Clinical trial NCT04916795
Conditions: Healthy
Sponsor: Pfizer
Start date: 2021-06-17; Completion date: 2021-10-19
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1, randomized, parallel-cohort, open-label study to characterize the pharmacokinetics, pharmacodynamics, safety and tolerability of vupanorsen following 80 mg and 160 mg single subcutaneous dose in healthy Chinese adults with elevated fasting triglyceride.

Detailed description:

Arms: arm 1: Participants will receive one, 0.8 milliliter (mL) subcutaneous injection with vupanorsen 100 mg/mL solution arm 2: Participants will receive two, 0.8 mL subcutaneous injections with vupanorsen 100 mg/mL solution
Interventions: intervention 1: Vupanorsen intervention 2: Vupanorsen
Intervention descriptions: intervention 1: 80 mg subcutaneous injection intervention 2: 80 mg subcutaneous injection

Protocol documents:
Prot_000.pdf: 
PF-07285557 (vupanorsen)
Protocol C4491004
Final Protocol, 28 August 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, RANDOMIZED, OPEN-LABEL, SINGLE DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY 
AND TOLERABILITY OF VUPANORSEN ADMINISTERED SUBCUTANEOUSLY 
TO HEALTHY CHINESE ADULTS 
Study Intervention Number:
PF-07285557
Study Intervention Name:
Vupanorsen 
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
C4491004
Phase:
1
Short Title: A Phase 1 Study To Investigate The Pharmacokinetics, Pharmacodynamics, Safety And 
Tolerability Of Single Dose Vupanorsen In Healthy Chinese Adults
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.


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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
28 August 2020
N/A


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Final Protocol, 28 August 2020
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities .............................................................................................11
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Overview.................................................................................14
2.2.2. Clinical Overview.......................................................................................15
2.2.2.1. Clinical Pharmacokinetics.........................................................15
2.2.2.2. Clinical Pharmacodynamics......................................................16
2.2.2.3. Clinical Safety...........................................................................16
2.3. Benefit/Risk Assessment.........................................................................................18
3. OBJECTIVES AND ENDPOINTS.....................................................................................19
4. STUDY DESIGN.................................................................................................................19
4.1. Overall Design.........................................................................................................19
4.2. Scientific Rationale for Study Design.....................................................................20
4.3. Justification for Dose ..............................................................................................21
4.4. End of Study Definition ..........................................................................................21
5. STUDY POPULATION......................................................................................................22
5.1. Inclusion Criteria.....................................................................................................22
5.2. Exclusion Criteria....................................................................................................23
5.3. Lifestyle Considerations..........................................................................................24
5.3.1. Meals and Dietary Restrictions...................................................................24
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................25
5.3.3. Activity .......................................................................................................25
5.3.4. Contraception..............................................................................................25
5.4. Screen Failures ........................................................................................................25
6. STUDY INTERVENTION..................................................................................................26


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6.1. Study Intervention(s) Administered........................................................................26
6.1.1. Administration............................................................................................26
6.2. Preparation/Handling/Storage/Accountability ........................................................26
6.2.1. Preparation and Dispensing........................................................................27
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................28
6.3.1. Allocation to Study Intervention ................................................................28
6.3.2. Breaking the Blind......................................................................................28
6.4. Study Intervention Compliance...............................................................................28
6.5. Concomitant Therapy..............................................................................................28
6.6. Dose Modification...................................................................................................29
6.7. Intervention After the End of the Study..................................................................29
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................29
7.1. Discontinuation of Study Intervention ....................................................................29
7.2. Participant Discontinuation/Withdrawal From the Study.......................................29
7.2.1. Withdrawal of Consent...............................................................................30
7.3. Lost to Follow up ....................................................................................................30
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................31
8.1. Efficacy Assessments..............................................................................................32
8.2. Safety Assessments .................................................................................................32
8.2.1. Physical Examinations................................................................................32
8.2.2. Vital Signs ..................................................................................................32
8.2.3. Electrocardiograms.....................................................................................33
8.2.4. Clinical Safety Laboratory Assessments ....................................................34
8.2.5. Pregnancy Testing ......................................................................................34
8.3. Adverse Events and Serious Adverse Events..........................................................34
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......35
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................35
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................36
8.3.2. Method of Detecting AEs and SAEs ..........................................................36
8.3.3. Follow-up of AEs and SAEs.......................................................................36
8.3.4. Regulatory Reporting Requirements for SAEs...........................................36


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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................37
8.3.5.1. Exposure During Pregnancy......................................................37
8.3.5.2. Exposure During Breastfeeding ................................................38
8.3.5.3. Occupational Exposure .............................................................39
8.3.6. Cardiovascular and Death Events...............................................................39
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................39
8.3.8. Adverse Events of Special Interest.............................................................39
8.3.8.1. Lack of Efficacy........................................................................39
8.3.9. Medical Device Deficiencies......................................................................39
8.3.10. Medication Errors.....................................................................................39
8.4. Treatment of Overdose............................................................................................40
8.5. Pharmacokinetics ....................................................................................................41
8.6. Pharmacodynamics..................................................................................................42
8.7. Genetics...................................................................................................................42
8.7.1. Specified Genetics ......................................................................................42
8.7.2. Banked Biospecimens for Genetics............................................................43
8.8. Biomarkers ..............................................................................................................43
8.9. Immunogenicity Assessments.................................................................................43
8.10. Health Economics .................................................................................................43
9. STATISTICAL CONSIDERATIONS ................................................................................43
9.1. Statistical Hypotheses .............................................................................................43
9.2. Sample Size Determination.....................................................................................43
9.3. Analysis Sets ...........................................................................................................43
9.4. Statistical Analyses .................................................................................................44
9.4.1. General Considerations...............................................................................44
9.4.2. Primary Endpoint(s)....................................................................................45
9.4.3. Secondary Endpoint(s)................................................................................46
9.4.3.1. Safety Endpoints .......................................................................46
9.4.3.2. Pharmacodynamic Endpoints....................................................46
9.5. Interim Analyses .....................................................................................................46


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9.6. Data Monitoring Committee or Other Independent Oversight Committee.............46
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................47
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............47
10.1.1. Regulatory and Ethical Considerations ....................................................47
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................47
10.1.2. Financial Disclosure .................................................................................48
10.1.3. Informed Consent Process ........................................................................48
10.1.4. Data Protection .........................................................................................49
10.1.5. Dissemination of Clinical Study Data ......................................................49
10.1.6. Data Quality Assurance ............................................................................51
10.1.7. Source Documents....................................................................................52
10.1.8. Study and Site Start and Closure ..............................................................52
10.1.9. Publication Policy.....................................................................................53
10.1.10. Sponsor’s Qualified Medical Personnel .................................................54
10.2. Appendix 2: Clinical Laboratory Tests .................................................................55
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................56
10.3.1. Definition of AE .......................................................................................56
10.3.2. Definition of SAE.....................................................................................57
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................58
10.3.4. Reporting of SAEs....................................................................................61
10.4. Appendix 4: Contraceptive Guidance ...................................................................63
10.4.1. Male Participant Reproductive Inclusion Criteria....................................63
10.4.2. Female Participant Reproductive Inclusion Criteria.................................63
10.4.3. Woman of Childbearing Potential ............................................................63
10.4.4. Contraception Methods.............................................................................64
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........66
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ...................................68
10.7. Appendix 7: Abbreviations ...................................................................................70
11. REFERENCES ..................................................................................................................73


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LIST OF TABLES
Table 1.
Plasma Vupanorsen Pharmacokinetic Parameters....................................45
Table 2.
Protocol Required Laboratory Assessments.............................................55


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 Study To Investigate The Pharmacokinetics, Pharmacodynamics, 
Safety And Tolerability Of Single Dose Vupanorsen In Healthy Chinese Adults. 
Rationale
The purpose of the study is to investigate the pharmacokinetics, pharmacodynamics, safety 
and tolerability of vupanorsen following 80 and 160 mg single subcutaneous dose in healthy 
Chinese adults. Results from this study will be used to inform clinical development of 
vupanorsen in China and to support China registration of vupanorsen.   
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 

To characterize the PK of vupanorsen
following 80 and 160 mg single 
subcutaneous dose in healthy Chinese 
adults.

Vupanorsen plasma PK parameters: 
AUC24h, AUC48h, AUClast, Cmax, AUCinf, 
Tmax, t½, CL/F and Vz/F, as data permit.
Secondary: 
Secondary: 

To evaluate the safety and tolerability 
of vupanorsen following 80 and 160 
mg single subcutaneous dose in 
healthy Chinese adults.

To characterize the PD effects of 
vupanorsen following 80 and 160 mg 
single subcutaneous dose in healthy 
Chinese adults.

AEs, clinical safety laboratory tests 
(serum chemistry, hematology, 
urinalysis, coagulation), vital signs (BP, 
PR), physical examination findings, 
12-lead ECGs.

Percentage change from baseline in 
ANGPTL3 on Day 2, Day 3, Day 8, Day 
15, Day 30, Day 60 and Day 90.

Percentage changes from baseline in 
Lipid Panel on Day 2, Day 3, Day 8, 
Day 15, Day 30, Day 60 and Day 90, 
including fasting TG, LDL-C, HDL-C, 
VLDL-C, non-HDL-C, and TC.

Percentage changes from baseline in 
ApoA-I, ApoB total (including 


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ApoB-48, ApoB-100), and ApoC-III on 
Day 15, Day 60, and Day 90.
Overall Design
This is a Phase 1, randomized, parallel-cohort, open-label study to characterize the PK, PD,
safety and tolerability of vupanorsen following 80 mg and 160 mg single subcutaneous dose 
in healthy Chinese adults with fasting triglyceride ≥90 mg/dL. 
Number of Participants
Approximately 18 participants will be enrolled in this study (N=9 for each cohort) with the 
goal of attaining approximately 8 evaluable participants in each cohort for a total of 
16 evaluable participants.
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, unless otherwise 
specified by the protocol. 
Intervention Groups and Duration
The total duration of participation in this study is approximately 118 days, including a 
screening period of up to 28 days to confirm eligibility and a follow-up period of 
approximately 90 days. Eligible participants will progress to admission to the clinical 
research unit on Day -1 for a 4-day (3-night) inpatient stay. Participants enrolled will receive 
a single 80 mg (cohort 1) or 160 mg (cohort 2) subcutaneous dose of vupanorsen on Day 1. 
Following discharge on Day 3, participants will return for an on-site post-treatment 
evaluation on Days 8, 15, 30, 60 and 90. 
Participants who discontinue prior to completion of the study for non-safety related reasons 
may be replaced, at the discretion of the principal investigator and sponsor study team.  
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
There is no statistical hypothesis for this study, therefore, the study sample size is not based 
on statistical decision rule. The sample size has been chosen based on the need to minimize 
exposure to humans of a new chemical entity and to fulfill the NMPA requirement for a PK 
study to support the registration in China. Considering the possibility of participant 
dropouts/withdrawals, approximately 18 participants (N=9 per each cohort) will be enrolled 
to ensure approximately 16 participants (N=8 per each cohort) will be evaluable for the 
primary endpoint.


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Plasma PK parameters and plasma concentrations of vupanorsen will be listed and 
summarized descriptively. Percentage changes from baseline in PD assessments will be 
summarized using descriptive statistics. Safety and tolerability data will be presented in 
tabular and/or graphical format and summarized descriptively. 
1.2. Schema
Not applicable. 


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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier
Abbreviations used in this table may be found in 
Appendix 7.
Screening
Single Dose and Post-Treatment Evaluation/Early Termination 
Days Relative to Day 1 
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 8
Day 15
Day 30
Day 60
Day 
90/ET
Visit Window (days)
-
0
0
0
0
±1
±2
±2
±2
±5
Hours After Dose
-
-
0
24
48
Informed consent
X
CRU confinement
X


X
Inclusion/exclusion criteria
X
X
Medical/medication history (update) 
X
X
Physical exam (including height and
body weight at Screening only)b
X
X
Safety laboratory (≥10-hour fasting) 
(hematology, chemistry, urinalysis, coagulation)
X
X
Xc
X
X
X
X
X
X
Lipid paneld
X
Xf
Xc
X
X
X
X
X
X
Extended lipoprotein panele
Xf
X
X
X
Demography
X
Pregnancy test (WOCBP only)
X
X
X
X
X
Contraception check
X
X
X
X
X
X
X
FSHg
X
Urine drug testing
X
X
12-Lead ECG 
X
Xh
Xc
X
X
Blood pressure and pulse rate
X
Xh
Xc
X
X
X
X
HIV, HBsAg, HCVAb, syphilis test
X
Study intervention administration
Xi
Pharmacokinetic blood samplingj
X
X
X
X
X
X
X
X
Pharmacodynamic blood sampling (ANGPTL3)
Xf
Xc
X
X
X
X
X
X


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Visit Identifier
Abbreviations used in this table may be found in 
Appendix 7.
Screening
Single Dose and Post-Treatment Evaluation/Early Termination 
Days Relative to Day 1 
Day -28 to 
Day -2
Day -1
Day 1
Day 2
Day 3
Day 8
Day 15
Day 30
Day 60
Day 
90/ET
Visit Window (days)
-
0
0
0
0
±1
±2
±2
±2
±5
Hours After Dose
-
-
0
24
48
CRU discharge 
X
Serious and nonserious adverse event monitoring
X




X
X
X
X
X
a.
Day relative to start of study intervention (Day 1).
b.
A full physical examination may be done at screening or Day -1; otherwise brief physical exam envisioned for findings during previous PE or new/open AEs, at 
Investigator discretion. 
c.
24 hours post-dose.
d.
Lipid panel should be obtained with participants in a fasted state (≥10-hour fasting as mentioned in Section 5.3.1). Lipid panel includes TG, non-HDL-C, direct 
LDL-C, TC, HDL-C, direct VLDL-C. 
e.
Extended lipoprotein panel should be obtained with participants in a fasted state (≥10-hour fasting as mentioned Section 5.3.1). Extended lipoprotein panel includes 
ApoB, ApoB-48, ApoB-100, ApoC-III, and ApoA-I.
f.
Pre-dose.
g.
FSH in females amenorrhoeic ≥12 months, only.
h.
Pre-dose and 4 hours post dose. 
i.
Participants should be monitored for a minimum of 2 hours after administration of vupanorsen to assess injection site reaction. 
j.
Refer to Pharmacokinetic Sampling Timepoints.


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Pharmacokinetic Sampling Timepoints
Visit Identifier 
Single Dose and Post-Treatment Evaluation
Study Day
1
2
3
8
15
30
60
90
Hours Before/After Dose
0a
0.5
1
1.5
2
3
4
6
8
12
24
48
-
-
-
-
-
Sampling Window
-
±10% ±10% ±10% ±10% ±10% ±10% ±10% ±10%
±1 hr
±1 hr
±1 hr
±1 day
±2 
days
±2 
days
±2 
days
±5 
days
Study intervention administration
X
PK blood sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Pre-dose sample collection.


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2. INTRODUCTION
PF-07285557 (vupanorsen) is a second-generation 2’-MOE ASO drug targeted to human 
ANGPTL3 mRNA that has been covalently bonded to triantennary GalNAc. Vupanorsen is 
being developed for CV risk reduction and for TG lowering in patients with severe HTG. 
2.1. Study Rationale 
The purpose of the study is to investigate the pharmacokinetics, pharmacodynamics, safety 
and tolerability of vupanorsen following 80 and 160 mg single subcutaneous dose in healthy
Chinese adults. Results from this study will be used to inform clinical development of 
vupanorsen in China and to support China registration of vupanorsen.  
2.2. Background 
Dysregulation of lipid metabolism is closely linked to a number of pathophysiological states 
including atherosclerosis, obesity, and insulin resistance. Despite effective LDL-C lowering 
therapies (eg, statins, ezetimibe and PCSK9 inhibitors), considerable residual risk for CVD 
remains. Emerging evidence suggests that TG and/or the cholesterol content within TG-rich 
lipoproteins may be important contributors to residual risk and may represent viable targets of 
therapy.
Vupanorsen is a second-generation 2’-MOE modified ASO drug targeted to ANGPTL3 that has 
been covalently bonded to triantennary GalNAc, a high affinity ligand for the hepatocyte-specific 
ASGPR. This GalNAc-conjugate approach results in enhanced ASO delivery to hepatocytes 
versus non-parenchymal cells and has increased ASO potency by approximately 10-fold in mice1
compared to unconjugated ASOs. The ASO portion of vupanorsen binds to the ANGPTL3 
mRNA by Watson-Crick base pairing and results in RNase H1-mediated degradation of the 
ANGPTL3 mRNA, thus preventing production of the ANGPTL3 protein. Maximal
antisense-mediated reduction of target mRNA levels is typically greater than 90% of control
levels in sensitive tissues.2,3 Furthermore, reduction in target mRNA levels using this 
approach correlates directly with a subsequent reduction in target protein levels.
ANGPTL3 is primarily synthesized and secreted by the liver and is a member of the 
angiopoietin-like family of proteins that binds reversibly to inhibit LPL and decrease the 
hydrolysis of TG in chylomicrons and VLDL.4,5 Mice deficient in ANGPTL3 have very low 
plasma TG and cholesterol levels, while over-expression produces the opposite effects.5,6,7
Human genetic studies have shown that carriers of ANGPTL3 LOF alleles have reduced 
concentrations of TG, LDL-C, HDL-C, VLDL-C, ApoB and ApoC-III.4,8,9,10,11,12 Additionally, 
sequencing of large epidemiological cohorts revealed that heterozygous carriers of ANGPTL3 
LOF mutations have a 30-40% reduced risk of coronary artery disease.13,14 Taken together these 
data indicate that inhibiting ANGPTL3 by an ASO approach could represent a promising 
therapeutic strategy to improve CV outcomes.
2.2.1. Nonclinical Overview
Detailed information concerning the nonclinical studies conducted with ANGPTL3 ASOs 
can be found in the current IB.


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2.2.2. Clinical Overview
As of 01 April 2020, 4 clinical studies have been completed where a total of 160 participants 
have received study treatment with vupanorsen or placebo; of these, 48 were healthy 
participants, 105 were participants with HTG, T2DM, and NAFLD, 3 were participants with 
FCS, and 4 were participants with FPL. 
Detailed information concerning the clinical studies conducted with vupanorsen can be found 
in the IB. 
A Phase 1 study (C4491006) to investigate the safety, tolerability, PK and PD of single doses 
of 80 mg and 160 mg of vupanorsen in Japanese healthy adult participants with elevated 
triglycerides has been planned, and the results are expected in 2021. 
2.2.2.1. Clinical Pharmacokinetics
Concentrations of total full-length oligonucleotide (reported as vupanorsen equivalent) in 
human plasma were determined by a validated hybridization method with ECL detection. 
Total full-length oligonucleotides 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.
2.2.2.1.1. PK in Healthy Participants (Study CS1)
Plasma PK determined from intensive PK sampling following 20 to 120 mg of vupanorsen 
SC injection in the SAD (Day 1) and 10 to 60 mg QW MAD (Days 1 and 36) cohorts in 
healthy participants (Study CS1) are summarized in the current IB.
Following single-dose or multiple-dose SC administration, vupanorsen was absorbed 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 that dominated the plasma clearance, followed by a slower elimination 
phase with t½ of 3 to 5 weeks in general. The geometric mean Cmax and AUC increased 
approximately dose proportionally from 20 to 120 mg after a single dose, and from 10 to 
60 mg after single and multiple QW dosing. No apparent accumulation of Cmax or AUC was 
observed after 6 weeks of QW doses. Plasma trough concentrations in the MAD cohorts 
indicated that steady state had not been reached after 6 weeks, consistent with the observed 
long half-life of the drug. Urinary excretion of total full-length ASO within the first 24 hours 
was <1% of administered dose after single and multiple SC doses of vupanorsen.


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2.2.2.1.2. PK in Participants with HTG, T2DM and NALFD (Study CS2)
Vupanorsen PK profiles were evaluated in a subset of CS2 study in participants with HTG, 
T2DM, and NAFLD. 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.
2.2.2.2. Clinical Pharmacodynamics
In the Phase 1 Study CS1, results from the SAD portion of the study showed dose dependent 
reductions in mean levels of serum ANGPTL3 protein at Day 15 (reductions of 5.5% to 
80.2% for 20 to 120 mg). After 6 weeks of QW treatment, participants in the multiple-dose 
groups showed time- and dose-dependent reductions in mean levels of serum ANGPTL3 
protein. The mean reductions of serum ANGPTL3 from baseline at Day 43 were 46.6% to 
84.5% for 10 to 60 mg QW, (P <0.01 for all doses versus placebo).
PD was evaluated in a Phase 2a study (Study CS2) in participants with HTG, T2DM, and 
NAFLD. The maximum lowering of the circulating ANGPTL3 protein was observed at 
vupanorsen 80 mg Q4W (reductions of 62% from baseline), with a similar effect at 
vupanorsen 20 mg QW (reductions of 59% from baseline) and smaller effect at vupanorsen 
40 mg QW (reductions of 45% from baseline).
2.2.2.3. Clinical Safety 
As of 01 April 2020, in completed studies, 121 participants have been treated with 
vupanorsen. Overall, vupanorsen was well tolerated as either single SC injections of 20, 40, 
80 and 120 mg or multiple SC injections of 10, 20, 40 or 60 mg weekly (QW) for 6 weeks in 
the Phase 1 study, and in the Phase 2a study as 40 mg Q4W, and 80 Q4W, and 20 mg QW 
for 26 weeks.
2.2.2.3.1. Safety in Healthy Participants (Study CS1)
A total of 16 participants were randomized and treated in the single dose cohorts. There were 
no SAEs or discontinuations due to AEs. All AEs were mild in severity. There were no AEs 
reported related to platelets, transaminase increases, or injection site reactions. One 
participant in the vupanorsen 40 mg SC group had AEs of bilirubin increased and
unconjugated bilirubin increased, considered possibly related to study drug by the
investigator.
A total of 32 participants were randomized and treated in the multiple dose cohorts. No 
deaths or SAEs were reported and no AEs or TEAEs led to study treatment discontinuation. 
There were no severe TEAEs; the majority of reported TEAEs were mild in severity. There 
were no platelet related AEs (changes in platelet counts or thrombocytopenia) and no events 
involving inflammation (inflammatory markers or flu-like reactions). There were no
clinically relevant changes in urinalysis and or urine protein. There were 2 participants with 
elevated ALT in the 60 mg QW dose cohort. These changes were reversible and both 


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participants completed study treatment and the increase in ALT was not associated with 
clinical symptoms or other laboratory abnormalities. Erythema and pruritus at the injection 
site were reported several times for a single participant. However, no local cutaneous 
reactions at the injection site were reported.
There were no platelet-related AEs and no events involving inflammation (inflammatory 
markers or flu-like reactions). There were no clinically relevant changes in hematology (no 
evidence of prothrombotic effects, or significant decreases in platelet count or 
thrombocytopenia), urinalysis, inflammatory markers, ECG, or vital signs and no bleeding 
episodes reported.
2.2.2.3.2. Safety in Participants with HTG, T2DM, and NAFLD-(Study CS2)
During the treatment period, a total of 65 (83.3%) participants in the vupanorsen treatment 
groups combined and 16 (59.3%) participants in the placebo treatment group experienced at 
least 1 AE. SAEs occurred in 4 (5.1%) participants in the pooled vupanorsen treatment 
groups and 1 (3.7%) participant in the placebo group. None of the SAEs were considered 
treatment related. 
AEs resulting in permanent discontinuation from treatment occurred in 6 (7.7%) participants 
in the vupanorsen treatment groups. No AEs resulting in discontinuation occurred in the 
placebo group. The AEs resulting in treatment discontinuation were injection site reactions 
(4 participants - 1 participant each in the vupanorsen 40 mg Q4W and 80 mg Q4W treatment 
groups and 2 participants in the vupanorsen 20 mg QW treatment group), transaminases 
increased (1 participant in the vupanorsen 20 mg QW treatment group), and dehydration and 
acute prerenal failure (1 participant in the vupanorsen 80 mg Q4W treatment group reporting 
both AEs).
AEs occurring more frequently in the vupanorsen treatment groups were injection site 
pruritus, injection site erythema, pharyngitis, and hyperglycemia. There was 1 AE of 
thrombocytopenia (verbatim term: intermittent thrombocytopenia), mild in severity, reported 
in a participant in the vupanorsen 20 mg QW treatment group. No participant had a 
confirmed platelet count below 100,000 /mm3. Two (7.7%) participants, both in the 
vupanorsen 20 mg QW group, had elevations in ALT >3 times but <5 times the ULN. These 
elevations were not associated with an increase in bilirubin or liver-related symptoms. 
Increases in mean AST and ALT from baseline to Week 25 were observed in all the 
vupanorsen treatment groups. The increases in AST and ALT were greatest in the 
vupanorsen 80 mg Q4W group. One (3.7%) participant in the placebo group, 1 (3.8%) 
participant in the vupanorsen 80 mg Q4W and 1 (3.8%) participant in the 20 mg QW group, 
had decline in eGFR by >25% from baseline. There were no notable differences between 
treatment groups in participants with new onset hematuria or proteinuria.
Safety and tolerability in Studies CS3 (participants with Familial Chylomicronemia 
Syndrome) and CS5 (participants with Familial Partial Lipodystrophy Syndrome) are 
summarized in the IB.


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2.3. Benefit/Risk Assessment
A single dose of vupanorsen is not expected to provide any clinical benefit to healthy 
participants. This study is designed primarily to generate safety, tolerability, pharmacokinetic 
and pharmacodynamic data for further clinical development. 
Vupanorsen has been administered as single doses and repeated doses in healthy adults and 
patients with hypertriglyceridemia, T2DM, and NAFLD. It has been observed to be 
well-tolerated with an acceptable safety profile at single subcutanous doses as high as 
120 mg and weekly repeated, subcutanous doses of up to 60 mg for a duration of up to 
6 weeks. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of vupanorsen may be found in the investigator’s brochure, which is 
the SRSD for this study. 


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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To characterize the PK of vupanorsen
following 80 and 160 mg single 
subcutaneous dose in healthy Chinese 
adults.

Vupanorsen plasma PK parameters: 
AUC24h, AUC48h, AUClast, Cmax, AUCinf, 
Tmax, t½, CL/F and Vz/F, as data permit.
Secondary: 
Secondary: 

To evaluate the safety and tolerability 
of vupanorsen following 80 and 
160 mg single subcutaneous dose in 
healthy Chinese adults.

To characterize the PD effects of 
vupanorsen following 80 and 160 mg 
single subcutaneous dose in healthy 
Chinese adults.

AEs, clinical safety laboratory tests 
(serum chemistry, hematology, 
urinalysis, coagulation), vital signs (BP, 
PR), physical examination findings, 
12-lead ECGs.

Percentage change from baseline in 
ANGPTL3 on Day 2, Day 3, Day 8, Day 
15, Day 30, Day 60 and Day 90.

Percentage changes from baseline in 
Lipid Panel on Day 2, Day3, Day 8, Day 
15, Day 30, Day 60 and Day 90, 
including fasting TG, LDL-C, HDL-C, 
VLDL-C, non-HDL-C, and TC.

Percentage changes from baseline in 
ApoA-I, ApoB total (including ApoB-
48, ApoB-100), and ApoC-III on Day 
15, Day 60 and Day 90.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, parallel-cohort, open-label study to characterize the PK, PD 
safety and tolerability of vupanorsen following 80 mg and 160 mg single subcutaneous dose 
in healthy Chinese adults with fasting triglyceride ≥90 mg/dL. Approximately 
18 participants will be enrolled in this study (N=9 for each cohort) with the goal of attaining 
approximately 8 evaluable participants in each cohort for a total of 16 evaluable participants. 


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The total duration of participation in this study is approximately 118 days, including a 
screening period of up to 28 days to confirm eligibility and a follow-up period of 
approximately 90 days. Eligible participants will progress to admission to the clinical 
research unit on Day -1 for a 4-day (3-night) inpatient stay. Participants enrolled will receive 
a single 80 mg (cohort 1) or 160 mg (cohort 2) subcutaneous dose of vupanorsen on Day 1. 
Following discharge on Day 3, participants will return for an on-site post-treatment 
evaluation on Days 8, 15, 30, 60 and 90. 
Participants who discontinue prior to completion of the study for non-safety related reasons 
may be replaced, at the discretion of the principal investigator and sponsor study team.  
4.2. Scientific Rationale for Study Design
This study is the first clinical study with vupanorsen in the Chinese population. The purpose 
of the study is to characterize the PK, PD, safety and tolerability of vupanorsen following 
80 mg and 160 mg subcutaneous dose in healthy male and female Chinese participants. 
There is no expected significant PK difference between Chinese and Westerners because 
uptake/efflux-transporters, oxidative metabolism and conjugation, which may cause ethnic 
differences, are not involved in the disposition of ASOs. PK and PD parameters generated 
from this study will be compared with results from the global studies to further evaluate the 
impact of ethnicity/race on the PK/PD of vupanorsen.
Single-dose rather than repeated dosing is planned in the study as the steady-state PK and PD 
can be well predicted from single dose data, especially given that after QW multiple SC 
doses, the Cmax and AUC increased approximately dose proportionally, and no apparent 
accumulation of Cmax or AUC was observed. In terms of safety and tolerability, vupanorsen 
was well-tolerated with an acceptable safety profile at single doses up to 120 mg, and weekly 
repeated doses of up to 60 mg for 6 weeks in healthy participants in study CS1, and after 
repeated doses up to 80 mg per month (either 80 mg Q4W or 20 mg QW) for 6 months 
treatment duration in study CS2. The safety and tolerability of vupanorsen was consistent 
after single- and multiple-dose treatments except for the late onset of ADA (a median onset 
of 5.5 months) after multiple doses with no apparent impact on efficacy and safety, which is 
consistent with other ASOs in the same class. Moreover, considering the long terminal 
plasma half-life of vupanorsen in humans (3 to 5 weeks) and it will take approximately 
21 weeks of vupanorsen dosing to reach steady-state, single-dose is planned to minimize the 
exposure duration of healthy participants to a new chemical entity.  
The study duration and frequency of each assessment were decided based on information 
from previous studies. It was considered that 90 days are the necessary period to allow 
adequate characterization of terminal t½ of vupanorsen to be eliminated. Sample collection 
points for PK were selected based on the results of PK profiles in Studies CS1 and CS2.
Serum ANGPTL3 and other lipid PD markers will be evaluated to confirm the target 
engagement of vupanorsen and the consistency with the results in Studies CS1 and CS2. 


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Vupanorsen has an unlikely risk of human teratogenicity/fetotoxicity. Participants who are 
WOCBP must use an acceptable contraceptive method (see Appendix 4). Also, the potential
risk of exposure to vupanorsen in a sexual partner of a male participant in this study via
ejaculate is low, and therefore no contraception (condom) use in male participants is required
(see Appendix 4). The calculated safety margin is ≥100-fold between the estimated maternal
exposure due to seminal transfer and the NOAEL for developmental toxicity in nonclinical
studies. The safety margin of 100-fold is based on applying a 10-fold safety factor for
interspecies extrapolation and a 10-fold safety factor for susceptible populations.15
4.3. Justification for Dose
The proposed single SC dose levels are 80 mg and 160 mg. These doses are selected based 
on the safety and tolerability in Studies CS1 and CS2, and the dosages for the Phase 2b study 
that is planned in patients with dyslipidemia (Study C4491011). In Study C4491011, the 
safety and efficacy of a dose range of 80 mg Q4W to 160 mg Q2W will be evaluated. Based 
on the simulation results using a preliminary population PK-PD model developed from the 
combined data in Studies CS1 and CS2, vupanorsen 80 mg Q4W is expected to be a minimal 
efficacious dose in non-HDL-C reduction, and to bridge the data from previous studies. 
Vupanorsen 160 mg Q2W is expected to achieve a >90% probability of a ≥35% mean 
reduction in non-HDL-C, in addition to maximizing ANGPTL3 and TG reductions. Thus, 
80 mg and 160 mg are selected as the proposed dose level in the current study to cover the 
potential range of Phase 3 doses (lowest to highest) per dose.
As described in Section 2.2.2.3, vupanorsen single SC doses of up to 120 mg and multiple 
SC doses of up to 60 mg QW × 6 doses were generally safe and well-tolerated in healthy 
participants in Study CS1. Assuming dose-proportional exposure based on the observed 
mean PK values following a single 80 mg dose of vupanorsen (higher dose-normalized 
exposure than 120 mg), plasma AUC48h and Cmax after single SC administration at 160 mg 
dose are predicted to be 7.94 µg•h/mL and 0.676 µg/mL, respectively. The predicted safety 
margins on AUC48h and Cmax are 12-fold and 20-fold, respectively, relative to the AUC48h of 
95.6 µg•h/mL and Cmax of 13.6 µg/mL at NOAEL (12 mg/kg/week) in monkeys. The PK, PD 
and safety data at these dose levels in the upcoming Japan Phase 1 study C4491006 will 
further support the dose selection in this study. 
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
the last participant in the trial.


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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 and female Chinese participants must be 18 to 65 years of age, inclusive, at the 
time of signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.

Chinese participant is defined as individuals currently residing in mainland China 
who were born in China and have both parents of Chinese descent.
Type of Participant and Disease Characteristics:
2. Male and female Chinese participants who are overtly healthy as determined by 
medical evaluation including medical history, physical examination, laboratory tests
(except for TG levels), and 12-lead ECG monitoring.
3. Fasting TG ≥90 mg/dL at Screening (up to 1 repeat allowed for TG and the second
TG value will be used for the eligibility).
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
5. BMI of 17.5 to 35.0 kg/m2; and a total body weight >50 kg (110 lb).
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.


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. History of human immunodeficiency virus (HIV) infection, syphilis, hepatitis B, or 
hepatitis C; positive testing for HIV, syphilis, HBsAg, or HCVAb. Prior Hepatitis B 
vaccination is allowed.
3. 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:
4. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.5 for additional details).
Prior/Concurrent Clinical Study Experience:
5. Previous administration with an investigational drug within 4 months or 5 half-lives 
preceding the first dose of study intervention used in this study (whichever is longer). 
Diagnostic Assessments:
6. A positive urine drug test.
7. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
8. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTc interval 
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
infarction, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the 
baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected 
using the Fridericia method and the resulting QTcF should be used for decision 


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making and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTc or QRS values should 
be used to determine the participant’s eligibility. Computer-interpreted ECGs should 
be overread by a physician experienced in reading ECGs before excluding 
participants.
9. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

AST or ALT level ≥1.25 × ULN;

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is≤ULN.
Other Exclusions:
10. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
11. Blood donation (excluding plasma donations) of approximately 400 mL or more 
within 60 days prior to dosing.  
12. History of sensitivity to heparin or heparin-induced thrombocytopenia.
13. History of substance abuse within 12 months of the screening visit.
14. Pregnant females; breastfeeding females. 
15. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
16. 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
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) for ≥10 hours prior to 
any safety laboratory evaluations.


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
While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing and during confinement in the CRU.  

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol during confinement in the CRU. Participants may 
undergo an alcohol breath test or blood alcohol test at the discretion of the 
investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU. 
5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use. At time points indicated in the schedule of activities (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.
5.4. 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. Screen failure data are 
collected and remain as source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 


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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.
6.1. Study Intervention(s) Administered
Participants will be randomized at Baseline to one of the following treatment cohorts, all 
participants will receive single SC dosing:
Treatment Cohort
Subcutaneous Treatment (SC)
1
Vupanorsen 80 mg single dose
2
Vupanorsen 160 mg single dose
Vupanorsen is presented as a sterile solution for subcutaneous administration, in a glass 
pre-filled syringe (PFS). Each PFS contains a sufficient amount of vupanorsen
(80 mg/syringe) to provide the intended dose of drug at a concentration of 100 mg/mL. 
All participants will be administered 1 or 2 PFS SC injections. The number of SC injections 
depends on the doses such that 1 SC injection for Cohort 1 (80 mg), and 2 SC injections for 
Cohort 2 (160 mg). Thus, the maximal number of SC injections will be 2.
Each prefilled syringe is packed in an individual carton. 
6.1.1. Administration
The SC administration of vupanorsen must be performed by trained investigator site 
personnel. SC injections should be administered into a lower quadrant of the abdomin. To 
minimize injection site reactions, the SC injection should not be administered in areas where 
the skin is burned, reddened, inflamed, swollen, or scarred. The 2 SC injections for 
participants in Cohort 2 (160 mg) should not be administered in the same location. 
Participants will receive investigational product at approximately 8 a.m. (plus or minus 
2 hours). Study medication does not require fasting, but it should be noted that the lipid panel 
test and the extended lipid panel test at Day 1 prior to the study medication requires a fast of 
≥10 hours. 
Administer investigational product according to the investigational product (IP) manual.
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. 


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2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum 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. 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.
7. 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.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 


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participant in accordance with this protocol. Local health authority regulations or investigator 
site guidelines may use alternative terms for these activities.
Vupanorsen 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. Each participant will 
receive a quantity of containers consistent with 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.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.3.2. Breaking the Blind
Not applicable since the study is open label.  
6.4. Study Intervention Compliance
Participants will be dosed at the site. They will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
6.5. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.


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All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
6.6. Dose Modification
By design, this study only includes administration of single, SC dose of vupanorsen at 
2 fixed dosage levels (80 mg and 160 mg) in parallel. As such, dose modifications will not be 
made during the 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
7.1. Discontinuation of Study Intervention
Since this is a single-dose study, this section is not applicable.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.


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If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
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.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;


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
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
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.
Participants will be screened within 28 days prior to administration of the study intervention 
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
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.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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The total blood sampling volume for individual participants in this study is approximately 
350 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.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Not applicable.
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. Physical Examinations
A full physical examination will include, at a minimum, head, ears, eyes, nose, mouth, skin, 
heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.  


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The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) is not 
recommended given the potential risk of discrepancies with ECGs acquired using standard 
limb lead placement. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 10 minutes in a supine position. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) a 
postdose QTc interval is increased by ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG. If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement. If the QTc values from these repeated ECGs remain above 
the threshold value, then a single ECG must be repeated at least hourly until QTc values from 
2 successive ECGs fall below the threshold value that triggered the repeat measurement.
If a) a postdose QTc interval remains ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner, 
at the discretion of the investigator); or c) QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 
if QTc intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.


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8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 month after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
Participants may undergo random urine drug testing at the discretion of the investigator. 
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.2.5. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP 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. 
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE 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 
approximately 90 days after the last administration of the study intervention or until study 
completion or withdrawal, whichever is longer.
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 AE or SAE 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 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.


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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 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.
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.
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 


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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 or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.


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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
Not applicable.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.3.8. Adverse Events of Special Interest 
Not applicable.
8.3.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
8.3.9. Medical Device Deficiencies
Not applicable. 
8.3.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.


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Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on 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 240 mg within a 24-hour time period will 
be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
vupanorsen can no longer be detected systemically (at least 3 months).  
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.


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide a minimum of 2 mL K2EDTA plasma, will 
be collected for measurement of plasma concentrations of vupanorsen as specified in the 
SoA. Instructions for the collection and handling of biological samples will be provided in 
the laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of 
each sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of vupanorsen. Samples collected for measurement 
of plasma concentrations of vupanorsen will be analyzed using a validated analytical method 
in compliance with applicable SOPs.
An additional 6 mL of pre-dose blood sample will be collected from each patient for matrix 
effect evaluation of the bioanalytic method for vupanorsen concentration detection, PD assay
and lipidprotein panel assays. These data will not be included in the CSR (clinical study 
report).
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. 


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Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Pharmacodynamics
Blood samples of approximately 4 mL, to provide a minimum of 2 mL serum, will be 
collected for measurement of ANGPTL3 as specified in the SoA.
Blood samples for measurement of TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, TG, 
ApoA-I, ApoB total (including ApoB-48, ApoB-100), and ApoC III will be collected from 
participants in a fasted state as specified in the SoA.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
As part of understanding the PD of the study intervention, samples may be used for 
evaluation of the bioanalytical method.
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 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.


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8.7.2. Banked Biospecimens for Genetics
Banked Biospecimens are not applicable in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments of vupanorsen are not included in this study due to the study 
duration of 90 days after single SC dose. In the non-clinical setting, following 9 months of 
treatment in Cynomolgus monkeys, the median onset time for ADA was Day 182 and the 
incidence rate appeared to increase with time. In the Phase 2a study (Study CS2), preliminary 
data showed that the median time of onset and the incidence of ADA were consistent with 
vupanorsen immunogenicity data in monkeys, and there was no evidence of altered safety 
profile or pharmacodynamics associated with the presence of ADA.  
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 a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
There are no statistical hypotheses for this study. However, the number of 8 participants in 
each cohort is considered to be sufficient to provide a precise clearance estimate based on the 
previous PK data.
9.2. Sample Size Determination
There is no statistical hypothesis for this study, therefore, the study sample size is not based 
on statistical decision rule. The sample size has been chosen based on the need to minimize 
exposure to humans of a new chemical entity and to fulfill the NMPA requirement for a PK 
study to support the registration in China. Considering the possibility of participant 
dropouts/withdrawals, approximately 18 participants (N=9 per each cohort) will be enrolled 
to ensure approximately 16 participants (N=8 per each cohort) will be evaluable for the 
primary endpoint.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:


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Participant Analysis 
Set
Description
Enrolled
All participants who sign the ICD.
Pharmacokinetics (PK)
The PK concentration population is defined as all participants 
enrolled and treated who have at least 1 vupanorsen
concentration.
The PK parameter analysis population is defined as all 
participants enrolled and treated who have at least 1 of the 
vupanorsen PK parameters of interest.
Pharmacodynamics 
(PD)
The PD parameter analysis population is defined as all 
participants enrolled and treated who have at least 1 of the 
PD parameters of interest.
Safety
All participants enrolled and who take at least 1 dose of study 
intervention.
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
Plasma PK parameters and plasma concentrations of vupanorsen will be listed and 
summarized descriptively. Percentage changes from baseline in PD assessments will be 
summarized using descriptive statistics. Safety and tolerability data will be presented in 
tabular and/or graphical format and summarized descriptively. 


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9.4.2. Primary Endpoint(s)
PK parameters of vupanorsen following 80 mg and 160 mg single subcutaneous dose will be 
derived from the concentration-time profiles using standard noncompartmental methods as 
follows:
Table 1.
Plasma Vupanorsen Pharmacokinetic Parameters
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time at which Cmax occurred
Observed directly from data as time 
of first occurrence
AUC24h
Area under the concentration-
time profile from time 0 to 24 
hour post-dose 
Linear/log trapezoidal method
AUC48h
Area under the concentration-
time profile from time 0 to 48 
hour post-dose 
Linear/log trapezoidal method
AUClast
Area under the concentration-
time profile from time 0 to the 
time of the last quantifiable 
concentration (Clast)
Linear/log trapezoidal method
AUCinf *
Area under the concentration-
time profile from time 0
extrapolated to infinite time
AUClast + (Clast*/kel), where Clast* was 
the predicted serum concentration at 
the last quantifiable time point 
estimated from the log-linear 
regression analysis
t½*
Terminal elimination half-life
Loge(2)/kel, where kel was the 
terminal phase rate constant 
calculated by a linear regression of 
the log-linear concentration-time 
profile
CL/F*
Apparent clearance
Dose/AUCinf
Vz/F*
Apparent volume of distribution
Dose/(AUCinf*kel)
* If data permitted. 
Pharmacokinetic parameters were calculated using an internally validated software system, 
electronic non-compartmental analysis (eNCA, version 2.2.4).
Actual PK sampling times will be used in the derivation of PK parameters. The vupanorsen
PK parameters will be listed and summarized descriptively in each vupanorsen dose group.
For AUC and Cmax, box whisker plots for individual participant parameters overlaid with 
geometric means will be plotted.
Plasma concentration of vupanorsen will be listed and summarized descriptively by treatment 
and PK sampling time. Mean and median concentration-time plots against nominal sampling 
time will be presented for each vupanorsen dose group respectively.


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9.4.3. Secondary Endpoint(s)
9.4.3.1. Safety Endpoints
All safety analyses will be performed on the safety population. 
AEs, ECGs, vital signs, and clinical safety laboratory tests data will be reviewed and 
summarized on an ongoing basis during the study to evaluate the safety of participants. Any 
clinical laboratory, ECG and vital signs abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. 
Medical history and physical examination, as applicable, collected during the course of the 
study will be considered source data and will not be required to be reported, unless otherwise 
noted. However, any untoward findings identified on physical examinations conducted 
during the active collection period will be captured as AEs, if those findings meet the 
definition of an AE. Data collected at screening that are used for inclusion/exclusion criteria, 
such as laboratory data, ECGs, and vital signs, will be considered source data, and will not be 
required to be reported, unless otherwise noted. Demographic data collected at screening will 
be reported.
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time. The number (%) of 
participants with maximum postdose 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
9.4.3.2. Pharmacodynamic Endpoints
Percentage changes from baseline in PD assessments will be summarized by treatment group 
and time using descriptive statistics. 
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a data monitoring committee. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor and submitted to an 
IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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.


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10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant 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 
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.


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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 
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 identification. 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.


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
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.
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.


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10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic 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), 
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.


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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.
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.


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or 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 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 


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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with 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. For 
sites other than a Pfizer CRU, 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 laboratory tests will be performed at times defined in the SoA section of this 
protocol. Additional laboratory results may be reported on these samples as a result of the 
method of analysis or the type of analyzer used by the clinical laboratory, or as derived from 
calculated values. These additional tests would not require additional collection of blood. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
Table 2.
Protocol Required Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
At screening only:

FSHb

Hepatitis B surface 
antigen

Hepatitis C antibody

Human 
immunodeficiency virus

Syphilis. 
As per SoA:

Urine drug screeningc

Pregnancy test (-hCG)d
Lipid Panel
Extended Lipoprotein 
Panel and PD Marker
Coagulation
Total cholesterol
LDL cholesterol –
direct measurement
HDL cholesterol
Non-HDL 
cholesterol
Triglycerides
VLDL cholesterol –
direct measurement

ANGPTL3

ApoB

ApoB-48

ApoB-100
ApoC-III
ApoA-I
aPTT (sec)
PT (sec)
INR
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, 
benzodiazepines, and amphetamines (others are site and study specific).
d.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine -hCG for female participants of childbearing potential.
Investigators must document their review of each laboratory safety report.


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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.


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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.


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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.

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 AEs; 


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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.
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.


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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.

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 


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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 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.


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
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.
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
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
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 below 
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
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. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.


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For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. In addition, a

High FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years old and not using hormonal 
contraception or HRT. 

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 men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
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: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
LFTs are not required as a routine safety monitoring procedure in this study. However, 
should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described 
below.
In the majority of DILI cases, elevations in AST and/or ALT precede 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).


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
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).
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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10.6. Appendix 6: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 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 SAEs

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <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 SAEs

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.7. Appendix 7: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
ADA
antidrug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANGPTL3
angiopoietin-like protein 3
ApoA-I
apolipoprotein A-1
ApoB
apolipoprotein B
ApoC-III
apolipoprotein C-III
aPTT
activated partial thromboplastin time 
ASGPR
asialoglycoprotein receptor
ASO
antisense oligonucleotide
AST
aspartate aminotransferase
AUC
area under the curve
AUC24h
AUC from time 0 to 24 hours post-dose
AUC48h
AUC from time 0 to 48 hours post-dose
AUCinf
AUC from time 0 extrapolated to infinite time
AUClast
AUC from time 0 to Tlast
AV
atrioventricular
-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations 
CIOMS
Council for International Organizations of Medical Sciences 
CK
creatine kinase 
CL/F
apparent clearance
Cmax
maximum observed concentration
CRF
case report form
CRU
clinical research unit
CSR
clinical study report 
CT
clinical trial
CVD
cardiovascular disease
DILI
drug-induced liver injury 
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
ECL
electrochemiluminescence 
eGFR
estimated glomerular filtration rate 
EMA
European Medicines Agency 


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Abbreviation
Term
ET
early termination
EU
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
Database
FPL
familial partial lipodystrophy
FSH
follicle-stimulating hormone
FCS
familial chylomicronemia syndrome
GalNAc
N-acetyl galactosamine
GCP
Good Clinical Practice 
GGT
gamma-glutamyl transferase 
HbsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol
IPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy 
HTG
Hypertriglycemia 
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonization 
IND
Investigational New Drug 
INR
international normalized ratio 
IPAL
investigational product accountability log 
IP manual
investigational product manual
IRB
institutional review board
IV
intravenous 
LDL-C
low density lipoprotein cholesterol
LFT
liver function test
LOF
loss-of-function 
MAD
multiple ascending doses
MCH
mean corpuscular hemoglobin 
MAHC
mean corpuscular hemoglobin concentration 
MCV
mean corpuscular volume 
MOE
methoxyethyl
mRNA
messenger ribonucleic acid
msec
millisecond
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NMPA
National Medical Products Administration 
NOAEL
no-observed-adverse-effect level
non-HDL-C
non-high-density lipoprotein cholesterol


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Abbreviation
Term
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PR
pulse rate
PT
prothrombin time
QW
weekly
Q2W
every 2 weeks
Q4W
every 4 weeks
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
RNA
ribonucleic acid
Rnase H1
an ubiquitous endonuclease that specifically hydrolyzes the RNA 
strand in RNA/DNA hybrids
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan 
SC
subcutaneous
SCr
serum creatinine
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SUSARs
suspected unexpected serious adverse reaction 
t½
terminal elimination half life
Tbili
total bilirubin
TC
total cholesterol
TEAE
treatment-emergent adverse event
TG
triglyceride
THC
tetrahydrocannabinol 
Tmax
time at which Cmax occurred
T2DM
type 2 diabetes mellitus
ULN
upper limit of normal 
US
the United States 
VLDL-C
very low density lipoprotein cholesterol
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
woman of childbearing potential


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11. REFERENCES
1.
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to 
hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in 
mice. Nucleic Acids Res. 2014;42:8796-807.
2.
Crooke ST, Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev 
Pharmacol Toxicol. 1996;36:107-29.
3.
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation 
pathway Factor XI by antisense oligonucleotides: a novel antithrombotic strategy with 
lowered bleeding risk. Blood. 2010;116:4684-92.
4.
Romeo S, Yin W, Kozlitina J, et al. Rare loss-of-function mutations in ANGPTL family 
members contribute to plasma triglyceride levels in humans. J Clin Invest.
2009;119(1):70-9.
5.
Koster A, Chao YB, Mosior M, et al. Transgenic angiopoietin-like (angptl)4 
overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride 
metabolism. Endocrinology. 2005;146(11):4943-50.
6.
Koishi R, Ando Y, Ono M, et al. Angptl3 regulates lipid metabolism in mice. Nat 
Genet. 2002;30(2):151-7.
7.
Fujimoto K, Koishi R, Shimizugawa T, et al. Angptl3-null mice show low plasma lipid 
concentrations by enhanced lipoprotein lipase activity. Exp Anim. 2006;55(1):27-34.
8.
Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and 
familial combined hypolipidemia. N Engl J Med. 2010;363(23):2220-7.
9.
Martin-Campos JM, Roig R, Mayoral C, et al. Identification of a novel mutation in the 
ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without 
APOB mutation. Clin Chim Acta. 2012;413(5-6):552-5.
10.
Minicocci I, Montali A, Robciuc MR, et al. Mutations in the ANGPTL3 gene and 
familial combined hypolipidemia: a clinical and biochemical characterization. J Clin 
Endocrinol Metab. 2012;97(7):E1266-75.
11.
Noto D, Cefalu AB, Valenti V, et al. Prevalence of ANGPTL3 and APOB gene 
mutations in subjects with combined hypolipidemia. Arterioscler Thromb Vasc Biol.
2012;32(3):805-9.
12.
Pisciotta L, Favari E, Magnolo L, et al. Characterization of three kindreds with familial 
combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ 
Cardiovasc Genet. 2012;5(1):42-50.


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13.
Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of 
ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377(3):211-21.
14.
Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against 
coronary artery disease. J Am Coll Cardio. 2017;69(16):2054-63.
15.
Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
Clin Transl Med. 2016;5(1):23-37.

SAP_001.pdf: 
Protocol C4491004 (PF-07285557) Statistical Analysis Plan
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Page 1
Protocol C4491004
A PHASE 1, RANDOMIZED, OPEN-LABEL, SINGLE DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY 
AND TOLERABILITY OF VUPANORSEN ADMINISTERED SUBCUTANEOUSLY 
TO HEALTHY CHINESE ADULTS
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
16 October 2020


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................4
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................5
3.1. Primary Endpoint(s) ..................................................................................................5
3.2. Secondary Endpoint(s) ..............................................................................................6
3.2.1. Safety Endpoints...........................................................................................6
3.2.2. Pharmacodynamics Endpoints......................................................................7
3.3. Other Endpoint(s)......................................................................................................7
3.4. Baseline Variables.....................................................................................................7
3.5. Safety Endpoints .......................................................................................................7
3.5.1. Adverse Events.............................................................................................7
3.5.2. Laboratory Data............................................................................................7
3.5.3. Vital Signs ....................................................................................................7
3.5.4. Electrocardiograms.......................................................................................8
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................8
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................9
5.1. Hypotheses and Decision Rules ................................................................................9
5.2. General Methods .......................................................................................................9
5.2.1. Analyses for Binary Endpoints.....................................................................9
5.2.2. Analyses for Continuous Endpoints .............................................................9
5.2.3. Analyses for Categorical Endpoints .............................................................9
5.3. Methods to Manage Missing Data ............................................................................9
5.3.1. Safety Data....................................................................................................9
5.3.2. Pharmacokinetic Data...................................................................................9
5.3.3. Pharmacodynamic Data..............................................................................10
6. ANALYSES AND SUMMARIES ......................................................................................10


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6.1. Primary Endpoint(s) ................................................................................................10
6.2. Secondary Endpoint(s) ............................................................................................12
6.2.1. Safety Endpoints.........................................................................................12
6.2.2. Pharmacodynamic Endpoints .....................................................................12
6.3. Other Endpoint(s)....................................................................................................12
6.4. Subset Analyses.......................................................................................................12
6.5. Baseline and Other Summaries and Analyses.........................................................12
6.5.1. Baseline Summaries....................................................................................12
6.5.2. Study Conduct and Participant Disposition................................................13
6.5.3. Concomitant Medications and Nondrug Treatments..................................13
6.6. Safety Summaries and Analyses .............................................................................13
6.6.1. Adverse Events...........................................................................................13
6.6.2. Laboratory Data..........................................................................................13
6.6.3. Vital Signs ..................................................................................................13
6.6.4. Electrocardiograms.....................................................................................14
7. INTERIM ANALYSES.......................................................................................................14
8. REFERENCES ....................................................................................................................14
9. APPENDICES .....................................................................................................................15
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
Table 2.
Plasma Vupanorsen Pharmacokinetic Parameters......................................5
Table 3.
PK Parameters to be Summarized Decsriptively by Treatment ...............11
APPENDICES
Appendix 1.
List of Abbreviations ................................................................................15
Appendix 2. 
Categorical Classes for Vital Signs ..........................................................16


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
16 October 2020
Original 
28 Aug 2020
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4491004.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
The followings are objectives and endpoints in this study.  Estimand framework is not 
applied to this phase 1 study.
Objectives
Endpoints
Primary: 
Primary: 

To characterize the PK of vupanorsen 
following 80 and 160 mg single 
subcutaneous dose in healthy Chinese 
adults.

Vupanorsen plasma PK parameters: 
AUC24h, AUC48h, AUClast, Cmax, AUCinf, 
Tmax, t½, CL/F and Vz/F, as data permit.
Secondary: 
Secondary: 

To evaluate the safety and tolerability 
of vupanorsen following 80 and 
160 mg single subcutaneous dose in 
healthy Chinese adults. 

To characterize the PD effects of 
vupanorsen following 80 and 160 mg 
single subcutaneous dose in healthy 
Chinese adults. 

Adverse events, clinical safety 
laboratory tests (serum chemistry, 
hematology, urinalysis, coagulation), 
vital signs (BP, PR), physical 
examination findings, 12-lead ECGs. 

Percentage change from baseline in 
ANGPTL3 on Day 2, Day 3, Day 8, 
Day 15, Day 30, Day 60 and Day 90.

Percentage changes from baseline in 
Lipid Panel on Day 2, Day3, Day 8, 
Day 15, Day 30, Day 60 and Day 90, 


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including fasting TG, LDL-C, HDL-C, 
VLDL-C, non-HDL-C, and TC.

Percentage changes from baseline in 
ApoA-I, ApoB total (including 
ApoB-48, ApoB-100), and ApoC-III on 
Day 15, Day 60 and Day 90.
2.2. Study Design
This is a Phase 1, randomized, parallel-cohort, open-label study to characterize the PK, PD 
safety and tolerability of vupanorsen following 80 mg and 160 mg single subcutaneous dose 
in healthy Chinese adults with fasting triglyceride ≥90 mg/dL. Approximately 18 
participants will be enrolled in this study (N=9 for each cohort) with the goal of attaining 
approximately 8 evaluable participants in each cohort for a total of 16 evaluable participants. 
The total duration of participation in this study is approximately 118 days, including a 
screening period of up to 28 days to confirm eligibility and a follow-up period of 
approximately 90 days. Eligible participants will progress to admission to the clinical 
research unit on Day -1 for a 4-day (3-night) inpatient stay. Participants enrolled will receive 
a single 80 mg (cohort 1) or 160 mg (cohort 2) subcutaneous dose of vupanorsen on Day 1. 
Following discharge on Day 3, participants will return for an on-site post-treatment 
evaluation on Days 8, 15, 30, 60 and 90. 
Participants who discontinue prior to completion of the study for non-safety related reasons 
may be replaced, at the discretion of the principal investigator and sponsor study team.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Primary endpoints are following vupanorsen plasma PK parameters:
Table 2.
Plasma Vupanorsen Pharmacokinetic Parameters
Parameter
Definition
Method of Determination
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time at which Cmax occurred
Observed directly from data as time 
of first occurrence
AUC24h
Area under the 
concentration-time profile from 
time 0 to 24 hour post-dose 
Linear/log trapezoidal method
AUC48h
Area under the 
concentration-time profile from 
time 0 to 48 hour post-dose 
Linear/log trapezoidal method


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Table 2.
Plasma Vupanorsen Pharmacokinetic Parameters
Parameter
Definition
Method of Determination
AUClast
Area under the 
concentration-time profile from 
time 0 to the time of the last 
quantifiable concentration (Clast)
Linear/log trapezoidal method
AUCinf*
Area under the 
concentration-time profile from 
time 0 extrapolated to infinite 
time
AUClast + (Clast*/kel), where Clast* 
was the predicted serum 
concentration at the last quantifiable 
time point estimated from the 
log-linear regression analysis
t½*
Terminal elimination half-life
Loge(2)/kel, where kel was the 
terminal phase rate constant 
calculated by a linear regression of 
the log-linear concentration-time 
profile
CL/F*
Apparent clearance
Dose/AUCinf
Vz/F*
Apparent volume of distribution
Dose/(AUCinf*kel)
* If data permitted. 
Pharmacokinetic parameters will be calculated using an internally validated software system,
electronic non-compartmental analysis (eNCA, version 2.2.4 or higher).
3.2. Secondary Endpoint(s)
3.2.1. Safety Endpoints
Safety endpoints are: 
•
Adverse events (AE);
•
Clinical safety laboratory measurements, including serum chemistry, hematology, 
urinalysis, and coagulation;
•
Vital signs, including blood pressure (BP) and pulase rate (PR);
•
Physical examination findings˗
•
Any untoward findings identified on physical examinations conducted during the 
active collection period will be captured as AEs, if those findings meet the 
definition of an AE.
•
12-lead ECGs. 
The details of the safety endpoints are described in Section 3.5.


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3.2.2. Pharmacodynamics Endpoints
PD endpoints are:

Percentage change from baseline in ANGPTL3 on Day 2, Day 3, Day 8, Day 15, Day 
30, Day 60 and Day 90;

Percentage changes from baseline in Lipid Panel on Day 2, Day3, Day 8, Day 15, 
Day 30, Day 60 and Day 90, including fasting TG, LDL-C, HDL-C, VLDL-C, non-
HDL-C, and TC;

Percentage changes from baseline in ApoA-I, ApoB total (including ApoB-48, ApoB-
100), and ApoC-III on Day 15, Day 60 and Day 90.
3.3. Other Endpoint(s)
Not applicable.
3.4. Baseline Variables
There are no baseline variables to be used as covariates or stratification factors in this study.
The demographic data will include age, sex, weight, body mass index.  Baseline variables are 
those collected on Day 1 prior to dosing or last measurement before Day 1.
3.5. Safety Endpoints
3.5.1. Adverse Events
All events that start on or after the first dosing day and time/start time, if collected, but before 
the last dose plus the lag time as defined in the protocol will be flagged as 
Treatment-Emergent Adverse Events (TEAEs).  If an AE starts on the same day as the first 
dose date, it will be considered treatment emergent unless the case report form data indicates 
otherwise via explicitly recording time for AE onset and treatment dosing.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
hematological, clinical chemistry, urinalysis, and coagulation safety tests will be assessed 
against the criteria specified in the sponsor reporting standards.  The assessment will not take 
into account whether each participant’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameters.  Baseline will be the last predose 
measurement collected on Day -1.
3.5.3. Vital Signs
Supine blood pressure and pulse measurements will be taken at all time points listed in the 
Schedule of Activities given in the protocol.  Baseline will be defined as the measurement 
obtained on Day 1 predose.


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The maximum decrease and increase from baseline over all measurements taken postdose for 
supine systolic and diastolic blood pressures will be determined.  The maximum increase 
from baseline will be calculated by first subtracting the baseline value from each postdose 
measurement to give the change from baseline.  The maximum of these values over the entire 
study will then be selected, except in the case where a participant does not show an increase.  
In such an instance, the minimum decrease should be taken.
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the change from baseline.  In cases where a participant does not show a 
decrease, the minimum increase should be taken.
3.5.4. Electrocardiograms
Standard 12-lead ECGs will be taken at all time points listed in the Schedule of Activities 
given in the protocol.  Baseline will be defined as the measurement obtained on Day 1 
predose.
The QT, QTcF, PR, QRS and heart rate (HR) will be recorded at each assessment time.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT/(RR)1/3
where respiratory rate (RR) = 60/HR (if not provided)
The maximum absolute value (postdose) and the maximum increase from baseline will be 
determined over all measurements taken postdose for QTcF, PR and QRS.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline.  The maximum of 
these values over the entire study will then be selected, except in the case where a participant 
does not show an increase.  In such an instance, the minimum decrease should be taken.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Enrolled
All participants who sign the informed consent document (ICD).
Pharmacokinetics 
(PK)
The PK concentration population is defined as all participants 
enrolled and treated who have at least 1 vupanorsen concentration.
The PK parameter analysis population is defined as all participants 
enrolled and treated who have at least 1 of the vupanorsen PK 
parameters of interest.
Pharmacodynamics 
(PD)
The PD parameter analysis population is defined as all participants 
enrolled and treated who have at least 1 of the PD parameters of 
interest.
Safety
All participants enrolled and who take at least 1 dose of study 
intervention.


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If a participant receives a treatment that is not consistent with the treatment they are assigned 
to, then the participant will be reported under the treatment that the participant actually 
received for all PK, PD and safety analyses, where applicable.
5. GENERAL METHODOLOGY AND CONVENTIONS
The study will be analyzed and reported once all participants have completed the study (or 
discontinued), ie, following the data set release.
5.1. Hypotheses and Decision Rules
There are no statistical hypotheses or decision rules. 
5.2. General Methods
All data will be descriptively summarized by treatment (vupanorsen 80 mg and 160 mg). 
5.2.1. Analyses for Binary Endpoints
Binary endpoints will be summarized by treatment and visit (if appropriate) with number and 
percentage of participants in each category, if not otherwise specified.
5.2.2. Analyses for Continuous Endpoints
Continuous endpoints will be summarized by treatment and visit using descriptive statistics, 
including n, arithmetic mean, median, standard deviation (SD), minimum and maximum, if 
not otherwise specified.
5.2.3. Analyses for Categorical Endpoints
Categorical endpoints will be summarized by treatment and visit (if appropriate) with number 
and percent of participants in the treatment group within each category, if not otherwise 
specified.
5.3. Methods to Manage Missing Data
5.3.1. Safety Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.2. Pharmacokinetic Data
Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)


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Deviations, Missing Concentrations and Anomalous Values
In summary tables, plots of mean profiles and plots of median profiles, summary statistics 
will be calculated setting concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond 
the day that a participant discontinues.) 
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular dose with ≥3 evaluable measurements.
If an individual participant has a known biased estimate of a PK parameter (eg, due to known 
loss of drug during subcutaneous administration), this will be footnoted in summary tables 
and will not be included in the calculation of summary statistics.
5.3.3. Pharmacodynamic Data
Missing values will not be imputed.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
To assess the pharmacokinetics of vupanorsen, the PK parameters detailed in Section 3.1 will 
be listed, summarized and plotted by treatment (vupanorsen 80 mg and 160 mg) for 
participants in the PK parameter analysis set (as defined in Section 4).  Missing values will 
be handled as detailed in Section 5.3.2.  Each PK parameter will be summarized by treatment
and will include the set of summary statistics as specified in the table below:


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Table 3.
PK Parameters to be Summarized Decsriptively by Treatment
Parameter
Summary Statistics
Cmax, AUC24h, AUC48h, AUClast, 
AUCinf, CL/F, Vz/F
n, arithmetic mean, median, SD, minimum, 
maximum, percent coefficient of variation (%CV), 
geometric mean and geometric %CV
Tmax
n, median, minimum, maximum
t½
n, arithmetic mean, median, %CV, SD, minimum, 
maximum
There will be one summary table presenting all PK parameters.
To assess the relationship between the PK parameters and dose, box and whisker plot of dose 
normalized Cmax, AUC24h, AUC48h, AUClast, and AUCinf will be plotted against dose, and will 
include individual participant values and geometric means for each dose.  Geometric means 
will have a different symbol than individual values.  The values will be dose normalized (to 
1 mg dose) by dividing the individual values and raw geometric means by dose.  A footnote 
will be added to the plots to indicate that geometric means are presented.
The PK concentrations will be listed and summarized for participants in the PK concentration 
analysis set.  Presentations for PK concentrations will include:

A listing of all concentrations sorted by subject ID, treatment and nominal time 
postdose.  The concentration listing will also include the actual times.  Deviations 
from the nominal time will be given in a separate listing. The listing will be paged by 
treatment.

A summary of concentrations by treatment and nominal time postdose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(cv), minimum, maximum and the number of concentrations above the lower limit of 
quantification.

Median concentrations time plots (on both linear and semi-log scales) against 
nominal time post dose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time post dose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose. There will be separate spaghetti plots for each treatment 
per scale.


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The length of time used for the x-axes of these plots will be decided on review of the data 
and will depend on how long vupanorsen concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used. For pre-dose, the actual PK sampling time will be set to 0 hour.
6.2. Secondary Endpoint(s)
6.2.1. Safety Endpoints
The details of safety analyses are described in the Section 6.6. 
6.2.2. Pharmacodynamic Endpoints
The PD analysis will be conducted in the PD analysis set (as defined in Section 4).  
Non-fasting results will not be included in the analysis.
The baseline, the actual values, changes and percent changes from baseline in the following 
endpoints will be summarized by treatment and visit using descriptive statistics.

ANGPTL3, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, TG, ApoA-I, ApoB total 
(including ApoB-48, ApoB-100), and ApoC-III.
Additionally, the following graphical summaries will be provided for the actual values, 
changes and the percent changes from baseline over time:

Mean ± SD by treatment and day (all treatments on the same plot);

Individual plots against day (there will be separate plots for each treatment).
A listing for the actual values, changes and percent changes from baseline with fasting status 
sorted by treatment, subject ID and day will be presented.
6.3. Other Endpoint(s)
Not applicable.
6.4. Subset Analyses
Not applicable.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographic and baseline characteristics (age, gender, weight, height and body mass index) 
collected prior to the first dose of the study intervention will be summarized following the 
CaPS.


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6.5.2. Study Conduct and Participant Disposition
The following participant dispositions will be reported following the sponsor reporting 
standards:

A summary of participant discontinuations up to the end of study;

Summary of participant dispositions analyzed for PK and PD, as well as for safety by 
treatment group;

Summary of numbers of participant treated by treatment group.
6.5.3. Concomitant Medications and Nondrug Treatments
All concomitant medications as well as nondrug treatments will be provided in the listings.
6.6. Safety Summaries and Analyses
The safety endpoints are presented in the Section 3.5.  A set of summary tables split by 
treatment will be produced to evaluate any potential risk associated with the safety and 
toleration of administering vupanorsen.
No formal analyses are planned for safety data.  The safety endpoints will be listed and 
summarized in accordance with the sponsor reporting standards, where the resulting data 
presentations will consist of participants from the safety analysis set.
6.6.1. Adverse Events
Adverse events will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.
6.6.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.5.2.
Incidence of laboratory test abnormalities (without regard to baseline abnormality) will be 
summarized by treatment based on CaPS.
6.6.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and postdose timepoints, according to the 
sponsor reporting standards.  Tables will be paged by parameter.  Baseline is as defined in
Section 3.5.3.
Maximum increase or decrease in vital signs will also be summarized; all planned and 
unplanned postdose timepoints will be included in these summaries.


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6.6.4. Electrocardiograms
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and postdose timepoints following the sponsor reporting standards.  
Tables will be paged by parameter.  Baseline is as defined in Section 3.5.4.
The number (%) of participants with maximum postdose 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.
Listings of participants with any single postdose value ≥500 msec will also be produced for 
QTcF.
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. As this is an open-label 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment.
8. REFERENCES
None.


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9. APPENDICES 
Appendix 1. List of Abbreviations
Abbreviation
Term
AE
adverse event
ANGPTL3
angiopoietin-like protein 3
ApoA-I
apolipoprotein A-1
ApoB
apolipoprotein B
ApoC-III
apolipoprotein C-III
AUC
area under the concentration-time curve
AUC24h
AUC from time 0 to 24 hours post-dose
AUC48h
AUC from time 0 to 48 hours post-dose
AUCinf
AUC from time 0 extrapolated to infinite time
AUClast
AUC from time 0 to Tlast
BLQ
below the limit of quantification
BP
blood pressure
CaPS
CDISC and Pfizer Standard
CDISC
clinical data interchange standards consortium
CL/F
apparent clearance
Cmax
maximum observed concentration
CV
coefficient of variation
ECG
electrocardiogram
HDL-C
high density lipoprotein cholesterol
HR
heart rate
ICD
informed consent document
ID
identification
LDL-C
low density lipoprotein cholesterol
LLQ
lower limit of quantification
N/A
not applicable
NC
not calculated
ND
not done
Non-HDL-C
non-high-density lipoprotein cholesterol
NS
no sample
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PR
pulse rate
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
RR
respiratory rate
SAP
statistical analysis plan
SD
standard deviation
t½
terminal elimination half life
TEAE
treatment-emergent adverse event
TC
total cholesterol


Protocol C4491004 (PF-07285557) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 16
Abbreviation
Term
TG
triglyceride
Tmax
time at which Cmax occurred
VLDL-C
very low density lipoprotein cholesterol
Vz/F
apparent volume of distribution
Appendix 2. Categorical Classes for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg)
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg)
change from baseline
max. decrease ≥20
max. increase ≥20
Seated pulse rate (bpm)
min. <40
max. >120
Measurements that fulfill these criteria are to be listed in report.