Clinical trial NCT05673889
Conditions: Healthy
Sponsor: Pfizer
Start date: 2023-01-27; Completion date: 2023-04-19
Enrollment: 24 participants; Allocation: NA; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to understand if ARV-471 affects how a medicine called, dabigatran etexilate, gets absorbed or processed into the body in healthy adults.

All participants in this study will receive one dose of dabigatran etexilate alone by mouth in Period 1. In Period 2, everyone will receive one dose of dabigatran etexilate by mouth approximately 90 minutes after receiving one dose of ARV-471 by mouth. The levels of dabigatran in Period 1 will be compared to the levels of dabigatran in Period 2. This will help us to determine if and how ARV-471 affects dabigatran gets absorbed into the body differently in healthy adults.

All participants will stay at the study clinic for approximately 8 days and 7 nights.

Detailed description:

Arms: arm 1: Dabigatran etexilate administered as a single dose in Period 1 and Period 2. ARV-471 administered as a single dose in Period 2.
Interventions: intervention 1: ARV-471 intervention 2: Dabigatran etexilate
Intervention descriptions: intervention 1: Experimental intervention 2: Probe substrate

Protocol documents:
Prot_000.pdf: 
ARV-471 (PF-07850327) 
Protocol C4891008 
Final Protocol, 04 November 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 
AN INTERVENTIONAL, PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD 
STUDY TO EVALUATE THE EFFECT OF A SINGLE ORAL DOSE OF ARV-471 
(PF-07850327) ON THE PHARMACOKINETICS OF DABIGATRAN IN HEALTHY 
PARTICIPANTS 
 
Study Intervention Number: 
PF-07850327 
Study Intervention Name: 
ARV-471 
US IND Number: 
CCI  
EudraCT/CTIS Number: 
2022-003397-23 
ClinicalTrials.gov ID: 
Not Applicable 
Pediatric Investigational Plan Number: 
Not Applicable 
Protocol Number: 
C4891008 
Phase: 
1 
Brief Title: Phase 1 Study to Estimate the Effect of ARV-471 on Dabigatran 
Pharmacokinetics in Healthy Participants 
 
 
 


ARV-471 (PF-07850327) 
Protocol C4891008 
Final Protocol, 04 November 2022 
PFIZER CONFIDENTIAL 
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Document History 
 
Document 
Version Date 
Original protocol 
04 November 2022 


ARV-471 (PF-07850327) 
Protocol C4891008 
Final Protocol, 04 November 2022 
PFIZER CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES ..................................................................................................................... 8 
1. PROTOCOL SUMMARY ..................................................................................................... 9 
1.1. Synopsis ..................................................................................................................... 9 
1.2. Schema .................................................................................................................... 16 
1.3. Schedule of Activities .............................................................................................. 17 
2. INTRODUCTION ................................................................................................................ 22 
2.1. Study Rationale ........................................................................................................ 22 
2.2. Background .............................................................................................................. 22 
2.2.1. Nonclinical Pharmacology .......................................................................... 22 
2.2.2. Nonclinical Pharmacokinetics and Metabolism .......................................... 23 
2.2.3. Nonclinical Safety ....................................................................................... 24 
2.2.4. Clinical Overview ....................................................................................... 25 
2.2.4.1. Summary of ARV-471 Pharmacokinetics in Humans ............... 26 
2.3. Benefit/Risk Assessment ......................................................................................... 27 
2.3.1. Risk Assessment ......................................................................................... 28 
2.3.2. Benefit Assessment ..................................................................................... 30 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 30 
3. OBJECTIVES AND ENDPOINTS...................................................................................... 30 
4. STUDY DESIGN ................................................................................................................. 30 
4.1. Overall Design ......................................................................................................... 30 
4.2. Scientific Rationale for Study Design ..................................................................... 33 
4.2.1. Probe P-gp Substrate Selection ................................................................... 33 
4.2.2. Administration of Study Interventions With Food ...................................... 34 
4.2.3. Inclusion of Females of Non-Childbearing Potential .................................. 34 
4.2.4. Inclusion of Male Participants .................................................................... 34 
4.2.5. Choice of Contraception/Barrier Requirements .......................................... 37 
4.2.5.1. Females – Non-Childbearing Potential ...................................... 37 
4.2.5.2. Males ......................................................................................... 37 
4.2.6. Collection of Retained Research Samples .................................................. 37 
4.3. Justification for Dose ............................................................................................... 37 
4.4. End of Study Definition ........................................................................................... 39 


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Protocol C4891008 
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PFIZER CONFIDENTIAL 
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5. STUDY POPULATION ..................................................................................................... 39 
5.1. Inclusion Criteria .................................................................................................... 39 
5.2. Exclusion Criteria ................................................................................................... 40 
5.3. Lifestyle Considerations ......................................................................................... 43 
5.3.1. Contraception ..............................................................................................43 
5.3.2. Meals and Dietary Restrictions .................................................................. 43 
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................44 
5.3.4. Activity ...................................................................................................... 45 
5.4. Screen Failures ....................................................................................................... 45 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................. 45 
6.1. Study Intervention(s) Administered ........................................................................ 45 
6.1.1. Administration ............................................................................................ 46 
6.2. Preparation, Handling, Storage, and Accountability ...............................................47 
6.2.1. Preparation and Dispensing ....................................................................... 48 
6.3. Assignment to Study Intervention ...........................................................................48 
6.4. Blinding .................................................................................................................. 48 
6.4.1. Blinding of Participants ...............................................................................48 
6.4.2. Blinding of Site Personnel ..........................................................................48 
6.4.3. Blinding of the Sponsor ............................................................................. 48 
6.5. Study Intervention Compliance .............................................................................. 48 
6.6. Dose Modification .................................................................................................. 49 
6.7. Continued Access to Study Intervention After the End of the Study ......................49 
6.8. Treatment of Overdose ........................................................................................... 49 
6.9. Prior and Concomitant Therapy ..............................................................................49 
6.9.1. Rescue Medicine ........................................................................................ 50 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................... 50 
7.1. Discontinuation of Study Intervention .....................................................................50 
7.1.1. Liver Injury ................................................................................................ 50 
7.1.2. ECG Changes ............................................................................................. 51 
7.1.3. Potential Cases of Acute Kidney Injury ......................................................51 
7.1.4. COVID-19 .................................................................................................. 51 


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PFIZER CONFIDENTIAL 
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7.2. Participant Discontinuation/Withdrawal From the Study ........................................ 52 
7.2.1. Withdrawal of Consent ............................................................................... 52 
7.3. Lost to Follow-up .................................................................................................... 53 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................... 53 
8.1. Administrative and Screening Procedures ............................................................... 53 
8.1.1. Baseline Procedures .................................................................................... 54 
8.2. Efficacy Assessments .............................................................................................. 55 
8.3. Safety Assessments .................................................................................................. 55 
8.3.1. Physical Examinations ................................................................................ 55 
8.3.2. Vital Signs ................................................................................................... 56 
8.3.2.1. Blood Pressure and Pulse Rate .................................................. 56 
8.3.3. Electrocardiograms ...................................................................................... 56 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 57 
8.3.5. COVID-19 Related Measures ..................................................................... 58 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 58 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 58 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 59 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 59 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 59 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 60 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 60 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 60 
8.4.5.1. Exposure During Pregnancy ...................................................... 61 
8.4.5.2. Exposure During Breastfeeding ................................................. 62 
8.4.5.3. Occupational Exposure .............................................................. 63 
8.4.6. Cardiovascular and Death Events ............................................................... 63 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 63 
8.4.8. Adverse Events of Special Interest ............................................................. 63 
8.4.8.1. Lack of Efficacy ........................................................................ 63 
8.4.9. Medical Device Deficiencies ...................................................................... 63 
8.4.10. Medication Errors ..................................................................................... 64 


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8.5. Pharmacokinetics .....................................................................................................64 
8.5.1. Pharmacokinetics for total dabigatran ........................................................ 65 
CCI 
 
8.6. Genetics .................................................................................................................. 66 
8.6.1. Specified Genetics ...................................................................................... 66 
8.6.2. Retained Research Samples for Genetics ................................................... 66 
8.7. Biomarkers .............................................................................................................. 66 
8.7.1. Retained Research Samples for Biomarkers .............................................. 66 
8.8. Immunogenicity Assessments ................................................................................ 67 
8.9. Health Economics ................................................................................................... 67 
9. STATISTICAL CONSIDERATIONS ................................................................................ 67 
9.1. Statistical Hypotheses ............................................................................................. 67 
9.2. Analysis Sets ........................................................................................................... 67 
9.3. Statistical Analyses ................................................................................................. 68 
9.3.1. Pharmacokinetic Analysis ...........................................................................68 
9.3.2. Statistical Methods for PK Data ..................................................................69 
9.3.3. Safety Analyses .......................................................................................... 70 
9.3.3.1. Electrocardiogram Analyses ..................................................... 70 
9.3.4. Other Analyses ........................................................................................... 71 
9.4. Interim Analyses ..................................................................................................... 71 
9.5. Sample Size Determination .................................................................................... 71 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.......................................................................................................... 73 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................73 
10.1.1. Regulatory and Ethical Considerations .................................................... 73 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP ........................................................................ 73 
10.1.2. Financial Disclosure ................................................................................. 74 
10.1.3. Informed Consent Process ....................................................................... 74 
10.1.4. Data Protection ......................................................................................... 75 
10.1.5. Committees Structure ............................................................................... 75 
10.1.5.1. Data Monitoring Committee ................................................... 75 
10.1.6. Dissemination of Clinical Study Data ...................................................... 75 


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PFIZER CONFIDENTIAL 
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10.1.7. Data Quality Assurance ........................................................................... 76 
10.1.8. Source Documents ................................................................................... 78 
10.1.9. Study and Site Start and Closure .............................................................. 78 
10.1.10. Publication Policy ...................................................................................79 
10.1.11. Sponsor’s Medically Qualified Individual ..............................................80 
10.1.12. Transfer of Obligations Statement ......................................................... 80 
10.2. Appendix 2: Clinical Laboratory Tests ................................................................ 81 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................... 82 
10.3.1. Definition of AE ...................................................................................... 82 
10.3.2. Definition of an SAE ................................................................................ 83 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ........................................................................... 84 
10.3.4. Reporting of SAEs ................................................................................... 88 
10.4. Appendix 4: Contraceptive and Barrier Guidance .................................................89 
10.4.1. Male Participant Reproductive Inclusion Criteria .................................... 89 
10.4.2. Female Participant Reproductive Inclusion Criteria ................................ 89 
10.4.3. Woman of Childbearing Potential .............................................................89 
10.4.4. Contraception Methods ............................................................................ 90 
10.5. Appendix 5: Genetics ........................................................................................... 93 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments ....... 94 
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines .............................................96 
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury ..............................................................................96 
10.7.2. Age-Specific Kidney Function Calculation Recommendations ................96 
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .......................................................................................... 96 
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................. 96 
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ....................................97 
10.9. Appendix 9: Overview of GLP Safety Pharmacology and Toxicology 
Testing Program for ARV-471 (PF-07850327) ........................................................ 99 
10.10. Appendix 10: Abbreviations ..............................................................................102 
11. REFERENCES ................................................................................................................ 108 


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PFIZER CONFIDENTIAL 
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LIST OF TABLES 
Table 1. 
Period 1 (Dabigatran etexilate [as mesylate] alone) and Period 2 
(Dabigatran etexilate [as mesylate] with ARV-471) ............................... 17 
Table 2. 
Period 1 (Single oral dose of dabigatran etexilate [as mesylate]): PK 
and ECG Sampling Schedule ....................................................................20 
Table 3. 
Period 2 (Single oral dose of dabigatran etexilate [as mesylate] with 
ARV-471): PK and ECG Sampling Schedule ...........................................21 
Table 4. 
Exposure Margin Determination for Testicular Toxicity in Rat and 
Dog Toxicity Studies ................................................................................35 
Table 5. 
Plasma PK Parameters ............................................................................. 68 
Table 6. 
Protocol-Required Safety Laboratory Assessments ................................. 81 
Table 7. 
Overview of GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) .................................................... 99 
Table 8. 
Facilities for GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) .................................................. 100 


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CCI 
CCI 
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: An Interventional, Phase 1, Open-Label, Fixed Sequence, 2-Period Study to 
Evaluate the Effect of a Single Oral Dose of ARV-471 (PF-07850327) on the 
Pharmacokinetics of Dabigatran in Healthy Participants 
Brief Title: Phase 1 Study to Estimate the Effect of ARV-471 on Dabigatran 
Pharmacokinetics in Healthy Participants 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
CCI  
EudraCT/CTIS Number: 
2022-003397-23 
ClinicalTrials.gov ID: 
Not applicable 
Pediatric Investigational Plan Number: 
Not applicable 
Protocol Number: 
C4891008 
Phase: 
1 
 
Rationale: 
ARV-471 is considered an in vitro P-gp inhibitor. Although ARV-471 does not show 
inhibition against P-gp in a 
 
 
assay format up to the 
maximum soluble concentration of CCI 
 and ARV-471 inhibits P-gp with an IC50 of 
CCI 
 in an CCI 
 assay format at the maximum soluble concentration of 
CCI 
The difference between the two assay formats is likely due to the CCI 
 of 
ARV-471 in the bidirectional monolayer. 
The theoretical maximum concentration of ARV-471 in the GI tract after a single oral dose 
of 200 mg ARV-471 is 0.8 mg/mL (1.1 mM) assuming a gastric fluid volume of 250 mL that 
is approximately CCI-fold higher than 
. While the in vitro risk assessment for 
CCI 
 can be CCI 
for drugs that have poor solubility (BCS Class 
II or IV), the in vivo potential for ARV-471 to inhibit P-gp activity in human GI tract cannot 
be excluded. Therefore, a clinical interaction study with a P-gp substrate is needed to assess 
the effect of ARV-471 on P-gp activity. 
Based on available data to date, it is possible that administration of a P-gp substrate, 
dabigatran etexilate (as mesylate), with ARV-471 may lead to increased plasma exposures of 
dabigatran. The purpose of this study is to estimate the effect of ARV-471 on the PK of 
dabigatran in healthy participants. 


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PFIZER CONFIDENTIAL 
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Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• To estimate the effect of a single oral 200 mg 
dose of ARV-471 on the single dose PK of 
dabigatran in healthy participants 
• Plasma total dabigatran (sum of unconjugated and 
glucuronide-conjugated dabigatran) PK 
parameters alone and following administration of 
a single 200 mg dose of ARV-471: Cmax, AUCinf 
(AUClast if AUCinf cannot be estimated) 
Secondary: 
Secondary: 
• To evaluate the safety and tolerability of 
dabigatran etexilate (as mesylate) alone and 
following administration with a single 200 mg 
dose of ARV-471 
• Safety: TEAEs, clinical laboratory tests, vital 
signs, PE, and ECGs 
Other: 
Other: 
• To characterize the CCI of ARV-471 and its 
epimer, ARV-473 after a single 200 mg dose of 
ARV-471 
• CCI 
, as data permit 
and as appropriate 
• Other total dabigatran PK parameters: Clast, 
AUClast, Tmax, Tlast, t1/2, CL/F, Vz/F, as data permit 
 
Overall Design: 
This will be a Phase 1, open-label, 2-period, fixed-sequence study to estimate the effect of 
a single oral dose of ARV-471 on the PK of a P-gp substrate, dabigatran etexilate (as 
mesylate), in healthy male participants and healthy female participants with nonchildbearing 
potential. An attempt will be made to enroll more than 50% participants as female 
participants with nonchildbearing potential in this study since ARV-471 is being developed 
for the treatment in a population that is predominately female. 
Number of Participants: 
A sufficient number of participants will be screened to ensure that at least 24 participants will 
be enrolled in the study. 
Note: "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 
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 


ARV-471 (PF-07850327) 
Protocol C4891008 
Final Protocol, 04 November 2022 
PFIZER CONFIDENTIAL 
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not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol. 
Study Population: 
Inclusion and exclusion criteria are listed below: 
Inclusion Criteria 
Age and Sex: 
1. Healthy male and/or female participants of non-childbearing potential who are overtly 
healthy as determined by medical evaluation and are between the ages of 18 and 
70 years, inclusive at the time of signing the ICD. Healthy participant is defined as no 
clinically relevant co-morbidities or abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure and pulse rate 
measurement, 12-lead ECG, or clinical laboratory tests. 
2. Female participants of non-childbearing potential must meet at least one of the 
following criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum FSH level 
confirming the post-menopausal state; 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy 
and/or bilateral salpingectomy; 
c. Have medically confirmed ovarian failure. 
All other female participants (including females with tubal ligations and females that 
do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian 
failure) will be considered to be of childbearing potential and therefore not eligible. 
Other Inclusion Criteria: 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures. 
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with requirements and restrictions listed in the ICD and in this 
protocol. 


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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). 
• Any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy, enterectomy). 
• Evidence or history of HIV infection, hepatitis B, or hepatitis C; positive testing 
for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 
• Positive test result for SARS-CoV-2 infection. 
2. Pregnant female participants, breastfeeding female participants, female participants of 
childbearing potential. Male participants with partners currently pregnant; male 
participants of childbearing potential who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for 90 days after the last dose of investigational product. 
3. Active bleeding or risk of bleeding including prior personal or familiar history of 
abnormal bleeding, hereditary or acquired coagulation or platelet disorder or 
abnormal coagulation test (PT/INR or PTT/aPTT greater than upper limit of normal) 
result at screening. Any significant risk factor for major bleeding and this may 
include but not limited to current or recent GI ulceration, presence of malignant 
neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal 
or ophthalmic surgery, recent intracranial hemorrhage, known or suspected 
esophageal varices, arteriovenous malformations, vascular aneurysms or major 
intraspinal or intracerebral vascular abnormalities. 
4. 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 that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy: 
5. Use of prescription or nonprescription medications, including vitamins, dietary and 
herbal supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products within 7 days or 5 half-lives (whichever is 


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longer) prior to the first dose of study intervention or a longer washout is required for 
those that fall into the categories below: 
• Moderate or strong CYP3A/P-gp inducers which are prohibited within 
14 days plus 5 half-lives prior to the first dose of study intervention. 
• Moderate or strong CYP3A/P-gp inhibitors which are prohibited within 
14 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. 
Prior/Concurrent Clinical Study Experience: 
6. Previous administration with an investigational product (drug or vaccine) within 
30 days (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: 
7. A positive urine drug test or alcohol breath test at the discretion of investigator. 
8. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine 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. 
9. 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, STT 
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. 
10. 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 >1.0 × ULN; 
• Total bilirubin level > 1.0 × ULN; 
• Renal impairment as defined by an eGFR in adults of < 75 mL/min/1.73 m2. 
Based upon participant age at screening, eGFR is calculated using the 


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recommended formulas in Section 10.7.2 to determine eligibility and to provide a 
baseline to quantify any subsequent kidney safety events; 
• PT/INR or PTT/aPTT > 1.0 × ULN. 
Other Exclusion Criteria: 
11. History of use of tobacco or nicotine-containing products in excess of the equivalent 
of 5 cigarettes/day or 2 chews of tobacco/day. 
12. 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. 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). 
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. History of sensitivity to heparin or heparin induced thrombocytopenia. History of 
sensitivity to heparin or heparin-induced thrombocytopenia. 
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
16. 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. 
17. History of sensitivity to ARV-471 or dabigatran etexilate (as mesylate) or any of the 
formulation components of ARV-471 or dabigatran etexilate (as mesylate). 
Study Arms and Duration: 
This fixed sequence study will consist of 2 periods: Period 1 = single oral dose of dabigatran 
etexilate (as mesylate) alone; Period 2 = single oral dose of dabigatran etexilate (as mesylate) 
+ single oral dose of ARV-471 with staggered dosing. A washout of at least 4 days must 
occur between the 2 successive single doses of dabigatran etexilate (as mesylate). Following 


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CCI 
administration of dabigatran etexilate (as mesylate) and/or ARV-471 in each period, 
participants will undergo serial PK sampling. 
 
Study Intervention(s) 
Intervention Name 
ARV-471 (PF-07850327) 
Dabigatran etexilate (as mesylate) 
(PRADAXA®) 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
Period 2 only 
Periods 1 and 2 
Unit Dose Strength(s) 
100 mg 
75 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Experimental treatment to assess as 
endpoints 
IMP or NIMP/AxMP 
IMP 
NIMP/AxMP 
 
Statistical Methods: 
Dabigatran PK exhibits relatively high inter-individual variability. Sample size calculation 
CCI 
was based on average intra-participant standard deviations obtained from 
internal 
dabigatran crossover studies CCI 
 
 and 
CCI previously completed 
external dabigatran study. Based on these studies, the estimates of within-participant standard 
deviations of CCI  and CCI  for loge AUCinf and logeCmax, respectively, were used in the 
calculation. A sample size of 24 participants will provide 90% CIs for the difference between 
treatments of CCI 
and of CCI  on the natural logarithmic scale for AUCinf and Cmax 
respectively with 80% coverage probability. 
Total dabigatran PK parameters following a single dose administration will be derived from 
total dabigatran plasma concentration versus time profiles using non-compartmental 
methods, as data permit and as appropriate. Total dabigatran PK parameters will be 
summarized descriptively by treatment. Individual participant total dabigatran PK parameters 
for AUCinf (as data permit), AUClast, and Cmax will be plotted by treatment and overlaid with 
geometric means. Total dabigatran concentrations will be listed and summarized 
descriptively by PK sampling time and treatment. Summary profiles (means and medians) of 
concentration versus time data will be plotted by treatment on linear and semi-log scale. 
Individual participant concentration vs time profiles will also be presented. 
 


ARV-471 (PF-07850327) 
Protocol C4891008 
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PFIZER CONFIDENTIAL 
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Natural log transformed parameters (AUCinf [as data permit], AUClast, and Cmax) of total 
dabigatran will be analyzed using a mixed effect model with treatment as a fixed effect and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. Dabigatran etexilate 
(as mesylate) administered alone will be the reference treatment and ARV-471 administered 
with dabigatran etexilate (as mesylate) will be the test treatment. 
Ethical Considerations: 
ARV-471 alone or in combination with dabigatran etexilate (as mesylate) will not provide 
any clinical benefit to healthy participants in this study. Any anticipated benefit to 
participants would be in terms of contribution to the process of developing a new therapy for 
the treatment of ER+/HER2- BC. 
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. 
Period 1 (Dabigatran etexilate [as mesylate] alone) and Period 2 (Dabigatran etexilate [as mesylate] with ARV-471) 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10 
Screen 
Period 1 
Period 2 
Follow- 
Up 
Early 
Termination/ 
Discontinua- 
tion 
Notes 
Days Relative to Day 1 
Days 
-28 to 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
1 
Day 
2 
Day 
3 
28-35 
Days 
• All screening should be done ≤28 days before the first dose. 
• Day relative to start of study intervention (Day 1). 
• 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 Section 10.1.3 for additional 
information. 
CRU confinement 
X 
X 
X 
X 
X 
X 
X 
X 
• Participants will be admitted to the CRU on the day prior to Period 1 
dosing (Day -1). 
• Participants will be discharged on Day 3 of Period 2 following PK 
sampling and study activities. 
Inclusion/ 
exclusion criteria 
X 
X 
• See Sections 5.1 and 5.2 for details 
Medical/ 
medication history 
X 
X 
• Medical history will include but not limited to a history of prior drug, 
alcohol, and tobacco use, as well as blood donation within prior 60 
days. Medical history will be recorded at Screening and updated on 
Day -1 of Period 1 only. 
PE 
X 
X 
• A full PE, without genitourinary evaluation will be performed by 
trained medical personnel at the investigator site at Screening or 
Day -1 of Period 1 only (height and weight must be obtained at 
Screening to obtain BMI for eligibility criteria). A limited PE may be 
performed at other designated time points at the discretion of the 
investigator. Only weight needs to be recorded thereafter. See 
Section 8.3.1 for details. 


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PFIZER CONFIDENTIAL 
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Table 1. 
Period 1 (Dabigatran etexilate [as mesylate] alone) and Period 2 (Dabigatran etexilate [as mesylate] with ARV-471) 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10 
Screen 
Period 1 
Period 2 
Follow- 
Up 
Early 
Termination/ 
Discontinua- 
tion 
Notes 
Days Relative to Day 1 
Days 
-28 to 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
1 
Day 
2 
Day 
3 
28-35 
Days 
• All screening should be done ≤28 days before the first dose. 
• Day relative to start of study intervention (Day 1). 
• Follow-up may occur via telephone contact and must occur 28 to 
35 days after administration of the final dose of study intervention. 
Safety laboratory 
X 
X 
X 
X 
X 
• Safety laboratory assessments including urinalysis, hematology, 
coagulation tests and chemistry will be performed at the indicated 
time-points. Additional safety laboratory assessments may be 
performed at any time at the discretion of the investigator. 
• Participants must abstain from all food and drink (except water) at 
least 4 hours prior to any safety laboratory evaluations. 
PTT/aPTT 
X 
X 
X 
X 
X 
• Participants will also be monitored clinically for signs of bleeding. 
PT/INR 
X 
X 
Demography 
X 
• Demographics will include participant, race, ethnicity, age, and gender 
during the screening visit. 
Contraception check 
X 
X 
X 
X 
X 
• On Screening and Day -1, the investigator or his/her designee will 
discuss with the participant the need to use highly effective 
contraception consistently and correctly according to contraception 
guidelines. 
FSH 
X 
• For postmenopausal (amenorrheic for at least 12 consecutive months) 
female participants only. 
Urine drug testing 
X 
X 
• Urine drug (mandatory) and alcohol breath test (at discretion of 
investigator) will be performed at Screening and on Day -1. These 
tests may be performed at any other time at the discretion of the 
investigator. 
12-Lead ECG 
X 
X 
Trip- 
licate 
X 
X 
X 
X 
• Singlet 12-lead ECG will be taken at specified times. Triplicate ECG 
will be collected at pre-dose on Day 1 of Period 1 only. All ECG 
assessments will be made after at least a 5-minute rest in a supine 
position and prior to any blood draws or vital sign measurement. Refer 
to Table 2 and Table 3 for singlet 12-lead ECG collections. 
Vital signs 
(BP/PR) 
X 
X 
X 
X 
X 
X 
• Refer to Table 2 and Table 3 for the specified timepoints. 
Serology: HIV, HBsAg, 
HBsAb, HBcAb, HCVAb 
X 
• HBsAb may be routinely tested or only if HBsAg and/or HBcAb are 
positive. HBsAb due to vaccination is permissible. 
COVID-19 related 
measures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Performed per local procedures 


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Protocol C4891008 
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PFIZER CONFIDENTIAL 
Page 19 
 
 
 
Table 1. 
Period 1 (Dabigatran etexilate [as mesylate] alone) and Period 2 (Dabigatran etexilate [as mesylate] with ARV-471) 
 
Visit Identifier 
Abbreviations used in this 
table may be found in 
Appendix 10 
Screen 
Period 1 
Period 2 
Follow- 
Up 
Early 
Termination/ 
Discontinua- 
tion 
Notes 
Days Relative to Day 1 
Days 
-28 to 
-2 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
1 
Day 
2 
Day 
3 
28-35 
Days 
• All screening should be done ≤28 days before the first dose. 
• Day relative to start of study intervention (Day 1). 
• Follow-up may occur via telephone contact and must occur 28 to 
35 days after administration of the final dose of study intervention. 
Dabigatran etexilate (as 
mesylate) administration 
X 
X 
• Refer to Section 6.1.1 for details of administration requirement. 
ARV-471 administration 
X 
• Refer to Section 6.1.1 for details of administration requirement. 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
• Please refer to Table 2 and Table 3 for detailed PK sampling schedule 
in each period. 
Retained Research 
Sample for Genetics (Prep 
D1) 
X 
• Prep D1 Retained Research Samples for Genetics: If not collected on 
the designated collection day, collect at the next available time point 
when biospecimens are being collected in conjunction with a 
participant visit. See Section 8.6.2. 
Retained Research 
Sample for biomarkers 
(Prep B2) 
X 
• If not collected on the designated collection day, collect at the next 
available time point when biospecimens are being collected in 
conjunction with a participant visit. See Section 8.1. 
CRU discharge 
X 
• Follow-up visit activities (if necessary) will be performed at the 
discretion of the principal investigator, if there is an unresolved AE(s) 
at discharge, or in the case of an early discontinuation. These activities 
may include physical examination, safety laboratory, contraception 
check, single 12-lead ECG and supine blood pressure and pulse rate. 
Serious and non-serious 
AE monitoring 
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 
Treatment Assessment 
X 
X 
X 
• Refer to Section 5.2 and Section 6.9 for details. 


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Table 2. 
Period 1 (Single oral dose of dabigatran etexilate [as mesylate]): PK and ECG Sampling Schedule 
 
Visit Identifier 
Abbreviations used in this table 
maybe found in Appendix 10 
Period 1 (single oral dose of dabigatran etexilate [as mesylate]) 
Notes 
Study Day 
Day 1 
Day 2 
Day 3 
Day 4 
Hours Before/After 
dabigatran etexilate (as 
mesylate) Dose 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
36 
48 
72 
• Hour 0 = pre-dose sample collection. 
Dabigatran etexilate (as 
mesylate) administration 
X 
• Refer to Section 6.1.1 for additional details of administration 
requirement. 
Dabigatran (total) PK blood 
sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Blood samples (4 mL) for PK analysis will be taken at specified 
timepoints. 
• Refer to Section 8.5 for additional details. 
12-Lead ECG 
X 
(tripl- 
icate) 
X 
• Singlet ECG will be taken at specified timepoints. Triplicate 
ECG will be collected at pre-dose on Day 1 of Period 1 only. All 
ECG assessments will be made after at least a 5-minute rest in 
supine position and prior to any blood draws or vital sign 
measurement. 
Vital signs (BP/PR) 
X 
X 
• Single supine blood pressure and pulse rate will be performed 
following at least a 5-minute rest in a supine position. BP and 
PR assessment will be performed after collection of ECGs and 
prior to collection of blood draws if scheduled at the same time. 


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PFIZER CONFIDENTIAL 
Page 21 
 
 
 
Table 3. 
Period 2 (Single oral dose of dabigatran etexilate [as mesylate] with ARV-471): PK and ECG Sampling Schedule 
 
Visit Identifier 
Abbreviations used in this table 
maybe found in Appendix 10 
Period 2 (single oral dose of dabigatran etexilate [as mesylate] with 
single oral dose of ARV-471) 
Notes 
Study Day 
Day 1 
Day 2 
Day 3 
Hours Before/After dabigatran 
etexilate (as mesylate) Dose 
-1.5 
0 
0.5 
1 
2 
3 
4 
6 
8 
12 
24 
36 
48 
• Hour 0 = pre-dose sample collection for dabigatran; 
CCI 
 
ARV-471 administration 
X 
• Refer to Section 6.1.1 for details of administration requirement. 
Dabigatran etexilate (as 
mesylate) administration 
X 
• 
Refer to Section 6.1.1 for details of administration requirements. 
CCI 
. 
Dabigatran (total) PK blood 
sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
• Pre-dose PK samples will also be collected prior to dabigatran 
etexilate (as mesylate) dosing. Blood samples (4 mL) for PK 
analysis will be taken at specified timepoints. Refer to Section 8.5 
for details. 
12-Lead ECG 
X 
X 
X 
• Singlet ECG will be taken at specified timepoints. All ECG 
assessments will be made after at least a 5-minute rest in a supine 
position and prior to any blood draws or vital sign measurement. 
Vital signs (BP/PR) 
X 
X 
X 
• Single supine blood pressure and pulse rate will be performed 
following at least a 5-minute rest in a supine position. BP and PR 
assessment will be performed after collection of ECGs and prior to 
collection of any blood draws if scheduled at the same time. 


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CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
2. INTRODUCTION 
ARV-471 (PF-07850327) is a potent, selective, orally bioavailable PROTAC® small 
molecule that induces degradation of the ER. ARV-471 is being developed for the treatment 
of patients with ER+/HER2- BC. 
2.1. Study Rationale 
ARV-471 does not show inhibition against P-gp on a 
assay format up to the maximum soluble concentration of CCI 
 while showing an IC50 
of 
in an CCI 
 assay format at the maximum soluble concentration of 
CCI  The difference between the 2 assay formats is likely due to the CCI 
 of 
ARV-471 in the bidirectional monolayer. ARV-471 is considered an in vitro inhibitor of 
P-gp (ARV-471 [PF-07850327] Investigator's Brochure) 
The theoretical maximum concentration of ARV-471 in the GI tract after a single oral dose 
of 200 mg ARV-471 is 0.8 mg/mL (1.1 mM) assuming a gastric fluid volume of 250 mL that 
is approximately CCI 
 
than 
While the in vitro risk assessment for 
can be 
for drugs that have poor solubility (BCS Class 
II or IV), the in vivo potential for ARV-471 to inhibit P-gp activity in human GI tract cannot 
be excluded. Therefore, a clinical interaction study with a P-gp substrate is needed to assess 
the effect of ARV-471 on P-gp activity. 
Based on available data, it is possible that administration of a P-gp substrate, dabigatran 
etexilate (as mesylate), with ARV-471 may lead to increased plasma exposures of dabigatran 
(active drug). The purpose of this study is to estimate the effect of ARV-471 on the PK of 
dabigatran in healthy participants. 
2.2. Background 
ARV-471 (PF-07850327) is a potent, selective, orally bioavailable PROTAC® small 
molecule that induces degradation of the ER. ARV-471 is a hetero-bifunctional PROTAC 
molecule that simultaneously binds the ER and the cereblon E3 ligase complex, enabling 
protein-protein interactions between ER and the ligase complex. As a result, the ER becomes 
poly-ubiquitinated on accessible lysine residues and subsequently undergoes targeted 
degradation by the proteasome to affect its elimination from cells. 
2.2.1. Nonclinical Pharmacology 
In a panel of ER+ cell lines, ARV-471 treatment resulted in CCI 
decreases in ER 
levels, similar to those observed with fulvestrant. In  
cells, ARV-471 achieved a DC50 
of 
with a maximum ER degradation of 
. In addition to ARV-471, its epimer, 
ARV-473, was assessed for ER degradation activity. While both ARV-471 and fulvestrant 
reduced ER levels, ARV-473 CCI 
ER levels, even when tested at 
. In an 
ER-dependent gene reporter assay, ARV-471 and ARV-473 had similar 
activity, 
indicating that ARV-471 has both  
and degradation activities against ER, whereas 
ARV-473 displays only 
activity. 


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CCI 
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CCI 
CCI 
CCI 
ARV-471 decreased levels of clinically relevant ER (CCI  and ER (CCI  mutations in a 
manner similar to fulvestrant. In the same study, ARV-471 inhibited growth 
of these CCI cell lines with GI50 values of CCI  and CCI for ER CCI  and ER CCI  
respectively. Taken together, ARV-471 demonstrates both ER degradation and 
anti-proliferative activity in cells expressing the most prevalent ER mutations. 
ARV-471 demonstrates superior TGI compared to fulvestrant in a Y537S ESR1 mutant 
patient-derived xenograft model. In the MCF7-xenograft mouse model, 3 to 30 mg/kg 
ARV-471, orally administered to mice once daily for 28 days, displayed dose-dependent 
efficacy with doses of 3 and 10 mg/kg/day inhibiting tumor growth by 85% and 98%, 
respectively and 30 mg/kg/day leading to tumor shrinkage (124% TGI). At study termination, 
the tumor ER levels were reduced by ≥94%, suggesting that higher doses are required for 
maximal efficacy than for maximal ER degradation. 
These nonclinical data suggest that ARV-471 has the potential to offer improved ER 
degradation as compared to fulvestrant. 
2.2.2. Nonclinical Pharmacokinetics and Metabolism 
ARV-471 is a BCS Class IV compound (low solubility/low permeability). The PK profile of 
ARV-471 in preclinical species (mouse, rat, dog, and monkey) was characterized by a 
clearance (CCI to 
of hepatic blood flow), CCI 
tissue distribution ( 
), CCI to 
 t1/2 (CCI to CCI hours), and CCI 
 to CCI oral 
bioavailability (CCI 
 ARV-471 can interconvert to its epimer, ARV-473. Plasma 
exposure of ARV-473 relative to ARV-471 upon ARV-471 dosing was limited in animal PK 
and TK studies. 
A CYP reaction phenotyping study was conducted using two orthogonal methods in human 
liver microsomes and recombinant CYP isoforms that are consistent with current FDA 
guidance.1 This study indicated CYP3A4 as the CCI 
 isoform responsible for CYP 
metabolism of ARV-471 (accounting for CCI  
Based on in vitro studies, ARV-471 is not a substrate for P-gp, BCRP, OATP1B1, and 
OATP1B3. 
ARV-471 at concentrations up to 24 μM had no or limited direct inhibition against CYP1A2, 
2C8, 2C9, 2C19, 2D6, and 3A4 (with either midazolam or testosterone as the probe 
substrate), indicating IC50 >24 μM. ARV-471 inhibited CYP2B6 with an IC50 of 16.0 μM. 
There was no evidence for mechanism-based inhibition against any of the CYP isoforms in 
the same study. Mechanistic static modeling, using bupropion as the probe CYP2B6 substrate 
drug, indicated a low potential for DDI due to ARV-471-mediated reversible inhibition of 
CYP2B6 at human exposures associated with the 500 mg QD ARV-471 dose. 
In a separate study, ARV-473 at concentrations of up to 24 μM had no or limited direct 
inhibition against CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (with either midazolam or 
testosterone as the probe substrate), indicating IC50 >24 μM. ARV-473 inhibited CYP2B6 
activity with an apparent IC50 value of 23.4 μM. There was no evidence for 
to CCI 


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PFIZER CONFIDENTIAL 
Page 24 
 
 
CCI 
CCI 
was 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
mechanism-based inhibition against any of the aforementioned CYP isoforms in the same 
study. 
Enzyme induction studies in human hepatocytes indicated that ARV-471 is not an in vitro 
inducer of CYP1A2, 2B6, and 3A4. 
ARV-471 does not show inhibition against human BCRP on a 
assay format up to the maximum soluble concentration of CCI 
 while 
showing CCI inhibition against BCRP in a CCI 
 assay format at the maximum soluble 
concentration of CCI 
 The difference between the 2 assay formats is likely due to the 
CCI 
 of ARV-471 in the bidirectional monolayer. Similarly, ARV-471 does not 
show inhibition against P-gp on a 
 
 
assay format up to 
the maximum soluble concentration of CCI 
 while showing an IC50 of CCI   in a 
assay format. The difference between the 2 assay formats is likely due to the CCI 
CCI 
 of ARV-471 in the bidirectional monolayer. 
ARV-471 showed no or minimum inhibition against OATP1B1, OATP1B3, OAT1, OAT3, 
OCT2, MATE1, and MATE2-K when tested at the maximum solubility of 2.5 μM in the test 
media. 
Dose-dependent increase in ARV-471 exposure was observed when ARV-471 was 
administered as an oral solution in the mouse (10, 30, and 100 mg/kg), rat (30, 100, and 
300 mg/kg), dog (15, 45, 90, 200 and 400 mg/kg), and monkey (1 and 3 mg/kg). 
A 3-fold increase in AUC and reduced inter-animal variability was observed in fed dogs; as 
such, the data indicated that the tablets should be administered with food in clinical trials. 
Refer to ARV-471 [PF-07850327] Investigator's Brochure for additional information. 
2.2.3. Nonclinical Safety 
A high-level review of key nonclinical safety data is summarized below, additional 
information can be found in the investigator’s brochure and Appendix 9. 
The potential for ARV-471 and ARV-473 to impact the cardiovascular system was assessed 
in vitro and in single- and repeat-dose in vivo studies. Neither compound directly CCI 
the 
CCI 
; however, 
in the CCI 
were 
noted after CCI 
CCI 
CCI 
(but not 1-month) ARV-471 administration in dogs. Changes in the 
were only observed after 
No indication of 
were observed in any study. There were no significant 
respiratory or CNS effects. ARV-471 and ARV-473 did not impact CCI 
initially assessed at the nominal concentration of CCI 
respectively. 
and CCI 
 
In a dedicated GLP cardiovascular assessment, a single dose of ARV-471 was administered 
via oral gavage to telemetered conscious male and female beagle dogs at doses of CCI 
 
. No ARV-471-related effects were noted after oral administration of 
ARV-471 at 
and 
Following administration of ARV-471 at 
a 
CCI 
CCI 


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CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
. A NOAEL was 
CCI 
CCI 
CCI 
of the drug. The 
CCI 
with 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
 7 ms CCI 
 of the CCI 
 was noted from 1 to CCI 
postdose. No other ARV-471 related effects were noted at CCI 
 At CCI 
 (the 
only dose studied in the TK phase), dogs (n=8, males and females combined) achieved a 
mean of CCI 
  for Cmax, CCI   for Tmax, and CCI 
 
 for AUC0-24. 
Nonclinical toxicology studies were conducted with ARV-471 to evaluate the potential 
toxicity and toxicokinetic profile of ARV-471 and its epimer ARV-473 when administered 
QD orally (by gavage). The toxicity program includes up to 3-month GLP-compliant 
repeat-dose studies in rats and dogs, GLP-compliant in vitro bacterial reverse mutation 
(Ames) assay, in vitro micronucleus assay, and a GLP-compliant in vitro 3T3 phototoxicity 
study. 
ARV-471 was CCI 
 in repeat dose rat studies up to 3-months in duration at doses up 
CCI 
CCI 
CCI 
. ARV-471-related CCI 
and included CCI 
The CCI 
were considered related to the 
in the CCI 
CCI 
were CCI 
and considered to be due to the CCI 
of ARV-471. The CCI 
CCI 
of CCI 
(compared to controls) of 
were noted in CCI in the CCI 
 
. No 
CCI 
have been noted in the CCI 
Subsequently, the CCI 
there were CCI 
in the CCI 
. Based on the CCI 
data evaluating CCI 
and 
function of ARV-471 in rat and dog, it is concluded that the CCI 
finding observed 
only in the 
was a CCI 
and CCI 
to CCI 
The 
NOAEL for CCI 
was determined to be the CCI 
CCI 
in male rats. A NOAEL was not identified in female rats as the effects on the 
reproductive tract were consider adverse. However, these findings are related to the primary 
pharmacology of ARV-471, reversible and not anticipated after short duration dosing. At the 
dose level, the Cmax was   and 
in males and females, 
respectively, and the AUC0-24 was 
and 
 in males and females, 
respectively. 
ARV-471 was well tolerated in repeat dose dog studies up to 3-months in duration at doses 
up 
. ARV-471 
in 
, 
was identified as the 
NOAEL for 
based upon CCI 
 
in the 
for 
that were considered adverse, but it is acknowledged that these effects 
were consistent with the pharmacological effects of ARV-471 and were also observed in the 
. In males and females at 
 
the Cmax was 
and 
and AUC0-24 was 
and 
on Day 91, respectively. 
2.2.4. Clinical Overview 
In the ongoing FIH study, Study ARV-471-mBC-101, ARV-471 is being assessed as a 
monotherapy and in combination with palbociclib in patients with advanced/metastatic 
ER+/HER2- BC. The FIH study has 3 parts: Part A is a monotherapy dose escalation, Part B 


ARV-471 (PF-07850327) 
Protocol C4891008 
Final Protocol, 04 November 2022 
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CCI 
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is a monotherapy expansion at two RP2Ds (200 mg QD and 500 mg QD), and Part C is 
evaluating the combination of ARV-471 and palbociclib. As of 06 Jun 2022, 176 participants 
have been treated in the FIH study (Part A, n=78; Part B, n=71; Part C, n=27). 
In study ARV-471-mBC-101, ARV-471 has been well-tolerated across total daily doses of 
30 mg to 700 mg in patients with mBC. No DLTs were observed and most TRAEs were 
Grade 1 or 2. In addition, palbociclib in combination with ARV-471 shows a safety profile 
similar to that of palbociclib alone or palbociclib in combination with endocrine therapy. 
The ongoing Phase 1 clinical pharmacology study, Study CCI 
, is evaluating 
the effect of food or a PPI and the rBA of different tablet formulations on the single-dose PK 
and safety of ARV-471 in healthy postmenopausal female participants. A single oral dose of 
200 mg ARV-471 has been well-tolerated in healthy participants, and no TRAEs of Grade 2 
or higher were reported in the study. 
Preliminary PK data from Study CCI 
(as of 06 Jun 2022) showed 
dose-dependent increases in Cycle 1 Day 15 AUC0-24 that were observed up to daily doses of 
500 mg. Doses above 60 mg QD achieved average AUC0-24 that exceeded the nonclinical 
exposure (AUCinf=CCI 
 at 30 mg/kg, single dose) associated with tumor shrinkage 
in MCF7-tumor-bearing NOD/scid mice. 
Analysis of 14 paired biopsies from Part A suggested robust ER degradation (median 
decrease = CCI [range: CCI 
 in patients with WT or mutant ER. Furthermore, there 
was evidence of preliminary clinical activity in the monotherapy dose escalation, with 
several patients achieving clinical benefit (by CBR). 
The results from these nonclinical pharmacology, PK and metabolism, and toxicology studies 
and available clinical data support continued clinical development of ARV-471 in 
ER+/HER2- advanced breast cancer. 
Refer to ARV-471 [PF-07850327] Investigator's Brochure for additional information. 
2.2.4.1. Summary of ARV-471 Pharmacokinetics in Humans 
Preliminary PK data from Part A monotherapy dose escalation of Study CCI 
 
(as of 06 Jun 2022) are available from dose levels ranging from 30 to 700 mg administered 
either as QD or BID. Preliminary results indicated dose-dependent increases in Cmax and 
AUCtau for ARV-471, ARV-473, and sum of ARV-471 and ARV-473 up to 500 mg total 
daily dose administered either as 250 mg BID or 500 mg QD on both Cycle 1 Day 1 and 
Day 15. The median Tmax ranged from 
 
 across the dose levels. The mean effective 
t1/2 at steady state ranged from CCI 
. Following 200 mg QD dosing, a geometric 
mean accumulation ratio based on AUCtau of 
was observed between Day 1 and Day 15. 
The ratio of ARV-473/ARV-471 based on AUCtau, on Cycle 1 Day 15 is CCI 
CCI 
 is a Phase 1, multi-part, open-label study to evaluate the effect of food 
or a PPI and to evaluate the relative bioavailability of different tablet formulations on the 
single 200 mg dose pharmacokinetics and safety of ARV-471 in healthy post-menopausal 


ARV-471 (PF-07850327) 
Protocol C4891008 
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PFIZER CONFIDENTIAL 
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CCI 
CCI 
CCI 
female participants. The median Tmax ranged from CCI 
 across the cohorts. The 
geometric mean t1/2 following a single oral 200 mg dose was approximately CCI 
 under 
fed condition. Food intake increased ARV-471 Cmax and AUCinf 3- to 2-fold, respectively, as 
compared with fasted conditions. Data indicated 
on exposure of ARV-471 
when administered with a CCI 
 (approximately 
 
with a fat content 
of approximately CCI  Exposures of ARV-471 (Cmax and AUC) of CCI drug-loaded SDD 
tablets (tests) were similar to the 
drug-loaded SDD tablets (reference) when 
administered with a CCI 
 . 
Refer to ARV-471 [PF-07850327] Investigator's Brochure for additional information. 
2.3. Benefit/Risk Assessment 
ARV-471 alone or in combination with dabigatran etexilate (as mesylate) is not expected to 
provide any clinical benefit to healthy participants. This study is designed primarily to 
generate safety, tolerability, and pharmacokinetic data for further clinical development. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ARV-471 may be found in the IB, which is the SRSD for this study. The 
SRSD for the dabigatran etexilate (as mesylate) (PRADAXA®) agent is the European 
approved SmPC. 


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2.3.1. Risk Assessment 
 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) ARV-471 
CCI 
 
CCI 
 based on CCI 
 to date as per 
Section 2.2.3. 
CCI 
modeling analysis revealed a 
CCI 
 in CCI  
Thirteen participants were reported withCCI 
CCI 
in the ongoing FIH study 
CCI 
 
, for 12 participants the event was 
considered related. An external CCI  
consultant review 
concluded that 2 participants had a true diagnosis of CCI 
CCI 
of which CCI 
and CCI 
CCI 
were confounding factors. 
Clinical safety is not yet fully characterized. 
Participants will receive a single 200 mg dose ARV-471 in 
Period 2. The Cmax of ARV-471 after a single 200 mg is expected 
to be less than that after repeated dosing at 200 mg in participants 
with mBC from Study ARV-471-mBC-101. CCI 
after a single dose of 200 mg 
ARV-471 in healthy post-menopausal femaleb. 
Participants will be monitored for CCI 
 changes with CCI 
CCI 
 at screening and at additional time points post study 
intervention dosing during the study intervention period. 
Participants with clinically relevant abnormalities demonstrated in 
the standard CCI 
 will be excluded (Section 5.2). 
Use of prescription or nonprescription drugs including dietary and 
herbal supplements, vitamins, grapefruit/grapefruit containing 
products, and Seville orange/Seville orange containing products 
are prohibited in this study. 
CCI 
 
Potential risk based on metastatic cancer setting and known 
class effect with CCI 
 
One Grade 3 related CCI 
, with confounding 
factors of obesity, diabetes and immobility due to recent 
biopsy procedure, and a Grade 3 serious CCI 
 case 
assessed as unlikely related to ARV-471 by the investigator, 
were reported in the FIH Study CCI 
 . 
Participants will receive a single 200 mg dose ARV-471 in 
Period 2 in this study. No VE AE was reported after a single dose 
of ARV-471 at any dose level in study ARV-471-mBC-101. 
Participants with a history of clinically significant 
CCI 
 events are excluded from 
participation in the study. 


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CCI 
 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) Dabigatran etexilate (as mesylate) 
Increased risk of 
bleeding 
Dabigatran etexilate (as mesylate) should be used with 
caution in conditions with an increased risk of bleeding or 
with concomitant use of medicinal products affecting 
hemostasis by inhibition of platelet aggregation. 
Bleeding can occur at any site during therapy. An unexplained 
fall in hemoglobin and/or hematocrit or blood pressure should 
lead to a search for a bleeding site. 
A single oral dose of 75 mg dabigatran etexilate (as mesylate) will 
be administered in both periods in this study with a minimum 
washout of 4 days between doses. 
Although dabigatran does not generally require routine 
anticoagulant monitoring, the measurement of dabigatran-related 
anticoagulation is applied in this study to detect excessive high 
exposure to dabigatran in the presence of additional risk factors. 
Measurement of PTT/aPTT in the study (screening and additional 
specified time points post dose in both period) as well as PT/INR 
measurement at Screening and Day -1 in Period 1. In addition, 
CBC to monitor platelets, Hgb, HCT, etc. as well as hemodynamic 
monitoring such as BP and PR are also being evaluated in the 
study. In additional, participants will be monitored clinically for 
signs of bleeding. 
Participants considered in imminent need for surgery or with 
elective surgery scheduled to occur during the study will be 
excluded from this study. 
a. 
-1373, Table 11, ARV-471 CCI 
 estimate (90% CI): CCI 
 
b. StudyCCI 
 CSR Table 14.2.2.3. 


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2.3.2. Benefit Assessment 
ARV-471 alone or in combination with dabigatran etexilate (as mesylate) will not provide 
any clinical benefit to healthy participants in this study. Any anticipated benefit to 
participants would be in terms of contribution to the process of developing a new therapy for 
the treatment of ER+/HER2- BC. 
2.3.3. Overall Benefit/Risk Conclusion 
ARV-471 alone or in combination with dabigatran etexilate (as mesylate) are not expected to 
provide any clinical benefit to healthy participants in this study. Taking into account the 
measures to minimize risk to study participants, the potential risks identified in association 
with ARV-471 and/or dabigatran etexilate (as mesylate) are justified by the anticipated 
benefits that may be afforded to future study participants with ER+ and HER2- mBC. 
3. OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary: 
Primary: 
• 
To estimate the effect of a single oral 
200 mg dose of ARV-471 on the single dose 
pharmacokinetic of dabigatran in healthy 
participants. 
• 
Plasma total dabigatran (sum of unconjugated and 
glucuronide-conjugated dabigatran) PK parameters 
alone and following administration of a single 
200 mg dose of ARV-471: Cmax, AUCinf (AUClast if 
AUCinf cannot be estimated). 
Secondary: 
Secondary: 
• 
To evaluate the safety and tolerability of 
dabigatran etexilate (as mesylate) alone and 
following administration with a single 
200 mg dose of ARV-471 
• 
Safety: TEAEs, clinical laboratory tests, vital 
signs, PE, and ECGs 
Other: 
Other: 
• 
To characterize the CCI of ARV-471 and its 
epimer, ARV-473 after a single 200 mg dose 
of ARV-471 
• 
CCI 
• 
Other total dabigatran PK parameters: Clast, 
AUClast, Tmax, Tlast, t1/2, CL/F, Vz/F, as data permit 
4. STUDY DESIGN 
4.1. Overall Design 
This will be a Phase 1, open-label, 2-period, fixed sequence study to estimate the effect of a 
single oral ARV-471 dose on the PK of a P-gp substrate, dabigatran etexilate (as mesylate), 
in healthy male participants or healthy female participants of nonchildbearing potential. An 
attempt will be made to enroll more than 50% participants as female participants with 


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Protocol C4891008 
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PFIZER CONFIDENTIAL 
Page 31 
 
 
nonchildbearing potential in this study since ARV-471 is being developed for the treatment 
in a population that is predominately female. 
This study will consist of 2 periods with a fixed sequence treatment design. On Period 1 
Day 1, a standard breakfast will be provided prior to dosing. The standard breakfast will be 
completely consumed within an approximately 20-minute period. A single dose of 75 mg 
dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg) will be administered approximately 
2 hours (120 minutes) after starting the standard breakfast. To adequately remove any drug 
effects of dabigatran, a minimum washout period of 4 days is followed after dabigatran 
etexilate (as mesylate) administration on Period 1 Day 1. Serial PK samples will be collected 
up to 48 hours after single dose administration to determine dabigatran PK parameters (total). 
On Period 2 Day 1, a standard breakfast will be provided prior to ARV-471 and dabigatran 
etexilate (as mesylate) dosing. The standard breakfast will be completely consumed within an 
approximately 20-minute period. A single dose of 200 mg ARV-471 (as 2 tablets of 100 mg) 
will be administered approximately 10 minutes after the completion of the breakfast. A single 
dose of 75 mg dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg) will be administered 
approximately 1.5 hour (90 minutes) after the start of ARV-471 dosing, which is 
approximately 2 hours (120 minutes) after the start of the breakfast. Serial PK samples will 
be collected up to 48 hours post dabigatran etexilate (as mesylate) dosing to determine the 
single dose PK parameters of CCI 
 CCI dabigatran (total). 
A sufficient number of participants will be screened to ensure that at least 24 participants will 
be enrolled in the study. Participants who withdraw may be replaced at the discretion of the 
sponsor. Healthy participants will be screened to determine eligibility within 28 days prior to 
study treatment (ie, within 28 days prior to Day 1 of Period 1). Medical history and results of 
physical examination, physical measurements, vital signs, 12-lead ECGs, and clinical 
laboratory evaluations will determine eligibility. 
Participants will report to the CRU at least 12 hours prior to Day 1 dosing in Period 1 and 
will be required to stay in the CRU for 8 days and 7 nights. Washout period will begin after 
the first dose of study treatment. 


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Fixed- 
Sequence 
Period 1 
Period 2 
Screening 
Day 1-4 
At least 4-Day 
washout 
Day 1- 3 
Follow-up 
All screening 
should be done 
2 to 28 days 
before the first 
dose 
(Reference) 
75 mg single oral dose of 
dabigatran etexilate (as 
mesylate) administered 
approximately 2 hours 
(120 minutes) after the start 
of a standard breakfast 
(Period 1 Day 1) 
The washout will 
begin after the 
first dose of 
study medication 
(Test) 
200 mg single oral dose of 
ARV-471 administered 
approximately 30 minutes 
after the start of the standard 
breakfast and 75 mg single 
oral dose of dabigatran 
etexilate (as mesylate) 
administered approximately 
1.5 hours (90 minutes) after 
the start of ARV-471 dosing, 
which is approximately 
2 hours (120 minutes) after 
the start of the breakfast 
(Period 2 Day 1). 
Follow-up must 
occur 28 to 
35 days after 
administration 
of the final 
dose of study 
intervention 
 
Period 1 Day 1 (dabigatran etexilate [as mesylate]): 
• 75 mg dabigatran etexilate (as mesylate) as commercially available PRADAXA® (as 
1 capsule of 75 mg). 
Period 2 Day 1 (ARV-471 + dabigatran etexilate [as mesylate]): 
• 200 mg single dose of ARV-471 (PF-07850327) (as 2 tablets of 100 mg) and 
• 75 mg dabigatran etexilate (as mesylate) as commercially available PRADAXA® (as 
1 capsule of 75 mg). 
ARV-471 (PF-07850327) will be supplied by Pfizer as 100 mg tablets. Dabigatran etexilate 
(as mesylate) (PRADAXA®) as 75 mg capsule will be sourced locally by the CRU. 
The total planned duration of participation, from Screening visit to the last Follow-up phone 
call, is approximately 10 weeks. 
Safety assessments will be performed during Screening, on Day -1 prior to dosing, and at 
specified time points in SoA. PEs, vital sign measurements, and clinical laboratory tests will 
be conducted, and AEs will be monitored to assess safety. The total participation time (eg, 
CRU confinement time for study procedures) for each participant in this study is 
approximately 7 days/6 nights (excluding screening and follow-up contact). Participants will 
be discharged on Period 2 Day 3 following completion of all assessments. 
A safety follow-up call will be made to participants approximately 28 to 35 days from 
administration of the final dose of study intervention. 


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CCI 
4.2. Scientific Rationale for Study Design 
4.2.1. Probe P-gp Substrate Selection 
Dabigatran etexilate (as mesylate) will be used as the P-gp probe substrate in this study. 
Dabigatran etexilate (as mesylate) is a small molecule prodrug with low systemic exposure 
that is rapidly absorbed and converted to dabigatran (active form) upon administration via 
CES hydrolysis in the intestine and liver. Dabigatran is a direct thrombin inhibitor with 
antithrombotic effects. Dabigatran etexilate (as mesylate) is a selective probe substrate of 
intestinal P-gp but not dabigatran.3 Thus, modulation of intestinal P-gp activity will affect 
dabigatran etexilate (as mesylate) absorption, which is reflected in dabigatran plasma 
exposure. The PK of dabigatran is highly sensitive to changes in P-gp activities given the low 
bioavailability. Dabigatran etexilate (as mesylate) has been recommended as a probe for 
intestinal P-gp inhibition by regulatory agencies.2 
It is important to note that inter-individual variability for dabigatran PK tend to be high 
possibly due to variabilities in individual P-gp and CES activities.3 In a DDI study, dosing 
time of dabigatran relative to perpetrator dosing time was one of the factors that affected 
interaction between dabigatran and verapamil (P-gp inhibitor). The maximum effect (~2.5- 
fold increase in exposure) was observed when dabigatran etexilate (as mesylate) was given 1 
hour after a single dose of verapamil.17 Thus, a staggered dosing approach will be used in this 
study. 
 
Other P-gp probe substrates include digoxin and fexofenadine. Fexofenadine is also one of 
the preferred substrates of intestinal P-gp. However, characterization of DDI effect can be 
challenging due to overlapping drug transporters that also regulate fexofenadine disposition 
(eg, OATP1A2,5 OATP1B3,5 OATP2B1,5 OAT3,6 BSEP,7 MRP2,8 MRP37). Single dose 
rifampicin (OATP inhibitor and P-gp inhibitor) has been shown to increase fexofenadine 
exposures up to 4-fold.9 Additionally, those homozygous for the SLCO1B1 521T>C SNP 
(associated with reduced OATP1B1 activity), were shown to have 127% higher fexofenadine 
exposures as compared to participants with the reference SLCO1B1 genotype (521TT).10 
Furthermore, probenecid, an index inhibitor of OATs, was shown to increase fexofenadine 
AUC by ~50% while decreasing its CLr by ~73%.11 
In the past, digoxin has been commonly used as the probe P-gp substrate. Digoxin is a 
cardiac glycoside indicated for treatment of cardiac arrhythmias and heart failure. The 


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CCI 
CCI 
CCI 
, ARV-471 may cause 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
clinical use of digoxin has decreased over the last 20 years due to approval of medications 
with a wider therapeutic range. Digoxin is not selective for P-gp in vitro or in vivo and 
exhibits low PK sensitivity to P-gp inhibition. Digoxin is not selective to intestinal P-gp and 
also substrate of hepatobiliary/renal P-gp. It can be a probe substrate of choice in scenarios, 
such as co-administration with digoxin would be expected in a clinical setting to ensure 
safety and/or predominate impact on hepatobiliary or renal P-gp (eg, pro-drug, intravenous 
drug, major circulating metabolites shown to be P-gp inhibitor). 
Based on the above considerations for each probe substrate, dabigatran etexilate (as 
mesylate) has been selected for this study based on its preferable safety and pharmacokinetic 
profiles compared to digoxin and fexofenadine. 
4.2.2. Administration of Study Interventions With Food 
CCI 
 is a Phase 1, multi-part, open-label study to evaluate the effect of food 
or a PPI and to evaluate the relative bioavailability of different tablet formulations on the 
single 200 mg dose pharmacokinetics and safety of ARV-471 in healthy participants. 
Preliminary results indicated that CCI  
 ARV-471 Cmax and 
AUCinf 
CCI to 
, respectively, as compared with fasted conditions. Cross cohort 
comparison showed similar or higher exposure increase using a CCI 
 
(approximately 
 
with a fat content of approximately 35%) versus a high fat meal 
(approximately 
 
 
, consisting of at least CCI calories from protein, CCI 
calories from carbohydrates and CCI  calories from fat) with the prior formulation (20% 
drug load with CCI SDD). ARV-471 is recommended to be CCI  
  for 
clinical studies. New formulation (CCI drug load with CCI SDD) showed similar exposure 
compared with prior formulation (CCI drug load with CCI  SDD). The median Tmax is 
hours and the t 1/2 of ARV-471 after a single 200 mg dose is approximately 
hours. 
Considering the available data known to date and formulation used in this study (CCI drug 
load with CCI SDD), ARV-471 will be  
(approximately CCI calories 
with a fat content of approximately 
to 
 
. 
4.2.3. Inclusion of Females of Non-Childbearing Potential 
ARV-471 is known to cause 
in the 
of female rats and dogs and male dogs, which may be regarded as 
, and which are considered related to the 
of 
ARV-471. Therefore, there is a 
of 
. Studies to evaluate the 
of ARV-471 in 
. However, based on 
when administered to CCI 
therefore 
. 
4.2.4. Inclusion of Male Participants 
Nonclinical toxicology studies are reviewed in Section 2.2.3 and the most recent IB is 
included for reference. 
CCI 


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and CCI 
of the animals following daily oral 
in rats and CCI 
in dogs. Across the studies, 
, or CCI 
there were CCI 
. 
CCI 
ARV-471-related CCI 
in animals administered CCI 
effects included CCI 
. A finding of CCI 
was 
CCI 
ARV-471-related CCI 
in recovery sacrifice males included CCI 
CCI 
which correlated with CCI 
of the CCI and CCI 
, and CCI 
. These 
CCI 
findings in CCI 
after degradation of the ER, compared to the CCI 
may have reflected the CCI 
A contributing factor to the effects on the CCI 
in the 28-day toxicity studies is likely the male dog sexually maturity at the 
CCI 
CCI 
and CCI 
with CCI 
. CCI 
CCI 
CCI 
CCI 
The repeat dose CCI 
 studies in rats and dogs have consistently shown ARV-471 to be 
CCI 
after once-daily dosing. The 3-month studies have shown CCI 
 of 
CCI  and CCI 
doses of ARV-471 up to 
 
 
In all studies, the pharmacologic effects of ARV-471 were on the 
in the toxicology studies in both rat and dog 
are known to express both ERa and ERb. Findings in the CCI 
low doses, CCI 
are consistent with the 
and, at 
of ARV-471 on the ER and have been observed for agents that target 
the ER (eg, fulvestrant). 
Findings in CCI 
were only observed in the dog and CCI 
were 
noted in the rat in studies up to 3-month in duration. In the 28-day toxicity study 
 
initiation of dosing (7-9 months old). The male specific findings were considered 
non-adverse and NOAEL of 
was determined. In a follow-up 3-month (91-day) 
study the key findings in males consisted of 
in the 
of 
the CCI 
toxicity study may be explained by the sexual maturity of the dogs at 
the initiation of dosing. 
 
Table 4. 
Exposure Margin Determination for 
in Rat and Dog 
Toxicity Studies 
 
Species 
Duration of 
ARV-471 
administration 
No effect or no 
adverse effect 
dose (mg/kg/day) 
Male Total 
AUC24 
(ng•h/mL) 
Male Exposure 
Margin (200 mg 
clinical AUC) a 
Male Exposure 
Margin (200 mg 
clinical AUC) HVb 
Rat 
7 days 
CCI
CCI
(NOEL) 
C I 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
Rat 
28 days 
(NOEL) 
CCI 
Rat 
91 days 
CC (NOEL) 
CCI 
Dog 
7 days 
CCI (NOAEL) 
CCI 
Dog 
28 days 
CCI 
CCI 
(NOAEL) 
CCI 
Dog 
91 days 
(NOAEL) 
CCI 
CCI 


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CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
CCI 
While a single dose of ARV-471 may carry CCI 
CCI 
. CCI 
based on the CCI 
of ARV-471, the risk of CCI 
of producing CCI 
. Learnings from 
Table 4. 
Exposure Margin Determination for CCI 
 in Rat and Dog 
Toxicity Studies 
Species 
Duration of 
ARV-471 
administration 
No effect or no 
adverse effect 
dose (mg/kg/day) 
Male Total 
AUC24 
(ng•h/mL) 
Male Exposure 
Margin (200 mg 
clinical AUC) a 
Male Exposure 
Margin (200 mg 
clinical AUC) HVb 
a. 
AUCtau taken from IB Version 4.0 for 200 mg dose of ARV-471 of CCI  ng•h/mL in participants with mBC. 
b. 
AUCinf taken from preliminary data of CCI 
rBA – test formulation arm (CCI drug load and CCI 
SDD) for a single 200 mg dose of ARV-471 of CCI  ng•h/mL in healthy participants. 
In vitro CCI 
 have been conducted with ARV-471 to CCI 
 of 
studies in healthy participants and results are CCI 
 
 
published literature support the position that male tissues would fully recover and there 
would not be a permanent effect on male fertility.12 The chronic administration of fulvestrant 
(selective estrogen receptor degrader) in dogs followed by a recovery period of 6 months 
demonstrated no long-term impact on fertility in male dogs (FDA website summary basis of 
approval) and full recovery of male tissues. These key data support the reversibility and 
resumed normal function in adult male animals when estrogen signaling is reengaged. 
Additionally, literature review of a total of 21 drugs administered at a single dose level and a 
single administration, to adult male mice, and groups of mice were euthanized and examined 
over the course of 56 days.13,14 Given the germ cell kinetics in the mouse testis, measuring 
testicular spermatid heads 56 days after treatment reflects the activity of the stem cell 
spermatogonia, and presumably the long-term spermatogenic activity of the testis thereafter. 
Using doses at or near the LD50, most drugs gave modest or no detectable change at 56 days. 
Nineteen conventional chemotherapeutic drugs, given to mice as a single administration at or 
near the LD50, caused no permanent sterility.13,14 Only 2 out of 21 drugs tested (thiotepa and 
ADR) produced a permanent reduction >50% in testicular spermatid heads. In addition, Lu et 
al pointed out that “the effects of ADR in humans appeared to be less drastic than in mice. 
Two of 4 patients who received ≥400 mg/m2 doses of ADR still possessed sperm counts of 
over 2 million.”13 Meistrich et al also pointed out that these 2 drugs, thiotepa and adriamycin, 
are strong mutagens, CCI 
.14 
In summary, given that the 
tested provided a 
of 
in the 3-month toxicity study, the 
 
to 
in 
dogs shown in all studies to date, the 
in the rat and also the profile in mice 
for the nongenotoxic drugs at doses around the LD50 in the literature, the risk of any 
is assessed to be 
when ARV-471 is administered as 
a single oral dose. 
The current study will be conducted in healthy participants who will receive ARV-471 
200 mg single dose alone in the fed state. Dabigatran is not an inhibitor or an inducer of 
CYP450 enzymes and is not expected to alter the metabolism of co-administered drugs that 


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CCI 
are substrate of CYP enzymes. As indicated above, for a single oral 200 mg dose the CCI 
provides a safety margin of CCI  with respect to the 
CCI 
 in the 3-month toxicity study recommended by ICH Guidance.15 
4.2.5. Choice of Contraception/Barrier Requirements 
ARV-471 is known to CCI 
humans or suspected on the basis of CCI 
in 
. Therefore, the use of a CCI 
(see Appendix 4). 
4.2.5.1. Females – Non-Childbearing Potential 
Female participants of childbearing potential will not be allowed in this study. 
Female participants of non-childbearing potential must meet at least one of the criteria 
defined in Section 5.1 (all other female participants, including females with tubal ligations, 
will be considered to be of childbearing potential; Inclusion Criterion #1 and #2). 
4.2.5.2. Males 
All fertile male participants who are, in the opinion of the investigator, sexually active and at 
risk for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
continue for at least 90 days after the last dose of investigational product (ARV-471). The 
investigator or his or her designee, in consultation with the participant, will confirm that the 
participant has selected an appropriate method of contraception for the individual participant 
and his partner from the permitted list of contraception methods and instruct the participant 
in its consistent and correct use. At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 
1 of the selected methods of contraception). In addition, the investigator or his or her 
designee will instruct the participant to call immediately if the selected contraception method 
is discontinued or if pregnancy is known or suspected in the participant or the participant’s 
partner. 
4.2.6. 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 
A dose of 200 mg ARV-471 administered as a single dose will be used in this study. This is 
the current, proposed Phase 3 dose of ARV-471. A single oral dose of 75 mg dabigatran 
etexilate (as mesylate) will be used in this study. 
In participants with ER+/HER2- mBC, multiple daily doses up to 700 mg ARV-471 have 
been shown to be safe and well tolerated in patients with mBC. A single dose of 200 mg has 


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Page 38 
 
 
been tested in a Phase 1, multi-part, open-label study to evaluate the effect of food or a 
proton-pump inhibitor and to evaluate the relative bioavailability of different tablet 
formulations in healthy post-menopausal female participants. CCI 
CCI 
CCI 
ARV-471 Cmax and AUCinf CCI 
, respectively, as compared with CCI  
A single oral dose of 200 mg ARV-471 has been well tolerated in healthy 
participants, and CCI   of CCI 
 were reported. Based on the safety data of 
ARV-471 and prior clinical experience described above, the 200 mg single dose is expected 
to be well tolerated by healthy adult participants. 
Dabigatran is approved to prevent or treat thromboembolic conditions, including the 
prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 
The clinical dose of dabigatran etexilate (as mesylate) varies depends on indication, organ 
function, and region (SmPC vs USPI). 150 mg BID is the commonly approved clinical dose 
across different countries and 220 mg QD or higher doses are also approved in the EU. 
Dabigatran was well tolerated after administration of single oral doses of 10 – 400 mg in 
healthy participants. Seven of 40 participants reported an AE, all of mild to moderate 
severity. The most frequently reported AE was headache. In the multiple ascending dose 
cohort, dabigatran was well tolerated with 14 participants reported at least 1 AE and all were 
mild to moderate in severity.16 In a DDI study, verapamil (a strong P-gp inhibitor) increased 
AUCinf and Cmax of dabigatran (dosed as 150 mg single dose) by 143% and 179%, 
respectively. Fifteen of the 20 participants reported treatment-related AEs and the most 
common related AEs were nervous system and gastrointestinal disorders. All AEs were of 
mild to moderate intensity, and there were no serious AEs, and all resolved by the end of the 
study.17 
Regulatory guidance does not provide recommendation on the dose of dabigatran etexilate 
(as mesylate) when it is used as P-gp probe substrate in DDI studies. Some DDI studies 
available in the published literature utilized a 150 mg single oral dose when using dabigatran 
etexilate (as mesylate) probe substrate;17,18 A single oral 75 mg dose of dabigatran etexilate 
(as mesylate) dose has also been used.19,20 A larger magnitude of effect (if any) would be 
expected following a lower dose of dabigatran etexilate (as mesylate). Thus, a single 75 mg 
oral dose of dabigatran etexilate (as mesylate) will be used for this study. 
Results of clinical trials have indicated that inhibition of P-gp activity generally results in 
changes in dabigatran exposures that are ≤2.5-fold and the increase was not associated with 
pharmacodynamic interactions.21 Given the above discussion and considering that ARV-471 
is also a BCS class IV drug (low solubility and permeability), ARV-471 CCI 
 to 
CCI  dabigatran by CCI than CCI . In addition, dabigatran is not an inhibitor or an 
inducer of CYP450 enzymes and is not expected to alter the metabolism of co-administered 
drugs that are substrate of CYP enzymes. Thus, the single dose combination of 200 mg 
ARV-471 and 75 mg dabigatran etexilate (as mesylate) should be well-tolerated by healthy 
adult participants. 


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4.4. End of Study Definition 
The end of the study is defined as the date of 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 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 
Participant eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before participants are included in the study. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Healthy male and/or female participants of non-childbearing potential who are overtly 
healthy as determined by medical evaluation and are between the ages of 18 and 
70 years, inclusive at the time of signing the ICD. Healthy participant is defined as no 
clinically relevant co-morbidities or abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure and pulse rate 
measurement, 12-lead ECG, or clinical laboratory tests. 
2. Female participants of non-childbearing potential must meet at least one of the 
following criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum FSH level 
confirming the post-menopausal state; 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy 
and/or bilateral salpingectomy; 


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c. Have medically confirmed ovarian failure. 
All other female participants (including females with tubal ligations and females that 
do NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian 
failure) will be considered to be of childbearing potential and therefore not eligible. 
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants. 
Other Inclusion Criteria: 
3. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, and other study procedures. 
5. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with requirements and restrictions listed in the ICD and in this 
protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. 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, enterectomy). 
• Evidence or history of HIV infection, hepatitis B, or hepatitis C; positive testing 
for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed. 
• Positive test result for SARS-CoV-2 infection. 
2. Pregnant female participants, breastfeeding female participants, female participants of 
childbearing potential. Male participants with partners currently pregnant; male 
participants of childbearing potential who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for 90 days after the last dose of investigational product. 
3. Active bleeding or risk of bleeding including prior personal or familiar history of 
abnormal bleeding, hereditary or acquired coagulation or platelet disorder or 
abnormal coagulation test (PT/INR or PTT/aPTT greater than upper limit of normal) 


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result at screening. Any significant risk factor for major bleeding and this may 
include but not limited to current or recent GI ulceration, presence of malignant 
neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal 
or ophthalmic surgery, recent intracranial hemorrhage, known or suspected 
esophageal varices, arteriovenous malformations, vascular aneurysms or major 
intraspinal or intracerebral vascular abnormalities. 
4. 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 that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for 
the study. 
Prior/Concomitant Therapy: 
5. Use of prescription or nonprescription medications, including vitamins, dietary and 
herbal supplements, grapefruit/grapefruit containing products, and Seville 
orange/Seville orange containing products within 7 days or 5 half-lives (whichever is 
longer) prior to the first dose of study intervention or a longer washout is required for 
those that fall into the categories below: 
• Moderate or strong CYP3A/P-gp inducers which are prohibited within 
14 days plus 5 half-lives prior to the first dose of study intervention. 
• Moderate or strong CYP3A/P-gp inhibitors which are prohibited within 
14 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. 
Prior/Concurrent Clinical Study Experience: 
6. Previous administration with an investigational product (drug or vaccine) within 
30 days (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: 
7. A positive urine drug test or alcohol breath test at the discretion of investigator. 
8. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine 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. 
9. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms, 


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complete LBBB, signs of an acute or indeterminate age myocardial infarction, STT 
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. 
10. 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 >1.0 × ULN; 
• Total bilirubin level >1.0 × ULN; 
• Renal impairment as defined by an eGFR in adults of < 75 mL/min/1.73 m2. 
Based upon participant age at screening, eGFR is calculated using the 
recommended formulas in Section 10.7.2 to determine eligibility and to provide a 
baseline to quantify any subsequent kidney safety events; 
• PT/INR or PTT/aPTT >1.0 × ULN. 
Other Exclusion Criteria: 
11. History of use of tobacco or nicotine-containing products in excess of the equivalent 
of 5 cigarettes/day or 2 chews of tobacco/day. 
12. 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. 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). 
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations 
section of this protocol. 
16. 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 


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delegate employees directly involved in the conduct of the study and their family 
members. 
17. History of sensitivity to ARV-471 or dabigatran etexilate (as mesylate) or any of the 
formulation components of ARV-471 or dabigatran etexilate (as mesylate). 
5.3. Lifestyle Considerations 
The following guidelines are provided: 
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner. 
5.3.2. 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 standard breakfast 
(approximately CCI 
 with a fat content of approximately CCI on Period 1 
Day 1 and Period 2 Day 1. Participants must also abstain from all food and drink 
(except water) at least 4 hours post dabigatran etexilate (as mesylate) dose on Period 
1 Day 1 and Period 2 Day 1, unless otherwise indicated (see water restriction below). 
Additionally, food or drinks (including water) will not be allowed after ARV-471 
dosing and before dabigatran etexilate (as mesylate) dosing in Period 2 Day 1. 
• Water may be consumed without restriction except from 1 hour before to 1 hour after 
study intervention dosing. Water intake consumed only during the standard breakfast 
on Period 2 Day 1 is allowed. 
• On Period 1 Day 1 following an overnight fast of at least 10 hours, participants will 
be provided the standard breakfast (approximately CCI 
 with a fat content of 
approximately CCI approximately 2 hours (120 minutes) prior to dabigatran 
etexilate (as mesylate) dosing. This breakfast will be completely consumed within an 


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approximately 20-minute period. Dabigatran etexilate (as mesylate) will be 
administered with approximately 240 mL of ambient temperature water at 
approximately 2 hours (120 minutes) after starting breakfast. 
• On Period 2 Day 1 following an overnight fast of at least 10 hours, participants will 
be provided the standard breakfast (breakfast must be the same as provided in Period 
1 Day 1). This breakfast will be completely consumed within an approximately 
20-minute period. ARV-471 will be administered approximately 10 minutes after the 
completion of the meal with approximately 240 mL of ambient temperature water. 
Dabigatran etexilate (as mesylate) will be administered approximately 1.5 hour 
(90 minutes) after the start of ARV-471 dosing, with approximately 240 mL of 
ambient temperature water, which should be approximately 2 hours (120 minutes) 
after the start of the breakfast. 
• Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices or 
Seville orange or Seville orange containing products —see below) may be consumed 
with meals and the evening snack. 
• Lunch will be provided at least 4 hours after dabigatran etexilate (as mesylate) 
dosing. 
• Dinner will be provided approximately 9 to 10 hours after dabigatran etexilate (as 
mesylate) 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. 
• 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. 
5.3.3. 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 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. 


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5.3.4. 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 non-investigational medicinal 
products/auxiliary medicinal products, 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 ARV-471 (PF-07850327) 
100 mg tablet and dabigatran etexilate (as mesylate) (PRADAXA®) 75 mg capsule. 
6.1. Study Intervention(s) Administered 
 
Study Intervention(s) 
Intervention Name 
ARV-471 (PF-07850327) 
Dabigatran etexilate (as mesylate) 
(PRADAXA®) 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
Period 2 only 
Periods 1 and 2 
Type 
Drug 
Drug 
Dose Formulation 
Tablet 
Capsule 
Unit Dose Strength(s) 
100 mg 
75 mg 
Dosage Level(s) 
200 mg 
75 mg 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Experimental treatment to assess as 
endpoint 


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Study Intervention(s) 
IMP or NIMP/AxMP 
IMP 
NIMP/AxMP 
Sourcing 
Provided centrally by the sponsor 
Provided locally by the trial site 
Packaging and Labeling 
Study intervention will be provided in 
high-density polyethylene bottle with 
child resistant cap. Each bottle will be 
labeled as required per country 
requirement. 
Study intervention will be provided in 
high-density polyethylene bottle with 
child resistant cap. Each bottle will be 
labeled as required per country 
requirement. 
Current/Former Name(s) 
or Alias(es) 
ARV-471 (PF-07850327) 
Dabigatran etexilate (as mesylate) 
(PRADAXA®) 
 
ARV-471 tablets will be supplied to the CRU as packaged bottles and labeled according to 
local regulatory requirements. Bottles will be provided to the site for dispensing by the 
pharmacy. 
Dabigatran etexilate (as mesylate) (PRADAXA®) capsules will be supplied locally by the 
CRU. 
6.1.1. Administration 
Period 1 Day 1: Following an overnight fast of at least 10 hours, participants will start the 
recommended standard breakfast approximately 2 hours (120 minutes) prior to dabigatran 
etexilate (as mesylate) (as 1 capsule of 75 mg) dosing. The standard breakfast will be 
required to be completely consumed within an approximately 20-minute period. 
Participants will receive study medication at approximately 0900 hours (plus or minus 
2 hours). Investigator site personnel will administer dabigatran etexilate (as mesylate) (as 
1 capsule of 75 mg) with ambient temperature water to a total volume of approximately 
240 mL approximately 2 hours (120 minutes) after the start of the standard breakfast. 
Participants will swallow the study medication whole and will not manipulate or chew the 
medication prior to swallowing. No additional food will be allowed for at least 4-hours post 
dose. 
Period 2 Day 1: Following an overnight fast of at least 10 hours, participants will start the 
recommended standard breakfast prior to administration of ARV-471 (as 2 tablets of 100 mg) 
and dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg). The standard breakfast will be 
required to be completely consumed within an approximately 20-minute period. 
Participants will receive study medication at approximately 0900 hours (plus or minus 
2 hours). Investigator site personnel will administer ARV-471 (as 2 tablets of 100 mg) 
approximately 10 minutes after the completion of the moderate breakfast with ambient 
temperature water to a total volume of approximately 240 mL. Investigator personnel will 
administer dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg) approximately 1.5 hours 
(90 minutes) after the start of ARV-471 dosing with ambient temperature water to a total 
volume of approximately 240 mL, which should be approximately 2 hours (120 minutes) 
after the start of the standard breakfast. Participants will swallow the study medications 


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whole and will not manipulate or chew the medications prior to swallowing. No additional 
food will be allowed for at least 4-hour post dabigatran dose. 
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 
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 PCRU local/site 
procedures. 
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 PCRU’s local/site procedures. 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. 


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9. Upon identification of a product complaint, notify the sponsor within 1 business day 
of discovery. 
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. 
ARV-471 tablets and dabigatran etexilate (as mesylate) 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’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled. 
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. 
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 
When participants are dosed at the site, they 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 


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time of dosing by a member of the study site staff. Study site personnel will examine each 
participant’s mouth to ensure that the study intervention was ingested. 
6.6. Dose Modification 
No dose modification is anticipated. 
6.7. Continued Access to Study Intervention After the End of the Study 
No intervention will be provided to study participants at the end of their study participation. 
6.8. Treatment of Overdose 
For this study, any dose of ARV-471 greater than 200 mg or dabigatran etexilate (as 
mesylate) greater than 75 mg within a 24-hour time period will be considered an overdose. 
An accidental overdose of dabigatran may lead to increased risk of bleeding. In the event of 
hemorrhagic complications, initiate appropriate clinical support, discontinue treatment, and 
investigate the source of bleeding. For dabigatran, a specific reversal agent (idarucizumab) is 
available.22 
There is no specific treatment for an overdose of ARV-471. 
In the event of an overdose, the investigator/treating physician 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 medications, including vitamins, dietary and herbal 
supplements, grapefruit/grapefruit containing products, and Seville orange/Seville orange 
containing products are prohibited in this study. A washout of 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of study intervention is required or a longer 
washout is required for those that fall into the categories below: 
• Moderate or strong CYP3A/P-gp inducers which are prohibited within 14 days plus 
5 halflives prior to the first dose of study intervention. 


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• Moderate or strong CYP3A/P-gp inhibitors which are prohibited within 14 days or 
5 halflives (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. Depo-Provera® must 
be discontinued at least 6 months prior to the first dose of study treatment. 
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. 
6.9.1. Rescue Medicine 
There is no rescue therapy to reverse the AEs observed with ARV-471. For dabigatran, the 
specific reversal agent (idarucizumab) is available. Standard medical supportive care must be 
provided to manage the AEs. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: 
• AE requiring discontinuation at the discretion of investigator 
• Positive COVID-19 test 
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention. 
7.1.1. Liver Injury 
Reasons for permanent discontinuation of study intervention due to potential liver injury are 
described in Appendix 6. 


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7.1.2. ECG Changes 
A participant who meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 
• QTcF >500 ms. 
• Change from baseline: QTcF >60 ms and QTcF >450 ms. 
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. 
7.1.3. Potential Cases of Acute Kidney Injury 
Abnormal values in SCr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 µmol/L) in SCr level relative to the participant’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness. 
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 µmol/L] in SCr 
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 µmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury. 
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
SCr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating SCr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal SCr. If ≥2 healthy participants in a given period are noted to have 2 consecutive 
SCr results of ≥0.3 mg/dL (or ≥26.5 µmol/L), an assessment of whether the finding may be 
considered an adverse drug reaction should be undertaken. 
7.1.4. COVID-19 
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. 


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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: 
• Unacceptable toxicity; 
• Significant protocol violation; 
• Lost to follow-up; 
• Refused further study procedures; 
• Study terminated by sponsor; 
• Withdraw consent; 
• Death; 
• Investigator decision. 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
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. 
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. 


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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/attend 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 Screening 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 
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 


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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 
209 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 Concomitant Therapy sections of the protocol. 
8.1.1. Baseline Procedures 
The following procedures will be completed: 
• Obtain written informed consent. 
• Review Inclusion and Exclusion criteria. 
• Confirm proper contraception is being used. 
• Demographics (race, age, gender and ethnicity). 
• Obtain medical history, including but not limited to history of prior drug, alcohol and 
tobacco use as well as blood donation within 60 days prior. 
• Obtain complete medication history of all prescription or nonprescription drugs, 
including vitamins, and dietary and herbal supplements, grapefruit/grapefruit 


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containing products, and Seville orange/Seville orange containing products taken 
within 28 days prior to the planned first dose. 
• Conduct full physical examination including height and weight to obtain BMI for 
eligibility criteria. The Screening physical examination may be performed on Day -1, 
Period 1. 
• Collect single 12-lead ECG. 
• Obtain supine blood BP and PR following at least a 5-minute rest in a supine position. 
• Following at least a 4-hour fast, collect blood and urine specimens for the following: 
o Safety laboratory tests (eg, urinalysis, hematology, chemistry, coagulation tests); 
o Urine drug test (alcohol breath and blood test at discretion of investigator); 
o Serum FSH concentration for any female who has been amenorrheic for at least 
12 consecutive months without an alternative pathological or physiological 
reason; 
o Collect blood for HBsAb, HBsAg, HBcAb, HCVAb, and HIV testing. 
To prepare for study participation, participants will be instructed on the use of the Lifestyle 
Considerations and Concomitant Treatment(s) sections of the protocol. 
8.2. Efficacy Assessments 
Not applicable. 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
8.3.1. Physical Examinations 
Physical examinations are to be performed at the nominal timepoints specified in the SoA. 
Additional physical examinations will be permitted, as necessary, to ensure appropriate 
collection of safety data. 
A full physical examination without genitourinary evaluation will include, at a minimum, 
head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, and 
gastrointestinal, musculoskeletal, and neurological systems. 
A limited physical examination will include, at a minimum, assessments of general 
appearance, the respiratory and cardiovascular systems, and participant-reported symptoms. 


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Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3. 
8.3.2. Vital Signs 
8.3.2.1. Blood Pressure and Pulse Rate 
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements. 
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data. 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 
8.3.3. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 5 minutes in a supine position. 


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To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTcF interval is increased by ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG. If either of these conditions occurs, 
then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to confirm the 
original measurement. If the QTcF values from these repeated ECGs remain above the 
threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement. 
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant 
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF 
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator). 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. 
ECG values of potential clinical concern are listed in Appendix 8. 
8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 48 hours after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 


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See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Related Measures 
Participants will undergo COVID-19 related measures per local procedures. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention), through and including a minimum of 28 calendar days, after the last 
administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 


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For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available. 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
8.4.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 


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Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3. 
8.4.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 


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8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 
• A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant or participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 
28 days after the last dose of ARV-471. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 


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preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
• Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.4.5.2. Exposure During Breastfeeding 
An EDB occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion, inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
information is not recorded on a CRF. However, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 


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An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB. 
8.4.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the CT SAE Report Form regardless of 
whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file. 
8.4.6. Cardiovascular and Death Events 
Not applicable. 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.4.8. Adverse Events of Special Interest 
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOP. 
AEs that are considered AESIs for ARV-471 include CCI 
. Based on 
current understanding of the safety profile, no expedited reporting by the investigator to 
sponsor is required for non-serious AESIs. Additional details and mitigation strategies are 
summarized in Section 2.3.1. 
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form. 
8.4.8.1. Lack of Efficacy 
This section is not applicable because efficacy is not expected in the study population. 
8.4.9. Medical Device Deficiencies 
Not applicable. 


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8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors are recorded and reported as follows: 
 
Recorded on the 
Medication Error Page 
of the CRF 
Recorded on the 
Adverse Event Page 
of the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
All (regardless of whether 
associated with an AE) 
Any AE or SAE associated 
with the medication error 
Only if associated with an 
SAE 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
8.5. Pharmacokinetics 
Blood sample collection for measurements of plasma concentration of dabigatran (total) is 
detailed in Section 8.5.1. CCI 
evaluation of dabigatran etexilate CCI 
Plasma samples may be used for 
 
For PK collections, 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 


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the collection is noted on the source document and the CRF. 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. 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. 
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. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.5.1. Pharmacokinetics for total dabigatran 
Blood samples of approximately 4 mL, to provide approximately 1.5 to 1.8 mL plasma, will 
be collected for measurement of plasma concentrations of total dabigatran (sum of 
unconjugated and conjugated dabigatran) 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. 
Samples will be used to evaluate the PK of total dabigatran. Each plasma sample will be 
divided into 2 aliquots (1 each for shipment to bioanalytical lab and back up sample at study 
site). Samples collected for analyses of total dabigatran plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study, for metabolite identification and/or evaluation of the bioanalytical method, or for other 
CCI 
. 
Samples collected for measurement of plasma concentrations of total dabigatran will be 
analyzed using a validated analytical method in compliance with applicable SOPs. 
CCI 
 
 


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. 
 
 
 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
8.6.2. Retained Research Samples for Genetics 
A 4 mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual. 
8.7. Biomarkers 
Biomarkers are not evaluated in this study. 
8.7.1. Retained Research Samples for Biomarkers 
These Retained Research Samples will be collected in this study: 
• 10 mL whole blood (Prep B2 optimized for serum). 
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA. 
Retained Research Samples may be used for research related to the study intervention(s) and 
safety biomarkers. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may 
be studied using the retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual and 
supporting documentation. 
CCI 


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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. 
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 
No statistical hypothesis will be tested in this study. 
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 
assigned 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. 
Full analysis set 
All participants enrolled and assigned to study intervention and 
who take at least 1 dose of study intervention. 
Safety analysis set 
All participants in the full analysis set. Participants will be 
analyzed according to the product they actually received. 
PK Concentration Set 
All participants who are in the safety analysis set and have at 
least 1 measurable concentration of CCI 
. 
PK Parameter Set 
All participants who are in the Safety Analysis Set and have at 
least 1 PK parameter of interest for CCI 
. 


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CCI 
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 Analysis 
The plasma PK parameters for total dabigatran will be derived (as data permit and as 
appropriate) from the concentration time profiles as detailed in Table 5 for CCI 
 and 
treatment. Actual PK sampling times will be used in 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 5. 
Plasma PK Parameters 
 
 
 
 
t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parameter 
Definition 
Method of Dete rmination 
AUClast 
Area under the plasma concentration- 
time profile from time 0 to the time 
of last quantifiable concentration 
(Clast). 
Linear/Log trape zoidal method. 
AUCinfa 
Area under the plasma concentration- 
time profile from time 0 extrapolated 
to infinite time. 
AUClast + (Clast*
plasma concentr
point estimated 
analysis. 
kel), Where Clast* 
ation at the last qu
from the log-
linear 
is 
an
re 
he predicted 
tifiable time 
gression 
Cmax 
Maximum plasma concentration 
Observe directly from data. 
Clast 
Last measurable observed 
concentration 
Observe directly from data. 
Tmax 
Time for Cmax 
Observe directly from data. 
Tlast 
Time for Clast 
Observe directly from data. 
t  a 
1/2 
Terminal elimination half-life 
Loge(2)/kel, whe 
CCI 
linear concentra 
points judged to 
decline will be u
re kel is the 
termin 
tion-time curve. 
On 
al 
ly
na
on
phase rate 
log- 
those data 
l log-linear 
. 
CL/Fa 
Apparent clearance 
Dose/(AUCinf) 
Vz/Fa 
Apparent volume of distribution 
Dose/(AUCinf *k el) 
CCI 


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CCI 
 
Table 5. 
Plasma PK Parameters 
 
Parameter 
Definition 
Method of Determination 
CCI 
 
𝑚𝑚𝑚𝑚 
 
 
 
a. if data permits and as appropriate. 
 
9.3.2. Statistical Methods for PK Data 
Natural log transformed parameters (AUCinf [if data permit], AUClast, and Cmax) of total 
dabigatran (sum of unconjugated or glucuronide-conjugated dabigatran) will be analyzed 
using a mixed effect model with treatment as a fixed effect and participant as a random 
effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
CIs will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CI for the ratios. Dabigatran administered alone will be the 
reference treatment and ARV-471 co-administered with dabigatran will be the test treatment. 
Total dabigatran PK parameters following a single dose administration will be derived from 
the plasma concertation versus time profiles using non-compartmental methods, as data 
permit and as appropriate. The plasma concentrations of total dabigatran will be listed and 
descriptively summarized 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 for CCI 
 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 comparison of total dabigatran only, AUCinf (as data permit), 
AUClast, and Cmax with and without ARV-471, box and whisker plots of these parameters will 
be plotted by treatment for CCI 
. 
 


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Additional specifications about the tables, listings, and figures will be outlined in the SAP. 
9.3.3. 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 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. 
9.3.3.1. Electrocardiogram Analyses 
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from baseline 
>30-60 
>60 
CCI 
. 


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If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point. If any of the 3 individual ECG tracings has a QTcF 
value >500 ms, but the mean of the triplicates is not >500 ms, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500-ms value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 ms will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 ms. Changes from 
baseline will be defined as the change between the postdose QTcF value and the average of 
the time -matched baseline triplicate values on Day -1, or the average of the predose triplicate 
values on Day 1. 
9.3.4. Other Analyses 
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR. 
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, facilitating PK/PD modeling, and/or supporting clinical 
development. 
9.5. Sample Size Determination 
A sample size of 24 participants will provide 90% confidence intervals for the difference 
between treatments of CCI  and of CCI  on the natural logarithmic scale for AUCinf 


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and Cmax respectively with 80% coverage probability. The following table presents the width 
of 90% confidence interval for a range of effects possibly seen in the study: 
 
Parameter 
Estimated Effect 
(100*Test/Reference) 
90% CI 
CI Width 
AUCinf 
80% 
100% 
120% 
140% 
160% 
180% 
200% 
220% 
240% 
260% 
0.6165, 1.0381 
0.7706, 1.2977 
0.9247, 1.5572 
1.0789, 1.8167 
1.2330, 2.0762 
1.3871, 2.3358 
1.5412 ,2.5953 
1.6954, 2.8548 
1.8495, 3.1144 
2.0036, 3.3739 
0.4216 
0.5270 
0.6324 
0.7378 
0.8433 
0.9487 
1.0541 
1.1595 
1.2649 
1.3703 
Cmax 
80% 
100% 
120% 
140% 
160% 
180% 
200% 
220% 
240% 
260% 
0.5758, 1.1114 
0.7198, 1.3893 
0.8638, 1.6671 
1.0077, 1.9450 
1.1517, 2.2228 
1.2957, 2.5007 
1.4396, 2.7785 
1.5836, 3.0564 
1.7275, 3.3342 
1.8715, 3.6121 
0.5356 
0.6694 
0.8033 
0.9372 
1.0711 
1.2050 
1.3389 
1.4728 
1.6067 
1.7405 
These calculations are based on estimates of within‑participant standard deviations of CCI  
and CCI  for loge AUCinf and loge Cmax, respectively, as average intra‑participant standard 
deviations obtained from previously completed dabigatran crossover studies (clinical studies 
CCI 
) and CCI external study.17 
If there are participants who withdraw or discontinue treatment and are considered to be 
non‑evaluable with respect to the primary PK objective, additional participants can be 
enrolled at the discretion of the investigator upon consultation with the sponsor. 


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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. Financial Disclosure 
Not applicable. 
10.1.3. 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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10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic 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. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC. 
10.1.6. 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. 
10.1.7. 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 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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10.1.8. 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. 
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document. 
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the Pfizer CRU. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the Pfizer CRU. 
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. 
10.1.9. 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 sponsor 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. 
10.1.10. 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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CCI 
. 
CCI 
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. 
10.1.11. Sponsor’s Medically Qualified Individual 
 
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, and (c) site 
emergency phone number active 24 hours/day, 7 days per week. 
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. 
10.1.12. Transfer of Obligations Statement 
 
For the purposes of this protocol, “sponsor” refers to Pfizer. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues. 
 
Table 6. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
If Hb/RBC abnormal: 
MCV, MCH, MCHC 
BUN/Urea and creatinine 
CystatinC and eGFR 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Uric acid 
Albumin 
Total protein 
Local dipstick: 
pHa 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Laboratory: 
Microscopy and 
cultureb 
SARS-CoV-2 RT-PCR 
aPTT/PTT 
PT/INR 
Urine drug screeningc 
Alcohol breath test (at the 
disretion of the investigator) 
At screening: 
• FSHd 
• HIV 
• HbsAg 
• HbcAb 
• HBsAbe 
• HCVAb 
a. 
May be performed on dipstick or pH-meter device 
b. Urinary culture only if deemed appropriate by the investigator (only if UTI is suspected and/or urine 
dipstick is positive for nitrites or leukocyte esterase or both). 
c. 
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study specific). 
d. For confirmation of postmenopausal status only. 
e. 
Hepatitis B surface antibody may be routinely tested or only if HBsAg and/or HBcAb are positive. 
HBsAb due to vaccination is permissible. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. CCI 
. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study. 


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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 an Electronic DCT 
• The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT. 
• If the electronic system is unavailable, then the site will use the paper SAE DCT 
(see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available. 
• After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone. 
 
 
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 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 90 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s). 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below: 
• Agree to use a male condom, and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak, when having sexual intercourse with a WOCBP who is not 
currently pregnant. 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4). 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she (a) is not pregnant or breastfeeding; and 
(b) agrees not to donate eggs (ova, oocytes) for the purpose of reproduction at least 28 days 
after the last dose of study intervention; and (c) at least 1 of the following conditions applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 


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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
2. Postmenopausal female. 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition: 
• A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 
• A female on HRT and whose menopausal status is in doubt will be required to 
use one of the highly effective nonestrogen hormonal contraception methods 
if she wishes to continue her HRT during the study. Otherwise, she must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 


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


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* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following: 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge 
with spermicide (double-barrier methods). 


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10.5. Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Therefore, where local regulations and 
IRBs/ECs allow, a blood sample will be collected for DNA analysis. 
• The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation. 
• The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a study 
report. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained as indicated: 
• Retained samples will be stored indefinitely or for another period as per local 
requirements. 
• Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses. 
• Samples for genetic research will be labeled with a code. The key between the code and 
the participant’s personally identifying information (eg, name, address) will be held 
securely at the study site. 


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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.” 
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below. 
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). 


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• 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. 
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 measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [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;385:1737-49.23 
 
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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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: Overview of GLP Safety Pharmacology and Toxicology Testing 
Program for ARV-471 (PF-07850327) 
Table 7. 
Overview of GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
Study Number 
(Sponsor 
Referencea) 
Study Title 
Test Facility in Which 
the Study Was 
Conducted 
Safety Pharmacology 
Date Range 
for Study 
Conductb 
CRO Contact 
DJ06CT 
(ARV471- 
00059-00- 
INVITRO) 
 
 
 
 
 
8382301 (ARV- 
471-TOX-003) 
 
 
 
 
 
8382302 (ARV- 
471-TOX-004) 
 
 
 
 
 
21GR195 
 
 
 
 
 
 
 
Genotoxicity 
8427274 
(ARV471- 
00061-00- 
INVITRO) 
 
 
8427276 
(ARV471- 
00062-00- 
INVITRO) 
ARV-471: Effects 
on hERG Tail 
Current Recorded 
from Stably 
Transfected HEK- 
293 Cells 
 
 
 
ARV-471: 28-Day 
GLP Oral Gavage 
Toxicity and 
Toxicokinetic 
Study in Rats with 
a 28-Day 
Recovery Phase 
ARV-471: 28-Day 
GLP Oral Gavage 
Study in Dogs 
with a 28-Day 
Recovery 
 
 
3-Month Oral 
Gavage Toxicity 
Study of ARV- 
471 in Beagle 
Dogs 
 
 
 
 
ARV-471: 
Bacterial Reverse 
Mutation Assay 
 
 
 
ARV-471: In 
Vitro Human 
Lymphocyte 
Micronucleus 
Assay 
Covance Laboratories 
Limited 
Woolley Road 
Alconbury 
Huntingdon 
Cambridgeshire 
PE28 4HS 
UK 
Repeat-Dose Toxicity 
Covance Laboratories 
Inc. 
671 South Meridian 
Road 
Greenfield, Indiana 
46140 
USA 
Covance Laboratories 
Inc. 
671 South Meridian 
Road 
Greenfield, Indiana 
46140 
USA 
Pfizer Worldwide 
Research & 
Development 
Drug Safety Research 
& Development 
Eastern Point Road 
Groton, CT 06340 
USA 
 
Covance Laboratories 
Ltd. 
Otley Road, Harrogate 
North Yorkshire, HG3 
1PY 
England 
Covance Laboratories 
Ltd. 
Otley Road, Harrogate 
North Yorkshire, HG3 
1PY 
England 
02 Apr 2020 
to 15 Apr 
2021 
 
 
 
 
 
 
13 Aug 2018 
to 06 Sep 
2019 
 
 
 
 
28 Aug 2018 
to 12 Sep 
2019 
 
 
 
 
26 Oct 2021 to 
06 Jul 2022 
 
 
 
 
 
 
 
22 May 2020 
to 19 Nov 
2020 
 
 
 
28 May 2020 
to 23 Nov 
2020 
PPD 
 
 
 
 
 
 
PPD 
 
 
 
 
PPD 
 
 
 
 
NA 
 
 
 
 
 
 
 
PPD 
 
 
 
 
PPD 


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Table 7. 
Overview of GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
Study Number 
(Sponsor 
Referencea) 
Study Title 
Test Facility in Which 
the Study Was 
Conducted 
Date Range 
for Study 
Conductb 
CRO Contact 
Carcinogenicity 
NA 
Reproductive and Developmental Toxicity 
NA 
Local Tolerance 
NA 
Other Toxicity Studies 
20325699 
(ARV471- 
Neutral Red 
Uptake 
Charles River 
Laboratories, Inc. 
17 Dec 2021 
to 17 Mar 
PPD 
00073-00- 
Phototoxicity 
905 Sheehy Drive 
2022 
INVITRO) 
Assay of ARV- 
Horsham, PA 19044 
471 in BALB/c 
USA 
3T3 Mouse 
Fibroblasts 
hERG = human ether-à-go-go-related gene; GLP = Good Laboratory Practice; HEK= human embryonic 
kidney; NA = not applicable. 
a. 
Where applicable, the sponsor reference number is provided in parentheses. 
b. Date study protocol signed to date study report signed. 
 
 
Table 8. 
Facilities for GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
Facility 
Inspection Date 
Documents provided 
Pfizer Worldwide Research & 
Development 
Drug Safety Research & 
Development 
Eastern Point Road 
Groton, CT 06340 
USA 
04 Jan 2021 to 08 Jan 2021 
FDA EIR 
Covance Laboratories Limited 
Woolley Road 
Alconbury 
Huntingdon 
Cambridgeshire 
PE28 4HS 
UK 
03 Apr 2020; 12 Jul 2020 to 13 Jul 
2020 
02 Dec 2020 to 03 Dec 2020; 05 
Feb 2021 to 15 Feb 2021; 14 Apr 
2021 to 15 April 2021 
Quality Assurance Inspection 
Reports 
Audit Reports 
Covance Laboratories Inc. 
671 South Meridian Road 
Greenfield, Indiana 46140 
USA 
March 2020 
FDA EIR 
Covance Laboratories Ltd. 
Otley Road, Harrogate 
North Yorkshire, HG3 1PY 
England 
NA 
GLP Declaration Statement 


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Table 8. 
Facilities for GLP Safety Pharmacology and Toxicology Testing Program 
for ARV-471 (PF-07850327) 
 
Facility 
Inspection Date 
Documents provided 
Charles River Laboratories, Inc. 
905 Sheehy Drive 
Horsham, PA 19044 
USA 
12 Jul 2021 to 16 Jul 2021 
FDA EIR 


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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 
Abs 
absolute 
ADL 
activity/activities of daily living 
ADR 
adriamycin 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
aromatase inhibitor 
AKI 
acute kidney injury 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ARV-471 
PF-07850327 
ARV-473 
the epimer metabolite of ARV-471 (PF-07850327) 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-144 
area under the concentration-time curve from time zero to 
114 hours 
AUC0-24 
area under the concentration-time curve from time zero to 
24 hours 
AUCinf 
area under the plasma concentration-time curve from time 0 to 
infinity 
AUCtau 
area under plasma concentration-time curve at steady state 
over dosing interval 
AUClast 
area under the plasma concentration-time profile from time 0 
to the time of last measurable concentration 
AV 
atrioventricular 
AxMP 
auxiliary medicinal product 
BA 
bioavailability 
BBS 
Biospecimen Banking System 
BC 
breast cancer 
BCRP 
breast cancer resistance protein 
BCS 
Biopharmaceutics Classification System 
BE 
bioequivalence 
BID 
twice a day 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BSEP 
bile salt export pump 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CES 
carboxylesterase 
CFR 
Code of Federal Regulations 


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Abbreviation 
Term 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CL/F 
apparent clearance of drug from eg, plasma 
Clast 
last quantifiable concentration 
CLr 
clearance value 
Cmax 
maximum observed concentration 
CO2 
carbon dioxide (bicarbonate) 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CRU 
clinical research unit 
CSR 
Clinical Study Report 
CT 
clinical trial 
CTIS 
Clinical Trial Information System 
CV 
cardiovascular 
CYP 
cytochrome P450 
DAB 
dabigatran 
DABE 
dabigatran etexilate (as mesylate) 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLT 
dosing limiting toxicity 
dTT 
diluted thrombin time 
E-DMC 
External Data Monitoring Committee 
EC 
ethics committee 
ECC 
emergency contact card 
ECG 
electrocardiogram or electrocardiography 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
ECT 
ecarin clotting time 
EDB 
exposure during breastfeeding 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
ER 
estrogen receptor 
ERa 
estrogen receptor a 
ERb 
estrogen receptor b 
eSAE 
electronic serious adverse event 
ESR 
erythrocyte sedimentation rate 
ESR1 
Estrogen Receptor 1 
ET 
endocrine therapy 
EU 
European Union 


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Abbreviation 
Term 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
FE 
food effect 
FIH 
first-in-human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
gastrointestinal 
GI50 
concentration for 50% of maximal inhibition of cell 
proliferation 
GLP 
Good Laboratory Practice 
Hb 
hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCT 
hematocrit 
HCVAb 
hepatitis C antibody 
HEK 
human embryonic kidney 
HER2 
human epidermal growth factor receptor 2 
hERG 
human ether-à-go-go-related gene 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
hs-CRP 
high-sensitivity C-reactive protein 
HV 
healthy volunteer 
IB 
Investigator’s Brochure 
IC50 
50% inhibitive concentration 
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 
IoR 
Importer of Record 
IPAL 
Investigational Product Accountability Log 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
K 
Proportionality constant for Bedside and Modified Schwartz 
Equations (kidney function) 
KDIGO 
Kidney Disease Improving Global Outcomes 
kel 
first-order elimination rate constant 


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Abbreviation 
Term 
Km 
Michaelis−Menten constant that corresponds to the substrate 
concentration at which the uptake rate is half of the maximum 
transport rate 
LBBB 
left bundle branch block 
LD50 
lethal dose 50% 
LFT 
liver function test 
loge 
the exponent or power to which a base must be raised to yield 
a given number 
MATE1 
multidrug and toxin extrusion protein 1 
MATE2 
multidrug and toxin extrusion protein 2, also known as 
MATE2-K 
mBC 
metastatic breast cancer 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MQI 
medically qualified individual 
CCI 
MRP 
multidrug resistance-associated protein 
NA 
not applicable 
NIMP 
non-investigational medicinal product 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
OAT1 
organic anion transporter 1 
OAT3 
organic anion transporter 3 
OATP1B1 
organic anion transporting polypeptide 1B1 
OATP1B3 
organic anion transporting polypeptide 1B3 
OCT2 
organic cation transporter 2 
P-gp 
p-glycoprotein 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PCRU 
Pfizer Clinical Research Unit 
PD 
pharmacodynamic(s) 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PPI 
proton pump inhibitor 
PR 
pulse rate 
PROTAC® 
PROteolysis TArgeting Chimeric 
PSSA 
Pfizer's Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
PTH 
parathormone 


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Abbreviation 
Term 
PTT 
partial thromboplastin time 
PVC 
premature ventricular contraction 
QD 
once daily 
QTc 
corrected QT interval 
QTcF 
QTc corrected using Fridericia’s formula 
QTL 
quality tolerance limit 
qual 
qualitative 
rBA 
relative bioavailability 
RBC 
red blood cell 
RP2D 
recommended Phase 2 Dose 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SCr 
serum creatinine 
Scys 
serum cystatin C 
SD 
single dose 
SDD 
spray dried dispersion 
SERD 
selective estrogen receptor degrader or downregulator 
SERM 
selective estrogen receptor modulator 
SmPC 
Summary of Product Characteristics 
SoA 
schedule of activities 
SOP 
standard operating procedure 
SRSD 
Single Reference Safety Document 
STT 
ST-segment and T-wave 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
terminal phase half-life 
T bili 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TGI 
tumor growth inhibition 
THC 
tetrahydrocannabinol 
Tlast 
time for Clast 
TK 
toxicokinetics 
Tmax 
time to reach Cmax 
TRAE 
treatment-related adverse event 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USADE 
unanticipated serious adverse device effect 
USPI 
United States Prescribing Information 
UTI 
urinary tract infection 
VE 
venous embolism 


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Abbreviation 
Term 
Vz/F 
apparent volume of distribution after oral dose 
WBC 
white blood cell 
WOCBP 
woman/women of childbearing potential 
WT 
wild type 


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European Medicines Agency, Guideline on the investigation of drug interactions, 21 
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Meistrich, ML, Finch M, da Cunha MF et al. Damaging effects of fourteen 
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Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and 
tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male 
subjects. Br J Clin Pharmacol. 2007;64(3):292-303. 
17 
Hartter S, Sennewald R, Nehmiz G, et al. Oral bioavailability of dabigatran etexilate 
(Pradaxa((R)) ) after co-medication with verapamil in healthy subjects. Br J Clin 
Pharmacol. 2013;75(4):1053-62. 
18 
Kumar P, Gordon LA, Brooks KM, et al. Differential Influence of the Antiretroviral 
Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein 
Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. 
Antimicrob Agents Chemother. 2017;61(11). 
19 
Zurth C, Koskinen M, Fricke R, et al. Drug-Drug Interaction Potential of Darolutamide: 
In Vitro and Clinical Studies. Eur J Drug Metab Pharmacokinet. 2019;44(6):747-59. 
20 
NDA 213871 abrocitinib tablets. Multi-disciplinary Review and Evaluation. Version 
date: October 12, 2018 Available from : 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213871Orig1s000Multidisci 
plineR.pdf. Accessed: 12 Aug 2022. 
21 
Food and Drug Administration. Pradaxa - Clinical Pharmacology and Biopharmaceutics 
Review(s). 2010. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000ClinPharm 
R.pdf. Accessed: 23 Aug 2022. 


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Protocol C4891008 
Final Protocol, 04 November 2022 
PFIZER CONFIDENTIAL 
Page 110 
 
 
 
22 
PRADAXA Summary of Product Characteristics. Available from : 
https://www.ema.europa.eu/en/documents/product-information/pradaxa-epar-product- 
information_en.pdf. Accessed: 12 Aug 2022. 
23 
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49. 

SAP_001.pdf: 
Protocol C4891008 (PF-07850327) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 1 of 19 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C4891008 
 
 
 
 
An Interventional, Phase 1, Open-Label, Fixed-Sequence, 2-Period Study to Evaluate the 
Effect of a Single Oral Dose of ARV-471 (PF-07850327) on the Pharmacokinetics of 
Dabigatran in Healthy Participants 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
 
Version: 
1 
Date: 
17 Jan 2023 


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TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................... 4 
APPENDICES ........................................................................................................................... 4 
1. VERSION HISTORY ........................................................................................................... 5 
2. INTRODUCTION ................................................................................................................. 5 
2.1. Modifications to the Analysis Plan Described in the Protocol ..................................5 
2.2. Study Objectives, Endpoints, and Estimands ............................................................5 
2.3. Study Design ............................................................................................................ 6 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS .................................................................................................................. 7 
3.1. Primary Endpoints .....................................................................................................7 
3.2. Secondary Endpoints .................................................................................................9 
3.3. Other Endpoints .........................................................................................................9 
3.4. Baseline Variables .................................................................................................... 9 
3.5. Safety Endpoints ....................................................................................................... 9 
3.5.1. Adverse Events .............................................................................................9 
3.5.2. Laboratory Data ........................................................................................... 9 
3.5.3. Vital Signs .................................................................................................. 10 
3.5.4. Electrocardiograms ..................................................................................... 10 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) .................................................. 10 
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................... 11 
5.1. Hypotheses and Decision Rules ...............................................................................11 
5.2. General Methods ..................................................................................................... 11 
5.2.1. Analyses for Binary/Categorical Endpoints ................................................11 
5.2.2. Analyses for Continuous Endpoints ............................................................11 
5.3. Methods to Manage Missing Data .......................................................................... 11 
5.3.1. Pharmacokinetic Data .................................................................................11 
5.3.2. Safety Data ................................................................................................. 12 
6. ANALYSES AND SUMMARIES ...................................................................................... 13 
6.1. Primary Endpoints ...................................................................................................13 
6.2. Secondary Endpoints ...............................................................................................13 
6.3. Other Endpoints .......................................................................................................13 


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6.4. Subset Analyses ....................................................................................................... 15 
6.5. Baseline and Other Summaries and Analyses ......................................................... 15 
6.5.1. Demographic Summaries ............................................................................ 15 
6.5.2. Study Conduct and Participant Disposition ................................................ 15 
6.5.3. Study Treatment Exposure .......................................................................... 15 
6.5.4. Concomitant Medications and Nondrug Treatments .................................. 15 
6.6. Safety Summaries and Analyses .............................................................................. 15 
6.6.1. Adverse Events ........................................................................................... 15 
6.6.2. Laboratory Data .......................................................................................... 16 
6.6.3. Vital Signs ................................................................................................... 16 
6.6.4. Electrocardiograms ...................................................................................... 16 
7. INTERIM ANALYSES ....................................................................................................... 16 
7.1. Introduction .............................................................................................................. 16 
7.2. Interim Analyses and Summaries ............................................................................ 16 
APPENDICES .......................................................................................................................... 17 


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LIST OF TABLES 
Table 1. Summary of Changes ...................................................................................................5 
Table 2. Plasma PK Parameters ................................................................................................ 8 
Table 3. PK Parameters to be Summarized Descriptively ...................................................... 14 
 
 
APPENDICES 
Appendix 1. SAS Code for Analyses .......................................................................................17 
Appendix 2. List of Abbreviations ...........................................................................................18 


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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 / 
17 Jan 2023 
Original 
04 Nov 2022 
N/A 
N/A 
 
2. INTRODUCTION 
ARV-471 (PF-07850327) is a potent, selective, orally bioavailable PROTAC® small molecule 
that induces degradation of the ER. ARV-471 is a hetero-bifunctional PROTAC molecule that 
simultaneously binds the ER and the cereblon E3 ligase complex, enabling protein-protein 
interactions between ER and the ligase complex. As a result, the ER becomes poly- 
ubiquitinated on accessible lysine residues and subsequently undergoes targeted degradation 
by the proteasome. 
Based on available data, it is possible that administration of a P-gp substrate, dabigatran 
etexilate (as mesylate), with ARV-471 may lead to increased plasma exposures of dabigatran 
(active drug). The purpose of this study is to estimate the effect of ARV-471 on the PK of 
dabigatran in healthy participants. 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4891008. 
2.1. Modifications to the Analysis Plan Described in the Protocol 
None. 
2.2. Study Objectives, Endpoints, and Estimands 
The following are the objectives and endpoints in this study. Estimand framework will not be 
applied to this Phase 1 study in healthy participants. 


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Objectives 
Endpoints 
Primary: 
Primary: 
• To estimate the effect of a single oral 200 
mg dose of ARV-471 on the single dose 
pharmacokinetic of dabigatran in healthy 
participants. 
• Plasma total dabigatran (sum of 
unconjugated and glucuronide- 
conjugated dabigatran) PK parameters 
alone and following administration of a 
single 200 mg dose of ARV-471: Cmax, 
AUCinf (AUClast if AUCinf cannot be 
estimated). 
Secondary: 
Secondary: 
• To evaluate the safety and tolerability of 
dabigatran etexilate (as mesylate) alone 
and following administration with a 
single 200 mg dose of ARV-471 
• Safety: TEAEs, clinical laboratory tests, 
vital signs, PE, and ECGs 
Other: 
Other: 
• CCI 
 
 
 
2.3. Study Design 
This will be a Phase 1, open-label, 2-period, fixed sequence study to estimate the effect of a 
single oral ARV-471 dose on the PK of a P-gp substrate, dabigatran etexilate (as mesylate), 
in healthy male participants or healthy female participants of nonchildbearing potential. An 
attempt will be made to enroll more than 50% participants as female participants with 
nonchildbearing potential in this study since ARV-471 is being developed for the treatment in 
a population that is predominately female. 
This study will consist of 2 periods with a fixed sequence treatment design. On Period 1 Day 
1, a standard breakfast will be provided prior to dosing. The standard breakfast will be 
completely consumed within an approximately 20-minute period. A single dose of 75 mg 
dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg) will be administered 
approximately 2 hours (120 minutes) after starting the standard breakfast. To adequately 
remove any drug effects of dabigatran, a minimum washout period of 4 days is followed after 
dabigatran etexilate (as mesylate) administration on Period 1 Day 1. 
On Period 2 Day 1, a standard breakfast will be provided prior to ARV-471 and dabigatran 
etexilate (as mesylate) dosing. The standard breakfast will be completely consumed within an 


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approximately 20-minute period. A single dose of 200 mg ARV-471 (as 2 tablets of 100 mg) 
will be administered approximately 10 minutes after the completion of the breakfast. A single 
dose of 75 mg dabigatran etexilate (as mesylate) (as 1 capsule of 75 mg) will be administered 
approximately 1.5 hour (90 minutes) after the start of ARV 471 dosing, which is 
approximately 2 hours (120 minutes) after the start of the breakfast. 
A sufficient number of participants will be screened to ensure that at least 24 participants 
will be enrolled in the study. Participants who withdraw may be replaced at the discretion of 
the sponsor. Healthy participants will be screened to determine eligibility within 28 days 
prior to study treatment (ie, within 28 days prior to Day 1 of Period 1). Medical history and 
results of physical examination, physical measurements, vital signs, 12-lead ECGs, and 
clinical laboratory evaluations will determine eligibility. 
Participants will report to the CRU at least 12 hours prior to Day 1 dosing in Period 1 and 
will be required to stay in the CRU for 8 days and 7 nights. Washout period will begin after 
the first dose of study treatment. 
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
The primary endpoints of the study are plasma AUCinf (if data permit, otherwise AUClast) and 
Cmax of total dabigatran (sum of uncongugated and glucuronide-congugated dabigatran) 
alone and following administration of a single 200 mg dose of ARV-471. Adjusted geometric 
mean ratios of AUCinf (if data permit, otherwise AUClast) and Cmax will be derived. 
The plasma PK parameters for total dabigatran will be derived (as data permit and as 
appropriate) from the concentration time profiles as detailed in Table 2 for each analyte and 
treatment. Actual PK sampling times will be used in 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. 


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𝑥𝑥
last 
Table 2. Plasma PK Parameters 
Parametera 
AUClast 
Analyte 
total dabigatran, 
CCI 
 
Definition 
Area under the plasma 
concentrationtime 
profile from time 0 to 
the time of last 
quantifiable 
concentration (Clast). 
Method of Determination 
Linear/Log trapezoidal method. 
AUC a 
total dabigatran, 
Area under the plasma 
AUC 
+ (C  */k ), 
inf 
last 
last 
el 
 
 
 
 
 
 
Cmax 
Clast 
 
Tmax 
Tlast 
CCI 
 
 
 
total dabigatran, 
CCI 
 
total dabigatran, 
CCI 
 
total dabigatran, 
CCI 
 
total dabigatran, 
CCI 
 
concentrationtime 
profile from time 0 
extrapolated to infinite 
time. 
Maximum plasma 
concentration 
Last measurable 
observed 
concentration 
Time for Cmax 
 
Time for Clast 
where C * is the predicted plasma 
concentration at the last quantifiable time 
point estimated from the log-linear 
regression analysis. 
Observed directly from the data. 
Observed directly from the data. 
 
Observed directly from the data. 
Observed directly from the data. 
t a 
total dabigatran, 
Terminal elimination 
Log (2)/k , where k is the terminal phase 
½ 
e 
el 
el 
 
 
 
 
CL/Fa 
CCI 
CCI 
 
CCI 
 
 
 
 
total dabigatran, 
 
 
half-life 
 
 
 
 
Apparent clearance 
rate constant calculated by a linear 
regression of the log-linear concentration- 
time curve. Only those data points judged to 
describe the terminal log-linear decline will 
be used in the regression. 
Dose/(AUCinf) 
 
 
 
 
 
 
 
 
 
 
 
 
a. if data permits and as appropriate. 
𝐴𝐴𝐴𝐴  
𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 
CCI 
𝑚𝑚𝑚𝑚 


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CCI 
3.2. Secondary Endpoints 
The secondary endpoints are the overall safety profile of dabigatran etexilate (as mesylate) 
alone and following administration with a single 200 mg dose of ARV-471, as characterized 
by adverse events, laboratory tests, vital signs, and ECGs (discussed in Section 3.5). 
3.3. Other Endpoints 
 
In addition, other total dabigatran PK parameters (Clast, AUClast, Tmax, Tlast, t1/2, CL/F, Vz/F, 
as data permit) will also be derived following the methodology described above. 
3.4. Baseline Variables 
Baseline participant characteristics will be collected according to the schedule of activities 
(SoA) as specified in the protocol. 
3.5. Safety Endpoints 
The following data will be considered in standard safety summaries (see protocol for 
collection days, baseline assessment, and list of parameters): 
• Adverse events (AE) 
• Laboratory data 
• Vital signs data 
• ECG results 
3.5.1. Adverse Events 
Any adverse event occurring following start of treatment will be considered a treatment 
emergent adverse event (TEAE). Events that occur during follow-up within the lag time of 
up to 28 days after the last dose of study intervention will be counted as treatment emergent 
and attributed to the last treatment taken. Events that occur during the washout period 
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 


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Page 10 of 19 
 
 
(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 
participant’s baseline test result is within or outside the laboratory reference range for the 
particular laboratory parameter. 
For both Periods, the baseline measurement is the predose measurement on Period 1 Day -1. 
Changes from baseline will be defined as the change between the baseline and postdose 
measurements. 
3.5.3. Vital Signs 
Supine blood pressure (BP) and pulse rate (PR) will be measured at times specified in the 
SoA in the protocol. 
For both Periods, the baseline measurement is the predose measurement on Period 1 Day 1. 
Changes from baseline will be defined as the change between the baseline and postdose 
measurements. 
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. If not supplied, QTcF will be derived using 
Fridericia’s heart rate correction formula: 
QTcF = QT / (RR)^(1/3) where RR = 60/HR (if not provided) 
For both Periods, the baseline value is the average of the triplicate ECG measurements 
collected before dose administration on Period 1 Day 1. Changes from baseline will be 
defined as the change between the baseline ECG and the postdose ECG measurement. 
The maximum absolute value (postdose) and the maximum increase from baseline for QTcF 
over all measurements taken postdose will be determined. 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken. 
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. Classifications will be 
documented per standard operating procedures. 


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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 
assigned 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. 
Safety Analysis Set 
All participants who have received at least 1 dose of study 
intervention. Participants will be analyzed according to the 
product they actually received. 
PK Concentration Set 
All participants who are in the Safety Analysis Set and have 
at least 1 measurable concentration of CCI 
. 
PK Parameter Set 
All participants who are in the Safety Analysis Set and have 
at least 1 PK parameter of interest for CCI 
. 
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 
No statistical hypothesis will be tested in this study. 
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. 


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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 one 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 as anomalous by the pharmacokineticist. 
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 
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 or pharmacokineticist. 
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 
(not calculated; NC values will not be generated beyond the day that a participant 
discontinues). In summary tables, statistics will be calculated by setting NC values to 
missing; and statistics will be presented for a particular treatment with ≥3 evaluable 
measurements. PK parameter analyses will not be performed for a particular parameter if 
more than 50% of the data are NC. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed 
from the gastrointestinal tract), this will be footnoted in summary tables and will not be 
included in the calculation of summary statistics or statistical analyses. 
5.3.2. Safety Data 
Missing values in standard summaries of AEs, laboratory data, vital signs, and ECGs will be 
imputed according to CaPS. 


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6. ANALYSES AND SUMMARIES 
6.1. Primary Endpoints 
The primary endpoints plasma AUCinf (if data permit, otherwise AUClast) and Cmax of total 
dabigatran (sum of uncongugated and glucuronide-congugated dabigatran) 
alone and following administration of a single 200 mg dose of ARV-471 will be summarized 
descriptively by treatment and will include the set of summary statistics as specified in 
Table 3. 
Total dabigatran PK parameters following a single dose administration will be derived from 
the plasma concentration versus time profiles using non-compartmental methods, as data 
permit and as appropriate. The plasma concentrations of total dabigatran will be listed and 
descriptively summarized 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 for each analyte 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 comparison of total dabigatran only, AUCinf (as data permit), 
AUClast, and Cmax with and without ARV-471, box and whisker plots of these parameters will 
be plotted by treatment for each analyte. 
Natural log transformed parameters (AUCinf [if data permit], AUClast, and Cmax) of total 
dabigatran (sum of unconjugated or glucuronide-conjugated dabigatran) will be analyzed 
using a mixed effect model with treatment as a fixed effect and participant as a random 
effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
CIs will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CI for the ratios. Dabigatran administered alone will be the 
reference treatment and ARV-471 co-administered with dabigatran will be the test treatment. 
Residuals from the model 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 provided in the clinical study report. 
6.2. Secondary Endpoints 
Safety data will be analyzed in accordance with the CaPS (see Section 6.6). 
6.3. CCI 
 
 


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Table 3. PK Parameters to be Summarized Descriptively 
 
Parameter 
Summary Statistics 
AUCinf, AUClast, Cmax, 
CCI 
N, arithmetic mean, median, SD, %CV, minimum, maximum, 
geometric mean and geometric %CV 
Tmax, Tlast 
N, median, minimum, maximum 
t½ 
N, arithmetic mean, median, SD, %CV, minimum, maximum 
 
For comparison of total dabigatran only, AUCinf (as data permit), AUClast, and Cmax with and 
without ARV-471, box and whisker plots will be plotted as detailed in Section 6.1 under 
primary endpoints. 
Supporting data from the estimation of t1/2 and AUCinf will be listed by analyte and 
treatment: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of Kel. These data may be included in the 
clinical study report. 
PK concentration summaries: 
The plasma concentrations of CCI 
 will be listed and descriptively summarized by 
nominal PK sampling time and treatment (dabigatran etexilate alone in Period 1, and 
dabigatran etexilate following administration of ARV-471 in Period 2) for the PK 
Concentration Analysis Set. Individual participant and summary profiles (mean and median 
plots) of the plasma concentration-time data will be plotted by treatment using actual and 
nominal times, respectively. Mean and median plasma concentration profiles will be 
presented on both linear and semi-log scales. 
Presentations for plasma concentrations for each analyte will include: 
• A listing of all concentrations sorted by participant ID, period, treatment and nominal 
time postdose. The concentration listing will also include the actual times. Deviations 
from the nominal time will be provided in a separate listing. 
• A summary of concentrations by treatment and nominal time postdose, where the set of 
statistics will include n, mean, median, SD, %CV, minimum, maximum and the number 
of concentrations above the LLQ. 
• Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose). 


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• Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by treatment (all treatments on the same plot per scale, based on the summary of 
concentrations by treatment and time postdose). 
• Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment per 
scale). 
• Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant (containing 
all treatments) per scale]. 
6.4. Subset Analyses 
There are no planned subset analyses. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Demographic Summaries 
Demographic characteristics will be summarized for enrolled population in accordance with 
the CaPS. 
6.5.2. 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 (dabigatran etexilate 
alone in Period 1, and dabigatran etexilate following administration of ARV-471 in Period 
2). Data will be reported in accordance with the CaPS. 
6.5.3. Study Treatment Exposure 
Study treatment exposure will be listed. 
6.5.4. Concomitant Medications and Nondrug Treatments 
All concomitant medication(s) as well as non-drug treatment(s) will be reported in the 
listings. 
6.6. Safety Summaries and Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
6.6.1. 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. 


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6.6.2. Laboratory Data 
Laboratory data will be listed and summarized by treatment in accordance with the CaPS. 
6.6.3. Vital Signs 
Vital signs data will be listed and summarized by treatment in accordance with the CaPS. 
6.6.4. Electrocardiograms 
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. 
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
 
Safety QTcF Assessment 
 
Degree of 
Prolongation 
Mild (ms) 
Moderate (ms) 
Severe (ms) 
Absolute value 
>450-480 
>480-500 
>500 
Increase from 
baseline 
30-60 
>60 
 
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. 
7.1. Introduction 
Not applicable. 
7.2. Interim Analyses and Summaries 
Available safety and PK data may be reviewed. 


Protocol C4891008 (PF-07850327) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 17 of 19 
 
 
APPENDICES 
Appendix 1. SAS Code for Analyses 
An example of the PROC MIXED code is provided below: 
For the primary objective: 
• 
Treatment B (Test) vs Treatment A (Reference) 
proc mixed data=tab.pk; 
class trt participant; 
model l&var=trt / ddfm=KR; 
random participant / subject=participant; 
lsmeans trt; 
estimate 'B 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: single dose of dabigatran etexilate 75 mg 
B: single dose of 200 mg ARV-471 + single dose of dabigatran etexilate 75 mg 
*/ 


Protocol C4891008 (PF-07850327) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
Page 18 of 19 
 
 
Appendix 2. List of Abbreviations 
 
Abbreviation 
Term 
%CV 
coefficient of variation 
AE 
adverse event 
ANOVA 
analysis of variance 
AUCextrap% 
the percent of AUCinf based on extrapolation 
AUCinf 
area under the plasma concentration-time profile from time zero 
extrapolated to infinite time 
AUClast 
area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration 
BLQ 
below the limit of quantitation 
BP 
blood pressure 
CaPS 
Clinical Data Interchange Standards Consortium and Pfizer 
Standards 
CI 
confidence interval 
CL/F 
apparent clearance 
Clast 
last measurable observed concentration 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CSR 
clinical study report 
CYP3A 
cytochrome P450, family 3, subfamily A 
ECG 
electrocardiogram 
ER 
estrogen receptor 
HR 
heart rate 
kel 
elimination rate constant estimated from the log-linear regression 
analysis 
LLQ 
lower limit of quantitation 
ms 
milliseconds 
CCI 
N/A 
not applicable 
NC 
not calculated 
ND 
not done 
NS 
no sample 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
QRS 
Combination of Q-, R- and S- wave on an electrocardiogram 
representing ventricular depolarization 
QTc 
corrected QT 
QTcF 
corrected QT (Fridericia method) 


Protocol C4891008 (PF-07850327) Statistical Analysis Plan 
PFIZER CONFIDENTIAL 
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Abbreviation 
Term 
r2 
goodness of fit statistic from the log-linear regression 
rBA 
relative bioavailability 
RR 
respiratory rate 
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
schedule of activities 
t1/2 
terminal plasma elimination half-life 
TEAE 
treatment emergent adverse event 
Tlast 
time for Clast 
Tmax 
time for Cmax 
Vz/F 
apparent volume of distribution after oral dose