 1.5 × ULN; 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
 
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 


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PFIZER CONFIDENTIAL 
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11. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
 
12. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
 
13. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
 
14. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
 
Study Arms and Duration: 
 
Eligible participants who continue to meet entry criteria will be admitted to the CRU on 
Day -1 and will be required to stay in the CRU for 8 overnight stays in each period. All 
participants will be discharged from the CRU following completion of the discharge 
evaluation, which includes adverse event monitoring, physical examination (at investigator 
discretion), vital signs, ECG measurements, and safety laboratory tests. 
 
Study Intervention(s) 
Intervention Name 
Tafamidis free acid tablet 
(fasted) 
Tafamidis meglumine soft 
gelatin capsule (fasted) 
Tafamidis free acid tablet 
(fed) 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
Treatment A 
Treatment B 
Treatment C 
Unit Dose Strength(s) 
12.2 mg 
20 mg 
12.2. mg 
Route of Administration 
Oral 
Oral 
Oral 
Use 
Experimental 
Experimental 
Experimental 
IMP or NIMP/AxMP 
IMP 
IMP 
IMP 
 
 
Study Arm(s) 
Arm Title 
Treatment A 
Treatment B 
Treatment C 
Arm Type 
Test - fasted 
Reference – fasted 
Test - fed 
Arm Description 
Participants will receive a 
single 12.2 mg tafamidis 
free acid tablet, fasted 
Participants will receive a 
single commercial 20 mg 
tafamidis meglumine 
capsule 
Participants will receive a 
single 12.2 mg tafamidis 
free acid tablet, fed 


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Statistical Methods: 
Natural log-transformed AUCinf, AUClast, CCI , and Cmax will be analyzed separately using 
a mixed effect model with sequence, period and treatment as fixed effects and participant 
within sequence as a random effect. Estimates of the adjusted mean differences 
(Test/Reference) and corresponding 90% confidence intervals will be obtained from the 
model. The adjusted mean differences and 90% confidence intervals for the differences will 
be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% confidence intervals for the ratios. Treatment A (12.2 mg 
tafamidis free acid tablet fasted) will be the Test treatment, while Treatment B (commercial 
20 mg tafamidis meglumine softgel capsule fasted) will be the Reference treatment. 
Bioequivalence of between the 2 formulations will be concluded if the 90% confidence 
intervals for the ratio of adjusted geometric means for both AUCinf (if data permit, otherwise 
AUClast) and Cmax fall wholly within the pre-specified criteria (80%, 125%). 
 
For the food effect comparison, Treatment C (12.2 mg tafamidis free acid tablet, fed) will be 
the Test treatment, while Treatment A (12.2 mg tafamidis free acid tablet, fasted) will be the 
Reference treatment. 
The PK parameters AUCinf, Cmax, AUClast, CCI 
 of tafamidis will be 
summarized descriptively by treatment. For AUCinf, AUClast, and Cmax, individual participant 
parameters will be plotted against treatment. Concentrations will be listed and summarized 
descriptively by treatment and PK sampling time. Individual participant, mean and median 
profiles of the concentration-time data will be plotted by treatment. For summary statistics 
and median plots by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used. 
 
Ethical Considerations: 
 
Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants must avoid vaccination with live 
attenuated vaccines throughout the study. When relevant, it is recommended that participants 
keep their diet habits constant throughout the study. 
 
1.2. Schema 
Not applicable. 


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1.3. Schedule of Activities 
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. 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this table 
may be found in Section 10.10 
Screen 
Periods 1, 2 and 3 
F/U 
Early Term/
Discont 
Notes 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 28-35 
days 
• 
All screening should be 
done ≤ 28 days before the 
first dose. 
• 
Day relative to start of study 
intervention (Day 1). 
• 
At least a 16 day washout 
interval between Day 1 in 
each subsequent period. 
• 
Follow-up may occur via 
telephone contact and must 
occur 28 to 35 days after 
administration of the final 
dose of study intervention. 
Informed consent 
X 
• 
Informed consent should be 
obtained prior to undergoing 
any study-specific procedures. 
• 
See Schedule of Activities 
CRU confinement 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
Inclusion/exclusion criteria 
X 
X 
• 
Period 1 only. 
Demography 
X 
Medical/medication history 
X 
X 
• 
Review medical, drug, 
alcohol, and tobacco history 
predose to determine any 
change from Screening 
evaluation (Period 1 only). 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this table 
may be found in Section 10.10 
Screen 
Periods 1, 2 and 3 
F/U 
Early Term/
Discont 
Notes 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 28-35 
days 
• 
All screening should be 
done ≤ 28 days before the 
first dose. 
• 
Day relative to start of study 
intervention (Day 1). 
• 
At least a 16 day washout 
interval between Day 1 in 
each subsequent period. 
• 
Follow-up may occur via 
telephone contact and must 
occur 28 to 35 days after 
administration of the final 
dose of study intervention. 
CCI 
FSH (postmenopausal females only) 
X 
• 
Serum FSH concentrations for 
any female who has been 
amenorrheic for at least 
12 consecutive months. 
Urine drug testing 
X 
X 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this table 
may be found in Section 10.10 
Screen 
Periods 1, 2 and 3 
F/U 
Early Term/
Discont 
Notes 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 28-35 
days 
• 
All screening should be 
done ≤ 28 days before the 
first dose. 
• 
Day relative to start of study 
intervention (Day 1). 
• 
At least a 16 day washout 
interval between Day 1 in 
each subsequent period. 
• 
Follow-up may occur via 
telephone contact and must 
occur 28 to 35 days after 
administration of the final 
dose of study intervention. 
CCI 
HIV, HBsAg, HBcAb, HCVAb 
X 
COVID-19 questionnaire 
X 
X 
• 
Check exposure to positive 
subject, residence or travel in 
area of high incidence, and 
COVID-19 related signs and 
symptoms. To be done at 
check in of each visit. 


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PFIZER CONFIDENTIAL 
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Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this table 
may be found in Section 10.10 
Screen 
Periods 1, 2 and 3 
F/U 
Early Term/
Discont 
Notes 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 28-35 
days 
• 
All screening should be 
done ≤ 28 days before the 
first dose. 
• 
Day relative to start of study 
intervention (Day 1). 
• 
At least a 16 day washout 
interval between Day 1 in 
each subsequent period. 
• 
Follow-up may occur via 
telephone contact and must 
occur 28 to 35 days after 
administration of the final 
dose of study intervention. 
COVID-19 testing 
X 
X 
X 
• 
The testing for COVID-19 
pathogen will be performed at 
each visit per local site 
procedures. For participants 
admitted for residence, a 
subsequent COVID-19 test 
will be performed after 4 days 
(ie, upon completion of 4 x 24 
hours in house), or if they 
develop COVID-19 like 
symptoms. 
COVID-19 check temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
To be done at least daily 
during residence. 
Study intervention administration 
X 
• 
Participants fasted overnight 
(minimum of 10 hours) prior 
to dosing and for 4 hours 
postdose on Day 1 (Periods 1 
and 2 only). 
Pharmacokinetic blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
Final visit procedures will be 
performed on the last day of 
the last period (Day 8 
Period 3), or upon study 
discontinuation. 


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PFIZER CONFIDENTIAL 
Page 18 
 
 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifier 
Abbreviations used in this table 
may be found in Section 10.10 
Screen 
Periods 1, 2 and 3 
F/U 
Early Term/
Discont 
Notes 
Day -1 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 28-35 
days 
• 
All screening should be 
done ≤ 28 days before the 
first dose. 
• 
Day relative to start of study 
intervention (Day 1). 
• 
At least a 16 day washout 
interval between Day 1 in 
each subsequent period. 
• 
Follow-up may occur via 
telephone contact and must 
occur 28 to 35 days after 
administration of the final 
dose of study intervention. 
CCI 
Serious and non-serious AE 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• 
See Section 8.4.3 for follow- 
up AE and SAE assessments. 
Prior/concomitant medication and 
treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRU discharge 
X 


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PFIZER CONFIDENTIAL 
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Pharmacokinetic Sampling Schema 
 
Visit Identifier 
Periods 1-3 
Notes 
Study 
Day 
1 
2 
3 
4 
5 
6 
7 
8 
Early Term/ 
Discont 
Hours Before/After 
Dose 
0 0.5 1 
2 3 
4 
6 
8 
12 24 48 72 96 120 144 168 
Hour 0 = predose sample collection 
Study intervention 
administration 
X 
PK blood sampling 
X X 
X X X X X 
X 
X 
X X X 
X 
X 
X 
X 
X 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
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CCI 
2. INTRODUCTION 
A 12.2 milligram (mg) tafamidis free acid tablet is being developed to replace the current 
commercial 20 mg tafamidis meglumine dosage formulation. 
 
2.1. Study Rationale 
The purpose of the study is to determine if a 12.2 mg tafamidis free acid tablet (Test) 
formulation is bioequivalent to the commercial 20 mg tafamidis meglumine soft gelatin 
capsule (Reference) and to estimate the effect of food on the bioavailability of the 12.2 mg 
tafamidis free acid tablet. 
 
2.2. Background 
Amyloidosis is a severely debilitating, and ultimately fatal, systemic condition induced by 
the accumulation of an insoluble fibrillar protein (amyloid) within tissues in amounts 
sufficient to impair normal function. 
 
The tafamidis salt (tafamidis meglumine, Vyndaqel®) 20 mg QD is approved in more than 
40 countries worldwide for the treatment of patients with ATTR-PN to delay neurologic 
impairment. 
 
In addition, the tafamidis salt (tafamidis meglumine, Vyndaqel) 80 mg QD is approved in the 
US and Japan, among other countries, for the treatment of patients with ATTRCM. The 
80 mg dose is administered as 4 × 20 mg tafamidis meglumine soft gelatin capsules. A 
tafamidis free acid 61 mg single oral dosage form is also approved in the US (tafamidis, 
Vyndamax®) and EU (tafamidis, Vyndaqel), among other countries, to facilitate patient 
convenience. 
 
 
 


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PFIZER CONFIDENTIAL 
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2.3. Benefit/Risk Assessment 
Tafamidis is not expected to provide any clinical benefit to healthy participants. This study is 
designed primarily to generate BE data to support a formulation change. 
 
In completed clinical studies, tafamidis was determined to be well-tolerated and to have an 
acceptable safety profile. More detailed information about the known and expected benefits 
and risks and reasonably expected AEs of tafamidis may be found in the IBi, which is the 
SRSD for this study. 
CCI 


 
PF-06291826 
Protocol B3461103 
Final Protocol, 19 May 2022 
 
 
2.3.1. Risk Assessment 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) 
Sorbitol is an inactive ingredient present 
in tafamidis meglumine 20 mg capsules. 
Each capsule contains no more than 44 mg 
of sorbitol, which, based on a 70 kg body 
weight, is equivalent to 0.63 mg/kg/day 
for tafamidis meglumine 20 mg dose (1 
capsule). 
Sorbitol (E 420) is a source of fructose 
and should be taken into account when 
monitoring dietary intake of sorbitol or 
fructose. 
Potential risks of liver abnormalities 
Risk is based on observations in animal 
studies (IBi Section 7.11.1.2 - 
Hepatotoxicity). 
Study will monitor liver enzymes at 
screening and during the study: AST, 
ALT, total bilirubin, alkaline phosphatase 
(Section 10.3 - Table 5). 
Potential risks of reproductive toxicity 
(abnormalities in babies exposed to 
tafamidis during pregnancy) 
Risk is based on observations in animal 
studies (IBi Section 7.11.2.2. Reproductive 
Toxicity). 
Study will only enroll females who are 
not of child bearing potential (Section 5.1 
_Item 2). 
Other potential risk: 
The COVID-19 pandemic may pose risks 
to study participation. 
Participants may have increased risk of 
SARS-CoV-2 infection by undergoing a 
study procedure at a study facility. 
Inclusion of COVID-19 specific 
assessments according to the SoA. 
 
 
 
 
 
PFIZER CONFIDENTIAL 
 
Page 22 


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PFIZER CONFIDENTIAL 
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CCI 
2.3.2. Overall Benefit/Risk Conclusion 
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with tafamidis or study procedures are justified by the anticipated 
benefits that may be afforded to patients with ATTR-CM and/or ATTR-PN. 
 
3. OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary: 
Primary: 
• To establish the bioequivalence of 12.2 mg 
tafamidis free acid tablet (Test) and commercial 
20 mg tafamidis meglumine soft gelatin capsules 
(Reference) in fasted healthy participants. 
Secondary: 
• To estimate the relative bioavailability of a 
single dose of the 12.2 mg tafamidis free acid 
tablet administered under fed conditions 
compared to a single dose of the 12.2 mg 
tafamidis free acid tablet administered under 
fasted conditions in healthy participants. 
• AUCinf (if data permit, otherwise AUClast) and 
Cmax of tafamidis. 
 
 
Secondary: 
• Not Applicable 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN 
4.1. Overall Design 
This study will be a Phase 1, open label, randomized, 3-way crossover, single dose study to 
determine the bioequivalence of PF-06291826 (tafamidis) 12.2 mg tafamidis free acid tablets 
versus commercial 20 mg tafamidis meglumine capsules administered under fasted 
conditions and to estimate the effect of food on the 12.2 mg tafamidis free acid tablet in 
healthy participants. 
 
Screening evaluation will occur within 28 days prior to the first dose in Period 1. 
Participants will be admitted to the CRU at least 12 hours prior to dosing on Day 1 and will 
be required to stay in the CRU for 8 days in each period. A total of 22 participants will be 
enrolled to ensure a minimum of 18 completers. Participants withdrawn from the study may 
be replaced. Each period will be separated by a washout of at least 16 days between 
administration of study drug. On Day 1 of each period, participants will receive a single dose 
of one of the two tafamidis formulations according to the study schema provided in Table 2. 
Participants are to be fasted 10 hours prior to dosing (excluding fed arm) and 4 hours post- 
dosing. For the administration, the drug products will be administrated with 240 mL of 


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Protocol B3461103 
Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
Page 24 
 
 
water. Medication will be administered at approximately 8:00 AM ±2 hours on Day 1 of 
each period according to a computer-generated randomization schedule. 
 
Participants will be randomized to receive one of the treatment sequences shown in Table 2: 
 
Table 2. 
B3461103 Treatment Sequence Schema 
 
Sequence 
Period 1 
Period 2 
Period 3 (Fed) 
1 (n = 11) 
A 
B 
C 
2 (n = 11) 
B 
A 
C 
The study medications are listed in Table 3. 
 
Table 3. 
Description of Tafamidis Treatment 
 
Treatment 
Study Medication 
A 
12.2 mg tafamidis free acid tablet, fasted (Test) 
B 
Commercial 20 mg tafamidis meglumine soft gelatin capsule, fasted (Reference) 
C 
12.2 mg tafamidis free acid tablet, fed 
The 12.2 mg tafamidis free acid tablet and commercial 20 mg tafamidis meglumine capsules 
will be supplied by Pfizer Worldwide Research and Development. 
 
4.2. Scientific Rationale for Study Design 
This study was designed to characterize the BE of a 12.2 mg tafamidis free acid tablet 
compared to the commercial 20 mg tafamidis meglumine soft gelatin capsule in healthy 
participants under fasted conditions and to estimate the effect of food on the 12.2 mg 
tafamidis free acid tablet. 
 
4.2.1. Choice of Contraception/Barrier Requirements 
Tafamidis is approved for use in ATTR-PN and ATTR-CM without any contraceptive 
precautions. There is no suspicion of human teratogenicity based on the intended 
pharmacology. 
 
4.2.2. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
 
4.3. Justification for Dose 
The 12.2 mg free acid tablet contains the same API as the tafamidis meglumine 20 mg 
formulation. One tafamidis meglumine 20 mg capsule contains 12.2 mg of tafamidis free 
acid. 
 
Tafamidis meglumine 20 mg is currently available as a soft gelatin capsule approved for the 
treatment of ATTR-PN (20 mg) and ATTR-CM (4 x 20 mg). 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
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4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial. 
 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit or the last scheduled procedure shown in the SoA. 
 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. Use of a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, and race, and ethnicity. 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. 
 
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. Participants aged 18 years or older (or the minimum age of consent in accordance 
with local regulations) at screening. 
 
2. Healthy female participants of nonchildbearing potential and/or male participants 
who are overtly healthy as determined by medical evaluation including medical 
history, physical examination, and laboratory tests. 
 
Other Inclusion Criteria: 
 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
 
Medical Conditions: 
 
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing). 


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• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy). 
 
• History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, 
HBsAg, HBcAb, or HCVAb. Hepatitis B vaccination is allowed. 
 
• Hypersensitivity to any component of the formulations 
2. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case, residence, 
or travel to an area with high incidence) that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
 
Prior/Concomitant Therapy: 
 
3. Use of prescription or nonprescription drugs, dietary and herbal supplements within 
7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details). 
 
4. Current use of any prohibited concomitant medication(s) or participant 
unwilling/unable to use a permitted concomitant medication(s). Refer to Section 6.9 
Prior and Concomitant Therapy. 
 
Prior/Concurrent Clinical Study Experience: 
 
5. Previous administration with an investigational product (drug or vaccine) within 6 
months (or as determined by the local requirement) or 5 half-lives preceding the first 
dose of study intervention used in this study (whichever is longer). 
 
Diagnostic Assessments: 
 
6. A positive urine drug test. 
 
7. Screening seated BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of seated rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility. 
 
8. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
Page 27 
 
 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice 
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant. 
 
9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
 
• AST or ALT level ≥ 1.5 × ULN; 
• Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ ULN. 
 
Other Exclusion Criteria: 
 
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine). 
 
11. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
 
12. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
 
13. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
 
14. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
 
15. Use of tobacco or nicotine-containing products in excess of the equivalent of 5 
cigarettes per day. 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
Page 28 
 
 
5.3. Lifestyle Considerations 
The following guidelines are provided: 
 
5.3.1. Meals and Dietary Restrictions 
• Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample (Treatments A and B). 
 
• Water is permitted until 1 hour prior to study intervention administration. For 
investigational product administered in the fed state (Treatment C), water may be 
allowed with breakfast prior to the dose. 
 
• Water may be consumed without restriction beginning 1 hour after dosing. 
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices—see 
below) may be consumed with meals and the evening snack. 
 
• If participants are assigned to a fed condition study period, they will be given a high- 
fat, high-calorie breakfast on Day 1 of that period, and a standardized breakfast on all 
other days of that period. A Food and Drug Administration (FDA) recommended 
breakfast of a high-fat (approximately 50% of total caloric content of the meal), high 
calorie (approximately 800-1000 calories) meal will be given on Day 1. A 
representative example of a high-fat, high-calorie meal would be: 2 eggs fried in 
butter, 2 strips of bacon, 2 slices of toast with butter, 100 g of hash brown potatoes, 
8 fluid ounce (240 mL) of whole milk (ie, approximately 150 protein calories, 
250 carbohydrate calories, 500-600 fat calories). 
 
• Lunch will be provided approximately 4 hours after dosing. 
• Dinner will be provided approximately 9 to 10 hours after dosing. 
• An evening snack may be permitted. 
• Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample. 
 
• Except during the fed condition, while participants are confined, their total daily 
nutritional composition should be approximately 55% carbohydrate, 30% fat, and 
15% protein. The daily caloric intake per participant should not exceed approximately 
3200 kcal. 


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PFIZER CONFIDENTIAL 
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5.3.2. Caffeine, Alcohol, and Tobacco 
• Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 
 
•  Participants will abstain from alcohol for 24 hours prior (or as specified above for 
red wine) to admission to the CRU and continue abstaining from alcohol until 
collection of the final PK sample of each study period. Participants may undergo an 
alcohol breath test or blood alcohol test at the discretion of the investigator. 
 
• Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU. 
 
5.3.3. Activity 
• Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted; 
 
• In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing; 
 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. Screen failure data are collected and remain as 
source and are not reported on the CRF. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational and medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct. 
 
For the purposes of this protocol, study intervention refers to 12.2 mg tafamidis free acid 
tablets and commercial 20 mg tafamidis meglumine capsules. 
 
6.1. Study Intervention(s) Administered 
Eligible participants who continue to meet entry criteria will be admitted to the CRU on 
Day -1 and will be required to stay in the CRU for 8 overnight stays in each period. All 
participants will be discharged from the CRU following completion of the discharge 
evaluation, which includes adverse event monitoring, physical examination (at investigator 
discretion), vital signs, ECG measurements, and safety laboratory tests. 


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Final Protocol, 19 May 2022 
 
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Page 30 
 
 
 
Study Intervention(s) 
Intervention Name 
Tafamidis free acid tablet 
(fasted) 
Tafamidis meglumine soft 
gelatin capsule (fasted) 
Tafamidis free acid tablet 
(fed) 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
Treatment A 
Treatment B 
Treatment C 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Tablets 
Softgel capsules 
Tablets 
Unit Dose Strength(s) 
12.2 mg 
20 mg 
12.2 mg 
Dosage Level(s) 
1 x tablet 
1 x capsule 
1 x tablet 
Route of Administration 
Oral 
Oral 
Oral 
Use 
Experimental 
Experimental 
Experimental 
IMP or NIMP/AxMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by the 
sponsor 
Refer to the IPM 
Provided centrally by the 
sponsor 
Refer to the IPM 
Provided centrally by the 
sponsor 
Refer to the IPM 
Packaging and Labeling 
Study intervention will be 
provided in bottles. Each 
bottle will be labeled as 
required per country 
requirement. 
The product will be 
provided as open supplies. 
Study intervention will be 
provided in bottles. Each 
bottle will be labeled as 
required per country 
requirement. 
The product will be 
provided as open supplies. 
Study intervention will be 
provided in bottles. Each 
bottle will be labeled as 
required per country 
requirement. 
The product will be 
provided as open supplies. 
Current/Former Name(s) 
or Alias(es) 
PF-06291826 
PF-06291826 / 
Vyndaqel® 
PF-06291826 
 
 
Study Arm(s) 
Arm Title 
Treatment A 
Treatment B 
Treatment C 
Arm Type 
Test - fasted 
Reference - fasted 
Test - fed 
Arm Description 
Participants will receive 
a single 12.2 mg 
Participants will receive 
a single commercial 20 
Participants will receive 
a single 12.2 mg 


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Final Protocol, 19 May 2022 
 
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Study Arm(s) 
tafamidis free acid 
tablet, fasted 
mg tafamidis 
meglumine capsule 
tafamidis free acid 
tablet, fed 
Associated 
Intervention Labels 
Tafamidis 12.2 mg 
tablets 
Tafamidis meglumine 
20 mg capsules 
Tafamidis 12.2 mg 
tablets 
 
 
Study interventions will be supplied by Pfizer as tafamidis 12.2 mg tablets and tafamidis 
meglumine 20 mg soft gelatin capsules. 
 
Pivotal BE study tablets and capsules will be supplied to the CRU in multidose labeled 
bottles (in sufficient number to allow unopened containers to be kept as retains). 
 
6.1.1. Administration 
On Day 1 of each period each participant will receive either tafamidis 12.2 mg tablet under 
fasting (Treatment A) or fed (Treatment C) conditions or tafamidis meglumine 20 mg soft 
gelatin capsule (Treatment B) under fasting conditions. 
 
Following an overnight fast of at least 10 hours, participants will receive study intervention 
at approximately 0800 hours (plus or minus 2 hours). Participants being administered the 
investigational product in the fed state should start a high-fat/high-calorie breakfast (as per 
the description in Section 5.3.1) approximately 30 minutes prior to administration of the 
treatment. The breakfast will be consumed over approximately 25 minutes and 
investigational product administered within approximately 5 minutes after completion of the 
meal. Investigator site personnel will administer study intervention during each period with 
ambient temperature water to a total volume of approximately 240 mL. Participants will 
swallow the study intervention whole, and will not manipulate or chew the study intervention 
prior to swallowing. 
 
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing. 
 
6.2. Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
 
3. 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 


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Final Protocol, 19 May 2022 
 
PFIZER CONFIDENTIAL 
Page 32 
 
 
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 temperatures since previously documented upon 
return to business. 
 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to the labeled storage conditions, 
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. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the IPM. 
 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
 
6. Study interventions should be stored in their original containers. 
 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. 
 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. 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. 
 
9. All pivotal BA/BE retains should be stored by the investigator site or with a third 
party vendor. Sample retention is the responsibility of the entity performing the 
BA/BE study. 
 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM. 
 
6.2.1. Preparation and Dispensing 
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities. 


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Tablets and capsules will be prepared at the CRU in the individual dosing containers by 
2 operators, 1 of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The tablets and capsules will be provided in unit dose 
containers and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements. 
 
6.3. Assignment to Study Intervention 
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number. 
 
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. 
 
6.4. Blinding 
This is an open-label study. 
 
6.4.1. Blinding of Participants 
Participants will be unblinded to their assigned study intervention. 
 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. 
 
6.4.3. Blinding of the Sponsor 
Sponsor staff will be unblinded to participants’ assigned study intervention. 
 
6.5. Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the CRF. The dose of study intervention 
and study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study intervention. Study site 
personnel will examine each participant’s mouth to ensure that the study intervention was 
ingested. 
 
6.6. Dose Modification 
As this is a single-dose study, no dose modification is permitted. 
 
6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 


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6.8. Treatment of Overdose 
For this study, any dose of PF-06291826 greater than 20 mg tafamidis meglumine or 12.2 mg 
tafamidis free acid within a 24-hour time period will be considered an overdose. 
 
There is no specific treatment for an overdose. 
 
In the event of an overdose, the investigator should: 
 
1. Contact the study medical monitor within 24 hours. 
 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
 
5. Obtain a blood sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a case- 
by-case basis). 
 
6.9. Prior and Concomitant Therapy 
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day. 
 
Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. 
 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit. 
 
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
Since this is a single-dose study, this section is not applicable. 
 
7.1.1. ECG Changes 
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE. 
 
7.1.2. COVID-19 
If a participant is diagnosed with COVID-19 during the study, it should be reported as an AE 
or SAE (as appropriate) and appropriate medical intervention should be provided. 
 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: 
 
• Refused further follow-up 
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
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. 
 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
 
If a participant withdraws from the study, they 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 will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 


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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention 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 them 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 follow-up, 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 
follow-up, 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 Follow-up 
A participant will be considered lost to follow-up if the participant 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 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; 
• Should the participant continue to be unreachable, the participant will be 
considered to have withdrawn from the study. 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Administrative and Baseline 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. 
 
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 


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record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria. 
 
A participant who qualified for this protocol but did not enroll from an earlier cohort/group 
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate. 
 
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 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 they have 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. 
 
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter. 
 
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 
228 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 550 mL during any period of 56 consecutive 
days. 
 
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Prior and Concomitant Therapy sections of the protocol. 
 
8.2. Efficacy Assessments 
Analysis of efficacy is not applicable to this study. 


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8.3. 5. COVID-19 Specific Assessments 
Participants will be tested for COVID-19 infection per local site procedures prior to being 
admitted to the clinic for confinement and a subsequent COVID-19 test will be performed 
after 4 days (ie, upon completion of 4 × 24 hours in house), or if they develop COVID- 
19-like symptoms. Additional testing may be required by local regulations or by the PI. 
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• 
 
 
 
 
 
8.5. Pharmacokinetics 
8.5.1. Plasma for Analysis of Tafamidis 
Blood samples of approximately 4 mL, to provide approximately 1.5 mL, will be collected 
for measurement of plasma concentrations of tafamidis as specified in the SoA. 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. 
 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF/DCT. Collection of samples more than 10 hours after dose 
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF/DCT. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows. 
 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained. 
 
Samples collected for measurement of plasma concentrations of tafamidis will be analyzed 
using a validated analytical method in compliance with applicable SOPs. 
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The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK 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. 
 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
CCI 
 
 
 
 
 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.7.1. Specified Gene Expression (RNA) Research 
Specified gene expression (RNA) research is not included in this study. 
 
8.7.2. Specified Protein Research 
Specified protein research is not included in this study. 
 
8.7.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
 
8.8. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
 
8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 


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9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the 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. Statistical Hypotheses 
The alternative hypothesis of bioequivalence (H1: qL ≤ mT - mR ≤ qU), and the null 
hypothesis of inequivalence (Ho: mT - mR < qL or mT - mR > qU) can be expressed as the 
following 2 separate one-sided hypotheses: 
 
HoA: mT - mR < qL 
H1A: qL ≤ mT - mR 
HoB: mT - mR > qU 
H1B: mT - mR ≤ qU 
where mT and mR represent the average bioavailability on a log scale for the Test and 
Reference products respectively and [qL, qU] defines the bioequivalence range. 
 
Bioequivalence of the Test treatment to Reference treatment will be concluded if the 90% 
confidence intervals for the ratios of adjusted geometric means for tafamidis AUCinf (if data 
permit, otherwise AUClast) and Cmax fall entirely within the acceptance region of (80%, 
125%). 
 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis 
Set 
Description 
Enrolled 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization/assignment to study intervention. A participant 
will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after 
screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 


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Description 
Participant Analysis 
Set 
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CCI 
 
 
 
Full analysis set 
 
Example: All participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention. 
 
 
 
 
 
PK Concentration 
The PK concentration population is defined as all participants 
who receive at least 1 dose of tafamidis and who have at least 1 
measurable concentration of tafamidis. 
 
 
 
 
 
 
 
9.3. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe 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. 
9.3.1. Pharmacokinetic Analyses 
9.3.1.1. Derivation of Pharmacokinetic Parameters 
Plasma PK parameters for tafamidis will be derived (as data permit) from the concentration- 
time data using standard noncompartmental methods as outlined in Table 4. Actual PK 
sampling times will be used in the derivation of PK parameters. In the case that actual PK 
sampling times are not available, nominal PK sampling time will be used in the derivation of 
PK parameters. 
 
Table 4. 
Plasma Tafamidis Pharmacokinetic Parameters Definitions 
 
Parameter 
Definition 
Method of Determination 
AUClast 
Area under the concentration-time 
curve from 0 to time of last 
measurable concentration 
Linear/Log trapezoidal method 
* 
AUCinf 
Area under the concentration-time 
curve from time 0 to infinity 
AUC(0-tlast) + (Clast*/kel), 
where Clast* is the estimated plasma 
concentration at the last quantifiable 
time point (Clast) estimated from the 
log-linear regression analysis 
Clast* = Clast x e(-KEL x Tlast) 
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Parameter 
Definition 
Method of Determination 
Cmax 
CCI 
Maximum observed concentration 
Observed directly from data 
CCI 
 
Table 4. 
Plasma Tafamidis Pharmacokinetic Parameters Definitions 
 
*if data permit 
 
 
9.3.2 Statistical Methods for PK Data 
 
For assessment of the bioequivalence objective of the study (Periods 1 and 2), natural log 
transformed AUCinf, AUClast, CCI  and Cmax will be analyzed separately using a mixed 
effect model with sequence, period and treatment as fixed effects and participant within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment A (12.2 mg tafamidis free acid tablet) will be 
the Test treatment, while Treatment B (commercial 20 mg tafamidis meglumine softgel 
capsule) will be the Reference treatment. 
 
Bioequivalence of between the 2 formulations will be concluded if the 90% confidence 
intervals for the ratio of adjusted geometric means for both AUCinf (if data permit, otherwise 
AUClast) and Cmax fall wholly within (80%, 125%). 
 
For assessment of the food effect objective of the study (where treatment comparison occurs 
via fixed-sequence), natural log transformed AUCinf, AUClast, CCI  and Cmax will be 
analyzed separately using a mixed effect model with treatment as fixed effects and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment C (12.2 mg tafamidis free acid tablet, fed) will 
be the Test treatment, while Treatment A (12.2 mg tafamidis free acid tablet, fasted) will be 
the Reference treatment. 


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The plasma concentrations for tafamidis will be listed and summarized descriptively by 
nominal PK sampling time and treatment. Individual participant as well as mean and median 
profiles of the plasma concentration time data will be plotted by treatment using actual (for 
individual) and nominal (for mean and median) times respectively. Mean and median profiles 
will be presented on both linear and semi-log scales. 
 
For summary statistics and median plots by sampling time, the nominal PK sampling time 
will be used. For individual participant plots by time, the actual PK sampling time will be 
used. 
 
Additional specifications about the tables, listings, and figures will be outlined in the SAP. 
 
9.3.2. Safety Analyses 
All safety analyses will be performed on the safety population. 
 
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
 
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study, will be considered source data and will 
not be required to be reported, unless otherwise noted. However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted. Demographic data collected at screening will be reported. 
CCI 
 
 
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9.4. Interim Analyses 
No interim analysis will be conducted for this study. As this is an open-label study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment and/or supporting clinical development. 
 
9.5. Sample Size Determination 
The sample size of 22 participants (11 participants per sequence in the fasted arms) to ensure 
a minimum of 18 PK evaluable participants for this 3-way crossover will provide 97% power 
that the 90% confidence interval for the ratio of Test to Reference for AUCinf will lie within 
the acceptance region of (80%, 125%) and 89% power that 90% confidence interval for the 
ratio of Test to Reference treatment for Cmax will lie within the acceptance region of (80%, 
125%). Consequently, this study has approximately 86% power overall to demonstrate 
bioequivalence of the Test treatment to the Reference treatment [ie, equivalence in both 
AUCinf and Cmax]. This estimate is based on the assumption that the true ratio between Test 
and Reference treatments for both AUCinf and Cmax is 0.9. 
The power calculations assumed the estimates of within participant standard deviations of 
0.098 and 0.119 for loge AUCinf and loge Cmax, respectively, obtained as an average from 
studies B3461030, B3461044 and B3461095. 


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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 CIOMS International Ethical Guidelines; 
 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, 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. 
 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, 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 study 
intervention, 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 the ICH GCP guidelines that the investigator 
becomes aware of. 
 
10.1.2. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant should be given sufficient time and opportunity to ask questions and to 
decide whether or not to participate in the trial. 
 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center. 
 
The investigator must ensure that each participant 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 their 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 their 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 is fully informed about their 
right to access and correct their personal data and to withdraw consent for the processing of 
their 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 on which 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 IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulations. 
 
A copy of the ICD(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICD. 


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10.1.3. 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 and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will 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 participants 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 their actual identity and medical record ID. 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. 
 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
 
10.1.4. Committees Structure 
Not applicable. 
 
10.1.4.1. Data Monitoring Committee 
This study will not use an E-DMC. 
 
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 EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its 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. 


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www.clinicaltrials.gov 
 
Pfizer posts clinical trial 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. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
 
EudraCT/CTIS 
 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
 
www.pfizer.com 
 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
 
Documents within marketing applications 
 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
 
Data sharing 
 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized. 
 
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. 
 
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. 


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Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room 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, including definition of study-critical data items and 
processes (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, virtual, or on-site monitoring), are provided in the data management plan [and 
monitoring plan] maintained and utilized by the sponsor or designee. 
 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
 
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 
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. 


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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 eCRF that are 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 and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor. 
 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The sponsor or designee will perform monitoring 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 guidelines, and all applicable regulatory requirements. 
 
10.1.8. Study and Site Start and 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, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. 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 CRO if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants. 


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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 the 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) 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 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer 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-intervention or 
Pfizer-related information necessary for the appropriate scientific presentation or 
understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication. 


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For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
 
10.1.10. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the CTMS. 
 
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol and 
study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number. 
 
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence 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 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, 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 
abnormal laboratory 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 drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition. 
• New condition detected or diagnosed after study intervention administration, 
even though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 


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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’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 
participant’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (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 start 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 term “life-threatening” in the definition of “serious” refers to an event in which 
the participant 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 participant 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 occur during hospitalization are 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 
necessary, 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. 


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d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f. Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize 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 
drug dependency or drug abuse. 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious 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 the 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 or 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 or 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 EDP or EDB 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)** 
Environmental or 
None. Exposure to a study 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported*** 
occupational exposure 
non-participant is not 
to the product under 
collected on the CRF 
study to a 
nonparticipant (not 
involving EDP or EDB) 


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• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant 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 information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
• Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL. 
• Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
• Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
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 occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine 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 ruled 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 information, for 
marketed products, in their assessment. 
• For each AE or SAE, the investigator must document in the medical notes that 
they have reviewed the AE or SAE and have provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information 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 their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
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 purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements. 
 
 
Follow-Up of AEs and SAEs 
• The investigator is obligated to perform or arrange 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 laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology. 


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• New or updated information 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 information. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames. 


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criterion below is part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. 
 
A female participant is eligible to participate if she is not pregnant or breastfeeding and the 
following condition applies: 
 
• Is not a WOCBP 
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. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up 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 DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.” 
 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili 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 T bili 
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 T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili 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 T bili 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 T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller). 
 
Rises in AST/ALT and T bili 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. 


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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 T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/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/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or 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, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the 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: Kidney Safety: Monitoring Guidelines 
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine Scr-based eGFR or eCrCl). Baseline and postbaseline serum Scys makes it feasible 
to distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after 
baseline, then reflex measurement of Scys is indicated to estimate the combined Scr-Scys 
eGFR calculation (for adults only). 
 
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care. 
 
10.7.2. Age-Specific Kidney Function Calculation Recommendations 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations 
 
2021 CKD- 
EPI 
Scr Only 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age 
Female 
if > 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age 
Male 
if ≤ 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age 
Male 
if > 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age 
2021 CKD- 
EPI 
Scr-Scys 
Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤ 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age 
Female 
if > 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if > 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤ 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤ 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if > 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if > 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Inker LA et al. N Engl J Med. 2021;385:1737-49. 
 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria. 


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10.8. Appendix 8: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 ms. 
• New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms 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 block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 ms. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset LBBB (QRS complex>120 ms). 
• New-onset right bundle branch block (QRS complex>120 ms). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 
• In awake, symptom-free participants 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 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 
• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR 
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 


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Page 75 
 
 
 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>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. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory 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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10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI 
Not applicable to this study. 


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10.10. Appendix 10: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
A1 to A3 
albuminuria (KDIGO albuminuria severity standardization) 
Abs 
absolute 
ADL 
activity/activities of daily living 
AE 
adverse event 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATTR-CM 
transthyretin cardiomyopathy 
ATTR-PN 
transthyretin polyneuropathy 
AUC 
area under the concentration-time curve 
AUC72 
area under the concentration-time curve from time 0 to 72 hours 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUClast 
area under the concentration-time curve from 0 to time of last 
measurable concentration 
AUMCinf 
area under the first moment curve from zero time to infinity 
AV 
atrioventricular 
AxMP 
auxiliary medicinal product 
β-hCG 
β-human chorionic gonadotropin 
BA 
bioavailability 
BBS 
Biospecimen Banking System 
BE 
bioequivalence 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
Cmax 
maximum observed concentration 
CMC 
Chemistry, Manufacturing and Controls 
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 


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Abbreviation 
Term 
CTMS 
clinical trial management system 
CTIS 
Clinical Trial Information System 
CV 
cardiovascular 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram or electrocardiography 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clincal Trials 
(European Clinical Trials Database) 
FDA 
US Food and Drug Administration 
FIH 
First-in-human 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
G1 to G5 
Grade (KDIGO eGFR category standardization) 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCVAb 
hepatitis C antibody 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ID 
identification 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPAL 
Investigational Product Accountability Log 
IPM 
investigational product manual 
IRB 
Institutional Review Board 


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Abbreviation 
Term 
IV 
intravenous(ly) 
KDIGO 
Kidney Disease Improving Global Outcomes 
kel 
first-order elimination rate constant 
LBBB 
left bundle branch block 
LDL 
low-density lipoprotein 
LFT 
liver function test 
loge 
natural logarithm 
MQI 
medically qualified individual 
CCI 
N/A 
Not Applicable 
NIMP 
noninvestigational medicinal product 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
PVC 
premature ventricular contraction 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
qual 
qualitative 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
single-reference safety document 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
CCI 
T bili 
total bilirubin 
THC 
tetrahydrocannabinol 
CCI 
ULN 
upper limit of normal 
US 
United States 
UTI 
urinary tract infection 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 


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11. REFERENCES 
 
 
 
i Investigator’s Brochure, B346 (PF-06291826) 19 Mar 2021 

SAP_001.pdf: 
Protocol B3461103 (PF-06291826) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 of 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol B3461103 
 
 
 
A Phase 1, Open-Label, Randomized, Crossover, Single Dose Study to Determine the 
Bioequivalence of 12.2 mg Tafamidis Free Acid Tablets and Commercial 20 mg Tafamidis 
Meglumine Capsules Administered Under Fasted Conditions and the Effect of Food on 
Oral Bioavailability of 12.2 mg Tafamidis Free Acid Tablets in Healthy Adult Participants 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
Version: 
1 
Date: 
07 Jul 2022 


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TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................3 
APPENDICES ............................................................................................................................3 
1. VERSION HISTORY ............................................................................................................4 
2. INTRODUCTION ..................................................................................................................4 
2.1. Modifications to the Analysis Plan Described in the Protocol ..................................4 
2.2. Study Objectives and Endpoints ................................................................................5 
2.3. Study Design..............................................................................................................5 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ...................................................................................................................6 
3.1. Primary Endpoints .....................................................................................................6 
3.2. Secondary Endpoint ...................................................................................................6 
CCI 
 
3.4. Baseline Variables .....................................................................................................7 
3.5. Safety Endpoints ........................................................................................................7 
3.5.1. Adverse Events .............................................................................................8 
3.5.2. Laboratory Data ............................................................................................8 
3.5.3. Vital Signs .....................................................................................................8 
3.5.4. Electrocardiograms ........................................................................................8 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .....................................................8 
5. GENERAL METHODOLOGY AND CONVENTIONS ......................................................9 
5.1. Hypotheses and Decision Rules ................................................................................9 
5.2. General Methods ......................................................................................................10 
5.2.1. Analyses for Binary/Categorical Endpoints ................................................10 
5.2.2. Analyses for Continuous Endpoints ............................................................10 
5.3. Methods to Manage Missing Data ...........................................................................10 
5.3.1. Pharmacokinetic Data .................................................................................10 
5.3.2. Safety Data ..................................................................................................11 
6. ANALYSES AND SUMMARIES .......................................................................................11 
6.1. Primary Endpoints ...................................................................................................11 
CCI 
 
 


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CCI 
 
6.3. Subset Analyses ....................................................................................................... 13 
6.4. Baseline and Other Summaries and Analyses .......................................................... 13 
6.4.1. Demographic Summaries ............................................................................ 13 
6.4.2. Study Conduct and Participant Disposition ................................................ 14 
6.4.3. Study Treatment Exposure .......................................................................... 14 
6.4.4. Concomitant Medications and Nondrug Treatments .................................. 14 
6.5. Safety Summaries and Analyses .............................................................................. 14 
6.5.1. Adverse Events ........................................................................................... 14 
6.5.2. Laboratory Data .......................................................................................... 14 
6.5.3. Vital Signs ................................................................................................... 14 
6.5.4. Electrocardiograms ...................................................................................... 14 
7. INTERIM ANALYSES ....................................................................................................... 14 
APPENDICES .......................................................................................................................... 15 
LIST OF TABLES 
Table 1. 
Summary of Changes .................................................................................. 4 
Table 2. 
B3461103 Treatment Sequence Schema ..................................................... 6 
CCI  
 
 
 
APPENDICES 
Appendix 1. SAS Code for Analyses ....................................................................................... 15 
Appendix 2. List of Abbreviations ........................................................................................... 16 


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NOTE: Italicized text within this document has been taken verbatim from the Protocol. 
 
1. VERSION HISTORY 
 
Table 1. 
Summary of Changes 
 
Version/ 
Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
1 
07 Jul 2022 
Original 
19 May 2022 
N/A 
N/A 
 
2. INTRODUCTION 
A 12.2 milligram (mg) tafamidis free acid tablet is being developed to replace the current 
commercial 20 mg tafamidis meglumine dosage formulation. 
 
The purpose of the study is to determine if a 12.2 mg tafamidis free acid tablet (Test) 
formulation is bioequivalent to the commercial 20 mg tafamidis meglumine soft gelatin 
capsule (Reference) and to estimate the effect of food on the bioavailability of the 12.2 mg 
tafamidis free acid tablet. 
 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B3461103. 
 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 


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2.2. Study Objectives and Endpoints 
 
 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• To establish the bioequivalence of 12.2 
mg tafamidis free acid tablet (Test) and 
commercial 20 mg tafamidis meglumine 
soft gelatin capsules (Reference) in 
fasted healthy participants. 
• AUCinf (if data permit, otherwise AUClast) 
and Cmax of tafamidis. 
Secondary: 
Secondary: 
• To estimate the relative bioavailability of 
a single dose of the 12.2 mg tafamidis 
free acid tablet administered under fed 
conditions compared to a single dose of 
the 12.2 mg tafamidis free acid tablet 
administered under fasted conditions in 
healthy participants. 
• Not Applicable 
CCI 
 
 
 
 
 
 
2.3. Study Design 
This study will be a Phase 1, open label, randomized, 3-way crossover, single dose study to 
determine the bioequivalence of PF-06291826 (tafamidis) 12.2 mg tafamidis free acid tablets 
versus commercial 20 mg tafamidis meglumine capsules administered under fasted 
conditions and to estimate the effect of food on the 12.2 mg tafamidis free acid tablet in 
healthy participants. 


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A total of 22 participants will be enrolled to ensure a minimum of 18 completers. 
Participants withdrawn from the study may be replaced. Each period will be separated by a 
washout of at least 16 days between administration of study drug. Participants will be 
randomized to receive one of the treatment sequences shown in Table 2: 
 
Table 2. 
B3461103 Treatment Sequence Schema 
 
Sequence 
Period 1 
Period 2 
Period 3 
1 (n=11) 
A 
B 
C 
2 (n=11) 
B 
A 
C 
A: 12.2 mg tafamidis free acid tablet, fasted (Test) 
B: Commercial 20 mg tafamidis meglumine soft gelatin capsule, fasted (Reference) 
C: 12.2 mg tafamidis free acid tablet, fed (Test) 
 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
The primary endpoints are plasma AUCinf (if data permit, otherwise AUClast) and Cmax of 
tafamidis administered as 12.2 mg tafamidis free acid tablet and commercial 20 mg tafamidis 
meglumine soft gelatin capsules, under fasted conditions. Adjusted geometric mean ratios of 
AUCinf, AUClast and Cmax will be derived to establish bioequivalence. 
In addition, adjusted geometric mean ratios of AUCinf, AUClast and Cmax of tafamidis 
administered as 12.2 mg tafamidis free acid tablet under fed conditions, relative to PK 
prameters under fasted conditions will be derived to estimate the relative bioavailability. 
 
3.2. Secondary Endpoint 
Not applicable. 
CCI 
 
 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*If data permit. 
 
 
Safety and tolerability data will also be evaluated and are discussed in Section 3.5. 
 
3.4. Baseline Variables 
Baseline characteristics will be collected according to the schedule of activities (SoA) as 
specified in the protocol. 
 
3.5. Safety Endpoints 
The following data are considered in standard safety summaries (see protocol for collection 
days, baseline assessment, and list of parameters): 
 
• adverse events (AE) 


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• laboratory data 
• vital signs data 
• ECG results 
3.5.1. Adverse Events 
Any adverse events occurring following start of treatment will be considered as treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 28 days after the last tafamidis dose will be counted as treatment emergent and 
attributed to the last treatment taken. Events that occur during the washout period (up to 28 
days from the last treatment) between study periods will be counted as treatment emergent 
and attributed to the previous treatment taken. The time period for collecting AEs (“active 
collection period”) for each participant begins from the time the participant provides 
informed consent. 
 
3.5.2. Laboratory Data 
Safety laboratory tests will be performed as described in the protocol. To determine if there 
are any clinically significant laboratory abnormalities, the haematological, clinical chemistry 
(serum) and urinalysis safety tests will be assessed against the criteria specified in the 
sponsor reporting standards. The assessment will not take into account whether each 
participants’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter. 
 
For each period, the baseline measurement is the predose measurement on Day -1. 
 
3.5.3. Vital Signs 
Seated blood pressure (BP), pulse rate (PR), and temperature will be measured at times 
specified in the SoA given in the protocol. 
 
The baseline measurement is the predose measurement on Day 1 Period 1. 
 
3.5.4. Electrocardiograms 
QT interval, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time 
indicated in the SoA given in the protocol. QTcF will be derived using Fridericia’s heart rate 
correction formula: 
 
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided) 
The baseline measurement is the predose measurement on Day 1 Period 1. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures. 


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Participant Analysis Set 
Enrolled 
 
 
 
 
 
 
 
 
 
Full analysis set 
Safety analysis set 
 
 
PK Concentration 
Description 
“Enrolled” means a participant’s, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization/assignment to study intervention. A participant 
will be considered enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after 
screening. Potential participants who are screened for the 
purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled, unless 
otherwise specified by the protocol. 
 
Example: All participants randomly assigned to study 
intervention and who take at least 1 dose of study intervention. 
 
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received. 
 
The PK concentration population is defined as all participants 
who receive at least 1 dose of tafamidis and who have at least 
1 measurable concentration of tafamidis. 
 
 
 
 
 
 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
Final analysis will be performed after study participant data set release following last 
participant last visit. 
 
5.1. Hypotheses and Decision Rules 
The alternative hypothesis of bioequivalence (H1: qL ≤ mT - mR ≤ qU), and the null 
hypothesis of inequivalence (Ho: mT - mR < qL or mT - mR > qU) can be expressed as the 
following 2 separate one-sided hypotheses: 
 
HoA: mT - mR < qL 
H1A: qL ≤ mT - mR 
HoB: mT - mR > qU 
H1B: mT - mR ≤ qU 
CCI 


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where mT and mR represent the average bioavailability on a log scale for the Test and 
Reference products respectively and [qL, qU] defines the bioequivalence range. 
 
Bioequivalence of the Test treatment to Reference treatment will be concluded if the 90% 
confidence intervals for the ratios of adjusted geometric means for tafamidis AUCinf (if data 
permit, otherwise AUClast) and Cmax fall entirely within the acceptance region of (80%, 
125%). 
 
5.2. General Methods 
5.2.1. Analyses for Binary/Categorical Endpoints 
For binary or categorical variables, number of participants, numbers and percentages of 
participants meeting the categorical criteria will be presented in accordance with the Clinical 
Data Interchange Standards Consortium and Pfizer Standards (CaPS). 
 
5.2.2. Analyses for Continuous Endpoints 
For continuous variables, the data will be summarized using the number of participants, 
mean, median, standard deviation (SD), minimum, and maximum in accordance with the 
CaPS. For appropriate PK parameters, geometric mean and geometric coefficient of variation 
(%CV) will also be summarized. 
 
5.3. Methods to Manage Missing Data 
5.3.1. Pharmacokinetic Data 
Methods to handle missing PK data are described below. 
 
Concentrations Below the Limit of Quantification: 
 
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.). 
 
Deviations, Missing Concentrations and Anomalous Values: 
 
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true: 
 
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample). 
 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist. 
 
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing. 
 
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 


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CCI 
participants. For example, a BLQ concentration that is between quantifiable values from the 
same dose is considered as anomalous. Anomalous concentration values may be excluded 
from PK analysis at the discretion of the PK analyst. 
 
PK Parameters: 
 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(ie, not calculated). (Note that NC values will not be generated beyond the day that a 
participant discontinues). 
 
In summary tables, statistics will not be presented for a particular treatment group if more 
than 50% of the data are NC. For statistical analyses, PK parameters coded as NC will also 
be set to missing. 
 
5.3.2. Safety Data 
Missing values in standard summaries of AEs, laboratory data, vital signs, and ECGs will be 
imputed according to CaPS. 
 
6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
For assessment of the bioequivalence objective of the study (Periods 1 and 2), natural log 
transformed AUCinf, AUClast, AUC72 and Cmax will be analyzed separately using a mixed 
effect model with sequence, period and treatment as fixed effects and participant within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment A (12.2 mg tafamidis free acid tablet) will be 
the Test treatment, while Treatment B (commercial 20 mg tafamidis meglumine softgel 
capsule) will be the Reference treatment. 


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Bioequivalence of the 2 formulations will be concluded if the 90% confidence intervals for 
the ratio of adjusted geometric means for both AUCinf (if data permit, otherwise AUClast) and 
Cmax fall wholly within (80%, 125%). 
 
For assessment of the food effect objective of the study (where treatment comparison occurs 
via fixed-sequence), natural log transformed AUCinf, AUClast, AUC72 and Cmax will be 
analyzed separately using a mixed effect model with treatment as fixed effects and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. Treatment C (12.2 mg tafamidis free acid tablet, fed) will 
be the Test treatment, while Treatment A (12.2 mg tafamidis free acid tablet, fasted) will be 
the Reference treatment. 
 
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be given in the report of the study. 
CCI 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
6.3. Subset Analyses 
There are no planned subset analyses. 
 
6.4. Baseline and Other Summaries and Analyses 
6.4.1. Demographic Summaries 
Demographic characteristics (age, gender, ethnicity, race, weight, height and body mass 
index) will be summarized for enrolled population in accordance with the CaPS. 
CCI 


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6.4.2. Study Conduct and Participant Disposition 
Participants evaluation groups will show end of study participant disposition. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. Data will be reported 
in accordance with the CaPS. 
 
6.4.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
 
6.4.4. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings. 
CCI 
 
 
 
 
6.5.1. Adverse Events 
Adverse events will be reported in accordance with the CaPS. 
 
Participant discontinuations due to adverse events will be detailed by treatment. Data will be 
reported in accordance with the CaPS. 
 
6.5.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the CaPS. 
 
6.5.3. Vital Signs 
Vital sign data will be databased and available upon request. 
 
6.5.4. Electrocardiograms 
ECG data will be databased and available upon request. 
 
7. INTERIM ANALYSES 
No formal interim analysis will be conducted for this study. As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating PK modeling, and/or supporting clinical 
development. 
 
Final analysis will follow the official database release. As this will be an open-label study, 
there is no formal unblinding of the randomization code. 


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APPENDICES 
Appendix 1. SAS Code for Analyses 
 
An example of the PROC MIXED code is provided below: 
 
For primary objective: Treatment A (Test) vs Treatment B (Reference) 
 
proc mixed data=tab.pk; 
where trt in (“A”, “B”); 
class seq period trt participant; 
model l&var=seq period trt/ ddfm=KR; 
random participant(seq) /participant=participant(seq); 
lsmeans trt; 
estimate 'A vs B' trt 1 -1 /cl alpha=0.1; 
 
 
 
 
 
run; 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
 
/* Letter assignments for treatments (trt) within the estimate statement above are as follows 
A: 12.2 mg tafamidis free acid tablet, fasted (Test) 
B: Commercial 20 mg tafamidis meglumine soft gelatin capsule, fasted (Reference) 
*/ 
 
For secondary objective: Treatment C (Test) vs Treatment A (Reference) 
 
proc mixed data=tab.pk; 
where trt in (“A”, “C”); 
class trt participant; 
model l&var=trt / ddfm=KR; 
random participant / subject=participant; 
lsmeans trt; 
estimate 'C vs A' trt -1 1 /cl alpha=0.1; 
 
ods 'Estimates' out=est&var; 
ods 'lsmeans' out=ls&var; 
ods 'covparms' out=cov&var; 
ods 'tests3' out=tst&var; 
run; 
 
/* Letter assignments for treatments (trt) within the estimate statement above are as follows; 
A: 12.2 mg tafamidis free acid tablet, fasted (Reference) 
C: 12.2 mg tafamidis free acid tablet, fed (Test) 
*/ 


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Appendix 2. List of Abbreviations 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
CCI 
AUCinf 
area under the concentration-time curve from time 0 to infinity 
AUClast 
area under the concentration-time curve from 0 to time of last 
measurable concentration 
AUMCinf 
area under the first moment curve from zero time to infinity 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CaPS 
Clinical Data Interchange Standards Consortium and Pfizer 
Standards 
CI 
confidence interval 
Clast 
estimated plasma concentration at the last quantifiable time point 
estimated form the log-linear regression analysis 
Cmax 
maximum observed plasma concentration 
CSR 
clinical study report 
ECG 
electrocardiogram 
HR 
heart rate 
kel 
the terminal phase rate constant calculated by a linear regression of 
the loglinear concentration-time curve 
LLQ 
lower limit of quantitation 
mg 
milligram 
mR 
CCI 
mT 
the average bioavailability on a log scale for the Reference product 
the average bioavailability on a log scale for the Test product 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
qL 
lower limit of bioequivalence 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 
qU 
upper limit of bioequivalence 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 


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Abbreviation 
CCI 
TEAE 
tlast 
CCI 
time of last measurable concentration 
treatment emergent adverse event 
Term