Conditions: Healthy
Allocation: NA | Intervention model: CROSSOVER
Enrollment: 12
Healthy volunteers: yes

Brief summary:
The purpose of this study is to understand if ARV-471 affects how a BCRP substrate (rosuvastatin) gets into the body in healthy adults.

All participants in this study will receive one dose of rosuvastatin alone by mouth in Period 1. In Period 2, everyone will receive one dose of ARV-471 by mouth 90 min before one dose of rosuvastatin by mouth. The levels of rosuvastatin in Period 1 will be compared to the levels of rosuvastatin in Period 2 to determine if ARV-471 affects how rosuvastatin gets into the body differently in healthy adults.

All participants will stay at the study clinic for 10 days and 9 nights.

Detailed description:

Arms:
arm 1: Rosuvastatin 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: Rosuvastatin
Intervention descriptions: intervention 1: Experimental intervention 2: Probe substrate

Protocol document:
Prot_000.pdf: 
ARV-471 (PF-07850327)
Protocol C4891029
Final Protocol, 04 November 2022
PFIZER CONFIDENTIAL
Page 1
                                            
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 ROSUVASTATIN IN HEALTHY 
PARTICIPANTS
Study Intervention Number:
PF-07850327
Study Intervention Name:
ARV-471
US IND Number:
EudraCT/CTIS Number:
Not Applicable
ClinicalTrials.gov ID:  
Not Applicable
Pediatric Investigational Plan Number:
Not Applicable
Protocol Number:
C4891029
Phase:
1
Brief Title: Phase 1 Study to Estimate the Effect of ARV-471 on Rosuvastatin 
Pharmacokinetics in Healthy Participants 
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.
CCI


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Protocol C4891029
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 C4891029
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 ....................................................................................................................14
1.3. Schedule of Activities .............................................................................................15
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.......................................................................................26
2.2.4.1. Summary of ARV-471 Pharmacokinetics in Humans ..............27
2.3. Benefit/Risk Assessment.........................................................................................28
2.3.1. Risk Assessment.........................................................................................29
2.3.2. Benefit Assessment.....................................................................................31
2.3.3. Overall Benefit/Risk Conclusion................................................................31
3. OBJECTIVES AND ENDPOINTS.....................................................................................31
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.2. Scientific Rationale for Study Design.....................................................................32
4.2.1. Probe Substrate Selection ...........................................................................32
4.2.2. Administration of Study Drugs With Food ................................................33
4.2.3. Inclusion of Females of Non-childbearing Potential..................................33
4.2.4. Inclusion of Male Participants....................................................................33
4.2.5. Choice of Contraception/Barrier Requirements .........................................35
4.2.6. Collection of Retained Research Samples..................................................35
4.3. Justification for Dose ..............................................................................................35
4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION......................................................................................................36
5.1. Inclusion Criteria.....................................................................................................37


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5.2. Exclusion Criteria....................................................................................................37
5.3. Lifestyle Considerations..........................................................................................40
5.3.1. Contraception..............................................................................................40
5.3.2. Meals and Dietary Restrictions...................................................................40
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................41
5.3.4. Activity .......................................................................................................41
5.4. Screen Failures ........................................................................................................41
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................42
6.1. Study Intervention(s) Administered........................................................................42
6.1.1. Administration............................................................................................43
6.2. Preparation, Handling, Storage, and Accountability...............................................43
6.2.1. Preparation and Dispensing........................................................................44
6.3. Assignment to Study Intervention...........................................................................45
6.4. Blinding...................................................................................................................45
6.4.1. Blinding of Participants..............................................................................45
6.4.2. Blinding of Site Personnel..........................................................................45
6.4.3. Blinding of the Sponsor..............................................................................45
6.5. Study Intervention Compliance...............................................................................45
6.6. Dose Modification...................................................................................................45
6.7. Continued Access to Study Intervention After the End of the Study......................45
6.8. Treatment of Overdose............................................................................................45
6.9. Prior and Concomitant Therapy..............................................................................46
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................47
7.1. Discontinuation of Study Intervention ....................................................................47
7.1.1. Liver Injury.................................................................................................47
7.1.2. ECG Changes..............................................................................................47
7.1.3. Potential Cases of Acute Kidney Injury .....................................................47
7.1.4. COVID-19 ..................................................................................................48
7.2. Participant Discontinuation/Withdrawal From the Study.......................................48
7.2.1. Withdrawal of Consent...............................................................................49
7.3. Lost to Follow-up....................................................................................................49


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8. STUDY ASSESSMENTS AND PROCEDURES...............................................................50
8.1. Administrative and Screening Procedures ..............................................................50
8.2. Efficacy Assessments..............................................................................................51
8.3. Safety Assessments .................................................................................................51
8.3.1. Physical Examinations................................................................................51
8.3.2. Vital Signs ..................................................................................................51
8.3.2.1. Blood Pressure and Pulse Rate..................................................51
8.3.3. Electrocardiograms.....................................................................................52
8.3.4. Clinical Safety Laboratory Assessments ....................................................53
8.3.5. COVID-19 Specific Assessments...............................................................53
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................53
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................54
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................55
8.4.2. Method of Detecting AEs and SAEs ..........................................................55
8.4.3. Follow-Up of AEs and SAEs......................................................................55
8.4.4. Regulatory Reporting Requirements for SAEs...........................................55
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................56
8.4.5.1. Exposure During Pregnancy......................................................56
8.4.5.2. Exposure During Breastfeeding ................................................58
8.4.5.3. Occupational Exposure .............................................................58
8.4.6. Cardiovascular and Death Events...............................................................58
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................58
8.4.8. Adverse Events of Special Interest.............................................................58
8.4.8.1. Lack of Efficacy........................................................................59
8.4.9. Medical Device Deficiencies......................................................................59
8.4.10. Medication Errors.....................................................................................59
8.5. Pharmacokinetics ....................................................................................................60
8.5.1. Pharmacokinetics for rosuvastatin..............................................................60
8.5.2. Pharmacokinetics for ARV-471 (PF-07850327) and ARV-473 (PF-
07850328) ........................................................................................................61


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8.6. Genetics...................................................................................................................61
8.6.1. Specified Genetics ......................................................................................61
8.6.2. Retained Research Samples for Genetics ...................................................61
8.7. Biomarkers ..............................................................................................................62
8.8. Immunogenicity Assessments.................................................................................62
8.9. Health Economics ...................................................................................................62
9. STATISTICAL CONSIDERATIONS ................................................................................62
9.1. Statistical Hypotheses .............................................................................................62
9.2. Analysis Sets ...........................................................................................................62
9.3. Statistical Analyses .................................................................................................63
9.3.1. Pharmacokinetic Analysis ..........................................................................63
9.3.2. Statistical Methods for PK Data .................................................................63
9.3.3. Safety Analyses ..........................................................................................64
9.3.3.1. Electrocardiogram Analyses......................................................64
9.3.4. Other Analyses............................................................................................65
9.4. Interim Analyses .....................................................................................................65
9.5. Sample Size Determination.....................................................................................65
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................67
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............67
10.1.1. Regulatory and Ethical Considerations ....................................................67
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................67
10.1.2. Financial Disclosure .................................................................................68
10.1.3. Informed Consent Process ........................................................................68
10.1.4. Data Protection .........................................................................................69
10.1.5. Committees Structure ...............................................................................69
10.1.5.1. Data Monitoring Committee ...................................................69
10.1.6. Dissemination of Clinical Study Data ......................................................69
10.1.7. Data Quality Assurance ............................................................................70
10.1.8. Source Documents....................................................................................72
10.1.9. Study and Site Start and Closure ..............................................................72
10.1.10. Publication Policy...................................................................................73


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10.1.11. Sponsor’s Medically Qualified Individual..............................................74
10.1.12. Transfer of Obligations Statement..........................................................74
10.2. Appendix 2: Clinical Laboratory Tests .................................................................75
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................76
10.3.1. Definition of AE .......................................................................................76
10.3.2. Definition of an SAE ................................................................................77
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................78
10.3.4. Reporting of SAEs....................................................................................82
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................83
10.4.1. Male Participant Reproductive Inclusion Criteria....................................83
10.4.2. Female Participant Reproductive Inclusion Criteria.................................83
10.4.3. Woman of Childbearing Potential ............................................................83
10.4.4. Contraception Methods.............................................................................84
10.5. Appendix 5: Genetics............................................................................................87
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......88
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ............................................90
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................90
10.7.2. Age-Specific Kidney Function Calculation Recommendations...............90
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................90
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................90
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................91
10.9. Appendix 9: Abbreviations ...................................................................................93
11. REFERENCES ..................................................................................................................99


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LIST OF TABLES
Table 1.
Period 1 (Rosuvastatin) and Period 2 (Rosuvastatin with ARV-471)......15
Table 2.
Period 1 (Single Oral Dose of Rosuvastatin): PK and ECG 
Sampling Schedule ...................................................................................20
Table 3.
Period 2 (Single Oral Dose of Rosuvastatin with ARV-471): PK 
and ECG Sampling Schedule....................................................................21
Table 4.
Exposure Margin Determination for Testicular Toxicity in Rat and 
Dog Toxicity Studies ................................................................................34
Table 5.
PK Parameters ..........................................................................................63
Table 6.
Protocol-Required Safety Laboratory Assessments .................................75






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Study Population:
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
1. Male and/or female participants of non-childbearing potential must be 18 to 65 years 
of age, inclusive at the time of signing ICD. 
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical exam, laboratory tests, vital sign and 
standard 12-lead ECGs.
3. BMI of 17.5 to 32 kg/m2; and a total body weight ≥45 kg.
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 which includes compliance with 
requirements and restrictions listed in the ICD and in this protocol.
Exclusion Criteria 
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).
2. Pregnant female participants; breastfeeding female participants; Male participants 
with partners currently pregnant; fertile male participants who have partners of 
childbearing potential and 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. Participants with known history of hypersensitivity to statin medication, sensitivity to 
ARV-471 or rosuvastatin or any of the formulation components of ARV-471 or 
rosuvastatin.
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.
5. Use of prescription or nonprescription medications, including vitamins, dietary and 
herbal supplements, within 7 days or 5 half-lives (whichever is longer) prior to the 


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first dose of study intervention. Additionally, a longer washout is required for the 
medications below:

Moderate or strong CYP3A/BCRP inducers which are prohibited within 14 days 
plus 5 half-lives prior to the first dose of study intervention. 

Moderate or strong CYP3A/BCRP inhibitors which are prohibited within 14 days 
or 5 half-lives (whichever is longer) prior to the first dose of study intervention. 
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). 
7. A positive urine drug test.
8. Screening supine BP ≥140 mm Hg (systolic) when age 60 years, ≥150 mm Hg 
(systolic) when age ≥60 years, or ≥90 mm Hg (diastolic), following at least 5 minutes 
of supine rest. If BP is ≥140 mm Hg (systolic) when age 60 years, ≥150 mm Hg 
(systolic) when age ≥60 years, 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, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV 
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT 
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice 
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant.
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 >ULN;

Total bilirubin level >ULN; 

Renal impairment as defined by an eGFR in adults of ≤60 mL/min/1.73m2.  

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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. 
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. Unwilling or unable to comply with lifestyle requirements described in this protocol.
15. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
Study Arms and Duration:
The fixed sequence study will consist of 2 periods: Period 1 = single oral dose of rosuvastatin 
alone; Period 2 = single oral dose of ARV-471 + single oral dose of rosuvastatin with 
staggered dosing times. A washout of at least 5 days must occur between the 2 successive 
single doses of rosuvastatin. Following administration of rosuvastatin in each period, 
participants will undergo serial PK sampling.
Study Intervention(s)
Intervention Name
ARV-471 (PF-07850327)
Rosuvastatin (CRESTOR®)
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
10 mg
Route of Administration
Oral
Oral
Use
Experimental
Experimental treatment to assess as 
probe substrate in current DDI study
IMP or NIMP/AxMP
IMP
NIMP/AxMP
Statistical Methods:
A sufficient number of participants will be screened to ensure that at least 12 participants will 
be enrolled in the study. The sample size is empirically selected and is not based on statistical 
power calculation. A sample size of 12 PK evaluable participants who have at least 1 of the 
rosuvastatin PK parameters of primary interest (AUCinf or Cmax) is expected to provide 90% 


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CIs for the difference between treatments of 
and 
 on the natural log scale for 
AUCinf and Cmax, respectively, with 80% coverage probability.
The plasma concentrations of rosuvastatin 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 period 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 
rosuvastatin AUCinf and Cmax with and without ARV-471, box and whisker plots of these 
parameters will be plotted by period.
Natural log transformed parameters (AUCinf [if data permit)], AUClast, and Cmax) of 
rosuvastatin will be analyzed using a mixed effect model with treatment as fixed effects and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% 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. Rosuvastatin 
administered alone will be the reference treatment and ARV-471 co-administered with 
rosuvastatin will be the test treatment.
Ethical Considerations:
Neither ARV-471 nor rosuvastatin will provide 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 in an area of unmet medical need.
1.2. Schema
Not applicable.
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Table 2.
Period 1 (Single Oral Dose of Rosuvastatin): PK and ECG Sampling Schedule
Visit Identifier 
Abbreviations used in this 
table maybe found in 
Appendix 9
Period 1 (Single oral dose of rosuvastatin)
Notes
Study Day
Day 1
Day 2
Day 3
Day 4
Hours Before/After Dose
0
1
2
3
4
6
8
12
24
36
48
72
Hour 0 = predose sample collection
Rosuvastatin administration
X

Refer to Section 6.1.1 for details of 
administration requirement.
Rosuvastatin PK blood 
sampling 
X
X
X
X
X
X
X
X
X
X
X
X

Refer to Section 8.5 for additional 
details.
12-Lead ECG
X
(triplicate)

Triplicate ECG will be collected for 
baseline measurement at pre-dose.
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.

See Section 8.3.3 for details.
Vital signs (BP/PR)
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.

See Section 8.3.2 for details.
















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2.3. Benefit/Risk Assessment
Neither ARV-471 nor rosuvastatin are expected to provide any clinical benefit to healthy 
participants. This study is designed primarily to generate safety, tolerability, and PK 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 rosuvastatin is the USPI of Crestor®.
















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ARV-471 Cmax for 
 and AUCinf for 
, as compared with fasted 
conditions. A single oral dose of 200 mg ARV-471 has been well tolerated in healthy 
participants, and 
 of 
 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.  
Rosuvastatin is a synthetic statin that has been developed for the treatment of patients with 
dyslipidemia. Rosuvastatin is administered orally and approximately 50% of the drug is 
absorbed resulting in 20% absolute bioavailability8. As the maximum contribution of 
intestinal BCRP to restricting rosuvastatin absorption is 50%, the impact of inhibiting 
intestinal BCRP by ARV-471 on rosuvastatin systemic exposure is expected to be less than 
2-fold. Inhibition of liver BCRP by ARV-471 is not expected to play a major role in potential
rosuvastatin systemic exposure increase.
In a single dose escalation study, rosuvastatin was safe and well tolerated at doses up to 
80 mg9. The most common AEs reported were headache and rash. There was no evidence of 
a relationship between the frequency of AEs and rosuvastatin dose. No SAEs were reported.
The therapeutic dose of rosuvastatin is from 5 mg up to 40 mg, and most DDI studies 
involving rosuvastatin as a substrate were conducted at the 10 mg or 20 mg dose level10,11,12,2. 
Administration with food (low-fat or high-fat) was reported to result in a near 40% reduction 
of rosuvastatin exposure13 while CRESTOR® USPI claims administration with food did not 
affect the AUC of rosuvastatin. However, 10 mg single dose with potential food effect should 
still lead to sufficient amount in the plasma for detection.
Rosuvastatin is not extensively metabolized through CYP450 pathway and 
 
 Thus, the single dose combination of 200 mg ARV-471 and 
10 mg rosuvastatin is expected to be generally safe and well tolerated by healthy participants.
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.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male and/or female participants of non-childbearing potential must be 18 to 65 years 
of age, inclusive at the time of signing ICD. Refer to Appendix 4 for reproductive 
criteria for male (Section 10.4.1) and female (Section 10.4.2) participants. 
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical exam, laboratory tests, vital sign and 
standard 12-lead ECGs.
Other Inclusion Criteria: 
3. BMI of 17.5 to 32 kg/m2; and a total body weight ≥45 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). 

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 at the time of admission.
2. Pregnant female participants; breastfeeding female participants; Male participants 
with partners currently pregnant; fertile male participants who have partners of 


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childbearing potential and 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. Participants with known history of hypersensitivity to statin medication. Participants 
with known history of sensitivity to ARV-471 or rosuvastatin or any of the 
formulation components of ARV-471 or rosuvastatin.
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, within 7 days or 5 half-lives (whichever is longer) prior to the 
first dose of study intervention. Additionally, a longer washout is required for the 
medications below:

Moderate or strong CYP3A/BCRP inducers which are prohibited within 
14 days plus 5 half-lives prior to the first dose of study intervention. 

Moderate or strong CYP3A/BCRP 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.
8. Screening supine BP ≥140 mm Hg (systolic) when age 60 years, ≥150 mm Hg 
(systolic) when age ≥60 years, or ≥90 mm Hg (diastolic), following at least 5 minutes 
of supine rest. If BP is ≥140 mm Hg (systolic) when age 60 years, ≥150 mm Hg 
(systolic) when age ≥60 years 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.


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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, ST-T 
interval changes suggestive of myocardial ischemia, second- or third- degree AV
block, or serious bradyarrhythmias or tachyarrhythmias). If the uncorrected QT
interval is >450 ms, this interval should be rate-corrected using the Fridericia method 
only and the resulting QTcF should be used for decision making and reporting. If 
QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice
and the average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant.
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 >ULN;

Total bilirubin level >ULN; 

Renal impairment as defined by an eGFR in adults of ≤60 mL/min/1.73m2. Based 
upon participant age at screening, eGFR is calculated using the recommended 
CKD-EPI formulas in Section 10.7.2 to determine eligibility and to provide a 
baseline to quantify any subsequent kidney safety events.  

Hypothyroidism
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. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
14. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
15. 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.


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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 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 rosuvastatin dose.

Water may be consumed without restriction except from 1 hour before to 1 hour after 
rosuvastatin dosing. In Period 2 Day 1, water is not allowed after ARV-471 dosing 
and before rosuvastatin dosing. 

On dosing days (Day 1 of Period 1 and 2), participants will be provided the 
recommended standard breakfast of approximately 700 calories with a fat content of 
approximately 35% 2 hours (120 minutes) prior to rosuvastatin administration. This 
meal will be consumed within a 20-minute period without study intervention 
(Period 1 Day 1) or with ARV-471 (Period 2 Day 1) administered within 
approximately 10 minutes after completion of the meal. The provided meal must be 
completely consumed prior to administration of ARV-471 (a single oral 200 mg dose 
with approximately 240 mL of ambient temperature water).

On non-dosing days, participants can resume normal intake of both food and water.

Noncaffeinated drinks (except grapefruit or grapefruit related citrus fruit juices—see 
below) may be consumed with meals and the evening snack.  


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
Lunch will be provided approximately 4 hours after rosuvastatin dosing.

Dinner will be provided approximately 9 to 10 hours after rosuvastatin dosing.

An evening snack may be permitted.

Participants will refrain from consuming grapefruit, grapefruit containing products or 
grapefruit related citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 14 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 refrain from consuming red wine from 7 days prior to the first dose 
of study intervention until collection of the final PK blood sample.  

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. 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 study medication 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.


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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 rosuvastatin (CRESTOR®) 10 mg tablet.
6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
ARV-471 (PF-07850327)
Rosuvastatin (CRESTOR®)
Arm Name
(group of participants 
receiving a specific 
treatment or no 
treatment)
Period 2 only
Period 1 and 2
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
100 mg 
10 mg
Dosage Level(s)
200 mg
10 mg
Route of Administration
Oral
Oral
Use
Experimental
Experimental treatment to assess as probe 
substrate in current DDI study
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)
Rosuvastatin (CRESTOR®)


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ARV-471 tablets will be supplied to the CRU as packaged bottles and labeled according to 
local regulatory requirements. The bottles will be provided to the site for dispensing by the 
pharmacy. 
Rosuvastatin (CRESTOR®) tablets 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 rosuvastatin
(as 1 tablet of 10 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 rosuvastatin (as 1 tablet of 10 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. 
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 rosuvastatin (as 1 tablet of 10 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 meal with ambient temperature water 
to a total volume of approximately 240 mL. Investigator site personnel will administer 
rosuvastatin (as 1 tablet of 10 mg) approximately 1.5 hours (90 minutes) after the ARV-471 
dosing with ambient temperature water to a total volume of approximately 240 mL, which is 
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. 
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 


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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.
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 and rosuvastatin tablets 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). A second staff member will verify the dispensing. The 


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tablets 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. 
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 
time of dosing by a member of the study site staff other than the person administering the 
study intervention. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
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 rosuvastatin greater than 10 mg
within a 24-hour time period will be considered an overdose.
There is no specific treatment for an overdose of ARV-471 or rosuvastatin.


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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 days 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, 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. Additionally, a longer washout 
is required for the medications below:

Moderate or strong CYP3A/BCRP inducers which are prohibited within 14 days plus
5 half-lives prior to the first dose of study intervention. 

Moderate or strong CYP3A/BCRP inhibitors which are prohibited within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study intervention. 
Limited use of nonprescription medications that are not believed to affect participant safety 
or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor. Acetaminophen/paracetamol may be used at doses of ≤1 g/day.
Females taking hormone replacement therapy may be eligible to participate in this study if 
they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. 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.


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: 

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.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, post-treatment study follow-up, 
and/or future collection of additional information.
7.1.1. Liver Injury
Reasons for permanent discontinuation of study intervention due to potential liver injury are 
described in Appendix 6.
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.


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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 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. 
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.


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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.
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. 


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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 
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.
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 
170 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.


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To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy 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 complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
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.


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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. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to the baseline measurement on Period 1 Day 1. 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.


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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.
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 Specific Assessments
Participants will undergo COVID-19 related measures per CRU 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 


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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.
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.


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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.
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.


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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.
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 


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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 
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 


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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.
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 


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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 
 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 
Section 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. 
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.
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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 rosuvastatin is detailed 
in Section 8.5.1. Blood sample collection for measurements of plasma concentration of 
ARV-471 and ARV-473 is detailed in Section 8.5.2.
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 
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. 
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 rosuvastatin
Blood samples of approximately 4 mL, to provide approximately 1.6 mL plasma, will be 
collected for measurement of plasma concentrations of rosuvastatin as specified in the SoA.
Instructions for the collection and handling of biological samples will be provided in the 




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8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
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 hypotheses 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 
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol.
Full analysis set 
All participants who take at least 1 dose of study intervention.
Safety analysis set
All participants enrolled and who take 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 rosuvastatin concentration measured.
PK Parameter Set
All participants who are in the Safety Analysis Set and have at 
least 1 PK parameter of interest (Cmax or AUC of rosuvastatin).


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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 will be derived from the concentration-time profiles as detailed in 
Table 5 for each analyte and treatment if applicable. 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.
PK Parameters
Parameter
Definition 
Method of Determination
AUClast
Area under the concentration-time 
profile from time 0 to the time of 
last quantifiable concentration 
(Clast).
Linear/Log trapezoidal method.
AUCinfa
Area under the concentration-time 
profile from time 0 extrapolated to 
infinite time.
AUClast + (Clast*/kel), Where Clast* is the predicted 
concentration at the last quantifiable time point 
estimated from the log-linear regression analysis and 
kel is the terminal phase rate constant calculated by a 
linear regression of the log-linear concentration-time 
curve.
Cmax
Maximum concentration
Observed directly from data.
Clast
Last measurable observed 
concentration
Observed directly from data.
Tmax
Time for Cmax
Observed directly from data.
Tlast
Time for Clast
Last measurable observed concentration
t½a
Terminal elimination half-life
Loge(2)/kel,. Only those data points judged to describe 
the terminal log-linear decline will be used in the 
regression.
CL/Fa
Apparent clearance
Dose/(AUCinf )
Vz/F a
Apparent volume of distribution
Dose/(AUCinf *kel)
 
 
a. if data permit and as appropriate.
9.3.2. Statistical Methods for PK Data
The plasma concentrations of rosuvastatin 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 period 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 
rosuvastatin AUCinf and Cmax with and without ARV-471, box and whisker plots of these 
parameters will be plotted by period.
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Natural log transformed parameters (AUCinf [if data permit)], AUClast, and Cmax) of 
rosuvastatin will be analyzed using a mixed effect model with treatment as fixed effects and 
participant as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% 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. Rosuvastatin
administered alone will be the reference treatment and ARV-471 co-administered with 
rosuvastatin will be the test treatment.
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 period 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 period: 
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


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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 sufficient number of participants will be screened to ensure that at least 12 participants will 
be enrolled in the study.
The sample size is empirically selected and is not based on hypothesis testing. A sample size 
of 12 PK evaluable participants who have at least 1 of the rosuvastatin PK parameters of 
primary interest (AUCinf or Cmax) is expected to provide 90% CIs for the difference between 
treatments of 
and 
on the natural log scale for AUCinf and Cmax, respectively, 
with 80% coverage probability. The following table presents the width of 90% CI for 
different estimated effects:
Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
AUCinf
100%
120%
140%
160%
180%
200%
0.8569, 1.1671
1.0282, 1.4005
1.1996, 1.6339
1.3710, 1.8673
1.5423, 2.1007
1.7137, 2.3341
0.3102
0.3722
0.4343
0.4963
0.5584
0.6204
CCI
CCI


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Parameter
Estimated Effect 
(100*Test/Reference)
90% CI
CI Width
Cmax
100%
120%
140%
160%
180%
200%
0.8387, 1.1923
1.0065, 1.4308
1.1742, 1.6692
1.3420, 1.9077
1.5097, 2.1461
1.6774, 2.3846
0.3536
0.4243
0.4950
0.5657
0.6364
0.7071
These calculations are based on estimates of within subject standard deviations of
and 
for loge AUCinf and loge Cmax respectively, as average intrasubject standard deviations 
obtained from previously completed rosuvastatin crossover studies 
 
and one external study13.
CCI
CCI
CCI


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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.


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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 sponsor’s designee (Pfizer CRU).
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor’s designee (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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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)
MCV, MCH, MCHC 
BUN/Urea and creatinine
CystatinC and eGFR
Glucose (fasting)
Calcium
Creatine kinase
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
COVID-19 testing (per
CRU procedures)
Urine drug screeningc
At screening:

FSHd

TSH

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 and 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 will be performed as reflex testing for any participant who is HBsAg and 
HBcAb positive.
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. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. 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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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.
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 
occupational exposure 
to the product under 
study to a 
nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
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.








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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 or homosexual 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 a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

Agree to use a male condom, 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) 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.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 


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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.
* 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;


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
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”.
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations 
(>2 × ULN) by several days or weeks. The increase in T bili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and T bili values will be 
elevated within the same laboratory sample). In rare instances, by the time T bili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of  ≥1 × ULN or if the value reaches ≥3 × ULN
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.


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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr 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 Equations14
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
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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10.9. Appendix 9: 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
ARV-471
PF-07850327
ARV-473
the epimer metabolite of ARV-471
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-144
area under the concentration-time curve from time zero to 
144 hours
AUC0-24
area under the concentration-time curve from time zero to 
24 hours
AUCinf
area under the concentration-time curve from time zero 
extrapolated to infinity
AUCtau
area under concentration-time curve over dosing interval
AUClast
area under the concentration-time profile from time 0 to the 
time of last quantifiable concentration (Clast).
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
BUN
blood urea nitrogen
CBC
complete blood count
CBR
clinical benefit rate
CES
carboxylesterase
CFR
Code of Federal Regulations
CI
confidence interval


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Abbreviation
Term
CIOMS
Council for International Organizations of Medical 
Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
CL/F
apparent clearance after oral dose
Clast
last quantifiable concentration
Cmax
maximum observed concentration
CNS
central nervous system
CoA
coenzyme A
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
CTMS
Clinical Trial Management System
CV
cardiovascular
CYP
cytochrome P450
CYP3A
Cytochrome P450 3A
CYP3A4
Cytochrome P450 3A4
DC50
Concentration at 50% degradation
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DL
drug load
DLT
dose-limiting toxicity
E-DMC
External Data Monitoring Committee
EC
ethics committee; exclusion criteria
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
ESR1
estrogen receptor 1
ET
endocrine therapy


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Abbreviation
Term
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical 
Trials (European Clinical Trials Database)
FDA
The United States Food and Drug Administration
FE
food effect
FIH
first in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gammaglutamyl 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
HER2
human epidermal growth factor receptor 2
Herg
human ether-à-go-go-related gene
Hgb
hemoglobin 
HIV
human immunodeficiency virus
HMG
hydroxy-3-methylglutaryl
HR
heart rate
HRT
hormone replacement therapy
hs-CRP
high-sensitivity C-reactive protein
HV
healthy volunteer
IB
Investigator’s Brochure
IC
inclusion criteria
IC50
half-maximal inhibitory concentration
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
Identification
IMNM
Immune-mediated necrotizing myopathy 
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)




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Abbreviation
Term
PR
pulse rate
PROTAC®
PROteolysis TArgeting Chimeric
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PTH
parathormone
PVC
premature ventricular contraction/complex
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
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
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
terminal elimination half-life
T bili
total bilirubin
TEAE
treatment emergent adverse event
TGI
tumor growth inhibition
THC
tetrahydrocannabinol
TK
toxicokinetics
Tlast
the time for last quantifiable concentration
Tmax
the time for maximum observed concentration
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


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Abbreviation
Term
UTI
urinary tract infection
VE
venous embolism
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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11. REFERENCES
1
Lee, CA, O’Connor MA, Ritchie TK, et al, Breast cancer resistance protein (ABCG2) in 
clinical pharmacokinetics and drug interactions: practical recommendations for clinical 
victim and perpetrator drug-drug interaction study design. Drug Metab Dispos 2015; 
43(4): 490-509.
2
Trivedi, A, Sohn W, Kulkarni P, et al, Evaluation of drug-drug interaction potential 
between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study 
in healthy subjects and using a physiologically-based pharmacokinetic model. Clin 
Transl Sci. 2021;14:2510–2520.
3
FDA Guidance for Industry. In vitro drug interaction studies – Cytochrome P450 
enzyme- and transporter-mediated drug interactions. January 2020. Available from: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-drug-
interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-
interactions.
4
CRESTOR®(rosuvastatin calcium) [Prescription Information]. Wilminton, DE: 
Astrazeneca Pharmaceuticals LP; 2021.
5
Lu CC and Meistrich ML, Cytotoxic effects of chemotherapeutic drugs on mouse testis 
cells. Cancer Res. 1979;39(9):3575-82.
6
Meistrich, ML, Finch M, da Cunha MF et al, Damaging effects of fourteen 
chemotherapeutic drugs on mouse testis cells. Cancer Res, 1982. 42(1):122-31.
7
ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals. Version date: January 2010. Accessed on: 
06 Sep 2022.
8
Martin, PD, Warwick MJ, Dane AL, et al, Absolute oral bioavailability of rosuvastatin 
in healthy white adult male volunteers. Clin Ther, 2003. 25(10): 2553-63.
9
Martin, PD, Warwick MJ, Dane AL, et al, A double-blind, randomized, incomplete 
crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers. 
Clin Ther 2003;25(8):2215-24.
10
Martin P, Gillen M, Ritter J, et al. Effects of fostamatinib on the pharmacokinetics of 
oral contraceptive, warfarin, and the statins rosuvastatin and simvastatin: results from 
Phase I clinical studies. Drugs RD 2016;16(1):93-107.
                                                


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11
Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics 
of rosuvastatin. Clin Pharmacol Ther 2003;73(4):322-9.
12
Stopfer P, Giessmann T, Holh K, et al. Effects of metformin and furosemide on 
rosuvastatin pharmacokinetics in healthy volunteers: implications for their use as probe 
drugs in a transporter cocktail. Eur J Drug Metab Pharmacokinet 2018;43(1): 69-80.
13
McLean CC, Teft WA, Morse BL, et al. Food Effect on Rosuvastatin Disposition and 
Low-Density Lipoprotein Cholesterol. Clin Pharmacol Ther. 2018 Sep;104(3):525-533. 
doi: 10.1002/cpt.973. Epub 2018 Jan 8. PMID: 29218707.
14
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;385:1737-49.

SAP_001.pdf: 
Protocol C4891029 (PF-07850327) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1 of 18
Protocol C4891029
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 
Rosuvastatin in Healthy Participants
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
23 Jan 2023


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Modifications to the Analysis Plan Described in the Protocol..................................4
2.2. Study Objectives, Endpoints, and Estimands............................................................4
2.3. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Primary Endpoints.....................................................................................................6
3.2. Secondary Endpoints.................................................................................................8
3.3. Other Endpoints.........................................................................................................8
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................8
3.5.2. Laboratory Data............................................................................................8
3.5.3. Vital Signs ....................................................................................................9
3.5.4. Electrocardiograms.......................................................................................9
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary/Categorical Endpoints ...............................................10
5.2.2. Analyses for Continuous Endpoints ...........................................................10
5.3. Methods to Manage Missing Data ..........................................................................10
5.3.1. Pharmacokinetic Data.................................................................................10
5.3.2. Safety Data..................................................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................12
6.1. Primary Endpoints...................................................................................................12
6.2. Secondary Endpoints...............................................................................................12
6.3. Other Endpoints.......................................................................................................12


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6.4. Subset Analyses.......................................................................................................14
6.5. Baseline and Other Summaries and Analyses.........................................................14
6.5.1. Demographic Summaries............................................................................14
6.5.2. Study Conduct and Participant Disposition................................................14
6.5.3. Study Treatment Exposure .........................................................................14
6.5.4. Concomitant Medications and Nondrug Treatments..................................14
6.6. Safety Summaries and Analyses .............................................................................14
6.6.1. Adverse Events...........................................................................................14
6.6.2. Laboratory Data..........................................................................................14
6.6.3. Vital Signs ..................................................................................................14
6.6.4. Electrocardiograms.....................................................................................15
7. INTERIM ANALYSES.......................................................................................................15
7.1. Introduction .............................................................................................................15
7.2. Interim Analyses and Summaries............................................................................15
APPENDICES .........................................................................................................................16
LIST OF TABLES
Table 1. Summary of Changes...................................................................................................4
Table 2. PK Parameters..............................................................................................................7
Table 3. PK Parameters to be Summarized Descriptively.......................................................12
APPENDICES
Appendix 1. SAS Code for Analyses.......................................................................................16
Appendix 2. List of Abbreviations...........................................................................................17


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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/
23 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.
Rosuvastatin is a prototypical substrate of BCRP. Administration of rosuvastatin with 
ARV-471 may lead to increased systemic exposure of rosuvastatin. The objective of this study 
is to estimate the effect of ARV-471 on the PK of rosuvastatin in healthy participants.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4891029.  
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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will be collected up to 72 hours following administration of rosuvastatin in each period to 
estimate the single dose PK parameters of rosuvastatin.
A sufficient number of participants will be screened to ensure that at least 12 participants 
will be enrolled in the study. Participants who withdraw may be replaced at the discretion of 
the sponsor.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The primary endpoints of the study are plasma Cmax, AUCinf (or AUClast if AUCinf cannot be 
reliably estimated) of rosuvastatin alone and following co-administration with a single oral 
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 of rosuvastatin will be derived from the concentration-time 
profiles as detailed in Table 2 for each period if applicable. 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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(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.
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 


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Participant Analysis Set
Description
assignment to study intervention. A participant will be 
considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening. 
Potential participants who are screened for the purpose of 
determining eligibility for the study, but do not participate in 
the study, are not considered enrolled, unless otherwise 
specified by the protocol. 
Safety Analysis Set
All participants enrolled and who take 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 rosuvastatin concentration measured.
PK Parameter Set
All participants who are in the Safety Analysis Set and have 
at least 1 PK parameter of interest (Cmax or AUC of 
rosuvastatin).
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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Supporting data from the estimation of t½ 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.  This data may be included in the clinical study 
report.
PK concentration summaries:
The plasma concentrations of each analyte will be listed and descriptively summarized by 
nominal PK sampling time and treatment for the PK Concentration 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).

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].


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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 and will show 
which participants were analyzed for pharmacokinetics, as well as for safety. Frequency 
counts will be supplied for participant discontinuation(s) by treatment. 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.
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.


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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.


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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 rosuvastatin 10 mg
B: single dose of 200 mg ARV-471 + single dose of rosuvastatin 10 mg
*/




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Abbreviation
Term
RR
respiratory rate
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
t1/2
terminal 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