A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of Vupanorsen (PF-07285557) in Statin-Treated Participants With Dyslipidemia
Phase: PHASE2
Conditions: Dyslipidemias, Hyperlipidemias, Hyperlipoproteinemias
Sponsor: Pfizer

Vupanorsen
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Title Page
A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 
Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of Vupanorsen 
(PF-07285557) in Statin-Treated Participants with Dyslipidemia
Compound: Vupanorsen (PF-07285557)
Regulatory Agency Identifier Number(s)
Registry
ID
IND
137,233
EudraCT
2020-002796-35
Protocol Number: C4491011
Amendment Number: 1
Phase: Phase 2b
Short Title: A Phase 2b Dose-Ranging Study with Vupanorsen (PF-07285557) 
(TRANSLATE-TIMI 70)
 
 

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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Amendment 1
18 September 2020

Section 10.13 (Appendix 13): New 
appendix was added describing 
alternative measures that may be 
allowed during a public emergency, 
such as COVID-19.

The Protocol Summary was revised as 
appropriate for consistency with 
changes in the body of the document.
Title page, Schedule of Activities, 
Section 2.1, Section 9.2, Section 10.14
(Appendix 14): Administrative changes 
were made for clarification.
Original protocol
03 June 2020
Not applicable
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs.

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TABLE OF CONTENTS
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities (SoA)...................................................................................15
2. INTRODUCTION ...............................................................................................................19
2.1. Study Rationale .......................................................................................................19
2.2. Background .............................................................................................................19
2.2.1. Atherosclerotic Cardiovascular Disease.....................................................19
2.2.2. Hypertriglyceridemia..................................................................................20
2.2.3. Rationale for ANGPTL3 Inhibition............................................................21
2.2.4. Clinical Overview.......................................................................................21
2.3. Benefit/Risk Assessment.........................................................................................22
2.3.1. Risk Assessment.........................................................................................23
2.3.2. Benefit Assessment.....................................................................................25
2.3.3. Overall Benefit/Risk Conclusion................................................................25
3. OBJECTIVES AND ENDPOINTS.....................................................................................25
4. STUDY DESIGN.................................................................................................................26
4.1. Overall Design.........................................................................................................26
4.2. Scientific Rationale for Study Design.....................................................................28
4.3. Justification for Dose ..............................................................................................28
4.4. End of Study Definition ..........................................................................................29
5. STUDY POPULATION......................................................................................................29
5.1. Inclusion Criteria.....................................................................................................29
5.2. Exclusion Criteria....................................................................................................30
5.3. Lifestyle Considerations..........................................................................................32
5.3.1. Contraception..............................................................................................32
5.3.2. Dietary Restrictions and Fasting.................................................................32
5.4. Screen Failures ........................................................................................................33
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study 
Intervention Administration ......................................................................................33
6. STUDY INTERVENTION..................................................................................................33

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6.1. Study Intervention(s) Administered........................................................................34
6.1.1. Administration............................................................................................35
6.1.2. Medical Devices .........................................................................................35
6.2. Preparation/Handling/Storage/Accountability ........................................................35
6.2.1. Preparation and Dispensing........................................................................37
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................37
6.3.1. Allocation to Study Intervention ................................................................37
6.3.2. Breaking the Blind......................................................................................37
6.4. Study Intervention Compliance...............................................................................38
6.5. Concomitant Therapy..............................................................................................38
6.5.1. Prohibited Therapy During the Study.........................................................38
6.5.2. Prohibited Prior Treatments........................................................................39
6.5.3. Rescue Medicine.........................................................................................39
6.6. Dose Modification...................................................................................................39
6.7. Intervention After the End of the Study..................................................................39
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................39
7.1. Discontinuation of Study Intervention ....................................................................40
7.1.1. Monitoring Criteria.....................................................................................40
7.1.2. Discontinuation Criteria..............................................................................41
7.2. Participant Discontinuation/Withdrawal From the Study.......................................41
7.2.1. Withdrawal of Consent...............................................................................42
7.3. Lost to Follow-up....................................................................................................42
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................43
8.1. Efficacy Assessments..............................................................................................44
8.1.1. Lipids ..........................................................................................................44
8.1.2. Lipoproteins and FFA.................................................................................44
8.1.3. hsCRP .........................................................................................................44
8.2. Safety Assessments .................................................................................................44
8.2.1. MRI-PDFF Assessments ............................................................................44
8.2.2. Physical Examinations................................................................................45
8.2.3. Vital Signs ..................................................................................................45

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8.2.4. Electrocardiograms.....................................................................................46
8.2.5. Clinical Safety Laboratory Assessments ....................................................46
8.2.6. Pregnancy Testing ......................................................................................47
8.2.7. Potential Severe Cases of Hypertriglyceridemia........................................47
8.3. Adverse Events and Serious Adverse Events..........................................................47
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......48
8.3.2. Method of Detecting AEs and SAEs ..........................................................49
8.3.3. Follow-up of AEs and SAEs.......................................................................49
8.3.4. Regulatory Reporting Requirements for SAEs...........................................49
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................50
8.3.6. Cardiovascular and Death Events...............................................................52
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................52
8.3.8. Adverse Events of Special Interest.............................................................52
8.3.9. Medical Device Deficiencies......................................................................53
8.3.10. Medication Errors.....................................................................................54
8.4. Treatment of Overdose............................................................................................55
8.5. Pharmacokinetics ....................................................................................................55
8.6. Pharmacodynamics..................................................................................................56
8.7. Genetics...................................................................................................................57
8.7.1. Specified Genetics ......................................................................................57
8.7.2. Banked Biospecimens for Genetics............................................................57
8.8. Biomarkers ..............................................................................................................57
8.8.1. Banked Biospecimens for Biomarkers .......................................................57
8.9. Immunogenicity Assessments.................................................................................57
8.10. Health Economics .................................................................................................58
9. STATISTICAL CONSIDERATIONS ................................................................................58
9.1. Estimands and Statistical Hypotheses.....................................................................59
9.1.1. Estimands....................................................................................................59
9.2. Sample Size Determination.....................................................................................59
9.3. Analysis Set.............................................................................................................59
9.4. Statistical Analyses .................................................................................................60

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9.4.1. General Considerations...............................................................................60
9.4.2. Primary Endpoint(s)....................................................................................61
9.4.3. Secondary Endpoint(s)................................................................................61
9.4.4. Tertiary/Exploratory Endpoint(s) ...............................................................61
9.4.5. Other Safety Analyse(s)..............................................................................61
9.4.6. Other Analyses............................................................................................62
9.5. Interim Analyses .....................................................................................................63
9.6. Data Monitoring Committee or Other Independent Oversight Committee ............63
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................63
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............63
10.1.1. Regulatory and Ethical Considerations ....................................................63
10.1.2. Financial Disclosure .................................................................................64
10.1.3. Informed Consent Process ........................................................................64
10.1.4. Data Protection .........................................................................................65
10.1.5. Dissemination of Clinical Study Data ......................................................66
10.1.6. Data Quality Assurance ............................................................................67
10.1.7. Source Documents....................................................................................68
10.1.8. Study and Site Start and Closure ..............................................................69
10.1.9. Publication Policy.....................................................................................69
10.1.10. Sponsor’s Qualified Medical Personnel .................................................70
10.2. Appendix 2: Clinical Laboratory Tests .................................................................71
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................73
10.3.1. Definition of AE .......................................................................................73
10.3.2. Definition of SAE.....................................................................................74
10.3.3. Recording/Reporting and Follow up of AEs and/or SAEs.......................75
10.3.4. Reporting of SAEs....................................................................................78
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................80
10.4.1. Male Participant Reproductive Inclusion Criteria....................................80
10.4.2. Female Participant Reproductive Inclusion Criteria.................................80
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................80

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10.4.4. Contraception Methods.............................................................................81
10.5. Appendix 5: Genetics............................................................................................83
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
and Study Intervention Rechallenge Guidelines .......................................................84
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................86
10.8. Appendix 8: Medical Device Adverse Events, Adverse Device Effects, 
Serious Adverse Events, and Device Deficiencies: Definition and Procedures 
for Recording, Evaluating, Follow-up, and Reporting..............................................88
10.8.1. Definition of AE and ADE .......................................................................88
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse 
Device Effect ...................................................................................................88
10.8.3. Definition of Device Deficiency...............................................................89
10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and 
Device Deficiencies .........................................................................................89
10.8.5. Reporting of SAEs....................................................................................91
10.8.6. Reporting of SADEs.................................................................................92
10.9. Appendix 9: Country-specific Requirements........................................................93
10.10. Appendix 10: Evaluation of Participants with Decreased Platelet Count...........94
10.11. Appendix 11: Evaluation of Participants with Worsening Renal Function ........95
10.12. Appendix 12: Management of Elevated AST or ALT ........................................96
10.13. Appendix 13: Alternative Measures During Public Emergencies.......................97
10.13.1. Eligibility................................................................................................97
10.13.2. Home Health Visits.................................................................................97
10.13.3. Telehealth Visits.....................................................................................98
10.13.4. Alternative Facilities for Safety Assessments ........................................98
10.13.5. Study Intervention ..................................................................................99
10.13.6. Adverse Events and Serious Adverse Events.......................................100
10.13.7. Efficacy Assessments ...........................................................................100
10.13.8. Independent Oversight Committees .....................................................100
10.14. Appendix 14: Abbreviations .............................................................................101
11. REFERENCES ................................................................................................................104

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LIST OF TABLES
Table 1.
Dosing Plan...............................................................................................26
LIST OF FIGURES
Figure 1.
Study Schematic .......................................................................................14

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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel 
Group, Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of 
Vupanorsen (PF-07285557) in Statin-Treated Participants with Dyslipidemia
Short Title: A Phase 2b Dose-Ranging Study with Vupanorsen (PF-07285557) 
(TRANSLATE-TIMI 70)
Rationale:
This multicenter, Phase 2b, double-blind, placebo-controlled, parallel group study is being 
conducted internationally to provide data on efficacy, safety, tolerability, and 
pharmacokinetics (PK) of PF-07285557 (hereafter, vupanorsen) administered subcutaneously 
(SC) at various doses and regimens in participants with dyslipidemia, defined in this study as 
participants with elevated non-HDL-C and TG who are receiving a stable dose of a statin. 
This study is intended to enable selection of a dose(s) for future development of vupanorsen 
for cardiovascular (CV) risk reduction and hypertriglyceridemia.
This study is also known as TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in 
AdulTs with dyslipidEmia (TRANSLATE-TIMI 70).
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on non-
HDL-C.

Percent change from baseline in non-HDL-C at 
Week 24
Secondary: 
Secondary: 

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on lipid 
parameters including TG, ApoB, and LDL-C.

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on 
ANGPTL3.

Percent change from baseline in TG, ApoB, and LDL-
C at Week 16 and Week 24

Percent change from baseline in non-HDL-C at 
Week 16

Percent change from baseline in ANGPTL3 at 
Week 16 and Week 24
Safety:
Safety:

To evaluate the safety, tolerability, and 
immunogenicity of multiple dose levels and regimens 
of vupanorsen.

To evaluate the effect of multiple dose levels and 
regimens of vupanorsen on HFF. 

Incidence of treatment-emergent SAEs and AEs 
throughout the study

Incidence of AESI 

Categorical summaries of clinical laboratory 
abnormalities

UACR

ADA

Change from baseline in AST, ALT, platelet counts, 
and eGFR

Change and percent change from baseline in HFF 
(assessed by MRI-PDFF) at Week 24

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Objectives
Endpoints
Tertiary/Exploratory:
Tertiary/Exploratory:

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on total 
cholesterol, HDL-C, VLDL-C, Lp(a), FFA, ApoB-48, 
ApoB-100, ApoC-III, and ApoA-I.

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on 
hsCRP.

To evaluate the PK of vupanorsen.

Percent change from baseline at Week 24 in total 
cholesterol, HDL-C, VLDL-C, Lp(a), FFA, ApoB-48, 
ApoB-100, ApoC-III, and ApoA-I

Percent change from baseline in hsCRP at Week 24

Plasma concentrations of vupanorsen at Weeks 12, 16 
and 24
Estimands: The primary estimand of this study will follow the hypothetical estimand 
approach to estimate the effect of treatment under the hypothetical condition that all 
participants maintained their randomized treatment through Week 24. This estimand is meant 
to estimate the pharmacological effect of the drug when taken as directed. It includes the 
following 4 attributes:

Population: Participants with dyslipidemia taking a statin who meet the 
inclusion/exclusion criteria.

Variable: The percent change from baseline in non-HDL-C at Week 24.

Intercurrent event: All off-treatment data (ie, occurring at least 1 dosing interval after 
discontinuation of treatment) or data collected post treatment of severe 
hypertriglyceridemia (ie, change in statin dose or addition of TG lowering therapy), if 
collected, will be excluded from analysis.

Population-level summary: Difference of variable means between vupanorsen and 
placebo.
Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging, 8-arm 
parallel-group study in adults ≥40 years of age with dyslipidemia who are on a stable dose of 
a statin (with or without ezetimibe). Following the Screening Period to confirm eligibility, a 
total of approximately 260 participants will be randomized in the study to receive SC doses 
of vupanorsen or placebo administered Q2W or Q4W for the purpose of assessing efficacy, 
safety, and tolerability of vupanorsen. The total duration of treatment in the study is 24 
weeks with an additional 12-week safety follow-up period.
The sponsor, along with academic leadership of the study (TIMI Study Group), will monitor 
the proportion of participants enrolled according to statin intensity to ensure that an adequate 
number of participants on high intensity statin are enrolled. High intensity statin use is 
defined as atorvastatin (40 mg or 80 mg per day) or rosuvastatin (20 mg or 40 mg per day). 
All other statin regimens are considered low or moderate intensity. Approximately 40% or 
more of participants enrolled should be on high intensity statin therapy, and enrollment of 
participants using low/moderate intensity statin may be capped.

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Vupanorsen dosing will be accomplished by administration of 1 or 2 prefilled syringes of 
either 60 mg or 80 mg strength according to required total dose. Placebo will be provided as 
a prefilled syringe and will be administered as either 1 or 2 syringes. See Table S1 for the 
dosing plan. 
Table S1. Dosing Plan
Treatment Arm
Total Monthly 
Dose
Injection Regimen
Number of 
Participants
Placebo
0 mg
Single or double injection Q2W or Q4W
40
80 mg Q4W
80 mg
Single injection Q4W
20
60 mg Q2W
120 mg
Single injection Q2W
20
120 mg Q4W
120 mg
Double injection Q4W
20
80 mg Q2W
160 mg
Single injection Q2W
40
160 mg Q4W
160 mg
Double injection Q4W
40
120 mg Q2W
240 mg
Double injection Q2W
40
160 mg Q2W
320 mg
Double injection Q2W
40
Treatment arm will be capped at 10 participants until E-DMC performs unblinded data review and 
recommends whether enrollment should be re-opened for this dose group for the remaining 30 participants.
During the Screening Period, sites will instruct participants or caregivers how to perform the 
SC injection, and participants (or caregivers) willing to perform the injection will be assessed 
for ability to inject correctly. Sites will determine whether a participant or caregiver is 
willing and able to correctly perform the SC injection. Participants receiving monthly 
injections will self-administer study intervention (or be injected by their caregiver) on-site.  
Participants receiving Q2W injections will self-administer study intervention (or be injected 
by their caregiver) on-site when study visits coincide with the dosing interval (Weeks 2 
and 6, and at designated monthly visits). The study site will dispense study intervention for 
the participant or caregiver to inject at home for the doses that do not coincide with a study 
visit (Weeks 10, 14, 18, and 22). 
Safety clinical laboratory parameters and AEs, including injection site reactions, will be 
monitored throughout the study. HFF will be assessed at Screening and Week 24 using 
MRI-PDFF, and blood samples will be collected for lipids, lipoproteins, PK, PD, hsCRP, and 
anti-vupanorsen antibodies at various time points during the study according to the SoA. 
MRI-PDFF will be read by a central reviewer, blinded to treatment group, lipid levels, and 
other clinical variables, such as concentrations of hepatic enzymes.
This study will include an E-DMC who will be responsible for ongoing, unblinded 
monitoring of efficacy and the safety of participants in the study according to the E-DMC 
charter. 
Since administration of 160 mg Q2W (total monthly dose of 320 mg) has not been studied 
previously, enrollment in this arm will be capped after 10 participants. Following unblinded 
data review by the E-DMC as described in the E-DMC charter, enrollment in this treatment 
arm may be re-opened for the remaining 30 participants or be stopped based on 
recommendation by the E-DMC. Separately, an interim analysis is planned and will also be 
reviewed by the E-DMC. The interim analysis will take place approximately 16 weeks after 

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50% of the planned participants (ie, approximately 110 participants), with the exception of 
the 160 mg Q2W group, are randomized. 
Efficacy and safety analyses will occur when all participants either complete 24 weeks of 
study participation or discontinue study participation. Additional summarizing of follow-up 
safety data will occur after the 12-week post-dose follow-up visit.
Number of Participants:
Approximately 260 participants will be randomly assigned/enrolled to study intervention. 
Note: "Enrolled" means a participant's, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. 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.
Intervention Groups and Duration:
Participants will be randomized to receive blinded placebo or 1 of 7 blinded vupanorsen
treatment regimens for 24 weeks. 
Data Monitoring Committee: Yes
Statistical Methods:
Assuming a common standard deviation of 17.5% (observed in the Month 6 data of the 
Phase 2a proof-of-concept and dose-ranging study) for the percent change from baseline in 
non-HDL-C at Week 24 and a treatment discontinuation rate of 15%, 20 participants per arm 
will correspond to a 95% CI of point estimate ±11.76% for the difference of treatment effect 
(versus placebo). These parameters correspond to a power of 91.5% using a 2-sided alpha of
0.05, to detect a difference of -20%, without adjustment for multiple comparison to placebo.
A permutation block schedule will be used in enrollment within each arm, including 
vupanorsen and matching placebo. If enrollment is stopped for the 160 mg Q2W arm, the 
corresponding matching placebo enrollment will also be stopped.
The primary statistical method of Mixed Model Repeated Measurements (MMRM) will 
apply to continuous endpoints.
Statistical efficacy comparison will be made between each dose of vupanorsen and placebo 
for primary and secondary endpoints, respectively. Placebo-adjusted LS mean difference, 
95% CI, and p-value will be presented. Since this study is exploratory in nature, no 
multiplicity adjustment of endpoints nor adjustment of multiple comparison to placebo will 
be made. Sensitivity analyses/supplementary analyses are defined in the SAP. Since the visit 
after Week 24 is considered safety follow-up, the statistical analyses at those visits will be 
presented but the p-value will be treated only as nominal.
In addition, a Bayesian Emax dose-response model will be estimated to illustrate the expected 
relationship between doses and their corresponding (percent) change from baseline at 

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Week 24 for primary and key secondary endpoints, respectively. For each endpoint, 95% CI 
at each studied dose level will also be constructed.
In addition to analyses, summary statistics, listings, and figures will be provided.

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1.2. Schema
Figure 1.
Study Schematic

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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct 
evaluations or assessments required to protect the well-being of the participant. In the event of a health care crisis, pandemic, or other 
emergency, some of the assessments may be performed via home health visits or other ways after discussion with the sponsor. See 
Appendix 13 for alternative measures that may be allowed during a public emergency, such as COVID-19.
Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 14.
Screeningb
(Days -28 to -1)
Day 
1
Day 
8
Day 
15
Day 
29
Day 
43
Day 
57
Day 
85
Day 113
Interim 
Analysis Time 
Point
Day 
141
Day
169
Follow-up
(+12 weeks after 
last dose)e,f
Early Termination/
Discontinuationg
Visit 
1c,d
Visit 
2
Visit 
3
Week
-4 to -1
0
1
2
4
6
8
12
16
20
24
32 or 34
Month
-1
1
2
3
4
5
6
8
Visit Window (Days)
±1
±1
±2
±2
±2
±3
±3
±3
±3
±7
Informed consent
X
Medical history
X
Inclusion/Exclusion Criteria
X
X
Physical examination
X
Vital signs (seated blood 
pressure and pulse rate)
X
X
X
X
X
Weight
X
X
X
X
Height
X
Provide contact card to 
participant
X
Dispense diary and instruct 
participant on use
Xh
Laboratory
Hematology
X
X
Xi
X
X
X
X
X
X
X
X
X
X
Blood chemistry
X
X
Xi
X
X
X
X
X
X
X
X
X
X
Lipid panel and ApoBj
X
X
X
X
X
X
X
X
X
X
Extended lipoprotein 
panel and FFAk
X
X
X
ANGPTL3l
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X

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Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 14.
Screeningb
(Days -28 to -1)
Day 
1
Day 
8
Day 
15
Day 
29
Day 
43
Day 
57
Day 
85
Day 113
Interim 
Analysis Time 
Point
Day 
141
Day
169
Follow-up
(+12 weeks after 
last dose)e,f
Early Termination/
Discontinuationg
Visit 
1c,d
Visit 
2
Visit 
3
Week
-4 to -1
0
1
2
4
6
8
12
16
20
24
32 or 34
Month
-1
1
2
3
4
5
6
8
Visit Window (Days)
±1
±1
±2
±2
±2
±3
±3
±3
±3
±7
Urinalysis
X
X
Xi
X
X
X
X
X
X
X
X
X
X
Urine albumin to 
creatinine ratio
X
X
Xi
X
X
X
X
X
X
X
X
X
X
FSH (women, if 
applicable)
X
Pregnancy testm
X
X
X
X
X
X
X
X
X
X
X
X
Plasma PK
Xn
Xn
Xo
X
hsCRP
X
X
X
PT, aPTT, INR
X
Xi
X
X
X
X
X
X
X
X
X
X
Anti-vupanorsen
antibodies (ADA)
Xp
Xp
Xp
Xp
Xp
X
X
Banked Biospecimen 
Samples Prep B1.5 
(plasma), B2.5 (serum), 
M4 (urine)q
X
Xo
X
Pfizer Prep D1 Banked 
Biospecimen(s)q
X
Contraception check
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG 
X
Xo
X
MRI-PDFFr
X 
Xo,s
X
Randomization
X
IRT interaction 
X
X
X
Xt
X
Xt
X
X
X
X
X
Study intervention
Placebo-injection 
instruction and training
X
Q2Wu,v
X
Xi
X
X
X
X
X
X
Q4Wu
X
Xi
X
X
X
X
Review diary to assess 
treatment compliance
X
X
X
X
X

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Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 14.
Screeningb
(Days -28 to -1)
Day 
1
Day 
8
Day 
15
Day 
29
Day 
43
Day 
57
Day 
85
Day 113
Interim 
Analysis Time 
Point
Day 
141
Day
169
Follow-up
(+12 weeks after 
last dose)e,f
Early Termination/
Discontinuationg
Visit 
1c,d
Visit 
2
Visit 
3
Week
-4 to -1
0
1
2
4
6
8
12
16
20
24
32 or 34
Month
-1
1
2
3
4
5
6
8
Visit Window (Days)
±1
±1
±2
±2
±2
±3
±3
±3
±3
±7
Prior and concomitant 
treatment(s)
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious and nonserious 
adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Visit Identifiera
Abbreviations used in this table 
may be found in Appendix 14.
Screeningb
(Days -28 to -1)
Day 
1
Day 
8
Day 
15
Day 
29
Day 
43
Day 
57
Day 
85
Day 113
Interim 
Analysis Time 
Point
Day 
141
Day
169
Follow-up
(+12 weeks after 
last dose)e,f
Early Termination/
Discontinuationg
Visit 
1c,d
Visit 
2
Visit 
3
Week
-4 to -1
0
1
2
4
6
8
12
16
20
24
32 or 34
Month
-1
1
2
3
4
5
6
8
Visit Window (Days)
±1
±1
±2
±2
±2
±3
±3
±3
±3
±7
a.
Day relative to start of study intervention (Day 1).
b.
Screening Period is a maximum of 28 days. Complete all inclusion/exclusion procedures and assessments denoted at Screening Visit 1; placebo injection training may be 
performed at Screening Visit 1 or Screening Visit 2. After participant has otherwise qualified for the study, including review of lipid and clinical laboratory results and 
completion of successful placebo training injections, perform MRI-PDFF at Screening Visit 3 or any time prior to randomization.
c.
If participants are not fasted for lipid panel and ApoB collection, perform other Screening activities and have participants return fasted for these tests.
d.
Screening Visit 1 activities should be completed within 7 days.
e.
Occurs 12 weeks after last dose: Week 32 for participants assigned to Q4W regimen or Week 34 for participants assigned to Q2W regimen.
f.
For participants who discontinue the study after Week 24, perform Follow-up procedures; do not perform Early Termination/Discontinuation procedures.
g.
For participants who discontinue study intervention or discontinue the study prior to Week 24, the procedures should be performed. Early Termination/Discontinuation 
procedures to be performed as soon as practically possible after decision to stop study intervention but participants should stay in study with continuation of scheduled visits 
unless participant withdraws consent from further study participation.
h.
Diary to be dispensed only to participants assigned to Q2W regimen.
i.
Laboratory results from Week 1 visit should be reviewed by the investigator prior to Week 2 dosing for participants dosing Q2W and prior to Week 4 dosing for participants 
dosing Q4W.
j.
Lipid panel and ApoB should be obtained with participants in a fasted state (Section 5.3.2). Lipid panel includes non-HDL-C, TG, direct LDL-C, total cholesterol, HDL-C, 
direct VLDL-C.
k.
Extended lipoprotein panel and FFA should be obtained with participants in a fasted state (Section 5.3.2). Extended lipoprotein panel includes Lp(a), ApoB-48, ApoB-100, 
ApoC-III, ApoA-I.
l.
ANGPTL3 should be obtained with participants in a fasted state (Section 5.3.2 and Section 8.6).
m.
For WOCBP. Perform serum pregnancy test at Screening. Perform urine pregnancy test prior to dosing at visits on Week 0, Week 2 through Week 24, Follow-up, and Early 
Termination/Discontinuation (if applicable).
n.
PK sample collected with participants in a fasted state (Section 5.3.2) at trough (prior to dosing with study intervention) and 2 to 4 hours after administration.
o.
Do not perform assessment/procedure at Day 169 for participants who continued scheduled visits after stopping study intervention and completed Early 
Termination/Discontinuation assessments/procedures.
p.
ADA samples to be collected prior to dosing with study intervention.
q.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a participant visit. 
r.
Assessment to be performed, following ≥4-hour fast, at site (as part of site visit) or separate visit(s) to Imaging facility (see Section 5.3.2).
s.
Attempts to be made to stay within ±2-hour window of the time when MRI-PDFF was performed at Screening.
t.
Dispense study intervention only to participants assigned to Q2W regimen for home dosing.
u.
For each site visit, perform all indicated procedures and assessments prior to participant self-injection (or caregiver administering injection).
v.
Dosing at home for participants in the Q2W regimens will occur on Weeks 10, 14, 18, and 22; the window for each scheduled dosing day is ±2 days. Study intervention will 
be dispensed at the prior visit for these doses. 

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2. INTRODUCTION
ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the 
angiopoietin-like family of proteins. ANGPTL3 is a genetically-validated target of lipid 
metabolism and CV disease.1
PF-07285557 (hereafter, vupanorsen) is a second-generation 2’-MOE ASO targeting hepatic 
ANGPTL3 mRNA. Vupanorsen is planned to be developed for CV risk reduction and for TG 
lowering in patients with severe hypertriglyceridemia.
Vupanorsen is a synthetic oligomer of 20 nucleotides that are connected sequentially by 
phosphorothioate and phosphodiester linkages (mixed backbone design) and covalently 
bound to GalNAc, which binds with high affinity to the ASGPR on hepatocytes, increasing 
hepatocyte delivery and potency. The mixed backbone design reduces the total number of 
phosphorothioate linkages in the MOE-modified regions, which reduces non-specific 
interactions with proteins and further enhances potency of GalNAc-conjugated ASOs.
Phase 1 and Phase 2a studies with vupanorsen administered SC have demonstrated marked 
reductions in ANGPTL3 protein and reductions in TG, VLDL-C, and non-HDL-C. The 
favorable lipid changes along with human genetic data indicate that inhibition of ANGPTL3 
with vupanorsen could represent a novel approach to decrease CV disease risk and reduce 
TG in participants with hypertriglyceridemia.
2.1. Study Rationale
This multicenter, Phase 2b, double-blind, placebo-controlled, parallel group study is being 
conducted internationally to provide data on efficacy, safety, tolerability, and PK of 
vupanorsen administered SC at various doses and regimens in participants with dyslipidemia, 
defined in this study as participants with elevated non-HDL-C and TG who are receiving a 
stable dose of a statin. This study is intended to enable selection of a dose(s) for future 
development of vupanorsen for CV risk reduction and hypertriglyceridemia.
This study is also known as TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in 
AdulTs with dyslipidEmia (TRANSLATE-TIMI 70). 
2.2. Background
2.2.1. Atherosclerotic Cardiovascular Disease
Individuals with established ASCVD, a prior history of ischemic events, or multiple risk 
factors for atherothrombosis are at high risk for future ischemic events and CV death.2 Both 
epidemiological and pharmacological intervention trials have demonstrated a strong and 
linear relationship between levels of LDL-C and CV events. Early intensive statin therapy to 
lower LDL-C has become a foundation of treatment for patients with ASCVD.3 However, 
even with guideline-based optimal LDL-C lowering treatment, patients with ASCVD remain 
at high risk for CV death and recurrent ischemic events.4
A growing body of clinical and epidemiological data indicate that non-HDL-C is a better 
predictor of CV risk than LDL-C alone.5,6 Non-HDL-C encompasses the cholesterol content 

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of all the atherogenic ApoB-containing lipoproteins including LDL, VLDL, IDL, Lp(a), 
chylomicrons, and chylomicron remnants. Thus, non-HDL-C provides a simple way to assess 
the total amount of atherogenic lipoproteins containing ApoB. Collectively, IDL, VLDL, and 
chylomicron remnants are termed TG-rich lipoproteins. Elevated plasma TG is a marker for 
elevated TG-rich lipoproteins. Several lines of evidence have established a likely causal role 
for TG-rich lipoproteins in atherogenesis, mediated by their cholesterol content rather than 
the TG content.7 TG-rich lipoproteins are strong independent predictors of ASCVD and 
all-cause mortality in epidemiological studies and genetic studies using Mendelian 
randomization.7 Genetic studies of various factors influencing the function of lipoprotein 
lipase, a key enzyme that degrades TG-rich lipoproteins in plasma and regulates the delivery 
of fatty acids to adipose tissue and muscle, provide evidence that TG-rich lipoproteins are a 
causal factor in ASCVD.5
In randomized controlled trials, reduction in TG (a surrogate of TG-rich lipoproteins) is 
associated with a lower risk of major vascular events, even after adjustment for LDL-C 
lowering, although the effect on vascular events is less than that for LDL-C or non-HDL-C 
reduction.8 Most previous non-statin trials of existing therapies to lower TG (fibrates, niacin, 
omega-3 fatty acids) have had modest reductions in non-HDL-C and TG and have been 
underpowered to detect reductions in CV events.6
Therapies that primarily reduce LDL-C such as statins, ezetimibe, and PCSK9 inhibitors 
have modest effects on TG (5% to 15%). Other therapies that reduce TG such as fenofibrate 
and niacin can result in larger reductions in TG but have not been shown to reduce CV risk. 
High doses of icosapent ethyl also has modest effects on TG (median reduction of 
approximately 20%) but reduced CV risk by 25%, suggesting effects on CV outcomes 
beyond lowering TG.9
Therapies that increase lipoprotein lipase activity through inhibition of ANGPTL3 have the 
potential for large reductions in non-HDL-C and TG-rich lipoproteins resulting in additional 
reduction in CV risk.
2.2.2. Hypertriglyceridemia
Two categories of hypertriglyceridemia have been defined: moderate hypertriglyceridemia 
(TG 150-499 mg/dL) and severe hypertriglyceridemia (TG ≥500 mg/dL). Moderate 
hypertriglyceridemia is commonly associated with obesity, T2DM, and insulin resistance, 
and the excess TG are primarily carried in VLDL.3 Patients with severe hypertriglyceridemia 
have an excess of chylomicrons (chylomicronemia) in addition to an excess of TG-rich 
lipoproteins.  
In addition to increased ASCVD risk, hypertriglyceridemia is a well-established cause of 
acute pancreatitis. The pancreatitis risk is highest in familial chylomicronemia syndrome, but 
there is evidence to indicate that pancreatitis risk is increased even in mild or moderate 
hypertriglyceridemia and the risk increases in a dose-dependent manner as TG levels 
increase.10

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Treatment of severe hypertriglyceridemia has 2 aspects: lowering lipid levels to decrease 
ASCVD risk and the more acute goal of reducing elevated TG to reduce risk of acute 
pancreatitis. LDL-C lowering treatments have only moderate effects on TG, but lower
ASCVD risk in patients with hypertriglyceridemia or mixed dyslipidemia. There is a need for 
therapies that decrease TG and reduce CV risk for individuals whose TG levels remain 
elevated despite treatment.
2.2.3. Rationale for ANGPTL3 Inhibition
ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the 
angiopoietin-like family of proteins. ANGPTL3 inhibits lipoprotein lipase, which is the 
primary mechanism by which TG-rich lipoproteins are cleared from the circulation.11
ANGPTL3 also inhibits endothelial lipase, which is involved in HDL metabolism. Genome 
sequencing studies of individuals with very low plasma lipids have identified 
loss-of-function mutations in ANGPTL3 which result in a distinct hypolipidemia 
phenotype.12 Individuals with complete ANGPTL3 loss-of-function mutations present with 
low levels of multiple atherogenic plasma lipids, including ApoB-100-containing 
lipoproteins, VLDL-C, and LDL-C, without an increase in prevalence of fatty liver or other 
adverse clinical effects and have lower glucose and less insulin resistance.13 Inhibition of 
ANGPTL3 lowers LDL-C through a mechanism that is independent of LDL 
receptor-mediated clearance.14 Epidemiological studies have shown that ANGPTL3 
deficiency is associated with a reduced risk of coronary artery disease.15
2.2.4. Clinical Overview
One Phase 1 single- and multiple-ascending dose study (CS1) (hereafter, Phase 1) in healthy 
volunteers, 1 Phase 2a proof-of-concept and dose-ranging study (CS2) (hereafter, Phase 2a), 
and 2 small, open-label, single-arm, proof-of-concept studies (in participants with Familial 
Chylomicronemia Syndrome and Familial Partial Lipodystrophy) have been conducted. 
Refer to the IB for more details on these studies, including clinical efficacy and safety results 
for the Phase 2a study.
Clinical PK results for the Phase 2a study are presented in Section 2.2.4.1.
2.2.4.1. Clinical Pharmacokinetics
Concentrations of total full-length oligonucleotide in plasma, including the parent compound 
vupanorsen, its full-length oligonucleotide metabolites with 1, 2, and/or 3 GalNAc sugar 
deletions and unconjugated vupanorsen, were quantitated as they are all potentially 
pharmacologically active. For simplicity, vupanorsen concentration refers to all full length 
oligonucleotides in the context of PK.
In the Phase 1 study, following single-dose or multiple-dose SC administration, vupanorsen
was absorbed rapidly into the systemic circulation, with median Tmax ranging from 1 to 
8 hours. After reaching Cmax, plasma concentrations of vupanorsen declined in a multi-phasic 
fashion with a rapid disposition phase, followed by a slower elimination phase with mean 
terminal elimination half-life of 3 to 5 weeks. Cmax and AUC increased approximately dose 
proportionally from 20 mg to 120 mg after a single SC dose, and from 10 mg to 60 mg after 

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single and multiple weekly SC doses. No accumulation was observed based on Cmax and 
AUC after weekly doses. Plasma trough concentrations indicated that steady-state was not 
reached after 6 weeks of weekly dosing, consistent with the observed long half-life of the 
drug.
Vupanorsen PK profiles were evaluated in a subset of participants in the Phase 2a study. 
Following 20 mg QW, 40 mg and 80 mg Q4W SC dosing, the observed preliminary 
vupanorsen PK in the Phase 2a study were consistent with those in the Phase 1 study. Plasma 
trough concentrations appeared to reach steady-state after 21 weeks of dosing. The presence 
of ADA showed no apparent impact on Cmax and AUC, but increased plasma trough 
concentrations based on preliminary analysis.   
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of vupanorsen may be found in the IB, which is the SRSD for this study. 

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2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) [vupanorsen] 
Decreased platelet counts, elevated 
transaminases, and decreased renal 
function are potential risks 
associated with vupanorsen.
The potential risks are based on 
reports of thrombocytopenia, 
elevated liver enzymes, and 
decreases in renal function in 
clinical and non-clinical studies of 
other non-GalNAc conjugated 
ASOs.16,17
Thrombocytopenia has not been 
observed in non-clinical and 
clinical studies of vupanorsen (see 
IB for non-clinical and clinical 
study results).
No vupanorsen-associated severe 
decline in platelet counts were 
reported in the Phase 1 or 2a study 
(see IB).
The potential risk of elevated 
transaminases is based on the 
results of the Phase 2a study where 
increases in mean ALT that 
appeared dose dependent were 
observed in all vupanorsen
treatment groups, and mild isolated 
transaminase increases that 
exceeded the 3 times the upper 
limit of normal occurred in 
2 participants at the 20 mg QW 
dose; the transaminase increases 
were not associated with an 
Eligibility criteria will ensure the appropriate participants enter the study (see 
Exclusion Criterion 4).  
AEs and clinical laboratories will be obtained and monitored throughout the study 
(see SoA). Also, the protocol includes monitoring and stopping criteria for 
abnormal platelet counts, elevated transaminases, and decrease in eGFR (see
Section 7.1). Instructions for managing potential liver injury are provided (see 
Appendix 6).

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
increase in bilirubin or 
liver-related symptoms (see IB).  
Injection site reactions are a 
potential risk of vupanorsen.
Injection site AEs were the most 
common side effects observed 
following SC administration of 
unconjugated 2’-MOE ASOs and 
were dose dependent.18
Injection site AEs have been 
observed in the Phase 1 and Phase 
2a (see IB) studies of vupanorsen
and have generally been mild.
Injection site instructions to minimize injection site AEs will be provided to the 
participant or caregiver (if applicable).
AEs will be monitored on an ongoing basis throughout the study (see SoA). Also, 
the protocol requires discontinuation of dosing if a severe injection site reaction 
occurs (see Section 7.1.2).
Study Procedures
MRI-PDFF will be used to assess 
liver fat.
MRI-PDFF can cause 
claustrophobia and also is 
contra-indicated in individuals 
with certain medical devices or 
other internal metallic objects.
Eligibility criteria will ensure the appropriate participants enter the study (see 
Exclusion Criterion 19).
Participants will self-inject (or 
caregivers will inject) study 
intervention.
Participants or caregivers may 
perform the injection incorrectly.
Participants may be uncomfortable 
self-injecting.
Sites will train participants or caregivers to perform the injection.
During Screening, participants or caregivers will inject placebo in order to 
determine whether study intervention can be correctly administered.

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2.3.2. Benefit Assessment
Treatment with vupanorsen may lower non-HDL-C, TG, and other lipids/lipoproteins 
associated with ASCVD and ischemic events. Participants will be followed closely by a 
physician for approximately 32 weeks (Q4W regimen) or 34 weeks (Q2W regimen) and will 
have measurements of lipids, blood pressure, and other clinical laboratories throughout the 
study. Measurements of liver fat using MRI-PDFF may, after unblinding of the study, 
identify elevated liver fat in some participants who were unaware that they had this condition 
and inform their post-study management by their primary health care provider. Finally, 
participants will be contributing to the development of a potential therapy to reduce risk of 
CV events and to treat individuals with elevated TG.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with vupanorsen and study procedures are 
justified by the anticipated benefits that may be afforded to participants with ASCVD or 
severe hypertriglyceridemia.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on non-
HDL-C.

Percent change from baseline in non-HDL-C at 
Week 24
Secondary: 
Secondary: 

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on lipid 
parameters including TG, ApoB, and LDL-C.

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on 
ANGPTL3.

Percent change from baseline in TG, ApoB, and 
LDL-C at Week 16 and Week 24

Percent change from baseline in non-HDL-C at 
Week 16

Percent change from baseline in ANGPTL3 at 
Week 16 and Week 24
Safety:
Safety:

To evaluate the safety, tolerability, and 
immunogenicity of multiple dose levels and regimens 
of vupanorsen.

To evaluate the effect of multiple dose levels and 
regimens of vupanorsen on HFF. 

Incidence of treatment-emergent SAEs and AEs 
throughout the study

Incidence of AESI 

Categorical summaries of clinical laboratory 
abnormalities

UACR

ADA

Change from baseline in AST, ALT, platelet counts, 
and eGFR

Change and percent change from baseline in HFF 
(assessed by MRI-PDFF) at Week 24

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Objectives
Endpoints
Tertiary/Exploratory:
Tertiary/Exploratory:

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on total 
cholesterol, HDL-C, VLDL-C, Lp(a), FFA, ApoB-48, 
ApoB-100, ApoC-III, and ApoA-I.

To estimate the effects of multiple dose levels and 
regimens of vupanorsen compared to placebo on 
hsCRP.

To evaluate the PK of vupanorsen.

Percent change from baseline at Week 24 in total 
cholesterol, HDL-C, VLDL-C, Lp(a), FFA, ApoB-48, 
ApoB-100, ApoC-III, and ApoA-I

Percent change from baseline in hsCRP at Week 24

Plasma concentrations of vupanorsen at Weeks 12, 16, 
and 24
The primary estimand of this study will follow the hypothetical estimand approach as 
described in Section 9.1.1.
4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging, 8-arm 
parallel-group study in adults ≥40 years of age with dyslipidemia who are on a stable dose of 
a statin (with or without ezetimibe). Following the Screening Period to confirm eligibility, a 
total of approximately 260 participants will be randomized in the study to receive SC doses 
of vupanorsen or placebo administered Q2W or Q4W for the purpose of assessing efficacy, 
safety, and tolerability of vupanorsen. The total duration of treatment in the study is 
24 weeks with an additional 12-week safety follow-up period.
The sponsor, along with academic leadership of the study (TIMI Study Group), will monitor 
the proportion of participants enrolled according to statin intensity to ensure that an adequate 
number of participants on high intensity statin are enrolled. High intensity statin use is 
defined as atorvastatin (40 mg or 80 mg per day) or rosuvastatin (20 mg or 40 mg per day). 
All other statin regimens are considered low or moderate intensity. Approximately 40% or 
more of participants enrolled should be on high intensity statin therapy, and enrollment of 
participants using low/moderate intensity statin may be capped.
Vupanorsen dosing will be accomplished by administration of 1 or 2 prefilled syringes of 
either 60 mg or 80 mg strength according to required total dose. Placebo will be provided as 
a prefilled syringe and will be administered as either 1 or 2 syringes. See Table 1 for the 
dosing plan. 
Table 1.
Dosing Plan
Treatment Arm
Total Monthly Dose
Injection Regimen
Number of 
Participants
Placebo
0  mg
Single or double injection Q2W or Q4W
40
80 mg Q4W
80 mg
Single injection Q4W
20
60 mg Q2W
120 mg
Single injection Q2W
20
120 mg Q4W
120 mg
Double injection Q4W
20
80 mg Q2W
160 mg
Single injection Q2W
40
160 mg Q4W
160 mg
Double injection Q4W
40

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Table 1.
Dosing Plan
Treatment Arm
Total Monthly Dose
Injection Regimen
Number of 
Participants
120 mg Q2W
240 mg
Double injection Q2W
40
160 mg Q2W
320 mg
Double injection Q2W
40
Treatment arm will be capped at 10 participants until E-DMC performs unblinded data review and 
recommends whether enrollment should be re-opened for this dose group for the remaining 30 participants. 
During the Screening Period, sites will instruct participants or caregivers how to perform the 
SC injection, and participants (or caregivers) willing to perform the injection will be assessed 
for ability to inject correctly. Sites will determine whether a participant or caregiver is 
willing and able to correctly perform the SC injection. Participants receiving monthly 
injections will self-administer study intervention (or be injected by their caregiver) on-site. 
Participants receiving Q2W injections will self-administer study intervention (or be injected 
by their caregiver) on-site when study visits coincide with the dosing interval (Weeks 2 
and 6, and at designated monthly visits). The study site will dispense study intervention for 
the participant or caregiver to inject at home for the doses that do not coincide with a study 
visit (Weeks 10, 14, 18, and 22). 
Safety clinical laboratory parameters and AEs, including injection site reactions, will be 
monitored throughout the study. HFF will be assessed at Screening and Week 24 using 
MRI-PDFF, and blood samples will be collected for lipids, lipoproteins, PK, PD, hsCRP, and 
anti-vupanorsen antibodies at various time points during the study according to the SoA. 
MRI-PDFF will be read by a central reviewer, blinded to treatment group, lipid levels, and 
other clinical variables, such as concentrations of hepatic enzymes.
This study will include an E-DMC who will be responsible for ongoing, unblinded 
monitoring of efficacy and the safety of participants in the study according to the E-DMC 
charter (Section 9.6). 
Since administration of 160 mg Q2W (total monthly dose of 320 mg) has not been studied 
previously, enrollment in this arm will be capped after 10 participants. Following unblinded 
data review by the E-DMC as described in the E-DMC charter, enrollment in this treatment 
arm may be re-opened for the remaining 30 participants or be stopped based on 
recommendation by the E-DMC. Separately, an interim analysis is planned and will also be 
reviewed by the E-DMC. The interim analysis will take place approximately 16 weeks after 
50% of the planned participants (ie, approximately 110 participants), with exception of the 
160 mg Q2W group, are randomized. 
Efficacy and safety analyses will occur when all participants either complete 24 weeks of 
study participation or discontinue study participation. Additional summarizing of follow-up 
safety data will occur after the 12-week post-dose follow-up visit. 

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4.2. Scientific Rationale for Study Design
As reviewed in the IB, vupanorsen demonstrated significant reductions in TG and multiple 
lipid endpoints in the Phase 2a study in participants with hypertriglyceridemia, NAFLD, and 
diabetes; however, the maximal reduction in ANGPTL3 achieved with the highest dose of 
80 mg Q4W in the study was below the magnitude needed to observe maximal lipid lowering 
with this mechanism (ie, ≥75% ANGPTL3 reduction). From a safety perspective, the 
numerical increases in liver fat at 20 mg QW and 40 mg Q4W, along with the larger increase 
noted at 80 mg Q4W need to be further evaluated.
In the current study, the participant population is focused on those with elevated non-HDL-C 
and TG and are on a stable dose of a statin to determine the optimum dose for future 
development for hypertriglyceridemia and CV risk reduction. To further evaluate potential 
changes in liver fat accumulation, participants will complete MRI-PDFF at Screening and 
end of treatment (Week 24). In addition, banked biospecimens will be collected and stored 
for further analyses which may, for example, provide greater understanding of vupanorsen.
Vupanorsen has an unlikely risk of human teratogenicity/fetotoxicity. However, participants 
who are WOCBP must use an acceptable contraceptive method (see Appendix 4). The risk of 
vupanorsen causing damage to the DNA of sperm is considered low, and the risk of exposure 
to vupanorsen in a sexual partner of a male participant in this study via ejaculate is low;
therefore, no contraception (condom) use in male participants is required (see Appendix 4). 
The highest dose of vupanorsen planned for this study would result in maternal systemic
exposures via seminal transfer well below (>5000-fold) the exposure at the NOAEL for 
developmental toxicity in nonclinical studies, including the conservative assumptions that an 
ASO ejaculate:serum ratio would be 1 and there is 100% uptake by the partner. 
4.3. Justification for Dose
A dose range of 80 mg Q4W to 160 mg Q2W will be evaluated for safety and efficacy in this 
study. Based on simulation results using a preliminary population PK/PD model developed 
from the combined data in the Phase 1 and Phase 2a studies, vupanorsen 80 mg Q4W is 
expected to be a minimal efficacious dose in non-HDL-C reduction (<8% probability of 
achieving 35% mean reduction) and is included to bridge the data from previous studies. 
Vupanorsen 160 mg Q2W is expected to achieve >90% probability of ≥35% mean reduction 
in non-HDL-C, which translates to a potential ≥20% CV relative risk reduction in CV events 
assuming non-HDL-C baseline of 125 mg/dL, in addition to maximizing ANGPTL3 and TG 
reductions. 
Both Q2W and Q4W dosing regimens are included for the total monthly doses of 120 mg and 
160 mg in order to discern if there is any effect of dosing frequency or any effect of  
maximum single dose administered at one time on the frequency of AEs.
Single doses of vupanorsen up to 120 mg SC and multiple doses up to 60 mg SC QW for 
6 doses (total exposure of 360 mg) were safe and well-tolerated in healthy volunteers in the 
Phase 1 study. There was no evidence of treatment-associated AEs or negative effects on 
platelets or renal function. At the highest multiple dose administered (60 mg QW), 2 out of 

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6 participants had elevations in liver enzymes, with 1 participant exceeding >3 × ULN and 
without elevation in bilirubin. Both participants with ALT elevations in Phase 1 completed 
the study.
Doses of vupanorsen up to 80 mg Q4W were well tolerated in the Phase 2a study. There were 
observations in the vupanorsen-treated participants that were not considered safety issues but 
warrant additional study in a larger sample size to understand if they are related to 
vupanorsen administration or could reflect a stochastic finding. These observations included 
increase in HFF and small increases in mean ALT. Injection-site reactions will also be 
assessed in a larger sample size relative to earlier studies. This Phase 2b study includes 
measures to mitigate these identified risks (Section 2.3.1) and provide close oversight of 
participants. 
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including follow-up visit.
The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants aged ≥40 years at Screening.

Refer to Appendix 4 for male and female reproductive inclusion criteria 
(Section 10.4.1, Section 10.4.2, and Section 10.4.3) and for contraceptive 
requirements for female participants (Section 10.4.4).
Type of Participant and Disease Characteristics:
2. Fasting non-HDL-C at Screening ≥100 mg/dL.
3. Fasting TG at Screening of 150 to 500 mg/dL, inclusive, which may be repeated once if 
deemed necessary.

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4. Participants must be on a stable dose of a statin for at least 1 month before Screening and 
plan to remain on the same medication and dose for the duration of the study. 
Weight:
5. Body weight ≥50 kg and ≤136 kg at Screening.
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the 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. Participant has active liver disease (other than NAFLD or NASH, which are permitted), 
including chronic active hepatitis B or C or primary biliary cirrhosis.
2. Uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood 
pressure >100 mmHg). Note: participants who are on an anti-hypertensive medication to 
treat hypertension should be on a stable dose at least 1 month prior to Screening. The 
investigator should ensure participant took anti-hypertensive medication as prescribed 
prior to evaluation of blood pressure. 
3. Participant with a known bleeding diathesis or coagulation disorder.
4. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screening, as assessed by the central laboratory and confirmed by a single repeat test, if 
deemed necessary:

HbA1c ≥9.5%

eGFR <30 mL/min/1.73 m2 (as determined by the CKD-Epi equation)

ALT or AST >2 × ULN

Total bilirubin ≥1.5 × ULN; participants with a history of Gilbert’s syndrome may 
have a direct bilirubin measured and would be eligible for this study provided the 
direct bilirubin is ≤ULN

Platelet count <LLN
5. History of clinically significant acute cardiac event within 3 months before Screening 
(includes ischemic stroke, transient ischemic attack, myocardial infarction, 
revascularization procedures, hospitalization for heart failure).

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6. Presence of New York Heart Association Functional Classification IV heart failure 
symptoms at Screening.
7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated.
8. Current history of alcoholism or drug addiction according to Diagnostic and Statistical 
Manual of Mental Disorders IV criteria within 12 months prior to Screening. Use of any 
recreational drugs within 12 months prior to Screening. 
9. Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
Prior/Concomitant Therapy:
10. Prior treatment at any time with vupanorsen.
11. Prior treatment with any oligonucleotide (including small interfering ribonucleic acid) 
within 6 months of Screening or prior treatment with inclisiran within 12 months of 
Screening.
12. Use of TG lowering medication (eg, Vascepa [icosapent ethyl]), non-prescription dietary 
supplements (eg, fish oil) or other cholesterol lowering medication (eg, fibric acid 
derivatives, niacin, PCSK9 inhibitors, bile acid sequestrants, bempedoic acid) 30 days 
prior to Screening, other than statins and ezetimibe. 
13. Use of warfarin or other coumarins, direct thrombin inhibitors, Factor Xa inhibitors,
heparins or heparinoids 30 days prior to Screening.
Prior/Concurrent Clinical Study Experience:
14. Previous administration with an investigational drug 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:
15. Participant has a clinically significant ECG abnormality during the Screening Period that 
requires further diagnostic evaluation or intervention (eg, new, clinically significant 
arrhythmia or a conduction disturbance).
Other Exclusions
16. Unstable weight (>5% shift in past month) or plan to start a diet for the purpose of 
significant weight loss.

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17. Hypersensitivity to the active substance or to any of the excipients or GalNAc.
18. Any major surgery, including bariatric surgery, within 3 months of Screening.
19. Participants with conditions contraindicated for MRI procedures including pacemakers or 
aneurysm clips; the presence of MRI incompatible implanted devices; metallic foreign 
bodies; metal tattoos (including permanent make-up); or severe claustrophobia impacting 
the ability to perform MRI. Participants who may require mild sedative or anxiolytic in 
order to complete the MRI may be enrolled.
20. Participants unwilling or unable to comply with study procedures, including follow-up, as 
specified by this protocol, or unwillingness to cooperate fully with the Investigator.
21. Investigator site staff or Pfizer employees directly involved in the conduct of the study, 
site staff otherwise supervised by the investigator, and their respective family members.
5.3. Lifestyle Considerations
5.3.1. Contraception 
Contraception is required only for female participants of childbearing potential (see 
Appendix 4 Section 10.4.3). The investigator or his or her designee, in consultation with the 
participant, will confirm that the participant has selected an appropriate method of 
contraception for the individual participant from the permitted list of contraception methods 
(see Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use. At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s affirmation in 
the participant’s chart (participants need to affirm their consistent and correct use of at least 
1 of the selected methods of contraception). In addition, the investigator or designee will 
instruct the participant to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the participant or partner.
5.3.2. Dietary Restrictions and Fasting
Participants should maintain their usual diet and exercise regimen throughout the study.
Participants should abstain from all food and drink (except water) for ≥10 hours prior to 
Screening Visit 1 and visits at Weeks 0, 4, 8, 12, 16, 20, 24, follow-up, and Early 
Termination/Discontinuation visit (if applicable) for testing of lipids, extended lipoprotein 
panel, FFA, ANGPTL3, hsCRP, or PK. Prior to the visit, the study site should contact the 
participant to remind him/her of the fasting requirement and specify the time the participant 
should stop eating relative to the time of the visit. Participants are permitted to take 
concomitant medications (provided that they can be taken in the fasting state), taken as 
prescribed with water, on the morning of a study visit.
Participants must abstain from all food and drink (except water) for ≥4 hours prior to 
MRI-PDFF assessment.

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5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened if they failed for a documented treatable condition. Individuals may not be 
rescreened if they did not meet inclusion requirements for TG and non-HDL-C.  
5.5. Criteria for Temporarily Delaying Enrollment/Randomization/Study Intervention 
Administration
Not applicable.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to vupanorsen or placebo 
administered SC.

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6.1. Study Intervention(s) Administered
Study Intervention
Vupanorsen
Placebo
ARM Name
80 mg 
Q4W
60 mg 
Q2W
120 mg 
Q4W
80 mg 
Q2W
160 mg 
Q4W
120 mg 
Q2W
160 mg 
Q2W
Placebo
Type
Drug
Placebo
Dose Formulation
100 mg/mL
0 mg/mL
Unit Dose Strength(s)
60 mg/syringe or 80 mg/syringe
0 mg/
syringe
Dosage Level(s)
80 mg 
Q4W
60 mg 
Q2W
120 mg 
Q4W
80 mg 
Q2W
160 mg 
Q4W
120 mg 
Q2W
160 mg 
Q2W
0 mg Q2W 
or Q4W
Route of 
Administration
SC
SC
Use
Experimental
Placebo
IMP or NIMP 
IMP
IMP
Sourcing 
Prefilled syringes will be provided centrally by the sponsor. See IP manual. 
Packaging and 
Labeling
Study intervention will be provided in masked, prefilled syringes. Each prefilled syringe will be labeled 
as required per country requirement.
Current/Former 
Name or Alias
PF-07285557
ISIS 703802

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6.1.1. Administration 
During the Screening Period, sites will instruct participants (or caregivers) how to perform 
the SC injection and proper sterile technique. Participants (or caregivers) will be dispensed a 
prefilled syringe of open-label placebo to inject, and sites will determine if a participant or 
caregiver is willing and able to correctly perform the SC injection.
On Day 1, the initial dose of study intervention administered by the participant or caregiver 
must be observed by study site personnel to ensure the participant or caregiver is using 
proper technique. 
Vupanorsen or placebo will be administered as a single or double SC injection at 2-week or 
4-week intervals depending on the treatment arm. At the study site or at home, SC injections 
should be administered by the participant or caregiver according to dosing instructions in any 
of the following locations: upper arm, thigh, or abdomen quadrant, as preferred by the 
participant. Participants receiving 2 injections should consecutively administer each injection 
in a different location. To minimize injection site reactions, the SC injection should not be 
administered in areas where the skin is burned, reddened, inflamed, swollen, or scarred. If a 
participant receiving study intervention Q2W or Q4W misses or delays their dose outside the 
dosing window and is within 7 or 14 days, respectively, of the next dose, the dose should be 
skipped altogether and recorded on the CRF. 
Participants receiving study intervention Q2W will receive a diary to record home dosing. 
Study intervention administration details will be recorded on the CRF.
6.1.2. Medical Devices
1. The sponsor manufactured medical devices provided for use in this study are 
vupanorsen 100 mg/mL (60 mg/syringe), vupanorsen 100 mg/mL (80 mg/syringe), or 
placebo (0 mg/syringe) for Solution for Injection.
2. Instructions for medical device use are provided in the IP manual.
3. All medical device deficiencies (including malfunction, use error and inadequate 
labeling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.3.8) and appropriately managed by the sponsor.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 

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must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. Only study intervention 
administered Q2W will be taken home by the participant; cooler bags will be 
provided for transporting study intervention from the site to the participant’s home. A 
biohazard sharps container will be provided to the participant for disposal of used 
syringes. When the biohazard sharps container is full or at end of study or early 
discontinuation visit, the participant will return the biohazard sharps container to the 
study site for destruction. All study intervention that is taken home by the participant, 
both used and unused, must be returned to the investigator by the participant. 
Returned study intervention must not be redispensed to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. 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 as described in the IP manual.

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6.2.1. Preparation and Dispensing
Vupanorsen and placebo will be provided as prefilled syringes packaged and dispensed in 
cartons with tamper-evident seals. Only single-use syringes will be used. Study intervention 
should be dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, state, and institutional guidance. The qualified staff 
member will dispense the study intervention using an IRT drug management system via 
unique container numbers in the cartons provided and in quantities appropriate to the SoA. A 
second staff member will verify the dispensing. The participant or caregiver should be 
instructed to maintain the product in the cartons provided, and the cartons should not be 
opened until the study intervention is to be administered. See the IP manual for detailed 
instructions. 
The following procedures should be followed to help protect the blind:

Used syringes should be placed immediately after use, whenever or wherever dosing 
occurs, in a biohazard sharps container, and the container will be returned to the study 
site, as needed, eg, when the biohazard sharps container is full or at end of study/early 
discontinuation visits.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(IWR). The site personnel (study coordinator or specified designee) will be required to enter 
or select information including but not limited to the user’s ID and password, the protocol 
number, and the participant number. The site personnel will then be provided with a 
treatment assignment, randomization number, and DU or container number when study 
intervention is being supplied via the IRT system. The IRT system will provide a 
confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files. 
Study intervention will be dispensed at the study visits listed in the SoA. 
Returned study intervention must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor or TIMI Hotline prior to 
unblinding a participant’s treatment assignment unless this could delay further management 

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of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
At site visits, study intervention will be dispensed by the investigator or designee, and 
participants will self-administer (or caregivers will administer) study intervention 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 ID will be confirmed at the time of dosing by a member of the study 
site staff other than the person dispensing the study intervention.
Participants receiving study intervention Q2W will receive a diary to record home dosing. 
When participants self-administer (or caregivers administer) study intervention at home, 
compliance with study intervention will be assessed at each on-site visit. Compliance will be 
assessed by reviewing the participant’s diary (Q2W only), direct questioning, and checking 
empty cartons during the site visits and documented in the source documents and CRF. 
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
A record of the number of vupanorsen and placebo syringes dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded in the CRF.
6.5. Concomitant Therapy
All concomitant medications taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. Attempts must be made to not alter the doses 
and regimens of background lipid lowering therapy (statin and ezetimibe [if applicable]) after 
randomization and for the duration of participation in this study. All participants must be 
questioned about concomitant medication at each visit to the clinical site.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
6.5.1. Prohibited Therapy During the Study

Use of TG lowering or cholesterol lowering medication (eg, fibric acid derivatives, 
niacin, PCSK9 inhibitors, bile acid sequestrants, bempedoic acid).

Use of TG lowering dietary supplements (eg, fish oil) and prescription products 
containing omega-3 fatty acids (eg, Vascepa [icosapent ethyl]). 

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
Use of warfarin or other coumarins, direct thrombin inhibitors, Factor Xa inhibitors, 
heparins or heparinoids is prohibited during the study.
6.5.2. Prohibited Prior Treatments

Use of any therapy listed in Section 6.5.1 30 days prior to Screening.

Prior treatment at any time with vupanorsen is prohibited.

Prior treatment with any oligonucleotide (including small interfering ribonucleic acid) 
within 6 months of Screening or prior treatment with inclisiran within 12 months of 
Screening is prohibited.

Prior administration with an investigational drug 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) is prohibited.
6.5.3. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with vupanorsen; standard medical 
supportive care must be provided to manage any AEs. 
6.6. Dose Modification
Dose modifications will not be performed during this study. 
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
Due to unforeseen circumstances, all participants may not complete the study as planned. 
Regardless of study intervention status, participants should continue in the study if willing. 
Possible discontinuations may include:
1. Discontinuation of study intervention: Participants will discontinue study intervention but 
continue in the study.
a.
Temporary discontinuation: If a participant temporarily discontinues study 
intervention for any reason other than safety, they should resume study intervention at 
the next scheduled dosing, if possible.
b. Definitive discontinuation: If study intervention is permanently discontinued (as 
requested by the investigator or the participant), the participant will remain in the 
study to be evaluated during the regular visit schedule (see Section 7.1.2 and
Section 7.2.1). At the time of discontinuing from the study intervention, if possible, 
an Early Termination/Discontinuation visit should be conducted. See the SoA for 

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assessments to be collected at the time of discontinuation of study intervention and 
for any further evaluations that need to be completed.
Whenever possible, restart of study intervention should be encouraged. Even if an 
Early Termination/Discontinuation visit was completed due to the discontinuation of 
study intervention, this should not prevent complete study follow-up procedures 
including restart of randomized treatment. All efforts must be taken to assure that the 
participant will be seen and assessed by an investigator. Participants fulfilling a 
study-specific discontinuation criteria should never be restarted on study intervention.
2. Participant discontinuation/withdrawal from the study: Participants will not continue in 
the study (see Section 7.2).
a.
Withdrawal of consent (see Section 7.2.1).
b. Lost to follow-up (see Section 7.3). 
7.1. Discontinuation of Study Intervention
7.1.1. Monitoring Criteria
In general, all laboratory assessments to monitor participant safety or to determine whether a 
participant may continue or resume dosing with study intervention should be done by the 
central laboratory, if possible. Local laboratory testing may be acceptable in some situations 
and should be discussed by contacting the TIMI Hotline on a case-by-case basis.
The following laboratory abnormalities require prompt retesting within 7 days of receipt of 
results:

Any platelet count <100,000 /mm3. The participant should be managed according to 
Appendix 10 flow chart for managing decreased platelet counts.

Any decrease in eGFR of ≥50% from baseline or eGFR <15 mL/min/1.73 m2. The 
participant should be managed according to Appendix 11 flow chart for managing eGFR 
decreases.

Either of the following AST or ALT abnormalities (Note: Participants meeting either of 
the following retesting criteria should be managed according to Appendix 12 for 
management of elevated AST or ALT. This should also prompt review of Appendix 6
[liver safety] to determine if additional investigations must be conducted):

Any single AST and/or ALT elevation >3 × ULN for participants with baseline AST 
and ALT within normal limits, regardless of accompanying symptoms or total 
bilirubin.

Baseline AST or ALT values above the reference range: AST or ALT values >2 times 
the baseline values AND >3 × ULN, regardless of accompanying symptoms or total 
bilirubin.

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7.1.2. Discontinuation Criteria
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

Platelet count is <75,000 /mm3 on a re-test (ie, initial platelet count is <100,000 /mm3
and the repeat platelet count is <75,000 /mm3 or both the initial and re-test are 
<75,000 /mm3). Refer to Appendix 10 for management of participants who 
discontinue due to decreased platelets as additional investigations must be conducted.

The participant’s eGFR falls to <15 mL/min/1.73 m2 and confirmed by a repeat 
laboratory measurement.

Participant meets criteria for DILI (Hy’s Law) as defined in Appendix 6.

AST or ALT elevations are >8 × ULN, confirmed on a repeat laboratory 
measurement, regardless of total bilirubin or accompanying symptoms.

A severe hypersensitivity reaction or severe injection site reaction occurs following a 
SC study intervention dose. Severe hypersensitivity reactions are defined as those 
causing anaphylaxis. Severe injection site reactions are defined as those in which 
ulceration or severe necrosis occurs.

Participant becomes pregnant.
Note that discontinuation of study intervention does not represent withdrawal from the study.  
If study intervention is definitively discontinued, the participant will remain in the study to 
be evaluated during the regular visit schedule. See the SoA for data to be collected at the time 
of discontinuation of study intervention and follow-up for any further evaluations that need 
to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for
stopping study participation include the following:

Refused further follow-up

Lost to follow-up

Death

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
Study terminated by sponsor
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
Participants should be questioned regarding their reason for withdrawal.  
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 procedures. The only exception to 
this is when a participant specifically withdraws consent for any further assessments or 
contact with his or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator of the decision to withdraw consent 
from future follow-up. Participants should be questioned regarding their reason for 
withdrawal. The investigator must inform the TIMI Hotline of the withdrawal of consent. 
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the participant is only stopping further receipt of study 
intervention or withdrawing from study procedures and/or posttreatment study follow-up, 
and entered on the appropriate CRF page. At the time of withdrawal from the study, if 
possible, an Early Termination/Discontinuation visit should be conducted. See the SoA for 
assessments to be collected at the time of study withdrawal.
If a participant withdraws consent from the study, he/she may request destruction of any 
remaining samples taken and not tested, and the investigator must document any such 
requests in the site study records and notify the sponsor accordingly.
If the participant withdraws consent for disclosure of future information, no further 
evaluations should be performed and no additional data should be collected. The sponsor 
may retain and continue to use any data collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Publicly available information should be used to determine vital status (whether the 
participant is alive or dead) only as appropriately directed in accordance with local law.
7.3. Lost to Follow-up
To prevent participants being lost to follow-up, their contact details, including next of kin 
contacts, should be collected initially and updated regularly by the site staff or representative. 
The investigator should educate the participant on the importance of contact with the 
investigator throughout the study.
Repeated attempts will be made to locate and obtain pertinent medical information for 
participants who are initially lost to follow-up. A participant will be classified as lost to 
follow-up only if he/she has failed to return for the required study visits and his/her vital 

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status remains unknown at the end of the study despite multiple attempts to contact him/her 
via telephone, fax, email, certified letter, or through patient locator agencies (if allowed by 
national regulation). Where permissible by local law, the ICD will include language to grant 
the option to employ outside companies to assist in obtaining updated contact information or 
ascertainment of vital status of lost participants using publicly available source.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
250 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.

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8.1. Efficacy Assessments
8.1.1. Lipids
Blood samples for measurement of TC, direct LDL-C, HDL-C, TG, and direct VLDL-C 
should be collected from participants in a fasted state (see Section 5.3.2) as indicated in the 
SoA; non-HDL-C will be calculated as TC – HDL-C.
Lipid results from Day 1 onward will not be reported to study sites or other blinded personnel 
until the study has been unblinded (see Section 8.2.7 for potential exception). 
8.1.2. Lipoproteins and FFA 
Blood samples for measurement of Lp(a), ApoB, ApoB-48, ApoB-100, ApoC-III, ApoA-I, 
and FFA should be collected from participants in a fasted state (see Section 5.3.2) as 
indicated in the SoA.
Lipoprotein and FFA results from Day 1 onward will not be reported to study sites or other 
blinded personnel until the study has been unblinded. 
8.1.3. hsCRP
Blood samples for measurement of hsCRP should be collected from participants in a fasted 
state (see Section 5.3.2) as indicated in the SoA.
hsCRP results will not be reported to study sites or other blinded personnel until the study 
has been unblinded.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. MRI-PDFF Assessments
At scheduled visits (refer to the SoA), liver fat will be assessed via MRI using the PDFF 
acquisition method. Each assessment will require the participants to be in a supine position in 
the confined space of the MRI scanner for approximately 25 minutes with the image 
acquisition undertaken following a fast (except water) of ≥4 hours, and as much as 
practically possible, at the same time (±2 hours) of the day relative to assessment at 
Screening.
Across the study sites selected for this study, the sponsor-identified central imaging vendor 
will train the imaging facility staff on the MRI-PDFF acquisition protocol, on just-in-time 
review of the acquired images for assessment of images being deemed evaluable, and on 
transfer (preferably electronically) of the images to the sponsor-identified central imaging 
vendor for analysis and quantification of liver fat. Only the staff members at the imaging 
facility who are trained by the sponsor-identified central imaging vendor are permitted 
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written approval of the sponsor. Complete details on the MRI-PDFF acquisition protocol, 
determination of quality of images, and transmission of data to sponsor-identified central 
imaging vendor will be provided in an Imaging Manual provided to the sites prior to the start 
of the study.
As much as practically possible, analysis of the MRI-PDFF images acquired at baseline and 
Week 24 will be undertaken by a single reviewer at the sponsor-identified central imaging 
vendor who will be blinded to individual participant’s clinical data, as well as randomization 
assignment. MRI-PDFF images will be blinded to study sites, blinded personnel, participants, 
and sponsor until the study has been unblinded.  
8.2.1.1. Management of Incidental Findings
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study. The images will be 
reviewed by a sponsor-identified central review facility. The purpose of this review is to 
evaluate images for the amount of fat in the liver. Central image review is not a complete 
medical review of the participant. If, during the central review process, an unexpected 
observation is identified and this finding could, in the opinion of the central reviewer, have a 
significant health or reproductive consequence, this finding may be shared with the study 
sponsor for disclosure to the PI. All follow-up testing and final diagnosis will be left to the 
discretion of the medical professionals at the site or those with an existing physician-
participant relationship. The PI will be responsible for reporting any AEs identified from 
incidental findings as described in the AE reporting section. Identification of such incidental 
findings during the central review process should not be expected, and the site maintains 
responsibility for performing a general safety review of all images as per site protocols.
8.2.2. Physical Examinations
Physical examination will be performed at Screening.
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.
Height will be measured and recorded at Screening, and weight will be measured and 
recorded at Screening, Day 1, Day 169, and Early Termination/Discontinuation, if applicable 
(see SoA).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.3. Vital Signs
Single seated blood pressure and pulse rate will be assessed at times specified in the SoA
with a completely automated device. Manual techniques will be used only if an automated 
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Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones).
8.2.4. Electrocardiograms
Standard 12-lead ECG utilizing limb leads (with 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 heart rate and measures PR, QT, and QTc intervals, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be done given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. 

All scheduled 12-lead ECGs should be performed with the participant in a supine 
position;

ECG values of potential clinical concern are listed in Appendix 7. 

If a machine-read QTc value is prolonged, as defined in Appendix 7, repeat 
measurements may not be necessary if a qualified physician’s interpretation 
determines that the QTc values are in the acceptable range;

Assessment of whether prolonged QTc interval meets criteria as defined in 
Appendix 7, must assess QTc interval using only the Fridericia’s correction (ie, 
QTcF) either as reported by the 12-lead ECG machine or QTcF derived using 
sponsor-provided tool and reported QT and RR intervals. 

In some cases, it may be appropriate to repeat abnormal 12-lead ECG to rule out 
improper lead placement as contributing to the ECG abnormality; as much as practically 
possible, it is important that leads be placed in the same positions each time in order to 
achieve precise ECG recordings.
8.2.5. 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. Safety assessments include blood chemistry, hematology, 
urinalysis, UACR, PT, aPTT, INR, HbA1c, and pregnancy test. All protocol-required 
laboratory assessments, as defined in Appendix 2, must be conducted in accordance with the 
laboratory manual and the SoA. Note: safety laboratory results from Week 1 visit should be 
reviewed by the investigator prior to Week 2 dosing for participants dosing Q2W and prior 
to Week 4 dosing for participants dosing Q4W. 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 relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease under study, unless judged by the investigator to be more severe than 
expected for the participant's condition.

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All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 12 weeks after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or TIMI Hotline.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified as much as possible and the sponsor 
notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at Screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ ECs or if required by local regulations. If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In 
such cases, the participant must be excluded and discontinued from study intervention if the 
serum pregnancy result is positive.
8.2.7. Potential Severe Cases of Hypertriglyceridemia
In certain circumstances, unblinding of TG results may occur during the study. In the event a 
participant’s fasting (see Section 5.3.2) TG is >1000 mg/dL, as reported by the sponsor-
identified central laboratory, the investigator and sponsor will receive an alert from the 
laboratory along with the unblinded TG level. The investigator is to repeat the TG test via the 
central laboratory, ideally within 7 days of receipt. The investigator should counsel the 
participant on diet and lifestyle factors to improve the TG level prior to the repeat 
measurement. For participants with a confirmed TG value of >1000 mg/dL, the investigator 
will again counsel the participant on diet and lifestyle, and the investigator can titrate the 
statin dose (if applicable) or can add a medication to lower TG at the investigator’s 
discretion. In only these circumstances (confirmed TG value of >1000 mg/dL), the prohibited 
TG lowering medications in Section 6.5.1 are not applicable. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 8. Device deficiencies are covered in Section 8.3.8.

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AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE (see Appendix 3) or caused the 
participant to discontinue the study intervention (see Section 7.1).
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.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 12 weeks, except as indicated below, after the last administration of the study 
intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator 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 definitively 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 AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 

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

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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.

A male family member of healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 21 weeks 
after the last dose. 

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.

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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs.  If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving study intervention 
or for a minimum of 21 weeks after discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 

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information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE. The information 
must be reported using the CT SAE Report Form. Since the information 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 is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Cardiovascular and death events will be reported according to Adverse Event reporting 
procedures.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Disease-related events are not applicable to this study.
8.3.8. Adverse Events of Special Interest 
Injection site reactions are AESI. In case of acute injection site reactions, the Investigator 
should institute treatment measures deemed medically appropriate such as topical therapy at 
the injection site. Such events and treatments are to be captured and reported on the 
appropriate CRF. If an injection site reaction occurs at more than 1 injection site location, 
each location should be captured as a separate injection site AE. For each injection site AE, 
an injection site assessment should be conducted and captured on the CRF. A separate 
injection site assessment should be conducted for each injection location where an injection 
site reaction occurs. The site should also complete the injection site reaction assessment and 
all concomitant treatments should be recorded and captured in the CRF, together with the 
Adverse Event of injection site reactions. AEs should be reported as serious per the criteria in 
Section 10.3.2.

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Additional AESI include increases in ALT/AST, decreases in platelet count, or decreases in 
eGFR (as described in Section 7.1.1) that result in a missed dose due to temporary dose 
interruption or permanent discontinuation.
All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.3.1 through 8.3.4. 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.
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer only if associated with an SAE (see Section 10.3.1).
8.3.9. Medical Device Deficiencies
Medical devices are being provided for use in this study as the study intervention is supplied 
in prefilled syringes. In order to fulfill regulatory reporting obligations worldwide, the 
investigator is responsible for the detection and documentation of events meeting the 
definitions of device deficiency that occur during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 8.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Sections 8.3.1 through 8.3.4 and Appendix 3 of the protocol.
8.3.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies or malfunctions of the device will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 8.
8.3.9.2. Follow-up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.3.9.3. Prompt Reporting of Device Deficiencies to Sponsor
Device deficiencies will be reported to the sponsor within 1 day after the investigator 
determines that the event meets the protocol definition of a medical device deficiency.  

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Information will be provided to the sponsor as described in the IP manual. The Medical 
Device Complaint CRF will also be completed.
Any device deficiency that is associated with an SAE must be reported to Pfizer Safety 
within 24 hours upon the investigator’s awareness as outlined in Sections 8.3.1.1 and 8.3.1.2.
The sponsor will be the contact for the receipt of device deficiency information.
8.3.9.4. Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.

Injection administered via any route (ie, intramuscular, intravenous) other than SC.

Injection administered in a location other than upper arm, thigh, or abdomen 
quadrant.

For dose regimens requiring 2 injections, both injections administered at the same
injection site.

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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of vupanorsen greater than 320 mg (more than four 80 mg/placebo 
syringes or more than five 60 mg/placebo syringes) given within a 21-day period will be 
considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the TIMI Hotline within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
vupanorsen can no longer be detected systemically (at least 5 half-lives [ie, 
150 days]).  
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the TIMI Hotline based on the clinical evaluation of the participant.  
8.5. Pharmacokinetics
For all participants, trough and post-treatment concentrations of vupanorsen in plasma (as 
total full-length oligonucleotides, including fully conjugated, partially conjugated, and 
unconjugated vupanorsen) will be determined as specified in the SoA. A listing of individual 
vupanorsen concentration sorted by treatment group, participant ID, planned visit, visit date 
and time, and time post the most recent dose will be reported and summarized by treatment 
with and without stratification by individual immunogenicity status using descriptive 
statistics. Population PK and PK/PD analyses may be explored using the combined data from 
this study and other clinical studies of vupanorsen and reported in a separate population 
analysis report.

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Blood samples of approximately 4 mL will be collected in K2 EDTA tubes, to provide a 
minimum of 2 mL plasma for measurement of plasma concentrations of vupanorsen from 
participants in a fasted state (see Section 5.3.2). Instructions for the collection and handling 
of biological samples will be provided in the laboratory manual or by the sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded.
Samples will be used to evaluate the PK of vupanorsen. Each plasma sample will be divided 
into 2 aliquots. Samples collected for analyses of vupanorsen plasma concentration may also 
be used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study, for metabolite identification and/or evaluation of the bioanalytical method, or for other 
internal exploratory purposes.
Samples collected for measurement of plasma PK concentrations of vupanorsen will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or exploratory methods.
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.
Drug concentration information that may unblind the study will not be reported to 
investigator sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned PK study assessments 
must be documented and then archived in the sponsor and site study files, but will not 
constitute a protocol deviation. 
8.6. Pharmacodynamics
Serum ANGPTL3 will be measured as the target PD endpoint in this study.
Blood samples of approximately 4 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of ANGPTL3 from participants in a fasted state (see 
Section 5.3.2) as specified in the SoA.
As part of understanding the PD of the study intervention, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes.  
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs.
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PD sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 

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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.
ANGPTL3 results will not be reported to investigator sites during the study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation (Prep D1) will be collected as local 
regulations and IRBs/ECs allow. 
Banked Biospecimens may be used for research related to the study intervention(s) and 
dyslipidemia or CV disease. Genes and other analytes (eg, proteins, RNA, nondrug 
metabolites) may be studied using the banked samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the Central Laboratory Manual.
8.8. Biomarkers
Biomarkers are not evaluated in this study. 
8.8.1. Banked Biospecimens for Biomarkers
Additional Banked Biospecimens in this study are:

6-mL whole blood (Prep B1.5) will be collected and isolate plasma retained.

6-mL whole blood (Prep B2.5) will be collected and isolate serum retained.

5-mL urine (Prep M4) will be collected and retained.
Banked Biospecimens will be collected as local regulations and IRB/ECs allow.  
Banked Biospecimens may be used for research related to the study intervention(s) and 
dyslipidemia. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the banked samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in central laboratory manual. 
8.9. Immunogenicity Assessments
Immunogenicity of vupanorsen will be assessed before, during, and after treatment. A listing 
of individual plasma ADA results (including ADA positive, negative, and unknown status 

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samples and titers) sorted by treatment group, participant ID, planned visit, and the visit 
date/time will be reported. The incidence (number) and incidence rate (percent) of ADA 
positive, negative and unknown participants will be summarized by treatment group and 
planned visit and for the overall study. The ADA positive participants will be further 
subcategorized into TEADA if the baseline ADA is negative. The incidence and incidence 
rate of TEADA will be summarized by treatment group and planned visit and for the overall 
study.  
Potential relationships of immunogenicity with selected efficacy, safety, and PK 
concentrations may be evaluated.
Blood samples of approximately 6 mL will be collected in K2 EDTA tubes, to provide a 
minimum of 3 mL plasma for determination of ADA as specified in the SoA. Instructions for 
the collection and handling of biological samples will be provided in the laboratory manual 
or by the sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded.
Samples collected for determination of ADA may also be used for additional characterization 
of the immune response or for other internal exploratory purposes. These data will be used 
for internal exploratory purposes.
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs. Samples determined to be positive for ADA may be further characterized.
The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity. Any deviations from the 
immunogenicity 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.
No immunogenicity data will be provided to study sites, blinded personnel, or the study team
until the study has been unblinded.
8.10. 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.

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9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The primary estimand of this study will follow the hypothetical estimand approach to 
estimate the effect of treatment under the hypothetical condition that all participants 
maintained their randomized treatment through Week 24. This estimand is meant to estimate 
the pharmacological effect of the drug when taken as directed. It includes the following 
4 attributes: 

Population: Participants with dyslipidemia taking a statin who meet the 
inclusion/exclusion criteria.

Variable: The percent change from baseline in non-HDL-C at Week 24.

Intercurrent event: All off-treatment data (ie, occurring at least 1 dosing interval after 
discontinuation of treatment), or data collected post treatment of severe 
hypertriglyceridemia (ie, change in statin dose or addition of TG lowering therapy; 
Section 8.2.7), if collected, will be excluded from analysis.  

Population-level summary: Difference of variable means between vupanorsen and 
placebo.
9.2. Sample Size Determination
Assuming a common standard deviation of 17.5% (observed in the Month 6 data of the 
Phase 2a proof-of-concept and dose-ranging study) for the percent change from baseline in 
non-HDL-C at Week 24 and a treatment discontinuation rate of 15%, 20 participants per arm 
will correspond to a 95% CI of point estimate ±11.76% for the difference of treatment effect 
(versus placebo). These parameters correspond to a power of 91.5% using a 2-sided alpha of
0.05, to detect a difference of -20%, without adjustment for multiple comparison to placebo.
A permutation block schedule will be used in enrollment within each arm, including 
vupanorsen and matching placebo. If enrollment is stopped for the 160 mg Q2W arm (see 
Section 4.1), the corresponding matching placebo enrollment will also be stopped.
9.3. Analysis Set
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly 
assigned to study 
intervention
"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. 
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.

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Evaluable
All participants who are randomized, take at least 1 dose of 
study intervention and have baseline measurements and at 
least 1 post-baseline measurement.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the treatment group they are 
randomized to unless the wrong study intervention is received 
throughout the study. 
Defined Analysis Set
Description
FAS_Primary
In the evaluable analysis set, for participants who discontinue 
treatment, all post-discontinuation observations will be 
censored to missing.
FAS
In the evaluable analysis set, for participants who discontinue 
treatment, all observations post-discontinuation will be 
included in the analysis set.
9.4. 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.
9.4.1. General Considerations
The primary statistical method of MMRM will apply to continuous endpoints.
Statistical efficacy comparison will be made between each dose of vupanorsen and placebo 
for primary and secondary endpoints, respectively. Placebo-adjusted LS mean difference, 
95% CI, and p-value will be presented. Since this study is exploratory in nature, no 
multiplicity adjustment of endpoints nor adjustment of multiple comparison to placebo will 
be made. Sensitivity analyses/supplementary analyses are defined in the SAP. Since the visit 
after Week 24 is considered safety follow-up, the statistical analyses at those visits will be 
presented but the p-value will be treated only as nominal.
In addition, a Bayesian Emax dose-response model will be estimated to illustrate the expected 
relationship between doses and their corresponding (percent) change from baseline at 
Week 24 for primary and key secondary endpoints, respectively. For each endpoint, 95% CI 
at each studied dose level will also be constructed.

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If the baseline value is not available, the last measurement prior to the randomization visit 
will be used. However, for non-HDL-C and other lipid parameters, the baseline value will be 
calculated using the average of all values obtained at Screening and on Day 1 prior to dosing, 
except that for TG, when the initial value is exclusionary, the repeat value after the initial 
value and Day 1 value will be used to derive the baseline value. 
In addition to analyses, summary statistics, listings, and figures will be provided.
9.4.2. Primary Endpoint(s)
The treatment effect of vupanorsen relative to placebo on the mean percent change/reduction 
from baseline in non-HDL-C at Week 24 will be estimated from the MMRM using the 
FAS_Primary analysis set, ie, assuming all participants in the analysis maintain their 
randomized treatments. The LS-mean percent change from baseline at Week 24 along with 
95% CI for each treatment group and placebo-adjusted LS-mean at Week 24 along with 95% 
CI and p-value for each vupanorsen treatment group will be presented. 
A Bayesian Emax dose-response model will be also be estimated using the FAS_Primary 
analysis set, incorporating with the prior distribution of the Emax model parameters estimated 
from the Phase 2a study. Sensitivity analyses will also be performed to evaluate the 
robustness of the primary analysis results (details are covered in the SAP).
9.4.3. Secondary Endpoint(s)
No multiplicity adjustments will be applied to secondary endpoints. All secondary endpoints 
will be primarily analyzed using the FAS_Primary analysis set.
For continuous secondary endpoints, MMRM analyses will be implemented, with both 
LS-mean and placebo-adjusted LS-mean along with 95% CI, p-value at Weeks 4, 8, 12, 16, 
20, and 24 estimated. The same type of Bayesian Emax dose-response model will be estimated 
using the FAS_Primary analysis set for each of the key secondary endpoints respectively. 
Sensitivity analyses will also only be performed on key secondary endpoints (details are 
covered in the SAP).
9.4.4. Tertiary/Exploratory Endpoint(s)
No multiplicity adjustments will be applied. All tertiary/exploratory endpoints will be 
analyzed using the FAS_Primary analysis set. 
For continuous tertiary/exploratory endpoints except for PK, MMRM analyses will be 
implemented, with both LS-mean and placebo-adjusted LS-mean along with 95% CI, p-value 
at Weeks 4, 8, 12, 16, and 24 estimated.
Listings of individual vupanorsen PK concentration values will be provided.
9.4.5. Other Safety Analyse(s)
All safety analyses will be performed on the safety population.
From the safety perspective, the following key laboratory endpoints will be explored:

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
Change and percent change from baseline in HFF at Week 24 

Change from baseline in eGFR 

Change from baseline in ALT/AST 

Percent change from baseline in UACR

Percent change from baseline in platelet counts

Summary of ALT/AST abnormalities

Summary of confirmed thrombocytopenia
TEAEs, SAEs, death, injection site reactions, ADA, ECGs, vital signs, immunogenicity, and 
other safety laboratory data, including categorical abnormalities in laboratory data, will be 
summarized/analyzed, listed, or presented in figures by treatment group or by treatment 
group and by visit where appropriate. All safety data, including data collected post the 
occurrence of intercurrent events, will be reported.
9.4.5.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and visit.
The number (%) of participants with maximum post-dose QTc values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Degree of 
Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.4.6. Other Analyses 
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during 
the trial and retained for future analyses; the results of such analyses are not planned to be 
included in the CSR. 
The population PK analysis will be performed using vupanorsen concentration data pooled 
from this study and previous studies and may be reported separately from the main CSR. 
Exploratory PK/PD analyses may also be performed for further characterization of biomarker 
and efficacy effects, eg, ANGPTL3, non-HDL-C, and TG levels.

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9.5. Interim Analyses 
An interim analysis will be performed to assess efficacy and safety. The interim analysis will 
take place approximately 16 weeks after 50% of the planned participants (ie, approximately 
110 participants), with the exception of the 160 mg Q2W group, are randomized. Interim 
analysis results, which will include all available data from enrolled participants at the time of 
data cutoff, may be used for internal business decisions regarding future study planning or 
adapting the study after the interim analysis. Before any interim analysis is instigated, the 
details of the objectives, decision criteria, dissemination plan, and method of maintaining the 
study blind as per Pfizer’s SOPs will be documented and approved in a DMC charter. In 
addition, the analysis details must be documented and approved in an interim analysis SAP 
or the finalized SAP.
9.6. Data Monitoring Committee or Other Independent Oversight Committee 
This study will use an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing, unblinded monitoring of the efficacy and safety 
of participants in the study according to the charter. The recommendations made by the 
E-DMC to alter the conduct of the study will be forwarded to the appropriate Pfizer 
personnel for final decision. Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of safety data, to regulatory authorities, as appropriate. 
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 and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

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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 guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant 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, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 

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associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples. The investigator or 
authorized designee will explain to each participant the objectives of the additional research.  
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. A separate signature will be 
required to document a participant's agreement to allow specimens to be used for additional 
research. Participants who decline to participate in this optional additional research will not 
provide this separate signature.
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 

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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 his or her 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.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial 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
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov.

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Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic 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 (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 

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methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the Study Monitoring Plan.
Description of the use of computerized system is documented in the Data Management Plan.  

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10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 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 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor and 
academic leadership 30 days before submission. This allows the sponsor to protect 
proprietary information and to provide comments and the investigator will, on request, 
remove any previously undisclosed confidential information before disclosure, except for any 

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study- or Pfizer intervention-related information necessary for the appropriate scientific 
presentation or understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, the coordinating investigator will be TIMI Study Group.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/study portal. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent. The contact card contains, at a minimum, protocol and study intervention identifiers, 
participant numbers, contact information for the investigator site, and contact details for a 
contact center in the event that the investigator site staff cannot be reached to provide advice 
on a medical question or problem originating from another healthcare professional not 
involved in the participant’s participation in the study. The contact number can also be used 
by investigator staff if they are seeking advice on medical questions or problems; however, it 
should be used only in the event that the established communication pathways between the 
investigator site and the study team are not available. It is therefore intended to augment, but 
not replace, the established communication pathways between the investigator site and the 
study team for advice on medical questions or problems that may arise during the study. The 
contact number is not intended for use by the participant directly, and if a participant calls 
that number, he or she will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests
The following clinical 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.
Clinical Chemistry Panel
Hematology Panel
Urinalysis
Lipid Panel

Sodium

Potassium

Chloride

Bicarbonate

Total protein

Albumin

Calcium

Magnesium

Glucose

BUN

Creatinine

eGFR based on CKD-
Epi

Uric acid

Total bilirubin

Direct (conjugated) 
bilirubin

Indirect 
(unconjugated) 
bilirubin

AST

ALT

Alkaline phosphatase

Red blood cells

Hemoglobin

Hematocrit

MCV, MCH, MCHC

Platelets

WBC differential
     (% and absolute)

Neutrophils

Eosinophils

Basophils

Lymphocytes

Monocytes

Routine urinalysis
  - Color
  - Appearance
  - Specific gravity
  - pH
  - Protein
  - RBC
  - Glucose
  - Ketones
  - Bilirubin
  - Urobilinogen
  - Leukocyte   
     esterase
  - Nitrate

Microscopic 
examination 
(reflex testing 
based on 
urinalysis results)

A/C ratio (UACR)

Total cholesterol

LDL cholesterol –
direct measurement

HDL cholesterol

Non-HDL 
cholesterol

Triglycerides

VLDL cholesterol 
– direct 
measurement
Extended Lipoprotein 
Panel, FFA
Coagulation
Pharmacokinetics
Immunogenicity

Lp(a)

ApoB

ApoB-48

ApoB-100

ApoC-III

ApoA-I

FFA

aPTT (sec)

PT (sec)

INR

Vupanorsen
concentration in 
plasma

Anti-vupanorsen
antibodies in 
plasma
PD
Inflammatory
Other

ANGPTL3

hsCRP

FSHa

Pregnancy test 
(-hCG), urine 
and serumb

HbA1c
a.
For confirmation of postmenopausal status only.
b.
For female participants of childbearing potential.
Investigators must document their review of each laboratory safety report.

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Lipid panel results, extended lipoprotein panel results, and inflammatory results that could 
unblind the study will not be reported to study sites or other blinded personnel until the study 
has been unblinded. 

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfill the definition of an AE or SAE and meet 
the requirements as per Section 8.3.8.1. Also, “lack of efficacy” or “failure of 
expected pharmacological action” does not constitute an AE or SAE.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
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.

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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded
All (and EDP supplemental 
form for EDP) 
Note: Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

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
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 

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assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.

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SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.

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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the highest dose 
of vupanorsen planned for this study would result in maternal systemic exposures via
seminal transfer well below (>5000-fold) the exposure at the NOAEL for developmental 
toxicity in nonclinical studies, including the conservative assumptions that an ASO 
ejaculate:sperm ratio would be 1 and there is 100% uptake by the partner.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3)
OR

Is a WOCBP and using an acceptable contraceptive method as described in 
Section 10.4.4 during the intervention period (for a minimum of 21 weeks after the 
last dose of study intervention). The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
10.4.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.

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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 of age and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Contraceptive use by women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. Women 
participants considered of childbearing potential must use at least one of the following 
acceptable contraception methods:
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 woman of childbearing potential 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.

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6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
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.
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. 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 vupanorsen 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 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:

Samples for banking 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 Banked 
Biospecimens 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.

Banked Biospecimens will be labeled with a code. The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.

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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments and 
Study Intervention Rechallenge Guidelines
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 an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2 × ULN) by several days or weeks.  The increase in TBili typically occurs while 
AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same laboratory sample). In rare instances, by the time TBili elevations 
are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).

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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, 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, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum 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 
TBili 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: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as Serious Adverse Events

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole 3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short
duration with relevant symptoms or lasting >1 minute).

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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR 
<40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications to the investigator and Pfizer study team, and not to be considered as all inclusive of what to be 
reported as AEs/SAEs.

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10.8. Appendix 8: Medical Device Adverse Events, Adverse Device Effects, Serious 
Adverse Events, and Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of a Medical Device Incident
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.8.1. Definition of AE and ADE
AE and ADE Definition 

An AE is defined as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory finding) in study 
participants, users, or other persons, whether or not related to the investigational 
medical device. This definition includes events related to the investigational 
medical device or comparator for study participants, users, and other persons. This 
definition also includes events considered related to procedures for study 
participants only. 

An ADE is defined as an adverse event related to the use of an investigational 
medical device. This definition includes any adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device 
as well as any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.8.2. Definition of SAE, SADE, and Unanticipated Serious Adverse Device Effect
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is an AE that:
a.
Led to death 
b. Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the participant was at risk of death at the time 

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of the event. It does not refer to an event, that hypothetically might have caused
death, if it were more severe.

A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization, planned hospitalization for a preexisting 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.
c.
Led to fetal distress, fetal death, or a congenital abnormality or birth defect.
SADE Definition

A SADE is defined as an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.
USADE Definition

A USADE is a serious adverse device effect which by its nature, incidence, 
severity or outcome has not been identified in the current version of the risk 
analysis management file.
10.8.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device deficiencies 
include malfunctions, use errors, and inadequate labeling.
10.8.4. Recording/Reporting and Follow-up of AEs and/or SAEs and Device 
Deficiencies
AE, SAE and Device Deficiency Recording

When an AE/SAE/device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory 
reports, and diagnostic reports) related to the event.

The investigator will then record all relevant AE/SAE/device deficiency 
information in the participant’s medical records, in accordance with the 
investigator’s normal clinical practice and on the appropriate form of the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process described 
in the IP manual and completing the Medical Device Complaint CRF.

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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.
o
A remedial action is any action other than routine maintenance or servicing 
of a medical device where such action is necessary to prevent recurrence of 
a device deficiency. This includes any amendment to the device design to 
prevent recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/device deficiency 
reported during the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as “serious” when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE/device deficiency.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB in his/her assessment.

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
For each AE/SAE/device deficiency, the investigator must document in the 
medical notes that he/she has reviewed the AE/SAE/device deficiency and has 
provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE/SAE/Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE/SAE/device deficiency as 
fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.8.5. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

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
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
10.8.6. Reporting of SADEs
SADE Reporting to Pfizer Safety
NOTE: There are additional reporting obligations for medical device incidents that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE. These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.

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10.9. Appendix 9: Country-specific Requirements
Not applicable.

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10.10. Appendix 10: Evaluation of Participants with Decreased Platelet Count

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10.11. Appendix 11: Evaluation of Participants with Worsening Renal Function

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10.12. Appendix 12: Management of Elevated AST or ALT

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10.13. Appendix 13: Alternative Measures During Public Emergencies
The alternative study measures described in this section may be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. This appendix is not intended for use during 
screening. 
Consult with the site monitor prior to utilizing this appendix.
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories).
10.13.1. Eligibility
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. Participants with active infections are excluded from study 
participation as per Exclusion Criterion 9 (other medical condition or laboratory abnormality 
that may increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study). When the infection resolves, the participant may be 
considered for re-screening if the participant has not been randomized.
10.13.2. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the participant’s location, rather than an in-person study visit at the site. If the 
participant does not allow blood draws for laboratory assessments, the participant will 
be discontinued from study intervention. The following may be performed during a home 
health visit:

Obtain vital signs (seated blood pressure and pulse rate).

Obtain weight.

Draw blood for laboratory assessments. (See Section 10.13.4.1 and Section 10.13.7).

Collect urine specimen for laboratory assessments. (See Section 10.13.4.1).

Perform 12-lead ECG.

Review and record study intervention, including compliance (review dosing diary, if 
available) and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

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
Review and record contraceptive method and results of pregnancy testing, if 
applicable. Confirm that the participant is adhering to the contraception method(s) 
required in the protocol. Refer to Appendix 4 regarding pregnancy tests.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.13.3. Telehealth Visits
In the event that in-clinic study visits or home health visits cannot be conducted, every effort 
should be made to follow up on the safety of study participants at scheduled visits per the 
Schedule of Activities or unscheduled visits. Telehealth visits may be used to continue to 
assess participant safety and collect data points. If the participant does not allow blood 
draws for laboratory assessments, the participant will be discontinued from study 
intervention. Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, video-conferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing, if 
applicable. Confirm that the participant is adhering to the contraception method(s) 
required in the protocol. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.13.4. Alternative Facilities for Safety Assessments
10.13.4.1. Laboratory Testing
All specimen collections under this appendix will be performed by home health care and will
be processed in the central laboratory. It is preferred that participants utilize home health care 
for safety and efficacy laboratory evaluations. Use of local laboratories will be allowed only 
if on site or home health care measures cannot be used. If a study participant is unable to visit 
the site or have home health utilized for protocol-specified laboratory evaluations, testing 
may be conducted at a local laboratory if permitted by local regulations. The local laboratory 
may be a standalone institution or within a hospital.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and 

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certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible. The local laboratory reports should be filed in the 
participant’s source documents/medical records. Relevant data from the local laboratory 
report should be recorded on the CRF.
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing or engage in home health care, a home urine pregnancy testing kit with a sensitivity of 
at least 25 mIU/mL may be used by the participant to perform the test at home, if compliant 
with local regulatory requirements. The pregnancy test outcome should be documented in the 
participant’s source documents/medical records and relevant data recorded on the CRF. 
Confirm that the participant is adhering to the contraception method(s) required in the 
protocol.
10.13.4.2. Imaging
If the participant is unable to visit the study site for MRI-PDFF assessment, the participant 
may visit an alternative facility to have the MRI-PDFF assessment performed. Qualified 
study site personnel must order, receive, and review results.
10.13.4.3. Electrocardiograms
All 12-lead ECG assessments under this appendix will be performed by home health care.
Qualified study site personnel must order, receive, and review results.
10.13.5. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.
Study intervention may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the study 
intervention. Pfizer does not permit the shipment of study intervention by mail. The tracking 
record of shipments and the chain of custody of study intervention must be kept in the 
participant’s source documents/medical records.
If in-home dosing is instituted, a dosing diary will be provided to the participant for 
documenting compliance. The dosing diary should be returned to the site for review as soon 
as possible.
The following is recommended for the administration of study intervention for participants 
who have active confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion) SARS-CoV2 infection:

For symptomatic participants with active SARS-CoV2 infection, study intervention 
should be delayed for at least 14 days from the start of symptoms. This delay is 
intended to allow the resolution of symptoms of SARS-CoV2 infection.

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
Prior to restarting treatment, the participant should be afebrile for 72 hours, and 
SARS-CoV2-related symptoms should have recovered for a minimum of 72 hours.
Notify the study team when treatment is restarted.

Continue to record any concomitant medication administered for treatment of 
SARS-CoV2 infection.
10.13.6. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an AE or SAE and 
appropriate medical intervention provided per standard process. If a participant has positive 
COVID-19 (SARS-CoV2) test, even if asymptomatic, this should be recorded as an AE (see 
Section 8.3).
Study treatment should continue unless the investigator/treating physician is concerned about 
the safety of the participant, in which case temporary or permanent discontinuation may be 
required.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.
10.13.7. Efficacy Assessments
There will be no alternative measures for efficacy assessments other than what is in the 
protocol, Section 8.1. It is preferred that participants utilize home health care for efficacy 
laboratory evaluations. Use of local laboratories will be allowed only if on site or home 
health care measures cannot be used. If a study participant is unable to visit the site or have 
home health utilized for protocol-specified laboratory evaluations, testing may be conducted 
at a local laboratory if permitted by local regulations.
10.13.8. Independent Oversight Committees
The External Data Monitoring Committee will be informed when this appendix has been 
utilized.

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10.14. Appendix 14: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A/C
albumin/creatinine
ADA
anti-drug antibodies
ADE
adverse device effect
AE
adverse event
AESI
adverse events of special interest
ALT
alanine aminotransferase
ANGPTL3
angiopoietin-like protein 3
ApoA
apolipoprotein A
ApoB
apolipoprotein B
ApoC
apolipoprotein C
aPTT
activated partial thromboplastin time
ASCVD
atherosclerotic cardiovascular disease
ASGPR
asialoglycoprotein receptor
ASO
anti-sense oligonucleotide
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
bpm
beats per minute
BL
baseline
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-Epi
Chronic Kidney Disease-Epidemiology Collaboration
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
corona virus disease 19
CRF
case report form
CRO
contract research organization
CS1
clinical study 1
CS2
clinical study 2
CSR
clinical study report
CT
clinical trial
CV
cardiovascular
DILI
drug-induced liver injury
DMC
data monitoring committee
DU
dispensable unit
E-DMC
external data monitoring committee

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Abbreviation
Term
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
Emax
maximal effect
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FFA
free fatty acids
FSH
follicle-stimulating hormone
GalNAc
N-acetylgalactosamine
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HbA1c
glycated hemoglobin
HDL
high-density lipoprotein
HDL-C
high-density lipoprotein cholesterol
HFF
hepatic fat fraction
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IDL
intermediate density lipoproteins
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
ISO
International Organization for Standardization
IWR
interactive web-based response
K2
dipotassium
LDL
low-density lipoprotein
LDL-C
low-density lipoprotein cholesterol
LFT
liver function test
LLN
lower limit of normal
Lp(a)
lipoprotein(a)

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Abbreviation
Term
LS
least squares
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MMRM
Mixed Model Repeated Measurements
MOE
methoxyethyl
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid 
msec
millisecond
n
number
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
Non-HDL-C
non-high-density lipoprotein cholesterol
PDFF
proton density fat fraction
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
premature ventricular contraction/complex
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
QW
every week
Q2W
every 2 weeks
Q4W
every 4 weeks
RBC
red blood cells
SADE
serious adverse device effect
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SC
subcutaneous(ly)
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TE
treatment-emergent
TEADA
treatment-emergent anti-drug antibodies
TEAE
treatment-emergent adverse event
TG
triglyceride(s)

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Abbreviation
Term
TIMI
Thrombolysis in Myocardial Infarction
T2DM
type 2 diabetes
Tmax
time to reach Cmax
UACR
urine albumin: creatinine ratio
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
VLDL
very low-density lipoproteins
VLDL-C
Very low-density lipoprotein cholesterol
WBC
white blood cell
WOCBP
woman of childbearing potential
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