Clinical trial NCT04399538
Conditions: Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Disease
Sponsor: Pfizer
Start date: 2020-08-10; Completion date: 2022-04-28
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will evaluate the effect of coadministration of a range of doses of DGAT2i with 1 dose of ACCi, on hepatic steatosis and the ability of DGAT2i to mitigate ACCi-induced elevations in serum triglycerides. The study has a 2-part design with sequential conduct of Part 1 and Part 2 with each part conducted in distinct/separate cohorts of participants. The overall study design, objectives/endpoints, eligibility criteria for both parts is envisioned to be identical, however, data from Part 1 will be used to determine whether to conduct Part 2.

Detailed description:

Arms: arm 1: Participants will receive medication for 6 weeks arm 2: Participants will receive medication for 6 weeks arm 3: Participants will receive medication for 6 weeks arm 4: Participants will receive medication for 6 weeks arm 5: Participants will receive medication for 6 weeks
Interventions: intervention 1: PF-06865571 intervention 2: PF-05221304 intervention 3: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Tablet

Protocol documents:
Prot_000.pdf: 
PF-06865571 + PF-05221304 (DGAT2i + ACCi)
Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 2A, 2-PART, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY 
PLACEBO-CONTROLLED, PARALLEL-GROUP (SPONSOR OPEN) STUDY TO 
ASSESS PHARMACODYNAMICS AND SAFETY OF PF-06865571 (DGAT2I) 
COADMINISTERED WITH PF-05221304 (ACCI) IN ADULT PARTICIPANTS 
WITH PRESUMED NONALCOHOLIC STEATOHEPATITIS (NASH)
Study Intervention Number:
PF-06865571 (DGAT2i)
PF-05221304 (ACCi)
Study Intervention Name:
N/A
US IND Number:
EudraCT Number:
N/A
Protocol Number:
C3711005
Phase:
2a
Short Title: Parallel-Group Study of PD and Safety of DGAT2i and ACCi Coadministered 
in Participants with Sponsor-defined Presumed NASH
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
CCI


PF-06865571 + PF-05221304 (DGAT2i + ACCi)
Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
27 March 2020
N/A


PF-06865571 + PF-05221304 (DGAT2i + ACCi)
Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities .............................................................................................12
2. INTRODUCTION ...............................................................................................................15
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Clinical Overview.......................................................................................17
2.2.2. Nonclinical Overview.................................................................................19
2.3. Benefit/Risk Assessment.........................................................................................19
2.3.1. Risk Assessment.........................................................................................20
2.3.2. Benefit Assessment.....................................................................................22
2.3.3. Overall Benefit/Risk Conclusion................................................................22
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................23
4. STUDY DESIGN.................................................................................................................24
4.1. Overall Design.........................................................................................................24
4.1.1. Part 1...........................................................................................................24
4.1.2. Optional Part 2............................................................................................25
4.2. Scientific Rationale for Study Design.....................................................................26
4.2.1. Participants of Child-bearing Potential.......................................................29
4.2.2. Rationale for Banked Biospecimen Collections.........................................29
4.3. Justification for Dose ..............................................................................................30
4.3.1. Part 1...........................................................................................................30
4.3.2. Optional Part 2............................................................................................31
4.4. End of Study Definition ..........................................................................................31
5. STUDY POPULATION......................................................................................................32
5.1. Inclusion Criteria.....................................................................................................32
5.2. Exclusion Criteria....................................................................................................33


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Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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5.3. Randomization Criteria ...........................................................................................38
5.4. Lifestyle Considerations..........................................................................................39
5.4.1. Contraception..............................................................................................39
5.4.2. Meals and Dietary Restrictions...................................................................39
5.4.3. Alcohol, Caffeine, and Tobacco .................................................................40
5.4.4. Activity .......................................................................................................40
5.4.5. Outpatient Visits to Site..............................................................................41
5.4.6. Outpatient Visits to Imaging/Radiology Facility........................................41
5.5. Screen Failures ........................................................................................................41
6. STUDY INTERVENTION..................................................................................................42
6.1. Study Intervention(s) Administered........................................................................42
6.1.1. Administration............................................................................................43
6.2. Preparation/Handling/Storage/Accountability ........................................................43
6.2.1. Preparation and Dispensing........................................................................44
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................45
6.3.1. Allocation to Study Intervention ................................................................45
6.3.1.1. Part 1 .........................................................................................45
6.3.1.2. Optional Part 2 ..........................................................................45
6.3.2. Breaking the Blind......................................................................................45
6.4. Study Intervention Compliance...............................................................................46
6.5. Concomitant Therapy..............................................................................................46
6.5.1. Medication for Glycemic Control...............................................................47
6.5.2. Lipid-modifying Medications.....................................................................47
6.5.3. Medications for Controlling Blood Pressure..............................................48
6.5.4. Other Acceptable Concomitant Medications..............................................48
6.5.5. Prohibited Medications...............................................................................49
6.5.6. Rescue Medicine.........................................................................................50
6.6. Dose Modification...................................................................................................51
6.7. Intervention After the End of the Study..................................................................51
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................51
7.1. Discontinuation of Study Intervention ....................................................................51


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Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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7.2. Participant Discontinuation/Withdrawal from the Study........................................51
7.2.1. Withdrawal of Consent...............................................................................53
7.3. Lost to Follow-up....................................................................................................53
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................53
8.1. Efficacy Assessments..............................................................................................54
8.2. Safety Assessments .................................................................................................54
8.2.1. Physical Examinations................................................................................54
8.2.1.1. Measurement of Waist Circumference......................................55
8.2.2. Body Weight...............................................................................................55
8.2.3. Electrocardiograms.....................................................................................56
8.2.4. Vital Signs ..................................................................................................56
8.2.5. Clinical Safety Laboratory Assessments ....................................................57
8.2.6. Pregnancy Testing ......................................................................................57
8.2.7. Alcohol Intake Assessment.........................................................................58
8.2.8. Triggered Requirements and Individual Participant Stopping Rules .........58
8.2.8.1. Potential Cases of Hypertriglyceridemia...................................58
8.2.8.2. Potential Cases of Thrombocytopenia.......................................58
8.3. Adverse Events and Serious Adverse Events..........................................................58
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......59
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................59
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................60
8.3.2. Method of Detecting AEs and SAEs ..........................................................60
8.3.3. Follow-up of AEs and SAEs.......................................................................60
8.3.4. Regulatory Reporting Requirements for SAEs...........................................60
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................61
8.3.5.1. Exposure During Pregnancy......................................................61
8.3.5.2. Exposure During Breastfeeding ................................................62
8.3.5.3. Occupational Exposure .............................................................63
8.3.6. Adverse Events of Special Interest.............................................................63
8.3.7. Medication Errors .......................................................................................64
8.4. Treatment of Overdose............................................................................................64


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8.5. Pharmacokinetics ....................................................................................................65
8.6. Pharmacodynamics..................................................................................................66
8.6.1. Assessment of Liver Fat Using MRI-PDFF ...............................................66
8.6.2. Assessment of Liver Fat and Stiffness – using FibroScan® .......................67
8.6.3. Assessment of Liver Fat and Stiffness – using Acuson Sequoia®..............67
8.7. Genetics...................................................................................................................68
8.7.1. Specified Genetics ......................................................................................68
8.7.2. Banked Biospecimens for Genetics............................................................69
8.8. Biomarkers ..............................................................................................................69
8.8.1. Banked Biospecimens for Biomarkers .......................................................70
8.9. Immunogenicity Assessments.................................................................................70
8.10. Health Economics .................................................................................................70
9. STATISTICAL CONSIDERATIONS ................................................................................71
9.1. Estimands and Statistical Hypotheses.....................................................................71
9.1.1. Estimands....................................................................................................71
9.1.2. Hypothesis Tests.........................................................................................72
9.2. Sample Size Determination.....................................................................................72
9.2.1. Part 1...........................................................................................................72
9.2.2. Part 2...........................................................................................................72
9.3. Analysis Sets ...........................................................................................................72
9.3.1. Part 1...........................................................................................................73
9.3.2. Part 2...........................................................................................................73
9.4. Statistical Analyses .................................................................................................73
9.4.1. Primary Endpoint(s)....................................................................................73
9.4.2. Secondary Endpoint(s)................................................................................74
9.4.3. Tertiary/Exploratory Endpoint(s) ...............................................................74
9.4.4. Pharmacokinetic Analysis ..........................................................................76
9.4.5. Other Safety Analyses ................................................................................76
9.4.5.1. Vital Signs Analyses .................................................................76
9.4.5.2. Electrocardiogram Analyses......................................................77
9.4.6. Other Analyses............................................................................................77


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Final Protocol, 27 March 2020
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9.5. Interim Analyses .....................................................................................................77
9.5.1. PK/PD Modeling ........................................................................................77
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............77
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................79
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............79
10.1.1. Regulatory and Ethical Considerations ....................................................79
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................79
10.1.2. Financial Disclosure .................................................................................80
10.1.3. Informed Consent Process ........................................................................80
10.1.4. Data Protection .........................................................................................81
10.1.5. Dissemination of Clinical Study Data ......................................................81
10.1.6. Data Quality Assurance ............................................................................83
10.1.7. Source Documents....................................................................................84
10.1.8. Study and Site Start and Closure ..............................................................84
10.1.9. Publication Policy.....................................................................................85
10.1.10. Sponsor’s Qualified Medical Personnel .................................................86
10.2. Appendix 2: Clinical Laboratory Tests .................................................................87
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................89
10.3.1. Definition of AE .......................................................................................89
10.3.2. Definition of SAE.....................................................................................90
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................91
10.3.4. Reporting of SAEs....................................................................................94
10.4. Appendix 4: Contraceptive Guidance ...................................................................95
10.4.1. Male Participant Reproductive Inclusion Criteria....................................95
10.4.2. Female Participant Reproductive Inclusion Criteria.................................95
10.4.3. Woman of Childbearing Potential ............................................................95
10.4.4. Contraception Methods.............................................................................96
10.5. Appendix 5: Genetics............................................................................................98
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........99


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Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................101
10.8. Appendix 8: Strong CYP3A Inhibitors and Inducers..........................................103
10.9. Appendix 9: Guidance to Investigators – Management of Individual 
Participants Glycemic Control – including Metformin Dose Starting at Run-
In/Visit 2 ..................................................................................................................104
10.10. Appendix 10: Guidance to Investigators – Management of Individual 
Participants with Elevation in Fasting Serum Triglycerides ...................................105
10.11. Appendix 11: Guidance to Investigators – Management of Individual 
Participants With Decrease in Platelet Count..........................................................106
10.12. Appendix 12: Abbreviations .............................................................................107
11. REFERENCES ................................................................................................................112
LIST OF TABLES
Table 1.
Procedures for Part 1 and Optional Part 2................................................13
Table 2.
Blood and Urine Collection in Part 1 and Optional Part 2.......................14
Table 3.
Planned Dosing Groups in Part 1 of Study C3711005 .............................24
Table 4.
Double-Blind, Double-Dummy Regimen in Part 1 of C3711005............43
Table 5.
Additional Tertiary/Exploratory Objectives and Endpoints.....................75
Table 6.
All Planned Protocol Required Safety-Related Laboratory Tests and 
Exploratory Biomarkers in Study C3711005 ...........................................87
LIST OF FIGURES
Figure 1.
Overall Study Design................................................................................24
Figure 2.
Study Design for Part 1 and Optional Part 2............................................25


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Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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In this document, the two investigational products are referred to as DGAT2i (for 
PF-06865571) and ACCi (for PF-05221304).
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: Parallel-Group Study of PD and Safety of DGAT2i and ACCi Coadministered 
in Participants with Sponsor-Defined Presumed NASH.
Rationale: The current study is to evaluate the effect of coadministration of a range of doses 
of DGAT2i with 1 (and potentially 2) doses of ACCi, on the primary pharmacology (effect 
on liver steatosis) and evaluate the ability of a range of doses of DGAT2i to mitigate 
ACCi-induced elevations in serum triglycerides. This is the first clinical study specifically 
designed to identify the lowest dose of DGAT2i which, when coadministered with ACCi, 
results in reduction in hepatic steatosis while mitigating the identified adverse reaction 
(ie, elevation in serum triglycerides) observed with administration of ACCi alone.
This study has a 2-part design with sequential conduct of Part 1 and Part 2 with each part 
conducted in distinct/separate cohorts of participants. While the overall study design, 
objectives/endpoints, eligibility criteria for both parts are envisioned to remain identical, data 
from Part 1 will be used to determine whether to conduct Part 2.  Observed data from Part 1 
will guide the selection of doses and dosing regimens (ie, QD vs BID) of DGAT2i + ACCi 
coadministration evaluated in optional Part 2. 
Objectives, Estimands, and Endpoints: The primary, secondary, and key
tertiary/exploratory endpoints of focus in Part 1 and optional Part 2 of this study include:
Objectives
Estimands
Endpoints
Primary: 
To evaluate effect on liver fat, 
determined by MRI-PDFF, of a range of 
DGAT2i doses coadministered with a 
fixed dose of ACCi compared to 
placebo in participants with presumed 
NASH.
Estimand 1: 
This estimand is intended to 
provide a population level estimate 
of the mean treatment effect 
(DGAT2i + ACCi relative to 
placebo) on a continuous endpoint 
at Week 6 for all 
randomized/evaluable participants
(see details in Section 9.1.1).
Percent change from 
baseline in liver fat as 
assessed via MRI-PDFF, at 
Week 6.
Secondary:
To evaluate effect on fasting serum 
triglyceride levels of a range of 
DGAT2i doses coadministered with a 
fixed dose of ACCi compared to 
placebo in participants with presumed 
NASH
Estimand 2: 
This estimand is intended to 
provide a population level estimate
of the mean treatment effect 
(DGAT2i + ACCi relative to 
placebo) on a continuous endpoint, 
over time, for all 
randomized/evaluable participants
(see details in Section 9.1.1).
Percent change from 
baseline in fasting serum 
triglyceride levels over time.


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Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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Objectives
Estimands
Endpoints
To assess safety and tolerability with a 
range of DGAT2i doses coadministered
with fixed dose of ACCi compared to 
placebo in participants with presumed 
NASH.
No estimand is defined for safety 
and tolerability endpoints.
Proportion of participants 
with TEAEs and 
clinically-significant, 
abnormal clinical laboratory 
tests, vital signs, and 12-lead
ECGs.
Tertiary/Exploratory: 
To evaluate effect on liver fat
determined by quantitative ultrasound 
(FibroScan®) of a range of DGAT2i 
doses coadministered with fixed dose of 
ACCi, compared to placebo in 
participants with presumed NASH.
This Endpoint will be analyzed
using Estimand 1.
Percent change from
baseline in liver fat at 
Week 6, as assessed by 
CAP™via FibroScan®.
To evaluate effect on liver fat
determined by quantitative ultrasound 
(Acuson Sequoia®) of a range of 
DGAT2i doses coadministered with 
fixed dose of ACCi, compared to 
placebo in participants with presumed 
NASH.
This Endpoint will be analyzed 
using Estimand 1.
Percent change from 
baseline in liver fat at 
Week 6, as assessed by 
UDFF™via Acuson 
Sequoia®.
For all endpoints, baseline is defined as the evaluable result closest but prior to dosing on Day 1.
Overall Design: This is a multicenter, 2-part, sequentially conducted, randomized, 
double-blind, double-dummy, placebo-controlled, parallel-group evaluation of 
DGAT2i + ACCi summarized below.
Number of Participants
In Part 1, approximately 90 participants (18 per group) with Sponsor-defined presumed 
NASH, will be randomly assigned to the study intervention to ensure approximately 
75 evaluable participants (15 per group) offer evaluable data.


PF-06865571 + PF-05221304 (DGAT2i + ACCi)
Protocol C3711005
Final Protocol, 27 March 2020
PFIZER CONFIDENTIAL
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In Part 2, it is envisioned that number of participants on each active dose of DGAT2i + ACCi 
or placebo may be adjusted. Those assigned to placebo may be reduced, given the intent to 
pool data from all participants receiving placebo when summarizing end-of-study results. 
The doses of DGAT2i in Part 2 will not exceed 300 mg BID or 300 mg QD. The doses of 
ACCi will not exceed 20 mg/day (administered BID or QD to mirror dosing of DGAT2i).  A
maximum of 4 active doses (plus placebo) will be evaluated in Part 2; furthermore, the total 
number of participants will not exceed 90 (with no more than approximately 27 participants 
per each active dose). 
Intervention Groups and Duration: In Part 1, study interventions planned to be 
administered up to 6-weeks are summarized below. 
Group
Each Dose Group in Part 1
DGAT2i dose
ACCi dose
DGAT2i:ACCi ratio
A
0 (placebo) BID
0 (placebo) BID
0: 0
B
25 mg BID
10 mg BID
2.5: 1
C
100 mg BID
10 mg BID 
10: 1
D
300 mg QD*
20 mg QD*
15: 1
E
300 mg BID
10 mg BID
30: 1
*To maintain double-blind, double-dummy design across all groups, this group will receive placebo as their 
evening dose 
In Part 2, if conducted, the doses, as well as dosing regimens (ie, QD vs BID) evaluated for
DGAT2i + ACCi will be guided by observed data in Part 1.  
Data Monitoring Committee or Other Independent Oversight Committee: An 
independent Internal Review Committee (IRC) will undertake periodic unblinded review of 
the safety data while the study is on-going. 
Statistical Methods: Natural log-transformed relative change from baseline in fasting liver 
fat values determined using MRI-PDFF, CAP™via FibroScan®, and UDFF™via Acuson 
Sequoia® for DGAT2i + ACCi relative to placebo at Week 6 for all randomized/evaluable
participants will be analyzed using an ANCOVA with treatment as fixed effect and baseline
as covariate.  Natural log-transformed relative changes from baseline in fasting serum 
triglycerides for DGAT2i + ACCi relative to placebo will be analyzed using mixed model 
repeated measures (MMRM) analysis including treatment, time, and treatment-by-time 
interaction as fixed effects, baseline as a covariate effect and participant as a random effect.
All safety data will be summarized descriptively through appropriate data tabulation, 
descriptive statistics, categorical summaries, and graphical presentations.


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1.2. Schema
The detailed set-up of the study is summarized below with identical design for Part 1 and 
optional Part 2 planned. 
Pre-Qualification (PreQ)
Run-In
(Stabilize Background Meds)
[+ ↓ Metformin dose if > 1gm/day]
Baseline 
[Single-Blind Placebo (BID)]
Randomization / Day 1
F/U #1
F/U #2
Week 2
14±2 days
Screen (SCR) 
Week 4
Week 6
Screening Phase 
Treatment Phase 
6- to 10- weeks
Follow-up
10-weeks
At least 4-weeks
Visit Window
±2 days
30±2 days post last dose
14±2 days post last dose
Double-confirmation of –
Presumed NASH
CAP ≥ 280 dB/m
On-site visit (blood draw + safety)
MRI-PDFF (to assess quantitative liver fat)
FibroScan® (quantitative ultrasound to assess 
liver fat [via CAP] and liver stiffness [via VCTE])
Acuson Sequoia® (quantitative ultrasound to assess 
liver fat [via UDFF] and liver stiffness [via SWE])
Telephone contact 
1.3. Schedule of Activities
The 2 Schedule of Activities (SoA) tables provide an overview of the protocol visits and
procedures.  Refer to the Section 8 of the protocol for detailed information on each procedure 
and assessment required for compliance with the protocol. The SoA tables are identical for
Part 1 and optional Part 2. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA
tables, in order to conduct evaluations or assessments required to protect the well-being of 
the participant.


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Final Protocol, 27 March 2020
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Table 1.
Procedures for Part 1 and Optional Part 2
Visit Identifier
PreQ
SCR
Run-In
Baseline
Treatment Phase 
[All, except Imaging procedures, before morning 
dose of blinded study intervention]
Follow-up
Study D/C
Weeksa Relative to Dosing on Day 1
-4
-2
0
Day 1
2
4
6
8
10b
Visit #
0
1
2
3
4
5
6
7
8
9
Informed consent & demography
x
x
(Update) Medical & Medication Information
x
x
x
x
x
x
x
x
x
x
Liver fat and stiffness (via FibroScan®)c,d
x
x
x
x
Liver fat via MRI-PDFFc,d
x
x
Liver fat and stiffness (via Acuson Sequoia®)c,d
x
x
Physical Exam (PE)e
x
x
x
x
x
x
x
x
x
Assess alcohol intake (AUDIT questionnaire)
x
x
x
x
Assess correct use of contraception, where applicable
x
x
x
x
x
x
x
xf
Counseling on diet/exercise guidelines
x
x
Open-ended inquiry for adverse events (AEs)
x
x
x
x
x
x
x
x
x
x
x
Single supine 12-lead ECG 
x
x
x
x
x
x
Single seated vitals (BP & pulse rate) and body weight
x
x
x
x
x
x
Registration of visit in study (via IRT)
x
x
x
x
x
x
x
x
x
x
x
Onsite administration of study intervention, with mealg
x
x
x
x
x
Dispensation (via IRT) of study intervention 
x
x
x
x
Compliance check of returned study interventionh
xg
x
x
x
x
a.
Defined relative to Day 1 with permitted ±2-day window for each visit starting at Baseline/Visit 3; for example: Week -2 = 14 (±2) days before Day 1; Week 4 = 28 (±2) days 
post Day 1.
b. Telephone contact can be switched to on-site visits for follow-up of AEs and/or abnormal laboratory tests; Week 10 visit at ≥28- and ≤32 days post last dose (Day 30±2 days).
c.
Procedure performed following ≥4-hour fast (except water), as part of on-site visit or separate visit(s) to Imaging/Radiology facility; attempts to be made to perform Week 6 
assessment within ±2-hour window of time of 1st assessment (PreQ for FibroScan® and Baseline/Visit 3 for MRI-PDFF and Acuson Sequoia®).
d. Baseline assessments performed at or after Visit 3 and before dosing on Day 1/Visit 4; Week 6 performed ≤2 days post last dose of blinded study intervention. 
e.
Complete PE at PreQ and SCR and includes arm circumference (at PreQ only) and height and waist circumference (at both PreQ and SCR); otherwise, brief PEfor open 
adverse events (AEs)/abnormal laboratory tests, at investigator discretion.
f.
WOCBP participants to be reminded to continue required contraception until at least 28 days post-last dose.
g. Onsite dosing should be performed with single-blind, double-dummy placebo dispensed at Baseline/Visit 3 through 1 day prior to Day 1; double-blind, double-dummy study 
intervention starting on Day 1/Visit 4.
h. Performed at on-site visits with Day 1/Day 4 reflecting compliance with single-blind, double-dummy placebo; at subsequent visits, reflects compliance with double-blind, 
double-dummy study intervention.


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Final Protocol, 27 March 2020
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Table 2.
Blood and Urine Collection in Part 1 and Optional Part 2
Visit Identifier
PreQ
SCR
Run-In
Baseline
Treatment Phase
[All procedures before morning dose of blinded study 
intervention, except post-dose PK samples]
Follow-up
Study D/C
Weeksa Relative to Dosing on Day 1
-4
-2
0
Day 1
2
4
6
8
10b
Visit #
0
1
2
3
4
5
6
7
8
9
Blood Collection (following fast of ≥8 hours)
No blood or urine collection
Serum FSH (females only), serology (HBsAg, HCVAb [and
if positive, reflex HCV RNA], HIV), 1-antitrypsin, 
ceruloplasmin
xc
xc
% CDT
xc
xc
x
x
Hematology, Chemistry (including Cystatin-C), Coagulation
(aPTT, PT, INR)
xc
xc
xc
x
x
x
x
x
xd
x
Pregnancy (all females)
xc
xc
xc
x
x
x
x
x
xd
x
Triglycerides, direct LDL-C, HDL-C, total cholesterol
xc
xc
xc
x
x
x
x
x
xd
x
HbA1C, Plasma Glucose 
xc
xc
xc
x
x
x
x
x
xd
x
Direct VLDL, Serum apolipoproteins: ApoA1, ApoBtotal, 
ApoB100, ApoB48, ApoC3, ApoE; Pro-C3, Pro-C6, and 
hs-CRP
x
x
x
x
x
x
Plasma PCSK9, Adiponectin, CK18-M30, CK18-M65, 
Plasma Insulin
x
x
x
x
x
x
Predose PK - DGAT2i and ACCie
x
x
x
x
Post dose PK - DGAT2i and ACCif
x
x
x
Pre-specified PGx and Biobanked Prep D1 (DNA)
x
Biobanked Prep B1.5 (plasma) and Prep B2.5 (serum)
x
x
x
spot urine collection for –
Urine drug test
xc
xc
xc
Urinalysis (and microscopy when appropriate)
xc
xc
xc
x
x
x
x
x
xd
x
On-site pregnancy test (WOCBP only)
xc
xc
xc
x
x
xd
x
a.
Defined relative to Day 1 with permitted ±2 day window for each visit starting at Baseline/Visit 3; for example: Week -2 = 14 (±2) days before Day 1/Visit 4; 
Week 4 = 28 (±2) days post Day 1/Visit 4.
b.
Telephone contact can be switched to on-site visits for follow-up of AEs and/or abnormal laboratory tests; Week 10 visit at ≥28 and ≤32 days post last dose (Day 30±2 days).
c.
Test results to be reviewed by medically qualified site staff and deemed acceptable before progression to next visit; for example: PreQ results must be reviewed prior to 
conduct of SCR.
d.
Collections to occur only if visit is an on-site visit; collections to be skipped if visit is via telephone contact.
e.
In addition to blood collection, date and time of 2 most recent doses should be noted in a dosing diary prior to each scheduled on-site visit plus date/time of study intervention 
taken on-site must be captured in the eCRF.
f.
Collection to occur between 0.5-1 hour post dose on Day 1; between 2-3 hours post dose at Week 2; and between 4-8 hours post dose at Week 4.


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2. INTRODUCTION
The current study is to evaluate the effect of coadministration of a range of doses of DGAT2i
with 1 (and potentially 2) doses of ACCi, on the primary pharmacology (effect on liver 
steatosis) and evaluate the ability of a range of doses of DGAT2i to mitigate ACCi-induced 
elevations in serum triglycerides. This is the first clinical study specifically designed to 
identify the lowest dose of DGAT2i which, when coadministered with ACCi, results in 
reduction in hepatic steatosis while mitigating the identified adverse reaction (ie, elevation in
serum triglycerides) observed with administration of ACCi alone.
DGATs catalyze the terminal step in triglyceride synthesis; specifically, the esterification of 
a fatty acid with DAG resulting in the formation of triglyceride.1 In mammals, 2 structurally
unrelated DGAT enzymes (DGAT1 and DGAT2) have been characterized. DGAT1 is highly 
expressed in the intestine and plays a central role in fat absorption2 whereas DGAT2 is 
highly expressed in liver and adipose.3 DGAT2i is postulated to decrease hepatic triglyceride 
synthesis and hepatic lipid burden in NAFLD and NASH. Based on observations in 
nonclinical studies conducted, it is hypothesized that DGAT2i will impact both physiological 
drivers contributing to NASH via direct inhibition of liver triglyceride synthesis, as well as 
adaptive responses leading to reduction in hepatic DNL. Following 2 weeks of dosing in 
participants with NAFLD, DGAT2i has been shown to reduce liver fat in a dose-responsive 
manner.
ACC is a biotin carboxylase that catalyzes the ATP dependent condensation of acetyl-CoA 
and carbonate to form malonyl-CoA.4 Inhibition of ACC stimulates fatty acid oxidation, 
suppresses hepatic de novo lipogenesis (DNL), and reduces steatosis in animal models and in 
humans.5 ACCi has been shown to decrease hepatic DNL (in healthy participants following 
14-days of dosing), reduce liver steatosis (in participants with NAFLD), as well as reduce 
markers of liver inflammation (ALT, AST) and markers of apoptotic activity (CK18-M30 
and CK18-M65), in participants with Sponsor-defined presumed NASH following 16 weeks 
of dosing. However, these potentially beneficial effects, in participants with 
NAFLD/presumed NASH, were accompanied with marked elevations in serum triglycerides 
and other lipid parameters which prohibit administration of ACCi alone. 
In nonclinical models of NAFLD/NASH, coadministration of DGAT2i + ACCi has been 
shown to be more efficacious at lowering hepatic steatosis, and reducing inflammation and 
fibrosis endpoints, than either DGAT2i or ACCi alone. In addition, coadministration of 
DGAT2i + ACCi fully reversed the increases in circulating fasting serum triglycerides 
observed with ACCi alone – overcoming the known mechanistic consequence of hepatic 
ACCi thought to be a result of sterol regulatory element binding protein (SREBP) activation. 
Clinically, the effect of ACCi alone on fasting serum triglycerides has been shown to be 
mitigated following 6-week of dosing of DGAT2i + ACCi in participants with NAFLD while 
maintaining significant reduction in hepatic steatosis. 


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2.1. Study Rationale
The current study is an extension of a recently concluded study (C3711001) assessing 
placebo, DGAT2i alone (300 mg BID), ACCi alone (15 mg BID), and coadministration of 
DGAT2i + ACCi for a treatment duration of up to 6 weeks in participants with NAFLD.  In 
Study C3711001, a placebo-adjusted LS mean reduction in liver fat of ≥35% was observed in 
all active groups. In addition, on average, the increases in fasting serum triglyceride levels 
observed with ACCi alone were mitigated by coadministration with DGAT2i. It is 
anticipated that via coadministration of DGAT2i + ACCi, hepatic lipid metabolism will be 
modulated in distinct and complementary ways, potentially resulting in greater efficacy than 
DGAT2i administered alone. However, whether the effect on primary pharmacology can be 
maintained along with mitigation of ACCi-induced elevation in fasting serum triglycerides 
via lower doses of DGAT2i as well as QD administration of both agents remains to be tested 
and forms the purpose of the current study.  While Study C3711001 population included 
participants with NAFLD, population in the current study is proposed as presumed NASH, 
as defined by the Sponsor as participants meeting all of following via double-confirmation
between the PreQ and SCR visits:

Liver fat as assessed via quantitative ultrasound parameter CAPTM of ≥280 dB/m,
assessed using FibroScan®;

Liver stiffness as assessed via quantitative ultrasound parameter VCTETM of ≥7 kPa, 
assessed using FibroScan®;

Presence of at least 2 of the 5 concomitant medical conditions which are associated 
with NAFLD – refer to criterion # 3 in Section 5; and

ALT > ULN (and ≤5 x ULN).
In the current study, a 2-part design with sequential conduct of Part 1 and Part 2 with each 
part conducted in distinct/separate cohorts of participants is proposed. While the overall 
study design, objectives/endpoints, eligibility criteria for both parts are envisioned to remain 
identical, data from Part 1 will be used to determine whether to conduct Part 2.  Observed 
data from Part 1 will guide the selection of doses and dosing regimens (ie, QD vs BID) of 
DGAT2i + ACCi coadministration evaluated in Part 2. 
2.2. Background 
The World Health Organization lists NAFLD and NASH as the most important conditions 
contributing to the global health burden due to liver diseases, with NASH acknowledged as a 
potentially fatal condition leading to cirrhosis, liver failure, and HCC. NASH is diagnosed 
clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning 
of liver hepatocytes, often with varying degrees of fibrosis. NASH progresses with 
increasing severity of fibrosis, with cirrhosis developing in a subset of participants6 and a 
common complication of cirrhosis being HCC.7 NASH is a subset of NAFLD (defined as 
presence of ≥5% hepatic steatosis in the absence of other liver disease etiologies) that is 
associated with increased all-cause mortality, cirrhosis and end stage liver disease, increased 


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cardiovascular mortality, and increased incidence of both liver related and non-liver related 
cancers.6
In a meta-analysis, the global prevalence of NAFLD was estimated at 25%, with the 
prevalence of NASH in the subset with biopsy-proven NAFLD assessed at 59%.8 The
majority of the population with NAFLD has simple steatosis which has, in general, a benign 
clinical course. A proportion of participants with NAFLD progress to having hepatocellular 
ballooning and lobular inflammation, taking close to a decade to progress from 1 stage to the 
next and 30-40 years to develop cirrhosis; however, a smaller subset of participants progress 
very rapidly (within 10 years) to liver cirrhosis from NAFLD.8 Patients with NASH may be 
asymptomatic or have non-specific symptoms such as fatigue, despite having significant 
disease on liver biopsy and associated risk for progression to cirrhosis and liver-related 
mortality. The 5-year (67%) and 10-year (38%) survival rates in participants with NASH is 
significantly different than in those with NAFLD. The pooled liver-specific and overall 
mortality incidence rate estimates among those with NAFLD were calculated at 0.8 and 15.4, 
respectively, per 1,000 person-years. In contrast, amongst the population with NASH, the 
incidence rate estimates were 11.8 (liver-specific) and 25.6 (overall) mortality.8  
Elevated rates of hepatic DNL have been reported to be a distinctive characteristic of 
NAFLD.9 Clinically, those with elevated liver fat showed a more than 3-fold increase in the 
rate of hepatic DNL relative to participants with normal liver fat, but no differences between 
the groups were detected in adipose FFA flux or in production of VLDL from FFAs. 
Furthermore, as exemplified by other metabolic disorders (eg, type 2 diabetes, dyslipidemias, 
etc), it is possible that a single drug may be insufficient to successfully treat NASH and 
therefore, combination therapy is being investigated as an early intervention strategy.  
2.2.1. Clinical Overview
As of January 2020, safety and efficacy of DGAT2i alone or when coadministered with 
ACCi in the target patient population (ie, those with biopsy-confirmed NASH with liver 
fibrosis stage 2 or 3) has not been evaluated although clinical activity and effectiveness of 
DGAT2i alone and when coadministered with ACCi has been assessed in participants with 
NAFLD with dosing up to 6 weeks.
Across the clinical studies completed/concluded with DGAT2i alone (n=6 studies), ACCi 
alone (n=6 studies) and DGAT2i + ACCi (n=2 studies), 736 unique participants have been 
randomized, with 120 (16%) exposed to placebo, 161 (22%) exposed to DGAT2i alone, 
407 (55%) exposed to ACCi alone, 44 (6%) exposed to DGAT2i + ACCi, and 4 exposed to 
metformin alone in the DGAT2i-Metformin DDI study. DGAT2i alone has been evaluated 
as single oral doses up to 1500 mg, repeated doses up to 1800 mg/day (administered Q8H) 
for up to 14 days, and repeated doses of 600 mg/day (administered Q12H) for up to 6 weeks. 
ACCi alone has been administered at single, oral doses up to 240 mg, repeated (≤14-days) 
doses up to 200 mg/day (administered QD and Q12H), and repeated (≤16 weeks) doses up to 
50 mg/day (administered QD). DGAT2i + ACCi has been evaluated at a single 
coadministered dose level of 300 mg BID (DGAT2i) + 15 mg BID (ACCi).  


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DGAT2i alone or as DGAT2i + ACCi has been evaluated in six Phase 1 studies in healthy 
adults (with 132 participants randomized) and two studies (1 Phase 1 and 1 Phase 2a) in 
participants with NAFLD (with 148 participants randomized). ACCi alone has been 
evaluated in five Phase 1 studies in adults (with 151 participants randomized) and one 
Phase 2a, dose-ranging study in participants with NAFLD (n=305 randomized including
68% with Sponsor-defined presumed NASH). 
Administration of DGAT2i alone has been found to be well tolerated with an acceptable 
safety profile with no special safety concerns identified. Upon repeated administration of 
DGAT2i, across the 20-fold dose range evaluated (ie, 90 to 1800 mg/day), TEAEs reported 
in ≥7 (3%) participants across all groups evaluated were headache (11%), diarrhea (6%), 
fatigue (5%), pruritus (4%), abdominal pain (3%), and nausea (3%). Upon repeated 
administration of ACCi, across a 100-fold dose range evaluated (ie, 2 to 200 mg/day), the
all-causality TEAEs reported in ≥1.5% of participants were headache (9%), diarrhea (7%), 
hypertriglyceridemia (6%), and nausea (5%).
Given DGAT2i is a dose-dependent inhibitor of the transporters OCT2/MATE in kidney, as 
expected, increases in serum creatinine without a change in renal function (as assessed via 
eGFR determined using Cystatin-C) was noted. Dosing with ACCi alone resulted in
2 identified adverse drug reactions – namely, increases in fasting serum triglycerides, and 
decrease in platelet count, with reversal in 1 to 2 weeks post discontinuation of ACCi alone 
observed, refer to Section 2.3.1. Based on review of pooled TEAEs, 12-lead ECG data, 
blood pressure data, and laboratory data, coadministration of DGAT2i + ACCi has been 
shown to not result in worsening of the safety profile relative to either agent administered 
alone.  However, coadministration of DGAT2i + ACCi at the doses tested in 
Study C3711001 (300 mg BID + 15 mg BID) was shown to mitigate the ACCi-induced
elevations in fasting serum triglycerides, ApoC3, and non-HDL. There were no clinically 
significant adverse effects noted in other safety-related assessments such as blood pressure, 
and cardiac conduction intervals [assessed on 12-lead ECGs] with DGAT2i, ACCi, and 
DGAT2i + ACCi. 
Upon repeated dosing of DGAT2i with standard meals, Cmax was achieved at 1.5-3 hours 
post dose. Steady-state plasma concentrations were achieved by Day 4, and the mean 
terminal t½ ranged from 3.3-6.9 hours. Dosing in the fasted state resulted in lower exposures 
(ie, AUCinf 39% lower and Cmax 34% lower than when a 1000 mg DGAT2i dose was 
administered with a standard meal). Following oral dosing of ACCi with a 
high-fat/high-caloric meal, Cmax was achieved at 3-5 hours post-dose, and the mean terminal 
t½ ranged from 13-18 hours. There was no clinically relevant effect on exposure with dosing 
of ACCi in the fasted versus fed state. Coadministration of DGAT2i (300 mg BID) and 
ACCi (15 mg BID) resulted in a slight decrease in the systemic exposure of ACCi with 
adjusted geometric mean (90% CI) of 12% (2-20%) lower (for Cmax) and 19% (12-26%) 
lower (for AUCtau). There was no marked effect on the systemic exposure of DGAT2i, when 
coadministered with ACCi, with adjusted geometric mean 8% higher (for Cmax and AUCtau). 


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2.2.2. Nonclinical Overview 
DGAT2i and ACCi have each individually been evaluated in a comprehensive nonclinical 
safety package that included rat and cynomolgus monkey toxicity studies up to 6 and 
9 months duration, respectively, and in reproductive and developmental toxicology studies in 
rats and rabbits, and together (ie, DGAT2i + ACCi) in combination toxicity studies in 
monkeys up to 13 weeks in duration.  
For DGAT2i alone, no adverse findings were identified in rats or cynomolgus monkeys. At 
the NOAEL in the 9-month study in cynomolgus monkeys, exposure margins relative to a 
highest clinical dose of 300 mg BID were 4.6x and 7.3x the unbound human Cmax and 
AUC24, respectively. At the NOAEL in the 6-month study in rats, exposure margins were 
1.6/6.8x (male/female) and 1.8/7.7x (male/female) the unbound human Cmax and AUC24, 
respectively. 
For ACCi alone, all adverse findings were related to the inhibition of fatty acid biosynthesis,
due to the pharmacology of ACCi, and were observed as changes in the lung, skin, 
nonglandular stomach, or Meibomian glands. At the NOAEL in the 9-month study in 
cynomolgus monkeys, exposure margins relative to the highest clinical dose of 20 mg/day
(with most conservative QD dosing and margins for Cmax) were 110x and 51x, the predicted 
human unbound Cmax and AUC24, respectively, and at the NOAEL in the 6-month study in 
rats exposure margins were 65x and 18x the predicted unbound human Cmax and AUC24, 
respectively.  
DGAT2i + ACCi were evaluated in cynomolgus monkey toxicity studies up to 13 weeks 
duration. All findings were attributed to ACCi and no new adverse findings were identified 
in monkeys administered DGAT2i + ACCi. Exposure margins in the 13-week study in 
cynomolgus monkeys relative to a DGAT2i clinical dose of 300 mg BID were 2.9x and 4.5x, 
the predicted human unbound Cmax and AUC24, respectively, and exposure margins relative 
to a ACCi clinical dose of 20 mg/day (with most conservative QD dosing and margins for 
Cmax) were 141x and 49x the predicted unbound human Cmax and AUC24, respectively.
For review of EFD findings in studies completed with DGAT2i and separately with ACCi 
alone, refer to Section 2.3.1.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of DGAT2i alone, DGAT2i + ACCi, and ACCi alone may be found in the IB 
for DGAT2i and separately for ACCi, which will serve as the 2 SRSDs for this study.
A high level summary of potential risks as well as benefits are offered in Section 2.3.1 and
Section 2.3.2. 


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2.3.1. Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention – DGAT2i (as part of DGAT2i + ACCi)
Drug-drug interactions 
resulting in change in 
DGAT2i exposure.
In vitro data indicate DGAT2i 
having low hepatic clearance and 
multi-pathway metabolism with:

CYP3A – major (fm 0.68);

CYP2B6 – minor (fm 0.16);

CYP2C19 – minor (fm 0.16).
Study excludes participant on potent 
inhibitors or inducers of CYP3A – refer 
to Section 6.5.
Study Intervention – DGAT2i (as part of DGAT2i + ACCi)
Drug-drug interactions 
resulting in change in 
exposure of 
background/concomitant 
medications.
Clinical data indicate that DGAT2i at 
300 mg BID can increase plasma 
metformin exposure by 2-fold.
Starting at Run-In (ie, approximately
4 weeks before randomization), 
participants on metformin dose 
>1 gm/day must agree to metformin dose
decreased by 1/3 or 1/2 with up-titration 
post randomization based on FPG results 
– refer to Section 6.5.1 and
Appendix 10.9.
In vitro data indicate DGAT2i at 
300 mg BID to be a: 

Potent BCRP inhibitor;

Inhibitor of P-gp;

Inhibitor of CYP2C9.
Use of specific medications that are 
substrates for BCRP, P-gp and/or 
CYP2C9 will be excluded (or restricted) 
– refer to Section 6.5.
Food effect resulting in 
change in DGAT2i 
exposure.
Clinical data indicate that DGAT2i 
exposures are lower in fasted state 
than in fed state.
Investigational products will be taken 
with a meal.
Fetal skeletal variations 
as a result of transient 
developmental delay.

In embryo-fetal development 
toxicity study in rats, lower fetal 
body weight and skeletal 
anomalies observed at all doses 
with NOAEL for this 
developmental toxicity not 
identified.

In embryo-fetal development 
toxicity study in rabbits, no 
developmental toxicity observed.

Risk of fetal toxicity communicated 
through the DGAT2i IB (Jan-2020).

Enrollment of women of childbearing 
potential restricted to those using 
effective contraception – refer to 
Section 5.4.1 and Appendix 10.4.

In males who are sexually active with 
a female partner of childbearing 
potential, use of barrier methods not
required/mandated given safety 
margins >100-fold – refer to 
Section 5.4.1 and Appendix 10.4.
Study Intervention – ACCi (as part of DGAT2i + ACCi)
Increase in serum 
triglycerides.
Identified adverse reaction with 
inhibition of hepatic ACC; 
observed upon repeated dosing of 
ACCi alone in healthy 
participants and in those with
NAFLD/presumed NASH.
Magnitude of elevation in 

Administration of ACCi alone not 
planned.

Study requires fasting serum
triglyceride ≤400 mg/dL 
(4.5 mmol/L) at multiple timepoints 
prior to randomization.

Given that elevations occurred early 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
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NAFLD/presumed NASH 
observed to be approximately 
2-fold higher than in healthy 
participants – based on 
exposure: response population 
PK.
post initiation of dosing, visits post 
randomization, initially, scheduled to 
be every 2 weeks.

Management of isolated and double-
confirmed elevations in fasting serum 
triglycerides planned – refer to 
Appendix 10.10.

Reversal in fasting serum 
triglycerides expected (and observed) 
upon discontinuation of ACCi.
Decrease in platelet 
count.
Identified adverse reaction with 
ACCi; observed upon repeated 
dosing of ACCi alone in healthy 
participants and those with 
NAFLD/presumed NASH.

Study requires platelet count to be 
≥LLN at multiple timepoints prior to 
randomization.

Management of isolated and double-
confirmed declines in platelet count 
planned – refer to Appendix 10.11.

Reversal in platelet count expected 
(and observed) upon discontinuation 
of ACCi.
Drug-drug interactions 
resulting in change in 
ACCi exposure.
In vitro data indicate ACCi cleared 
via OATP-mediated hepatic uptake 
and metabolism (predominantly 
via 3A4). 
Study excludes participant on potent 
inhibitors of OATP and potent inhibitors 
and inducers of CYP3A4 – refer to
Section 6.5.
Fetal external 
malformation and 
skeletal variations and 
malformations.
In EFD study in rats, ACCi at 
highest dose, resulted in higher 
incidence of fetal skeletal 
variations (ie, structural changes 
to ribs, skull, sternebrae and 
vertebrae) plus delay in 
ossification of skull and 
sternebrae.
In EFD study in rabbits, ACCi at 
highest dose produced fetal 
skeletal malformations including 
absent skull bones, malformed 
ribs, and malformed vertebrae; 
ACCi delayed ossification of 
thoracic vertebrae and produced 
variations in development of 
skull, ribs, and vertebrae.

Risk of fetal toxicity communicated 
through the ACCi IB (Dec-2019).

Enrollment of women of childbearing 
potential restricted to those using 
effective contraception – refer to 
Section 5.4.1 and Appendix 10.4.

As a measure of caution, serum 
pregnancy testing to be 
undertaken in all females.

In males who are sexually active with 
a female partner of childbearing 
potential, use of barrier methods not
required/mandated given safety 
margins >100-fold – refer to 
Section 5.4.1 and Appendix 10.4.
Study Procedures
Conduct of different 
imaging assessments of 
liver fat during study 
(ie, quantitative 
ultrasound-based 
FibroScan® and Acuson 
Sequoia® as well as 
Procedures are relatively safe; 
potential risk for non-evaluable 
images include: 

Too much motion, for example, 
due to increased anxiety, 
claustrophobia.

Ferric implants/devices, 

Permitting pre-procedure use of 
anxiolytics to manage anxiety (in 
case of MRI-PDFF).

Excluding participants if they have 
contraindications for MRI, or 
quantitative ultrasound based 
assessments (FibroScan® and 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
MRI-PDFF).
paramagnetic objects within/on 
body, ferric-containing tattoos in 
area of interest (abdomen, chest, 
arms).

Minimum duration of a priori 
fast not followed.
Acuson Sequoia®).

Clear communication via ICD of 
preparation for each visit including
duration of fast before 
procedures/visits.
Other Factors Potentially Impacting Study Results
Distinction of 
drug-induced liver 
injury from 
disease-related baseline 
elevations in LFTs.
Population eligible likely to have 
elevated ALT and AST (though not 
Alkaline phosphatase, total 
bilirubin).

Study requires double-confirmation of 
stable ALT, AST, alkaline 
phosphatase (ie, ≤50% variability10)
plus total bilirubin ≤ULN before
proceeding with screening/ baseline.
Coadministration of DGAT2i + ACCi, based on completed toxicity studies in rats and 
monkeys, as well as completed clinical studies, does not afford any additional adverse 
findings above and beyond those identified with administration of ACCi alone.  Thus, in the 
current study, any adverse clinical impact of the above findings are expected to be minimized 
through: (1) the proposed frequent visits to site to permit close oversight of participants’ 
safety via medical monitoring of a range of clinical assessments including safety-related 
laboratory tests, 12-lead ECGs, vitals, assessment of AEs; (2) inclusion of provisions for
management of glycemic control (refer to Appendix 10.9) and the 2 identified adverse 
reactions ie, increases in fasting serum triglycerides (refer to Appendix 10.10) and reduction 
in platelet count (refer to Appendix 10.11); and (3) institution of an independent, IRC (refer 
to Section 9.5) to undertake unblinded review of the safety data while the study is on-going.
2.3.2. Benefit Assessment
For the participants in this study, close monitoring of their medical condition and safety will 
occur as outlined in this protocol. In Part 1, 4 out every 5 participants randomized will 
receive DGAT2i + ACCi and therefore, may potentially derive short-term benefit from the 
primary pharmacology, namely, reduction in hepatic steatosis. Those randomized to placebo 
(1 in every 5 participants) are not expected to obtain any specific benefit, beyond close 
monitoring of their medical condition and overall close follow-up of their safety. All 
participants will receive general, standard-of-care guidance/counseling regarding the overall 
benefits of diet/exercise. In Part 2, if conducted, similar benefits are likely inferred to 
participants who will be randomized.
2.3.3. Overall Benefit/Risk Conclusion
Additional details about the known and expected benefits and risks and reasonably expected 
adverse events with administration of DGAT2i alone, DGAT2i + ACCi, and ACCi alone 
may be found in the IB for DGAT2i and separately for ACCi, which serve as the 2 SRSDs 
for this study. Considering all available clinical and nonclinical data, the benefit:risk profile 
of DGAT2i and DGAT2i+ACCi supports continued clinical development as outlined in this 
protocol.


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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
The planned identical objectives, estimands, and endpoints for Part 1 and optional Part 2 of 
this study are summarized below.
Objectives
Estimands
Endpoints
Primary: 
To evaluate effect on liver fat, 
determined by MRI-PDFF, of a range 
of DGAT2i doses coadministered with 
a fixed dose of ACCi compared to 
placebo in participants with presumed 
NASH.
Estimand 1: 
This estimand is intended to provide
a population level estimate of the 
mean treatment effect (DGAT2i + 
ACCi relative to placebo) on a 
continuous endpoint at Week 6 for 
all randomized/evaluable participants
(see details in Section 9.1.1).
Percent change from 
baseline in liver fat as 
assessed via MRI-PDFF, at 
Week 6. 
Secondary: 
To evaluate effect on fasting serum 
triglyceride levels of a range of 
DGAT2i doses coadministered with a 
fixed dose of ACCi compared to 
placebo in participants with presumed 
NASH.
Estimand 2: 
This estimand is intended to provide 
a population level estimate of the 
mean treatment effect (DGAT2i + 
ACCi relative to placebo) on a 
continuous endpoint, over time for 
all randomized/evaluable participants 
(see details in Section 9.1.1).
Percent change from 
baseline in fasting serum 
triglyceride levels over time. 
To assess safety and tolerability with 
a range of DGAT2i doses 
coadministered with fixed dose of 
ACCi compared to placebo in 
participants with presumed NASH. 
No estimand is defined for safety and 
tolerability endpoints.  
Proportion of participants 
with treatment-emergent 
adverse events (TEAEs) and 
clinically significant, 
abnormal clinical laboratory 
tests, vital signs, and 12-lead 
ECGs.
Tertiary/Exploratory: 
To evaluate effect on liver fat
determined by quantitative ultrasound 
(FibroScan®) of a range of DGAT2i 
doses coadministered with fixed dose 
of ACCi, compared to placebo in 
participants with presumed NASH. 
This endpoint will be analyzed using 
Estimand 1. 
Percent change from 
baseline in liver fat at 
Week 6, as assessed by 
CAP™via FibroScan®.
To evaluate effect on liver fat
determined by quantitative ultrasound 
(Acuson Sequoia®) of a range of 
DGAT2i doses coadministered with 
fixed dose of ACCi, compared to 
placebo in participants with presumed 
NASH.
This endpoint will be analyzed using 
Estimand 1. 
Percent change from 
baseline in liver fat at 
Week 6, as assessed by 
UDFF™via Acuson 
Sequoia®.
For all endpoints, baseline is defined as the evaluable result closest but prior to dosing on Day 1.
Additional tertiary/exploratory objectives and endpoints are listed in Section 9.


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4. STUDY DESIGN
4.1. Overall Design
This is a multicenter, 2-part, sequentially conducted, randomized, double-blind, 
double-dummy, placebo-controlled, parallel-group evaluation of DGAT2i + ACCi as 
summarized in Figure 1.
Figure 1.
Overall Study Design
4.1.1. Part 1
Study interventions planned are summarized in Table 3. 
Table 3.
Planned Dosing Groups in Part 1 of Study C3711005
Group
DGAT2i Dose
ACCi Dose
DGAT2i:ACCi Ratio
A
0 (placebo) BID
0 (placebo) BID
0: 0
B
25 mg BID
10 mg BID
2.5: 1
C
100 mg BID
10 mg BID 
10: 1
D
300 mg QD*
20 mg QD*
15: 1 
E
300 mg BID
10 mg BID 
30: 1
* In order to maintain double-blind, double-dummy design across all groups, this group will receive placebo 
as their evening dose.
Dosing in all groups will be accommodated via administration of 3 tablets per dose, and 
6 tablets per day. The use of blister packed supplies is planned to minimize dosing errors and 
to enhance compliance, refer to Table 4 in Section 6.1 for details.
Determination of eligibility will occur via a sequential, 2-step process starting with 
Prequalification visit (PreQ). Participants identified to be eligible at PreQ will transition to 
the main study, starting with Screening (SCR) visit. The double-confirmation (at PreQ and 
SCR) will permit progression of only a selected subset of participants confirmed to meet 
Sponsor-defined presumed NASH criteria (along with other eligibility criteria) to the 


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Run-In/Visit 2. At the Run-In/Visit 2, stabilization of concomitant medicines may occur, as
needed/appropriate (refer to Section 6.5). All eligible participants must complete the 
Run-In/Visit 2, followed by Baseline/Visit 3. On Day 1/Visit 4, participants who meet the 
randomization criteria (Section 5.3) will be assigned to receive 1 of 5 double-blind, 
double-dummy regimens (refer to Table 3) for a duration of up to 6 weeks, refer to Figure 2. 
Figure 2.
Study Design for Part 1 and Optional Part 2
Pre-Qualification (PreQ)
Run-In
(Stabilize Background Meds)
[+ ↓ Metformin dose if > 1gm/day]
Baseline 
[Single-Blind Placebo (BID)]
Randomization / Day 1
F/U #1
F/U #2
Week 2
14±2 days
Screen (SCR) 
Week 4
Week 6
Screening Phase 
Treatment Phase 
6- to 10- weeks
Follow-up
10-weeks
At least 4-weeks
Visit Window
±2 days
30±2 days post last dose
14±2 days post last dose
Double-confirmation of –
Presumed NASH
CAP ≥ 280 dB/m
On-site visit (blood draw + safety)
MRI-PDFF (to assess quantitative liver fat)
FibroScan® (quantitative ultrasound to assess 
liver fat [via CAP] and liver stiffness [via VCTE])
Acuson Sequoia® (quantitative ultrasound to assess 
liver fat [via UDFF] and liver stiffness [via SWE])
Telephone contact 
Approximately 90 participants (18 per group) with Sponsor-defined presumed NASH will be 
randomly assigned to the study intervention to ensure approximately 75 evaluable 
participants (15 per group) offer evaluable data.  
4.1.2. Optional Part 2
Part 2 may be initiated after unblinded review of the data from Part 1 by selected members of 
the Sponsors’ study team (the investigators/site staff as well as site-facing study team 
members will remain blinded), refer to Section 9.5. This interim analysis will include review 
of primary endpoint data (effect on hepatic steatosis as assessed via MRI-PDFF) as well as 
overall safety/tolerability including degree of mitigation of ACCi-induced effect on fasting 
serum triglycerides achieved across the range of DGAT2i:ACCi dose ratios evaluated. 
Guided by these data, Part 2 may enroll up to 5 dose groups (including placebo) with intent 
to evaluate additional permutations of doses of both DGAT2i and ACCi administered BID or
QD. However, the doses of DGAT2i in Part 2 will not exceed 300 mg BID or 300 mg QD
and the dose(s) of ACCi will not exceed 20 mg/day (administered BID or QD to mirror 
dosing of DGAT2i). A maximum of 4 active doses (plus placebo) will be evaluated in 
Part 2; furthermore, the total number of participants will not exceed 90 (with no more than 
approximately 27 participants per each active dose). 


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Following aspects are envisioned to remain identical between Part 1 and optional Part 2: 

Eligibility (refer to Section 5.1 and Section 5.2) and randomization (refer to
Section 5.3) criteria;

Schedule of activities including assessment of standard safety/tolerability (via vitals, 
12-lead ECG, laboratory tests), refer to SoA – Table 1 and SoA - Table 2; 

Overall study design including duration of dosing, refer to Figure 2.
In order to enable accumulation of safety experience in the clinical program, minimize 
potential carry over effect, as well as control selection bias, participants randomized and 
dosed double-blind, double-dummy study intervention in Part 1 of this study are not eligible 
for Part 2.
4.2. Scientific Rationale for Study Design
Reduction in hepatic steatosis with DGAT2i alone, ACCi alone, and DGAT2i + ACCi have 
been shown in participants with NAFLD with dosing of the intervention for as little as 
2 weeks (DGAT2i alone), 6 weeks (DGAT2i alone plus DGAT2i + ACCi), and up to 
16 weeks (with ACCi alone). The current study is an extension of a recently concluded study 
(C3711001) assessing placebo, DGAT2i alone (300 mg BID), ACCi alone (15 mg BID), and 
coadministration of DGAT2i + ACCi, for a treatment duration of 6 weeks in participants
with NAFLD. The current study is designed to find the lowest dose of DGAT2i which will 
mitigate ACCi-induced elevations in fasting serum triglyceride, while maintaining 
effectiveness (as assessed via reduction in hepatic steatosis). Data from Part 1 will dictate 
conduct of, the doses, and the dosing regimens (ie, QD vs BID) of DGAT2i + ACCi, 
potentially evaluated in Part 2. 
In this study, 2 separate informed consents will be obtained: the first consent is limited to 
PreQ visit activities only; and the second consent is for the main study only (from Screening 
through participant completion/Early Termination) in those deemed to meet eligibility 
criteria based on non-invasive procedures completed at PreQ. Between the PreQ and SCR 
visits, many of the non-invasive procedures and clinical laboratory tests assessed are 
identical. This is motivated by the intent to confirm that the population progressed to 
Run-In/Visit 2 is consistently characterized as Sponsor-defined presumed NASH. As a 
measure of additional diligence and as an attempt to remove variability due to laboratory-to-
laboratory differences, the clinical laboratory tests assessed at PreQ and SCR are proposed to 
be analyzed by the Sponsor-identified central laboratory. The assessments to narrow the 
population ultimately progressed to Run-In/Visit 2 consist of double-confirmation between
assessment at PreQ and SCR of: (a) blood-based markers of liver function (ie, ALT, AST, 
alkaline phosphatase, total bilirubin) and ensuring participants have stable results (defined by 
≤50% variability in ALT/AST/alkaline phosphatase10 plus total bilirubin ≤ULN, unless 
Gilbert’s syndrome); and (b) a constellation of clinical and liver imaging characteristics 
which are highly suggestive of a NASH diagnosis (in the absence of a liver biopsy) referred 
to as Sponsor-defined presumed NASH.


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ACCi alone is not planned for evaluation in this study given the previously described 
undesirable changes in fasting serum triglycerides encountered with liver-targeted ACC
inhibitors and their potential implications for long term cardiometabolic health. 
In this study, based on a combination of thorough medical history (including assessment of 
ethanol intake and administration of the interview-version of the AUDIT-10 -item 
questionnaire11), and clinical laboratory tests (ie, %CDT), medically qualified site-staff will 
be required to rule out alcohol based as well as and/or other causes of hepatic 
steatosis/inflammation/fibrosis12, and ensure that the population enrolled is confirmed, as 
best as possible, to have Sponsor-defined presumed NASH. These assessments (AUDIT and 
%CDT) will be re-assessed prior to randomization and at end of dosing to confirm that while 
in the study alcohol intake remained in moderation. Participants with previously confirmed 
genetic polymorphisms, for example, PNPLA3 carriers, are eligible given that these 
polymorphisms are known to modify/increase risk for steatohepatitis but do not by 
themselves cause steatohepatitis.
An explicit intent in this study is to exclude those with severe hepatic impairment
(eg., ascites, hepatic encephalopathy, cirrhosis, and HCC) and severe renal impairment 
(ie, eGFR using CKD-EPI-Cystatin-C13 ≤30 mL/min) via specific eligibility criteria (refer to
Section 5.1 and Section 5.2). This is in line with the clinical data to date showing ≤3-fold 
increase in plasma exposure in severe hepatic impairment as defined by Child-Pugh 
classification for ACCi and preliminary, partial PK data from 2 (of planned 6) participants 
with mild, 3 (of planned 6) participants with moderate plus 5 (of planned 6) participants with 
severe hepatic impairment in the on-going Phase 1 Study (C2541009) with DGAT2i in 
participants with varying degrees of hepatic impairment compared to historical data in 
healthy participants in Study C2541001; as well as renal elimination confirmed to represent 
<2% of unchanged drug for both DGAT2i and ACCi. The major clearance mechanism for 
DGAT2i and ACCi is predicted to be multi-pathway. Thus, the inclusion/exclusion criteria 
have been defined to help limit pharmacokinetic variability while also capturing a population 
that is characteristic of the intended target population. Plasma samples (both pre- and 
post-dose) to permit population-pharmacokinetic analysis will be collected to further 
examine the effect of demographics on pharmacokinetic variability and to explore the 
relationship of PK to PD endpoints. 
The current study also undertakes assessment for potential improvement of safety-related, 
metabolic markers and selected biomarkers. The parameters include markers of liver
function tests (ALT, AST, Alkaline phosphatase, GGT, total bilirubin), NASH-related 
biomarkers14 (CK18-M30 and CK18-M65, markers of apoptotic activity; ProC3, a marker of 
fibrinogenesis; ProC6, a marker of fibrinolysis), glycemic parameters (HbA1C, FPG, FPI, 
HOMA-IR, adiponectin), and fasting lipid parameters/markers of target engagement (total 
cholesterol, triglycerides, direct LDL-C, HDL-C, direct VLDL, apolipoprotein A1, Btotal, 
B100, B48, C3, and E plus PCSK9, hs-CRP). In addition, banking of plasma (Prep B1.5) and 
serum (Prep B2.5) collections are planned to enable retrospective analysis of (yet to be 
identified) sensitive/specific biomarkers of disease diagnosis, and/or treatment effect. 


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For the assessment of liver fat (via MRI-PDFF, CAP™using FibroScan®, and UDFF™via 
Acuson Sequoia®) and liver stiffness (via VCTE™using FibroScan®, and SWE™via Acuson 
Sequoia®), participants will be required to fast (water permitted) for ≥4 hours given the 
ability of food to potentially impact these results. As an additional measure to limit 
variability, attempts will be made to standardize the nominal time of these assessments. The 
clock time of day when these assessments are made should fall within a practical window 
(±2 hours) relative to clock time at the time of 1st assessment in this study (ie, PreQ for 
FibroScan®; Baseline for MRI-PDFF and Acuson Sequoia®).
In this study, while exploratory comparison of observed effect on liver fat is planned, 
comparing MRI-PDFF, CAP™using FibroScan®, and UDFF™via Acuson Sequoia®, a 
comparison of treatment effect on liver stiffness (via VCTE™using FibroScan®, and SWE™
via Acuson Sequoia®), is not planned especially considering the short duration of dosing 
(ie, 6 weeks). However, 1 of the exploratory objectives included in this study (refer to 
Table 5) is comparison of the performance of the two quantitative ultrasound technologies 
(FibroScan® and Acuson Sequoia®) in their ability to assess liver stiffness (via VCTE™and 
SWE™), respectively.
In this study, measures to ensure participant safety include: (a) frequent (every 2 weeks),
outpatient visits up to Week 6/Visit 7, with provisions for unplanned visits for follow-up of 
AEs; (b) off study intervention observation via an on-site follow-up visit 14±2 days post-last 
dose and a telephone contact ≥28 and ≤32 days post-last dose; (c) as much as practically 
doable, the use of same-day shipment of safety-related blood/urine samples to 
Sponsor-identified central laboratory with rapid turn-around of safety-related results; 
(d) standardized management of metformin dose as well as overall glycemic control in those 
with T2DM ± managed via metformin (Appendix 10.9); (e) standardization of blinded
management of the two identified adverse drug reactions with administration of 
ACCi - namely increases in fasting serum triglycerides (refer to Appendix 10.10) and 
reductions in platelet count (refer to Appendix 10.11); (f) establishment of IRC (refer to 
Section 9.5 to undertake unblinded review of safety data while the study is on-going; and 
(g) monthly blinded review of safety by the Sponsor’s clinical team members to assess for 
potential trigger for additional unblinded review(s) of cumulating safety data while the study 
is on-going. 
Plasma exposure of ACCi following a high fat/high caloric breakfast was similar relative to 
administration of ACCi following an overnight fast; however, plasma exposure of DGAT2i 
is reduced by 39% (AUCinf) and 35% (Cmax) when administered following an overnight fast 
versus with standard meal. Therefore, administration of the study interventions in this study 
will be requested to occur with the morning (and evening) meals – given the importance of 
regular meals to the standard of care diet counselling for the planned population.
For all participants deemed eligible after SCR visit, transition to Run-In/Visit 2 is 
mandatory for stabilizing background medications (including simply compliance) and 
accompanying monitoring parameters in order to minimize placebo response post 
randomization. In addition, a fixed, single-blind, 2 week baseline period from


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Baseline/Visit 3 to one day prior to Day 1/Visit 4 is included in this study with the explicit 
purpose of familiarizing the participants with the dosing instructions for the study 
intervention (refer to SoA -Table 1), and to exclude participants who are not compliant with 
the single-blind placebo prior to randomization in an attempt to minimize medications errors 
post randomization.
4.2.1. Participants of Child-bearing Potential
Human reproductive safety data are not available for DGAT2i + ACCi. 
In the completed, nonclinical embryo-fetal developmental studies with DGAT2i alone and 
ACCi alone (and hence DGAT2i + ACCi in this study) findings have been noted, refer to 
Section 2.3.1. Therefore, the use of a highly effective method of contraception is required
by females of childbearing potential, refer to Section 5.4.1 and Appendix 10.4 for additional 
details.
The potential risk of exposure, via ejaculate, to DGAT2i + ACCi in a female sexual partner 
of childbearing potential of a male participant in this study is low. As such, use of barrier 
methods of contraception is not required/mandated in the male participants. The calculated 
safety margin is >100-fold between the estimated partner exposure due to seminal transfer 
and the NOAEL for serious manifestations of 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
4.2.2. Rationale for Banked Biospecimen Collections
Banked Biospecimens will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. Comparing the DNA,
RNA, protein, and metabolite variation patterns of participants who respond well and those 
who respond poorly to treatment may help to better define the most appropriate group of 
participants in which to target a given treatment. Collecting biospecimens for exploratory 
pharmacogenomic/genomic/biomarker analyses and retaining them in the BBS make it 
possible to better understand the investigational product’s mechanism of action and to seek 
explanations for differences in, for example, exposure, tolerability, safety, and/or efficacy not 
anticipated prior to the beginning of the study. Banked biospecimens retained in the BBS 
also can be used in research for NAFLD/NASH. Refer to Section 8.8.1 for additional details. 
Providing these biospecimens is a required study activity for study sites and participants, 
unless prohibited by local regulations or EC decision.


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4.3. Justification for Dose
4.3.1. Part 1 
In Part 1, a range of doses of DGAT2i will be coadministered with fixed dose of ACCi 
(20 mg/day). Doses selected (refer to Table 3) were based on the observed effect on liver fat 
following 2 weeks of dosing with DGAT2i in Study C2541005, 6 weeks of dosing of 
DGAT2i alone, ACCi alone, and coadministration in Study C3711001, as well as 16 weeks 
of dosing with ACCi alone in Study C1171002.
In Study C3711001, administration of DGAT2i 300 mg BID and ACCi 15 mg BID alone and 
when coadministered over 6 weeks in participants with NAFLD, a placebo-adjusted LS mean 
reduction in liver fat of ≥35% was observed in all groups. In addition, on average, fasting 
serum triglyceride increases observed with ACCi alone were mitigated by coadministration 
with DGAT2i.  In the current study, coadministration of DGAT2i + ACCi (at a ratio of 20:1) 
was selected as the highest dose; it contains the same DGAT2i dose assessed in 
Study C3711001 (DGAT2i 300 mg BID + ACCi 15 mg BID; at a ratio of 30:1) though a 
slightly lower ACCi dose (10 mg BID) is proposed in the current study acknowledging that 
while mitigation of ACCi-induced effect on fasting serum triglycerides with coadministration 
of DGAT2i was seen, this response had an upper 90% CI of an increase of 28% in 
placebo-adjusted change from baseline for DGAT2i + ACCi, in Study C3711001. 
The lower doses of 50 mg/day and 200 mg/day of DGAT2i, administered BID
(ie, 25 mg BID and 100 mg BID), in this study are proposed in order to assess the 
dose-response for mitigation of ACCi-induced elevations in fasting serum triglycerides, as 
well as to assess the effect of these coadministered doses on liver steatosis.  Given that 
DGAT2i decreases PCSK9 with an ED50 of 7 mg BID and that PCSK9 is a marker of SREBP 
activity (mechanism postulated to be responsible for the DGAT2i-mediated mitigation of 
ACCi-induced elevations in fasting serum triglycerides), it is possible that doses significantly 
lower than 300 mg BID may mitigate ACCi-mediated lipid changes.  Spacing of the DGAT2i 
doses by 3-4 fold allow for covering a 12-fold range of DGAT2i doses (ie, 50 to 600, 
mg/day).
In addition to a range of BID doses, a QD group is included where 300 mg DGAT2i will be 
coadministered with 20 mg ACCi.  As 300 mg dose of DGAT2i represents the highest 
currently feasible QD dose, the purpose of this group is to assess the effect of a QD dosing 
regimen on hepatic steatosis as well as the potential to evaluate whether DGAT2i dose to 
mitigate ACCi-mediated elevations in fasting serum triglycerides can be administered QD.  
Depending on the observed profile with this QD dosing regimen in Part 1, additional dose 
ranging with QD doses may be considered in Part 2 of this study.
The DGAT2i and ACCi doses selected have been demonstrated to be safe and well-tolerated 
in previous clinical studies and are supported by the safety margins from the nonclinical, 
chronic toxicity studies completed in rats and monkeys for each of the agents alone and up to 
13-week combination toxicity studies completed in monkeys. In the current study, the 
highest DGAT2i dose (300 mg BID) and ACCi dose (10 mg BID) proposed are 3 times (for 
DGAT2i) and 10 times (for ACCi) lower than the highest repeated dose evaluated for each


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agent in previous clinical studies (refer to Section 2.2.1) as well as afford adequate safety
margins compared to completed nonclinical chronic toxicity studies (refer to Section 2.2.2).
The overall selection of doses of DGAT2i and ACCi were also influenced by the aim to 
evaluate the study objectives using the tablet strengths available (ie, 25, 50, and 150 mg for 
DGAT2i; 10 mg and 20 mg for ACCi) as efficiently as possible. As proposed, the 
dose-range planned in Part 1 will necessitate each participant to self-administer 
3 tablets/dose, twice daily, in order to maintain the double-blind, double-dummy design of 
the study. To aid compliance by the participants, study intervention will be packaged and 
dispensed as blister cards (not bottles) with each card permitting 7 days of dosing, refer to
Section 6.1. 
4.3.2. Optional Part 2
The planned dose range for DGAT2i + ACCi (both BID and QD) in Part 1 are envisioned to 
permit selection of dose(s) to be evaluated in Part 2.
Based on observed data in Part 1 (refer to Section 9.5), doses and/or dosing regimen selected 
in Part 2 will be in accordance with the following considerations: 

Total daily doses of DGAT2i, administered QD, will range from 25 mg (lowest) to 
300 mg (highest);

Total daily doses of DGAT2i, administered BID, will range from 50 mg (lowest) to 
600 mg (highest);

With DGAT2i doses projected to be sufficiently separated based on plasma exposure;

Coadministered with ACCi dose of 10 mg/day or 20 mg/day with frequency 
mirroring DGAT2i dosing regimen – BID or QD;

DGAT2i + ACCi dose(s) evaluated in Part 1 may be repeated to permit better 
characterization of effectiveness of DGAT2i to mitigate ACCi-induced elevation in 
fasting serum triglycerides;

And each dose will be limited to ≤4 tablets (ie, up to 8 tablets per day) with drug 
packaged and dispensed as blister cards (not bottles) with each card permitting 7 days 
of dosing.
While data from Part 1 (via an interim analysis) will be used to guide dose groups evaluated 
in Part 2, data for any dose groups repeated in Part 1 and Part 2 (at a minimum placebo), will 
be pooled for purposes of reporting in the clinical study report. 
4.4. End of Study Definition
End of the study is defined as the date of conduct of the very last 2nd Follow-up visit in a 
participant randomized into this trial, globally. 


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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 or female participants between the ages of 18 and 75 years, inclusive, at PreQ 
and SCR.

Refer to Appendix 10.4 for reproductive criteria for male (Appendix 10.4.1) and 
female (Appendix 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. At PreQ and SCR, meet the following criteria, based on assessment via FibroScan®, 
with a single repeat permitted, on a separate day, to assess eligibility, if needed, at 
each of these 2 visits: 

CAP™≥280 dB/m;

VCTE™≥7.0 kPa.
3. At PreQ and SCR, meet ≥2 of the following criteria [for laboratory parameters, 
results must be as assessed by the Sponsor-identified central laboratory, with a single 
repeat permitted to assess eligibility, if needed, at each of these 2 visits]:

Fasting Plasma Glucose (FPG) ≥100 mg/dL (5.6 mmol/L), or on pharmacological 
agents with explicit purpose of improving glycemic control (refer to Section 6.5.1
for acceptable versus prohibited medications);

Fasting serum HDL-C <40 mg/dL (1 mmol/L) for males and <50 mg/dL 
(1.3 mmol/L) for females, or on pharmacological agents with explicit purpose to 
increase HDL-C (refer to Section 6.5.2 for acceptable versus prohibited 
medications);


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
Fasting serum triglyceride ≥150 mg/dL (1.7 mmol/L), or on pharmacological 
agents with explicit purpose to decrease serum triglycerides (refer to Section 6.5.2
for acceptable versus prohibited medications);

Seated blood pressure (BP) ≥130 / 85 mm Hg, or on pharmacological agents with 
explicit purpose for BP control (refer to Section 6.5.3 for acceptable versus 
prohibited medications);

Waist circumference ≥40 inches (102 cm) for males and ≥35 inches (89 cm) for 
females.
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 ≥25 kg/m2 with upper limit of 40 kg/m2 (inclusive) at PreQ and SCR with a 
single repeat assessment of body weight and/or BMI permitted on a different day to 
assess eligibility, if needed, at each of these 2 visits.
6. Body weight must be stable (not vary by ≥5% for at least 12 weeks before SCR), as 
reported by the participant.
Informed Consent:
7. Participants are capable of giving signed informed consent as described in
Appendix 10.1 which includes compliance with the requirements and restrictions 
listed in the ICDs and in this protocol at PreQ and SCR.

For participants who qualify based on PreQ procedures, at SCR, evidence of a 
separate personally signed and dated informed consent document indicating that 
the participant has been informed of all pertinent aspects of the main study, is 
required.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Current significant alcohol consumption at PreQ and SCR defined as any one of 
these parameters – with a single repeat assessment of laboratory-related parameters 
permitted using the Sponsor-identified central laboratory, to assess eligibility, if 
needed, at each of these 2 visits: 


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
>14 drinks/week (men) and >7 drinks/week (women) where 1 drink = 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard 
liquor;

% CDT (carbohydrate deficient transferrin) ≥1.5x ULN;  

Total score of ≥8 on the AUDIT questionnaire.
2. Evidence of other causes of liver disease at PreQ or SCR, with a single repeat 
assessment of laboratory-related parameters permitted using the Sponsor-identified 
central laboratory, to assess eligibility, if needed, at each of these 2 visits – including: 

Alcoholic steatohepatitis;

Compensated and decompensated cirrhosis;

Active viral hepatitis B – defined by presence of HBsAg;

Active viral hepatitis C – defined as presence of HCVAb;

HIV infection defined as presence of HIV antibody;

Hepatocellular carcinoma or other types of liver cancer;  

Wilson’s disease, defined as ceruloplasmin level <0.1 g/L; 

A1AT deficiency, defined as A1AT level <LLN; 

Upper gastrointestinal bleed due to esophageal varices, liver transplant, or current 
MELD-Na score16 >12; 

Evidence of presumptive cirrhosis based on assessments performed as part of this 
study.
3. History of pancreatitis or T1DM, at PreQ.
4. Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection), at PreQ:

Participants who have undergone cholecystectomy and/or appendectomy are 
eligible for this study so long as the surgery occurred >6 months prior to PreQ.
5. Diagnosis of T2DM which requires management with >3 oral medications within 
12 weeks prior to SCR or management with excluded agents for glycemic control, 
refer to Section 6.5.1.


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6. Dyslipidemia which requires management with >3 lipid-modifying agents within
12 weeks prior to SCR or use of excluded agents for lipid management: 

In addition, specific restrictions need to be satisfied at SCR in order to progress
to randomization;

Those on gemfibrozil will need to agree to be switched to another agent once 
deemed eligible (at initiation of Run-In) and for duration of study; 

Those on statins will be permitted based on review of the total daily dose,
refer to Section 6.5.2.
7. At PreQ or SCR, those with severe hypertension defined as seated systolic BP 
≥180 mmHg and diastolic BP ≥105 mm Hg with a single repeat permitted, if needed, 
to assess eligibility at each of these 2 visits; and/or managed with >3 agents to 
control BP within 12 weeks prior to SCR (refer to Section 6.5.3 for acceptable 
medications):

BP must be assessed using a blood pressure cuff size available at individual sites 
and compatible with the arm circumference of the participant, refer to 
Section 8.2.4;

Participants with seated BP ≥160/100 mmHg at PreQ or SCR to use the Run-In 
period to revise/adjust medications to improve BP control;

In those with hypertension, BP must be well-controlled in order to progress 
with randomization, refer to Section 5.3.
8. Cardiovascular event within 12 months prior to PreQ:

A history of myocardial infarction, stroke, transient ischemic attack or 
revascularization procedure to prevent any of these events;

A history of congestive heart failure (NYHA class III or IV) or unstable angina. 
9. Recent (within 5 years of PreQ) systemically administered treatments for malignancy
including (but not limited to) the use of chemotherapy, radiotherapy, or
immunotherapy.

Or any other active malignancy (within 3 years of PreQ), except for adequately 
treated basal cell or squamous cell skin cancer, or carcinoma in situ.
10. 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.


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Prior/Concomitant Therapy:
11. At SCR, on any prohibited concomitant medication(s) or those unwilling/unable to 
switch to permitted concomitant medication(s), refer to Section 6.5.5.
Prior/Concurrent Clinical Study Experience:
12. Known prior participation in a trial involving DGAT2i or ACCi (ie, randomized and 
received at least 1 dose of study intervention, including placebo).
13. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention 
in this study (whichever is longer). 
Diagnostic Assessments:
14. Results as reported by Sponsor-identified central laboratory, at PreQ and SCR, as 
below with a single repeat of any of these parameters permitted to assess eligibility, if 
needed, at each of these 2 visits:

ALT <ULN or >5x ULN;

AST >5x ULN;

Alkaline phosphatase (ALP) >2x ULN; 

Total bilirubin >ULN and direct bilirubin >ULN; 

Note: Participants with a history of Gilbert syndrome would be eligible for 
this study provided direct bilirubin level is ≤ULN, and hemoglobin and 
reticulocyte count are within the reference range of the Sponsor-identified 
central laboratory;

Note: If there is a >50% variability between the PreQ (or PreQ repeat, if 
performed) and SCR results for ALT, AST, or alkaline phosphatase or total 
bilirubin is > ULN, these LFTs must be repeated 1 additional time, ≥2 weeks 
after SCR, with the variability between the PreQ (or PreQ repeat, if 
performed) and the 1 additional measurement confirmed to be ≤50% for ALT, 
AST, and alkaline phosphatase, and total bilirubin ≤ULN, and within the 
parameters above to confirm eligibility, as reported by the Sponsor-identified 
central laboratory, prior to progressing to the Run-In/Visit 2;

HbA1C >9% (75 mmol/mol), as assessed using NGSP certified method and 
standardized to DCCT assay;

Fasting Plasma Glucose >270 mg/dL (15 mmol/L);


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
Fasting serum triglycerides >400 mg/dL (4.5 mmol/L);

Platelet count < LLN;

INR ≥1.3;

Albumin < LLN;

eGFR (using CKD-EPI-Cystatin-C) of <30 ml/min/1.73 m2;

A positive urine drug test for illicit drugs (with this 1 assessment not permitted to 
be repeated at each visit to confirm eligibility).
15. At PreQ or SCR, supine 12-lead ECG demonstrating QTc interval >480 msec or QRS 
interval >120 msec;

If QTc interval exceeds 480 msec or QRS interval exceed 120 msec, the 12-lead 
ECG should be repeated twice (on the same or different day) and the average of 
three QTc/QRS intervals used to determine eligibility;

Note: if uncorrected QT interval is >480 msec, this interval must be 
rate-corrected using the Fridericia method, with the resulting QTcF used for 
decision making and reporting.
Other Exclusions:
16. Participants meeting criteria for contraindication to undergoing imaging assessments 
at PreQ and SCR. 

Active placement of medical devices in/on thoracic cavity – such as pacemakers, 
defibrillators [as these interfere with use of ultrasound based imaging modalities,
and MRI];

History/evidence of any of the following:

Contraindication to MRI such as ferric implant;

History of severe claustrophobia impacting ability to perform MRI during the 
study even despite mild sedation/treatment with an anxiolytic; 

Inability to lie still within the closed environment of the MRI scanner or
maintain a breath hold for the required period to acquire images even despite
mild sedation/treatment with an anxiolytic.


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17. 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. Randomization Criteria
A computer-generated randomization code using the method of random permuted blocks will 
be utilized to randomize participants equally balanced across the study interventions on 
Day 1/Visit 4 prior to the first dose of the double-blind, double-dummy study intervention 
provided participants satisfy all the following criteria:
1. Eligibility criteria outlined in Section 5.1 and Section 5.2;
2. A negative urine drug test for illicit drugs for sample collected at Baseline/Visit 3, as 
reported by Sponsor-identified central laboratory (with repeat assessment not
permitted for this visit);
3. Fasting (≥8 hours overnight, with water permitted) serum triglyceride result of 
≤400 mg/dL (4.5 mmol/L), for sample collected at Baseline/Visit 3, as reported by
Sponsor-identified central laboratory;

A single repeat assessment permitted using Sponsor-identified central laboratory, 
though results of this repeat, when done, must be available ahead of 
randomization;
4. Fasting (≥8 hours overnight, with water permitted) plasma glucose result of 
≤270 mg/dL (15 mmol/L), for sample collected at Baseline/Visit 3, as reported by 
Sponsor-identified central laboratory;

A single repeat assessment permitted using Sponsor-identified central laboratory, 
though results of this repeat, when done, must be available ahead of
randomization, refer to Appendix 10.10.
5. In females, a negative serum pregnancy test result for sample collected at
Baseline/Visit 3, as reported by Sponsor-identified central laboratory;

Plus, in females of childbearing potential, urine pregnancy test on Day 1/Visit 4,
as reported on-site using supplies offered by Sponsor-identified central laboratory, 
must be negative for pregnancy, refer to Section 8.2.6;
6. In those with hypertension, BP controlled via adjustment of concomitant medications 
for BP control during the Run-In period with seated BP on Day 1/Visit 4 of 
<160/100 mmHg;
7. Compliance of ≥90% and ≤110% with doses of single-blind placebo administered
(based on tablet count) from Baseline/Visit 3 to 1 day before Day 1/Visit 4, inclusive, 
refer to Section 6.4; 


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8. Total score of <8 on the AUDIT questionnaire, as assessed on Day 1/Visit 4;
9. An evaluable MRI-PDFF, as assessed by Sponsor-identified central imaging vendor, 
collected between Baseline/Visit 3 and prior to dosing with study intervention on 
Day 1/Visit 4.
5.4. Lifestyle Considerations
After confirmation of eligibility at PreQ and SCR, at Run-In/Visit 2, participants will be 
instructed to maintain the guidelines described below for the duration of their participation in 
the study. These guidelines must be reiterated on Day 1/Visit 4.
5.4.1. Contraception
The investigator or his or her designee, in consultation with the participant of childbearing 
potential, will confirm that the participant has selected an appropriate method of 
contraception for the individual participant from the permitted list of contraception methods 
(see Appendix 10.4) and will confirm that the participant has been instructed in its consistent 
and correct use. At time points indicated in the SoA – Table 1, 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.
5.4.2. Meals and Dietary Restrictions
1. Participants must abstain from all food and drink (except water) for ≥8 hours prior to 
any blood sample collections for clinical laboratory tests, pre-dose PK, and 
exploratory biomarker related collections: 

Note: Water may be consumed as desired (ad libitum). 
2. Participants must abstain from all food and drink (though water is permitted) for 
≥4 hours prior to conduct of any of the imaging assessments – ie, MRI-PDFF, 
FibroScan® and Acuson Sequoia®.
3. Blinded study intervention must be administered twice daily with: 

Morning dose at approximately 08:00 AM (±2 hours), local time with 
breakfast/meal;

Second dose, at approximately ≥8 and ≤12 hours after the morning dose, with the 
evening meal. 


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4. At scheduled outpatient visits to the site, in the morning, from Baseline/Visit 3 
through Week 6/Visit 7, participants must be instructed to arrive without having 
consumed the morning meal/breakfast and without taking the morning dose of the 
blinded study intervention and concomitant medications for management of glycemic 
control (Section 6.5.1), lipid control (Section 6.5.2), and blood pressure 
(Section 6.5.3): 

At Baseline/Visit 3 through Week 6/Visit 7, inclusive, following completion of all 
pre-dose procedures, the morning meal will be consumed with above-mentioned 
medications at the site;

The morning meal during site visits will be either provided by the site, or the 
participant provided a voucher [or similar] by the site to purchase the meal before 
arriving at the site for each visit.
5. Participants will be counseled on appropriate dietary and lifestyle guidelines: 

Counseling on dietary guidelines should be individualized in accordance with 
local medical standards of care for these participants and appropriate for the 
concomitant medical condition(s) of each participant;

Participants will be asked to maintain these guidelines throughout the study 
(ie, up to the Follow-up/Visit 8). 
5.4.3. Alcohol, Caffeine, and Tobacco

Intake of alcohol is permitted in moderation, refer to exclusion criterion 1 in
Section 5.2 for limits on amount of alcohol consumption;

Consumption of caffeinated drinks and nicotine-containing products is permitted 
during participation in the study, except:

There may be a need for brief interruption while at the site and/or imaging 
facility, depending on local policy;

Consumption is prohibited for at least 1 hour prior to any vital sign measurement.
5.4.4. Activity
Participants will not be permitted to engage in physically strenuous exercise (for example: 
heavy lifting, weight training, calisthenics, and aerobics): 

Within 48 hours before each blood sample collection for clinical laboratory tests for 
the duration of participation in the study;

Physical activity at an individual participant’s normal pace is permitted.


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5.4.5. Outpatient Visits to Site 

For each participant, every outpatient visit to the site is envisioned to occur with the 
participant arriving at the site between approximately 6 AM and 10 AM local time 
with each visit lasting approximately 2 hours.

At selected visits, to permit collection of post dose blood samples for PK, participants 
may either extend their stay on-site after dosing or leave and return later the 
same day, refer to Section 8.5 for details. 
5.4.6. Outpatient Visits to Imaging/Radiology Facility 

Quantitative ultrasound-based assessments via FibroScan® and Acuson Sequoia® will 
occur either at the site or the imaging facility, depending on where these devices are
located;

The location of these devices must be kept consistent at individual sites 
throughout study execution ie, either both devices reside at the site or both
devices reside at the imaging facility – for the duration of the study; 

For each participant, the assessment of MRI-PDFF and quantitative ultrasound (via 
FibroScan® and Acuson Sequoia®) must occur at the same time of day (±2 hours)
relative to 1st time of assessment while in study, as much as practically possible, 
refer to Section 8.6 for additional details. 
5.5. 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/entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details, and any SAE.
In this study, participants who screen fail in Part 1 may be considered for Part 2. In addition, 
in rare cases, participants may be re-screened if due to logistical/administrative constraints, 
the maximum period between PreQ and Day 1/Visit 4, of 10 weeks, is exceeded. In both of 
these cases, 

Individual circumstances must be reviewed with a member of the Sponsor’s Clinical 
team before the given participant is re-consented;

All PreQ and SCR procedures must be repeated under a new 8-digit SSID number;

Participants must be deemed to meet all the eligibility criteria including double 
confirmation of Sponsor-defined presumed NASH status under the new 8-digit SSID 
number.


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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, the term investigational product (ie, IP) may be used 
synonymously with study intervention and refers to all of the following:

Placebo matching DGAT2i;

Placebo matching ACCi;

DGAT2i;

ACCi.
6.1. Study Intervention(s) Administered
The following tablet strengths will be provided centrally by the Sponsor for use as study 
interventions in this study:

For DGAT2i – 25 mg, 50 mg and 150 mg PF-06865571 tablets and matching 
placebo;

For ACCi – 10 mg and 20 mg PF-05221304 tablets and matching placebo.
The study interventions above, will be packaged together in blinded blister cards, according 
to the treatment groups as noted in Table 4, and will be dispensed by the IRT system in 
sufficient quantities to enable dosing during the intervals between visits outlined in the
SoA - Table 1. One extra blister card will be dispensed at each dispensation visit to support 
the flexibility provided by the visit windows. Each blinded blister card supports oral dosing 
for 7 days and will be labeled according to individual country regulatory requirements. 
In Part 1, across the 5 treatment groups, double-blind, double-dummy administration of 
study intervention will be maintained as outlined in Table 4. Each dose will consist of 
3 tablets, ie, 2 large tablets (DGAT2i/matching placebo) plus 1 small tablet (ACCi/matching 
placebo).


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Table 4.
Double-Blind, Double-Dummy Regimen in Part 1 of C3711005
Regimen
# of DGAT2i Tablets
(mg strength)
# of ACCi Tablets
(mg strength)
placebo
25
50
150
placebo
10
20
A
Placebo, BID
AM
2
-
-
-
1
-
-
PM
2
-
-
-
1
-
-
B
DGAT2i 25 mg BID 
+ ACCi 10 mg BID
AM
1
1
-
-
-
1
-
PM
1
1
-
-
-
1
-
C
DGAT2i 100 mg BID 
+ ACCi 10 mg BID
AM
-
-
2
-
1
PM
-
-
2
-
1
D
DGAT2i 300 mg QD 
+ ACCi 20 mg QD
AM
-
-
-
2
-
-
1
PM
2*
-
-
-
1*
-
-
E
DGAT2i 300 mg BID 
+ ACCi 10 mg BID
AM
-
-
-
2
-
1
-
PM
-
-
-
2
-
1
-
* To maintain double-blind, double-dummy design across all groups, this group will receive placebo as evening dose.
For Part 2, updated dosing details will be offered via Investigational Product (IP) Manual 
for the site and separately for the participants via Dosing Diary Instructions once the data 
from Part 1 are reviewed and doses for Part 2 are identified. 
6.1.1. Administration
Participants will either self-administer on-site (during scheduled visits) or at home/outpatient
with meals – twice daily. Participants will swallow the study intervention whole and will not 
manipulate or chew the study intervention prior to swallowing. Each day, the participants 
will be instructed to consume orally, the 3 tablets with the morning meal and 3 tablets with 
the evening meal as outlined in Table 4.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage
conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
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.


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3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or Sponsor-approved equivalent.  All study interventions will be accounted for 
using a study intervention accountability form/record. All study intervention that is 
taken home for outpatient dosing by the participant, both used and unused, must be 
returned to the investigator by the participant.  Returned study intervention must not
be redispensed to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions
provided by Pfizer.
Upon identification of a product complaint, notify the Sponsor within 1 business day of 
discovery as described in the IP manual.
6.2.1. Preparation and Dispensing
The investigational product will be dispensed using the IRT system at visits identified in the 
SoA – Table 1.  A qualified staff member will dispense the study intervention via unique 
container numbers on the blister cards provided, in quantities appropriate for the visit 
schedule. A second staff member will verify the dispensing. 
The participant should be instructed to maintain the product in the blister cards provided 
throughout the course of dosing and return all blister cards, both used and unused to the site 
at the next study visit.


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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
6.3.1.1. Part 1
Approximately 90 participants will be randomized in a balanced ratio to receive either 
double-blind, double-dummy placebo, or 1 of 4 doses of DGAT2i + ACCi (with 3 entailing 
BID dosing of DGAT2i + ACCi and 1 dose-level of QD dosing but with blind maintained 
via dosing of placebo as the 2nd dose each day). A computer-generated randomization code 
using the method of random permuted blocks will be utilized to assign participants to any 
1 of the 5 dosing groups on Day 1/Visit 4.
Allocation of participants to treatment groups will proceed through the use of an IRT system 
(IWR). The site personnel (study coordinator or specified designee) will be required to enter
or select information including but not limited to the user’s ID and password, the protocol 
number, and the unique 8-digit participant number. The site personnel will then be provided 
with a treatment assignment, randomization number, and DU or container number(s) from 
the IRT system. The IRT system will provide a confirmation report containing the 
participant number, randomization number, and DU or container number(s) assigned. The 
confirmation report must be stored in the site’s files. 
The investigational product will be dispensed at the study visits summarized in the 
SoA - Table 1; returned study intervention should not be redispensed to the participants.
The study specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.1.2. Optional Part 2
The allocation of treatment in Part 2, will be in accordance to options described in 
Section 4.3.2, after the review of data from Part 1.
6.3.2. Breaking the Blind 
The blind should only be broken in emergency situations for reasons of participant safety and
when knowing the specific investigational product that the participant received alters the 
course of medical management. 
The IRT will be programmed with blind breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the Sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the Sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF.


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The study-specific IRT reference manual and IP manual will provide the contact information
and further details on the use of the IRT system.
6.4. Study Intervention Compliance 
Compliance with investigational product will be assessed at each on-site visit starting on 
Day 1/Visit 4 and continuing until Week 6/Visit 7, refer to SoA - Table 1. Compliance (as 
assessed by counting returned blister cards and/or tablets) will be defined as self-
administration, by the participants, of:

Baseline period (Visit 3 to 1 day prior to Day 1/Visit 4, inclusive): ≥90% and 
≤110% compliance with single-blind, double-dummy, placebo based on the number 
of doses consumed for the specific duration of dosing; for example;

If duration of dosing was 12 days, participant can miss a maximum of 2 doses
(or take a maximum of 2 extra doses) and still qualify for randomization;

If duration of dosing was 16 days, participant can miss a maximum of 3 doses
(or take a maximum of 3 extra doses) and still qualify for randomization;

Day 1/Visit 4 to last day of dosing or Week 6/Visit 7, inclusive: ≥80% compliance 
with self-administration of the study intervention is expected;

Investigators must closely monitor non-compliant participants in order to enhance 
participants’ adherence to the study intervention; 

Post randomization, at each dispensation visit (refer to SoA - Table 1), 
participants who are <80% compliant, based on tablet count plus review of 
dosing diary performed, must be re-educated by the site staff on the 
importance of daily self-administration of study intervention;

Overall aim: maintain ≥80% compliance over the duration of dosing with 
double-blind, double-dummy study intervention.
6.5. Concomitant Therapy
Given the relatively short duration of the double-blind, double-dummy dosing in this study, 
whenever possible, attempts must be made to not alter the doses and regimens of the 
background/concomitant medications after randomization, Day 1/Visit 4 and until the
required on-site Follow-up (ie, Visit 8). 
All concomitant medications taken during the study must be recorded with indication of use. 
In addition, agents used for glycemic control, lipid control, and blood pressure control, daily 
dose, start and stop dates of administration must be captured. All participants must be 
questioned about concomitant medication at each outpatient visit to the site. 


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Medications started before Day 1/Visit 4 will be documented as prior medications. 
Medications started after dosing of double-blind, double-dummy investigational product on 
Day 1/Visit 4 and until the required on-site Follow-up (ie, Visit 8), inclusive, will be 
documented as concomitant medications.
6.5.1. Medication for Glycemic Control
The use of the following classes of agents is not permitted within 8 weeks prior to SCR 
visit and until the required on-site Follow-up (ie, Visit 8), inclusive:

TZDs such as pioglitazone and rosiglitazone; 

Subcutaneously administered agents for glycemic control (eg, insulin, exenatide, 
liraglutide, pramlintide).
Participants are permitted to be on stable doses of up to a maximum of 3 oral agents for 
glycemic control, starting at ≥12 weeks prior to SCR and until the required on-site 
Follow-up (ie, Visit 8), inclusive, across the country-specific, approved classes of agents 
including (but not limited to) the following:

Biguanide such as metformin, refer to Appendix 10.9 for protocol-required 
dose-adjustment in participants on metformin dose >1 gm/day; 

Sulphonylureas such as acetohexamide, chlorpropamide, tolazamide, tolbutamide, 
glimepiride, glipizide, glyburide;

Meglitinide analogues such as repaglinide, nateglinide;

Dipeptidyl peptidase-IV inhibitors (DPP-IVi) such as sitagliptin, saxagliptin, 
vildagliptin;

-glucosidase inhibitors such as acarbose, miglitol;

Sodium-glucose cotransporter 2 inhibitors such as canagliflozin, dapagliflozin, 
empagliflozin.
6.5.2. Lipid-modifying Medications
The use of any injectable agent (eg, those which inhibit monoclonal antibodies inhibiting 
proprotein convertase subtilisin/kexin type 9 (PCSK9) such as alirocumab, evolocumab, or 
inclisiran) is not permitted within 12 weeks prior to SCR and until the required on-site 
Follow-up (ie, Visit 8), inclusive. 
Participants are permitted up to a maximum of 3 lipid-modifying oral agents if they are on 
stable doses, starting from ≥12 weeks prior to SCR and until the required on-site Follow-up
(ie, Visit 8), inclusive, across the country-specific, approved classes of agents including (but 
not limited to) the following:


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
Those on selected statins which are BCRP substrates will only be permitted if on: 

Rosuvastatin doses up to 10 mg/day;

Atorvastatin doses up to 40 mg/day;

Simvastatin or Fluvastatin doses up to half-maximum in-country approved dose;
Note: pravastatin and pitavastatin are permitted at doses up to the maximum 
approved, in-country dose;

Bile acid sequestrants such as cholestyramine, colestipol, or colesevalam;

Fenofibrate, a fibric acid derivative;

Nicotinic acid/niacin;

Ezetimibe.
Note: Use of gemfibrozil, an OATP inhibitor, is not permitted starting at Run-In/Visit 2 and
until the required on-site Follow-up (ie, Visit 8) – participants on this agent, at SCR, will 
need to agree to be switched to another acceptable agent starting at Run-In/Visit 2, with 
stable dose of the acceptable agent achieved for ≥4 weeks before Day 1/Visit 4, in order to 
continue to randomization in this study.
6.5.3. Medications for Controlling Blood Pressure
Across the many classes of agents for management of hypertension, participants are 
permitted to be on stable doses of up to a maximum of 3 agents, starting at ≥12 weeks prior 
to SCR visit and until the required on-site Follow-up (ie, Visit 8), across the many approved 
classes of agents.
Note: Starting at Run-In/Visit 2, medications ± doses of medications for BP control can be 
adjusted to a maximum of 3 agents in order to meet BP criteria needed to progress to 
randomization [refer to Section 5.3].
6.5.4. Other Acceptable Concomitant Medications
As much as possible, participants on the following list of medications must be on stable 
doses (ie, ≥12 weeks prior to SCR and until the required on-site Follow-up/Visit 8), 
inclusive]:

Use of multi-vitamins is permitted though those on Vitamin E must be on stable dose 
for ≥24 weeks before SCR;

Use of aspirin at doses of ≤325 mg/day;


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
Use of oral agents that alter stomach pH – eg, antacids, histamine-2 receptor 
antagonists, proton-pump inhibitors;

Use of inhaled and topical corticosteroids;
Note: Intercurrent treatment with systemic steroids, during participation in the study, 
may be permitted if treatment does/will not exceed 7 days;

Thyroid replacement therapy;

Postmenopausal hormone therapy;

Hormonal contraceptives that meet requirements of this study are allowed to be used 
in participants who are WOCBP (see Appendix 10.4);

Antipsychotic medications such as olanzapine, risperidone;

Antidepressant medications such as tricyclic agents, selective serotonin reuptake 
inhibitors and serotonin/norepinephrine reuptake inhibitors;

Selected (herbal) supplements (or approved agents), below, in countries where they 
are part of standard of care to lower LFTs (based on limited/weak scientific evidence);

Glutathione;

Glycyrrhizic acid;

Polyene phosphatidylcholine;

Silymarin;

Ursodeoxycholic acid;

Chronic and intermittent use of NSAIDs (such as ibuprofen, ketoprofen, diclofenac, 
naproxen, indomethacin, meloxicam; and celecoxib) is permitted;

Intermittent use of acetaminophen/paracetamol at doses up to 2 grams per day 
(for example: for short-term pain management) is deemed acceptable.
6.5.5. Prohibited Medications

Certain medications for glycemic control, lipid-modification, and BP control are not
permitted as per restrictions in Section 6.5.1, Section 6.5.2, or Section 6.5.3.

Use of drugs historically associated with fatty liver are prohibited within any
≥4 weeks interval in the previous 12-months prior to SCR and until the required 
on-site Follow-up (ie, Visit 8), inclusive;


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
Examples include amiodarone, methotrexate, systemic glucocorticoids (such as 
prednisone, dexamethasone, triamcinolone, budesonide, betamethasone), anabolic 
steroids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, valproic acid, other known hepatotoxins. 

Use of the following medications within 12 weeks prior to SCR and until the 
required on-site Follow-up (ie, Visit 8), inclusive, is prohibited:

Chronic use of immunosuppressants such as cyclosporine and tacrolimus;

Pharmacological agents with approved indication for weight loss such as orlistat 
and sibutramine;

Over-the-counter appetite- simulant or appetite- suppressant, as advertised;

P-gp substrates with narrow TI (eg, digoxin);

Potent inducers and inhibitors of CYP3A (refer to Appendix 10.8) including but 
not limited to the following:

Inducers – eg, rifampin, phenytoin, carbamazepine, St John’s wort, 
phenobarbital;

Inhibitors – eg, ketoconazole/itraconazole, clarithromycin, many protease 
inhibitors;

CYP2C9 substrates with narrow TI (eg, warfarin or phenytoin); 

Blood thinner(s) – eg, apixaban, dabigatran, rivaroxaban, edoxaban, 
fondaparinux, heparin, as well as Vitamin K antagonists (eg, warfarin);

Clinically significant OATP inhibitors – eg, cyclosporine, gemfibrozil, rifampin.
6.5.6. Rescue Medicine
There is no rescue therapy to reverse the AEs (including identified adverse drug reactions) 
observed with any of the study interventions; standard medical supportive care must be 
provided to manage the AEs. 
Participant with T2DM with repeated fasting plasma glucose values >270 mg/dL 
(15 mmol/L) as reported by the Sponsor-identified central laboratory, at 2 sequential visits 
(eg, a combination of 2 consecutive scheduled visits or 1 scheduled visit followed by an 
unplanned visit to confirm the elevated result), post randomization, must either:

Have the dose of background metformin for glycemic control optimized, refer to 
Section 6.5.1 and Appendix 10.9;


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
Or be withdrawn from the study (if not on metformin prior to randomization) for loss 
of glycemic control.
For the identified adverse drug reactions, guidance to investigators is offered (refer to
Appendix 10.10 and Appendix 10.11) on the basis that reversal of effect towards baseline 
expected/observed in previous studies with ACCi upon discontinuation of study intervention. 
6.6. Dose Modification 
Dose modification of double-blind, double-dummy study intervention in individual 
participants in this study is not permitted to be modified.
The decision to pause or stop dosing at a study-level, for 1 or more active dose(s) of 
DGAT2i + ACCi may be considered based on recommendation from the IRC based on their 
review of unblinded, study-level emerging, observed safety data, refer to Section 9.6. 
6.7. Intervention After the End of the Study
This is the first study to evaluate a range of doses of DGAT2i + ACCi. As such, multiple 
active groups are being included, to enable identification of efficacious dose(s) upon its’ 
completion (not at start of study). In addition, considering duration of treatment period 
(ie, 6 weeks), benefit of the doses being studied cannot be claimed simply on the results from 
this study.  Hence, study intervention will not be provided to participants at the end of the 
study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include adverse events or some other (administrative) reason. 
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See SoA - Table 1 and SoA - Table 2 for data to be collected at the 
time of discontinuation of study intervention.  
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;


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
Study terminated by Sponsor;

Discretion of the Investigator or Sponsor for safety or behavioral reasons, or the 
inability of the participant to comply with the protocol-required schedule of study
visits or procedures at a given study site. 
As soon as practically possible after the decision to withdraw from the study, an on-site visit 
should be considered:

Participants should be questioned regarding their reason for withdrawal;

See SoA – Table 1 and SoA - Table 2 – for assessments to be collected at the time of 
study discontinuation and follow-up for any further evaluations that need to be 
completed. 
In this study, any participant who discontinues participation after the PreQ visit but prior to 
randomization and administration of the 1st dose of double-blind, double-dummy study 
intervention will have no additional procedures completed.
The early discontinuation visit applies only to participants who are 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.
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.


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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with 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 site 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;

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 at PreQ. In addition, a separate 
signed/dated ICD must be obtained before performing any study-specific procedures at SCR. 
Study procedures and their timing are summarized in the SoA – Table 1 and SoA- Table 2.
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 
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requirements, including those specified in the SoA – Table 1 and SoA - Table 2 - is essential 
and required for study conduct. All screening evaluations must be completed and reviewed 
to confirm that potential participants meet all eligibility criteria.  The investigator will 
maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in Part 1 of this study will be 
approximately 325 mL. Blood volume collected in Part 2 is envisioned to be the same as in
Part 1 given intent to maintain the same design – refer to Section 4.1.2.
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.  
8.1. Efficacy Assessments
No efficacy assessments are being undertaken in this study. 
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA – Table 1 and
SoA - Table 2. Unscheduled clinical laboratory measurements may be obtained at any time 
during the study to assess any perceived safety issues.
8.2.1. Physical Examinations
In this study, physical examinations are to be performed at nominal time points specified in
the SoA – Table 1.

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.  

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).


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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
8.2.1.1. Measurement of Waist Circumference 
Waist circumference will be measured at the nominal time points specified in SoA - Table 1
using a flexible anthropometric tape and ideally, reporting the measurement in centimeters 
with accuracy to the nearest 0.1 centimeter (or 1/16th inch).
Measurement will be undertaken as follows:

While participant is in a standing position with arms resting comfortably at the side;

At the end of a normal expiration (when lungs are at their residual capacity);

And the measurement will consider the following anatomical features as benchmarks:

Circumference of the narrowest part of the torso as viewed from the anterior 
aspect or;

If the narrowest part of the torso cannot be identified, the measurement must be
made of the smallest horizontal circumference in the area between the ribs and the 
iliac crest.
8.2.2. Body Weight
In this study, assessment of body weight will occur at the nominal time points specified in
SoA - Table 1 per the following specifications:

Weight will be recorded using a scale placed on a stable, flat surface in a 
(semi)-private area;

Same scale, as much as practically possible, will be used with the scale reporting 
weight in kilograms or pounds, and accuracy to the nearest 0.1 kg [or 0.2 pounds]
-ie, the device used for this study must be able to distinguish a difference between 
68.4 kg and 68.3 kg;

Measurement must be undertaken and documented to 1 decimal place;

Assessment performed at approximately the same time of the day at each nominal 
time point, as much as practically possible;

Under standard conditions (eg, participants must wear light clothing with content of
their pockets emptied or hospital gown and not be wearing shoes or bulky layers of 
clothing/jackets).


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8.2.3. Electrocardiograms
Standard single 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in SoA – Table 1 using an ECG machine that automatically 
calculates the RR interval (or 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 12-lead ECGs should be performed after the participant has rested 
quietly for ≥10 minutes in a supine position;

Starting at Day 1/Visit 4, if a machine-read QTc value is prolonged, as defined in
Appendix 10.7, repeat measurements may not be necessary if a qualified physician’s 
interpretation determines that the QTc values are in the acceptable range;

Assessment of whether prolonged QTc interval meets criteria as defined in
Appendix 10.7, must assess QTc interval using only the Fridericia’s correction 
(ie, QTcF) either as reported by the 12-lead ECG machine or QTcF derived using 
Sponsor-provided tool and reported QT and RR intervals;

In some cases, it may be appropriate to repeat abnormal 12-lead ECGs to rule out 
improper lead placement as contributing to the ECG abnormality; as much as 
practically, possible, it is important that leads be placed in the same positions 
each time in order to achieve precise ECG recordings.
Additional ECG values of potential clinical concern are listed in Appendix 10.7.
8.2.4. Vital Signs
In this study, assessment of vital signs (including seated blood pressure, and pulse rate) will
occur at the nominal time points specified in SoA – Table 1 per the following specifications:

At the PreQ visit, the participants’ arm circumference should be measured (using a 
flexible anthropometric tape) at the midpoint of the length of the upper arm and the
appropriate cuff selected and used throughout the study to measure BP/pulse rate via
an automated device using an oscillometric method (not auscultation);

Participants with arm circumference greater than the largest cuff size available at
each site are not eligible;

Single seated blood pressure/pulse rate will be measured with the participant’s arm
supported at the level of the heart, and recorded to the nearest mm Hg, following a
rest of ≥5 minutes.

Same arm (preferably the dominant arm) will be used for blood pressure/pulse rate
assessment throughout the study.


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8.2.5. Clinical Safety Laboratory Assessments 
See Appendix 10.2 for the list of clinical safety laboratory tests to be performed and 
SoA - Table 2 for the timing and frequency.  All protocol-required laboratory assessments, as 
defined in Appendix 10.2, must be conducted in accordance with the laboratory manual and 
SoA - Table 2.  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 28 days 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 10.6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
8.2.6. Pregnancy Testing
Pregnancy tests may be urine or serum tests but must have a sensitivity of at least 
25 mIU/mL and performed using supplies offered by the Sponsor-identified central 
laboratory. Serum (all females) and urine pregnancy tests (in WOCBP) will be performed at 
the times listed in SoA - Table 2. Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced (or continued) and a second negative 
pregnancy test result will be required at the baseline visit prior the participant’s receiving the 
study intervention (ie, single-blind, double-dummy placebo starting at Baseline/Visit 3 and
double-blind, double-dummy study intervention starting at Day 1/Visit 4). Pregnancy tests 
will also be done whenever 1 menstrual cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at the end of the study. Pregnancy 
tests may also be repeated if requested by IRBs/ECs or if required by local regulations. If a 
urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test 
is required. In such cases, the participant must be discontinued if the serum pregnancy result 
is positive.


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8.2.7. Alcohol Intake Assessment
In this study, the interview-based AUDIT questionnaire11 will be completed by the site staff 
based on responses offered by the participants – at the visits outlined in SoA – Table 1. 
Training for the site staff completing this questionnaire will be offered by the Sponsor as part 
of the protocol-specific training ahead of the initiation of the study.
8.2.8. Triggered Requirements and Individual Participant Stopping Rules
8.2.8.1. Potential Cases of Hypertriglyceridemia
In the current study, fasting serum triglycerides as reported by the Sponsor-identified central 
laboratory, with or without any accompanying signs/symptoms, will be assessed versus the 
threshold outlined in Appendix 10.10. 
Individual participants with consistently increasing fasting serum triglycerides over time (or
double-confirmed result) ultimately reaching the threshold of ≥800 mg/dL (≥9 mmol/L) as 
outlined in Appendix 10.10 should stop dosing with study intervention and an AE of 
hypertriglyceridemia captured.
NOTE: dose(s) of background agent(s) for lipid control (refer to Section 6.5.2) must not be 
adjusted while in this study as it compromises ability to evaluate effectiveness of 
DGAT2i + ACCi to mitigate ACCi-induced elevations in serum triglycerides.
8.2.8.2. Potential Cases of Thrombocytopenia
In the current study, platelet count as reported by the Sponsor-identified central laboratory,
with or without any accompanying signs/symptoms, will be assessed versus the threshold 
outlined in Appendix 10.11.

In participants observed to have platelet count below the LLN should have an
unplanned visit occur as soon as practically possible to:

Inquire about adverse events via open-ended inquiry; 

And collect blood sample to permit safety-related laboratory assessments included 
hematology panel assessment by the Sponsor-identified central laboratory.
Participants observed to have a consistent decline over time (or double-confirmed result) 
ultimately reaching the threshold of <75,000/mm3 in platelet count as outlined in
Appendix 10.11 should stop dosing with study intervention and an AE of thrombocytopenia 
captured.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 10.3.
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 a 
minimum of 28 calendar days, except as indicated below, 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 AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in
Appendix 10.3. 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 as 
described in Section 8.3 are recorded on the CRF. AEs and SAEs that begin after obtaining 
informed consent but before the start of study intervention will be recorded on the Medical 
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs
that begin after the start of study intervention are 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 10.3.
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 10.3.
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.

A male family member or healthcare provider who has been exposed to the study
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 
28 days after the last dose of study intervention.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file.


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


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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.
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. Adverse Events of Special Interest
In this study, adverse event of special interest are the identified adverse reactions with 
administration of ACCi:

Increase in fasting serum triglyceride result of ≥800 mg/dL (9 mmol/L) – refer to 
Appendix 10.10 ideally via double-confirmation provided participant is 
asymptomatic;

Reduction in platelet count to <75,000/mm3 – refer to Appendix 10.11 ideally via 
double-confirmation provided participant is asymptomatic.
All AESIs must be reported as an AE or SAE following the procedures described in 
Section 8.3.1 through Section 8.3.4. An AESI is to be recorded as an AE or SAE on the 
CRF. In addition, an AESI that is also an SAE must be reported using the CT SAE Report 
Form.


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8.3.7. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
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 immediately.
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 DGAT2i greater than 1800 mg, or any dose of ACCi greater than 
200 mg, within a 24 hour time period will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose. However, in the event of 
an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until
the study intervention can no longer be detected systemically (at least 5 days).


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3. Obtain a blood sample for PK analysis as soon as practically possible.
4. Document the quantity of the excess doses as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
8.5. Pharmacokinetics 
In this study, blood samples (4 mL each) to provide sufficient plasma for pharmacokinetic 
analysis of PF-06865571 and PF-05221304 will be collected into separate, appropriately 
labeled tubes containing K2-EDTA, at times defined in the SoA - Table 2. The date and time 
of 2 most recent doses should be noted in a dosing diary (or similar) by the participants prior 
to each scheduled, on-site visit; plus date/time of double-blind, double-dummy study 
intervention taken on-site, must be captured in the eCRF.

The PK samples must be processed and shipped as indicated in the study-specific 
laboratory manual provided to the site, prior to initiation of study, to maintain sample 
integrity:

Any deviations from the PK sample handling procedure (eg, sample collection 
and processing steps, interim storage or shipping conditions), including any 
actions taken, must be documented and reported to the Sponsor. On a 
case-by-case basis, the Sponsor may make a determination as to whether sample
integrity has been compromised. Any deviation from the specified sample 
handling procedure resulting in compromised sample integrity will be considered 
a protocol deviation.

Any of the following errors in scheduled collection of blood samples for PK (refer to
SoA - Table 2) will be captured as protocol deviations even if results are deemed to 
be evaluable: 

Predose collection (ie, Ctrough) obtained post dose;

Post dose PK sample not collected within collection window following morning 
dose;

PK sample (pre- or post- dose) not collected.


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
As part of understanding the pharmacokinetics of the study intervention, samples may 
be used for metabolite identification and/or evaluation of the bioanalytical method, as 
well as for other internal exploratory purposes including endogenous biomarkers for 
drug metabolizing enzymes and/or drug transporters. These data will not be included 
in the clinical report.

Samples will be analyzed for DGAT2i and ACCi using a validated analytical method 
in compliance with Pfizer standard operating procedures.
8.6. Pharmacodynamics
This study will assess effectiveness of DGAT2i + ACCi for reducing hepatic steatosis as 
assessed via MRI-PDFF.  This evaluation however is labeled as a pharmacodynamic 
assessment (and not efficacy) in line with the evaluation being that of pharmacological 
activity.
8.6.1. Assessment of Liver Fat Using MRI-PDFF 
At scheduled visits (refer to the SoA - Table 1), liver fat (via MRI-PDFF) and total liver 
volume (via MR volume acquisition protocol) will be assessed. 
Transportation of the participants to the Imaging facility does not need to be supervised by 
the site staff. Each assessment will require the participants to be in a supine position in the 
confined space of the MRI scanner for approximately 25 minutes with the image acquisition 
undertaken following a fast (except water) of ≥4 hours, and as much as practically 
possible, at the same time (±2 hours) of the day relative to assessment at Baseline 
(ie, between Baseline/Visit 3 and prior to 1st dose on Day 1/Visit 4).
Across the study sites, the Sponsor-identified central imaging vendor will train the staff at the 
imaging facility on the MRI acquisition protocols, on just-in-time review of the acquired 
images for assessment of images being deemed evaluable, and on transfer (preferably 
electronically) of the images to the Sponsor-identified central imaging vendor for analysis 
and quantification of liver fat. Only the staff members at the imaging facility who are 
trained by the Sponsor-identified central imaging vendor are permitted to acquire 
images, however in rare/limited situations, exceptions may be granted with written approval 
of the Sponsor. Complete details on the MRI-PDFF acquisition protocol, determination of 
quality of images, and transmission of data to Sponsor-identified central imaging vendor will 
be provided in an Imaging Manual provided to the sites prior to the start of the study.
At the selected visits (refer to the SoA – Table 1) when liver fat is assessed via MRI-PDFF, 
additional MR sequences may be acquired for exploratory purposes including liver volume. 
These additional MR sequences and any additional MR endpoints, if analyzed, will not be 
included in the clinical study report but will be summarized via a standalone report.


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Management of Incidental Findings
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study.
The images will be reviewed by a Sponsor-identified central review facility. The purpose of 
this review is to evaluate images for the amount of fat in the liver. Central image review is 
not a complete medical review of the participant. If, during the central review process, an 
unexpected observation is identified and this finding could, in the opinion of the central 
reviewer, have a significant health or reproductive consequence, this finding may be shared 
with the study Sponsor for disclosure to the PI. All follow-up testing and final diagnosis will 
be left to the discretion of the medical professionals at the site or those with an existing 
physician-participant relationship. The PI will be responsible for reporting any AEs 
identified from incidental findings as described in the AE reporting section. Identification of 
such incidental findings during the central review process should not be expected, and the 
site maintains responsibility for performing a general safety review of all images as per site
protocols.
8.6.2. Assessment of Liver Fat and Stiffness – using FibroScan®
In this study, assessments of liver fat and stiffness using FibroScan® will occur at scheduled 
visits outlined in the SoA – Table 1. Each assessment will require the participants to be in a 
supine position for approximately 15 minutes with the image acquisition undertaken 
following a fast (except water) of ≥4 hours, and as much as practically possible, at the 
same time (±2 hours) of the day relative to assessment at PreQ visit. The results for liver fat 
(via CAP™) in dB/m and liver stiffness (via VCTE™) in kPa to determine whether an 
individual participant qualifies at PreQ to progress to SCR will be displayed on the 
FibroScan® device at the end of each assessment. Acquisition results do not need 
independent over-reading, but steps to ensure that acquisition was complete and accurate are 
required. Training is to be offered to at least 2 site staff (who may be sonographers or
comparable) by EchoSens and certified as operators based on this training by EchoSens, at 
the start of the study. As much as practically possible, attempts will be made to ensure each 
individual participants’ assessment is performed by the same site staff throughout the study.
The summary of numerical results (including quality-related outputs) must be printed and 
saved by the study site (or imaging facility, as applicable) as part of each participant’s source 
documents. In addition, all images and output reports acquired must be saved by the study 
site until the conclusion of the study.
8.6.3. Assessment of Liver Fat and Stiffness – using Acuson Sequoia®
The assessment of liver fat (UDFF™in %) and liver stiffness (via SWE™in kPa) using 
Acuson Sequoia® will occur at scheduled visits outlined in the SoA – Table 1.  Each 
assessment will require the participants to be in a supine position for approximately 
15 minutes with the image acquisition undertaken following a fast (except water) of 
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relative to assessment at Baseline (ie, between Baseline/Visit 3 and prior to 1st dose on 
Day 1/Visit 4).
The results will be displayed on the Acuson Sequoia® device at the end of each assessment. 
Acquisition results do not need independent over-reading, but steps to ensure that acquisition 
was complete and accurate are required. Training is to be offered to at least 2 site staff (who 
may be sonographers or comparable) by Siemens and certified as operators based on this 
training by Siemens, at the start of the study. As much as practically possible, attempts will 
be made to ensure each individual participants’ assessment is performed by the same site 
staff throughout the study.
The summary of numerical results (including quality-related outputs) must be printed and 
saved by the study site (or imaging facility, as applicable) as part of each participant’s source 
documents. In addition, all images and output reports acquired must be saved by the study 
site until the conclusion of the study. The SWE endpoints, if analyzed, will not be included 
in the clinical study report but will be summarized via a standalone report.
Complete details regarding acquisitions using FibroScan® to assess CAP™and VCTE™as 
well as use of Acuson Sequoia® to assess liver fat (UDFF™in %) and liver stiffness (via 
SWE™in kPa) will be provided in a study-specific manual supplied by the Sponsor before 
initiation of this study.
Post-Hoc Analyses
As a means to understand the effects on liver fat, the Sponsor may undertake retrospective 
analyses of the participant-level, coded data acquired using 3 imaging modalities -
ie, MRI-PDFF, FibroScan® and Acuson Sequoia®. Similarly, retrospective analyses of the 
participant-level, coded data may be undertaken to understand the performance of liver 
stiffness, as assessed using FibroScan® and Acuson Sequoia®.  Any such analyses will not
be included in the clinical study report; a separate supplemental report will be written to 
capture this work, if undertaken. 
8.7. Genetics
8.7.1. Specified Genetics
A 4 mL blood sample for DNA isolation, for pre-specified PGx, will be collected into plastic 
K2-EDTA tubes, as defined in SoA - Table 2. The DNA samples will be analyzed for the 
purpose of assessing the impact of allelic variants of SLCO1B1 (encodes for OATP1B1), 
SLCO1B3 (encodes for OATP1B3), SLCO2B1 (encodes for OATP2B1), SLC10A1 (encodes 
for NTCP), ABCG2 (encodes for BCRP), PNPLA3, and HSD17b13. As part of these 
analyses, genome-wide markers may be used to control for ethnic-based genetic associations.
Additionally, these samples may also be used for retrospective evaluation of additional 
genetic variants associated with variation in PK, biomarker response, or to explore AEs 
should these be observed. Samples will be retained for a period of up to 3 years after 
regulatory approval.


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See Appendix 10.5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in Sponsor-identified study-specific 
central laboratory manual.
This pre-specified PGx sample must be processed and shipped as indicated in the 
instructions provided to the investigator site, to maintain sample integrity. Any deviations 
from the PGx processing steps, including any actions taken, must be documented and 
reported to the Sponsor. On a case-by-case basis, the Sponsor may make a determination as 
to whether sample integrity has been compromised. Any sample deemed outside of 
established stability, or of questionable integrity, will be considered a protocol deviation.
As part of further understanding the biological response to study intervention, samples may 
be used for evaluation of other related genotyping as well as development and validation of 
bioanalytical methods.
Any data outside of the SLCO 1B1/1B3/2B1, SLC10A1, ABCG2, PNPLA3 and HSD17b13 
genotyping will be used for internal exploratory purposes and will not be included in the 
clinical study report. 
8.7.2. Banked Biospecimens for Genetics
A 4 mL blood sample optimized for DNA isolation (Prep D1) will be collected as local 
regulations and IRBs/ECs allow – refer to SoA - Table 2.
Banked Biospecimens may be used for research related to the study intervention(s) and 
NAFLD/NASH. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the banked samples.
See Appendix 10.5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in Sponsor-identified study-specific 
central laboratory manual.
8.8. Biomarkers
Blood, serum, and plasma samples for exploratory biomarkers (refer to Table 6) including 
NAFLD/NASH-related biomarkers, potential mechanism-related parameters, metabolic 
parameters, and aide in understanding the study interventions, will be collected at the
nominal time points defined in the SoA - Table 2.

Collection of these samples for exploratory biomarker research is part of this study;

These samples must be processed and shipped as indicated in the study-specific 
laboratory manual provided by the Sponsor to the site, prior to initiation of study, to 
maintain sample integrity:


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
Any deviations from the sample handling procedure (eg, sample collection and 
processing steps, interim storage or shipping conditions), including any actions 
taken, must be documented as protocol deviation and reported to the Sponsor. On 
a case-by-case basis, the Sponsor may make a determination as to whether sample 
integrity has been compromised;

Any scheduled collection prior to next dose of blinded study intervention, if
undertaken postdose, will be captured as a protocol deviation even if results are 
deemed evaluable;

Samples will be analyzed using a validated analytical method (which need not meet 
GLP standards, especially for these exploratory endpoints) but in all cases, the 
method will be in compliance with Pfizer standard operating procedures.
In addition, as part of further understanding the biological response to study intervention, 
samples may be used for evaluation of other related biomarkers as well as development and 
validation of bioanalytical methods. These data will be used for internal exploratory 
purposes and will not be included in the clinical study report. 
8.8.1. Banked Biospecimens for Biomarkers
Additional Banked Biospecimens in this study are as follows and collected at the time points 
outlined in the SoA - Table 2:

4 mL Prep B1.5 blood collection tube (for plasma); 

6 mL Prep B2.5 blood collection tube (for serum). 
Banked Biospecimens will be collected as local regulations and IRB/ECs allow. 
Banked Biospecimens may be used for research related to the study intervention(s) and 
NAFLD/NASH. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the banked samples. 
Collection of these samples for exploratory biomarker research is part of this study.  
See Appendix 10.5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in Sponsor-identified study-specific 
central laboratory manual. 
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.


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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined in this section of the protocol 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. Estimands and Statistical Hypotheses
9.1.1. Estimands
Two estimands are defined for this study. Estimand 1 will be used in Part 1 and Part 2 to 
support objectives related to imaging assessments for continuous endpoints assessed at 
Week 6. Estimand 2 will be used in Part 1 and Part 2 to support all other objectives for 
continuous endpoints assessed over time.
Estimand 1: For a given endpoint, the estimand will be the estimated population based 
average treatment effect on natural log-transformed relative change from baseline for 
DGAT2i + ACCi relative to placebo at Week 6 for all randomized/evaluable participants.
Intercurrent Events: 

Non evaluable baseline – All data collected post-randomization will be excluded.

Withdrawal from study intervention after randomization – All data collected after a 
participant stops taking study intervention will be excluded. 

Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the primary endpoint will be omitted from the 
analysis. The list of concomitant medications would be reviewed prior to database 
lock to determine which would be classed as “prohibited” for this estimand.

Inadequate compliance – All randomized/evaluable participants with compliance 
<80%, over the entire duration of dosing with double-blind, double-dummy study 
intervention, will not have their endpoint measurement used as recorded in the 
analysis.  
Population level summary: 

The population level summary will be the mean difference in natural log-transformed 
relative change from baseline between DGAT2i + ACCi groups and placebo groups 
for the endpoint of interest at Week 6.
Estimand 2: For a given endpoint, the estimand will be the estimated population based 
average treatment effect on natural log-transformed relative change from baseline for 
DGAT2i + ACCi relative to placebo over time for all randomized/evaluable participants.


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Intercurrent Events:

Non evaluable baseline – All data collected post-randomization will be excluded.

Withdrawal from study intervention after randomization – All data collected after a 
participant stops taking study intervention will be included.

Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the endpoint will be omitted from the analysis. The 
list of concomitant medications would be reviewed prior to database lock to 
determine which would be classed as “prohibited” for this estimand.

Inadequate compliance – All randomized/evaluable participants, regardless of the 
level of compliance, will have their endpoint measurement used as recorded in the 
analysis.
9.1.2. Hypothesis Tests
No formal hypothesis tests are planned for Part 1 or Part 2.
9.2. Sample Size Determination
9.2.1. Part 1
The proposed sample size for this study is approximately 90 participants randomized 
(18 participants per group) to ensure at least 75 participants (15 participants per group) offer 
evaluable data.  With a sample size of 15 completers per group and with natural 
log-transformed SD of 0.221 for liver fat (assessed via MRI-PDFF), a 25% placebo-adjusted 
liver fat decrease can be detected at a significance level of 5% 1-sided with a power >90%.
9.2.2. Part 2
In Part 2, it is envisioned that number of participants randomized to each active dose of 
DGAT2i + ACCi or placebo may be adjusted.  Those assigned to placebo may be reduced, 
given intent to pool data from all participants receiving placebo when summarizing 
end-of-study results. And while a maximum of 4 active doses (plus placebo) will be 
evaluated in Part 2, the total number of participants will not exceed 90 (with no more than 
approximately 27 participants per each active dose). 
9.3. Analysis Sets
Data for any dose groups repeated in Part 1 and Part 2 (at a minimum placebo), will be 
pooled for purposes of summarizing end-of-study results and reporting these data in the 
clinical study report.


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9.3.1. Part 1
For purposes of analysis, the following analysis sets are defined:
Participants Analysis 
Set
Description
Enrolled 
All participants who sign the preQ ICD.
Randomly assigned to 
investigational product
All participants randomly assigned to IP regardless of whether or not study 
intervention was administered.
Evaluable
All participants randomly assigned to IP and who take at least 1 dose of IP.  
Participants will be analyzed according to the randomized intervention.
Safety
All participants randomly assigned to IP and who take at least 1 dose of IP.  
Participants will be analyzed according to the product they actually received.
Defined Population for 
Analysis
Description
Estimand Set 1 
All evaluable participants randomly assigned to study intervention and who take 
at least 1 dose of study intervention (ie Placebo/DGAT2i + ACCi).  
PK Concentration Set
All participants randomly assigned to study intervention and who take at least 
1 dose of DGAT2i + ACCi and in whom at least 1 concentration value is
reported.
9.3.2. Part 2
Analysis set for Part 2 is envisioned to be identical to Part 1.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses of Part 1 (eg, interim analysis) 
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 for Part 1 and optional Part 2 of the study.
9.4.1. Primary Endpoint(s)
Endpoint
Statistical Analysis Methods
Percent change from 
baseline in liver fat as 
assessed via MRI-PDFF at 
Week 6

An ANCOVA analysis will be performed on the natural log-transformed
relative change from baseline in fasting liver fat values at Weeks 6 from 
the Estimand Set 1 to estimate the treatment effect related to the 
Estimand 1.

The model will include treatment as fixed effect, baseline as a covariate 
effect. 

No adjustments will be made for multiplicity.


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9.4.2. Secondary Endpoint(s)
Endpoint
Statistical Analysis Methods
Percent change from 
baseline in fasting serum 
triglyceride levels over 
time

A mixed model repeated measures (MMRM) analysis will be fitted to 
natural log-transformed relative change from baseline in fasting serum 
triglycerides at Weeks 2, 4, 6, and Follow-Up from the Estimand Set 2 to 
estimate the treatment effect related to the Estimand 2.

The MMRM will include treatment, time, and treatment-by-time interaction 
as fixed effects, baseline as a covariate effect and participant as a random 
effect.  An unstructured correlation matrix will be used, and the
Kenward-Roger approximation will be used for estimating degrees of 
freedom for the model parameters.

Missing values will be imputed as part of the MMRM model assumptions.

No adjustments will be made for multiplicity.
9.4.3. Tertiary/Exploratory Endpoint(s)
Endpoints
Statistical Analysis Methods
Refer to Table 5
Will be described in the SAP finalized before any analyses of Part 1 (eg interim 
analysis).
Beyond the objectives, estimands, and endpoints outlined in Section 3 this study will also 
evaluate the objectives/endpoints summarized in Table 5.


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Table 5.
Additional Tertiary/Exploratory Objectives and Endpoints
Objectives
Endpoints
To evaluate concordance between effect on liver fat 
of a range of DGAT2i doses coadministered with 
fixed dose of ACCi, compared to placebo, determined 
by MRI-PDFF, versus 2 different quantitative 
ultrasound techniques (CAP™by FibroScan®, and 
UDFF™by Acuson Sequoia®) in participants with 
presumed NASH
Percent change from baseline at Week 6 in:
MRI-PDFF
CAP™
UDFF™
To evaluate concordance between liver stiffness
determined by 2 different quantitative ultrasound 
techniques (VCTE™by FibroScan®, and SWE by 
Acuson Sequoia®) in participants with presumed 
NASH
Values at baseline and Week 6 in:
VCTE™
SWE™
To evaluate effect on liver function tests of a range 
of DGAT2i doses coadministered with fixed dose of 
ACCi, compared to placebo in participants with 
presumed NASH
Percent change from baseline, over time, in: 
ALT
AST
Alkaline Phosphatase
Total Bilirubin and
GGT
To evaluate effect on metabolic parameters of a 
range of DGAT2i doses coadministered with fixed 
dose of ACCi, compared to placebo in participants 
with presumed NASH
Percent change from baseline, over time, in:
Total cholesterol
Direct LDL
HDL-C
Direct VLDL
Apolipoprotein A1, Btotal, B100, B48, C3, and E 
Change from baseline, overtime, in:
HbA1C
FPG
FPI
HOMA-IR
To evaluate the effect on mechanism/disease-related
biomarkers of a range of DGAT2i doses 
coadministered with fixed dose of ACCi, compared to 
placebo in participants with presumed NASH

Percent change over time in: 
CK 18-M30, -M65
Pro-C3, and Pro-C6
PCSK9
Adiponectin
hsCRP
To summarize plasma PK of DGAT2i and ACCi, 
across the active doses of DGAT2i + ACCi evaluated
in participants with presumed NASH
Predose DGAT2i and ACCi plasma concentrations (ie, Ctrough) 
To enable the exploratory research through collection 
of banked biospecimens, unless prohibited by local 
regulations or ethics committee decision
Biobanking of blood-based specimens (including Prep D1, 
B1.5, and B2.5 collections to permit retrospective analysis of 
yet-to-be identified biomarkers) 
These results may or may not be generated in the context of 
the present study
For all endpoints, baseline is defined as the evaluable result closest prior to dosing on Day 1.


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9.4.4. Pharmacokinetic Analysis
All pharmacokinetic analyses will be performed on the PK concentration set. 
Plasma concentration data for DGAT2i and ACCi will be listed and summarized (Ctrough
only) by treatment. 
In addition, as permitted by data and determined by the Sponsor, exposure-response 
relationships between plasma concentrations of DGAT2i and/or ACCi and effect on primary, 
secondary and tertiary endpoints may be characterized using a population PK/PD approach. 
The objectives of such an analysis, if conducted, would aim to characterize 
exposure-response relationships and explore potential covariates (eg, age, race, gender, and 
body weight, etc.) influencing the observed PK and/or response to DGAT2i and/or ACCi. 
The population PK and/or PK/PD analyses, if conducted, will be reported separately from the 
main clinical study report. 
9.4.5. Other Safety Analyses
All safety analyses will be performed on the safety population.
The safety data will be summarized in accordance with Pfizer Data Standards.  All 
participants who receive study intervention (safety population) will be included in the safety
analyses.  All safety data will be summarized descriptively through appropriate data 
tabulation, descriptive statistics, categorical summaries, and graphical presentations.
Endpoint
Statistical Analysis Methods
Secondary
(refer to 
Section 3)

The secondary endpoint will be analyzed in accordance with Pfizer Data Standards as 
above.

The primary analyses will be on the incidence and severity of all treatment emergent 
adverse events (TEAE), that will be reported by treatment group.  The number of 
participants and percent will be presented.
The MedDRA dictionary will be used to classify all AEs with respect to system organ class 
and preferred term. Summaries of AEs will include treatment-emergent AEs according to 
treatment group. 
9.4.5.1. Vital Signs Analyses
Changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate will 
be summarized by treatment and time. The number (%) of participants with maximum 
increases from baseline will be tabulated by treatment as defined in the SAP. Numbers and 
percentages of participants meeting the categorical criteria will be provided and individual 
values listed in the study report. No formal inferential statistics will be applied to the vital 
signs data.


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9.4.5.2. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will be summarized by treatment and time. QTcF will be derived
using Fridericia’s heart rate correction formula. The number (%) of participants with 
maximum increases from baseline will be tabulated by treatment as defined in the SAP. 
Numbers and percentages of participants meeting the categorical criteria will be provided and 
individual values listed in the study report. No formal inferential statistics will be applied to 
the ECG data.
9.4.6. Other Analyses
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned to 
be included in the CSR.
9.5. Interim Analyses
Interim analyses will be performed after completion of Part 1 (refer to Figure 1) to determine 
whether to conduct Part 2 and if so, guide selection of doses of DGAT2i and/or ACCi to 
evaluate in Part 2.  Interim analysis results may be used to conduct a sample size 
re-estimation (eg, observed variability in Part 1 is higher than assumed for derivation of 
sample size for Part 1), facilitate PK/PD modeling, and internal business decisions regarding 
planning of future trials with DGAT2i and/or DGAT2i+ACCi.  Before the interim analysis is 
instigated, the details of the objectives, decision criteria, dissemination plan, and method of 
maintaining the study blind as per Sponsor’s SOPs will be documented and approved in an 
interim analysis SAP or final SAP.
9.5.1. PK/PD Modeling 
A limited number of individuals not on the study team will be unblinded according to 
Sponsor SOPs with the purpose of composing PK/PD analysis sets and conducting PK/PD 
analysis. Data draws are expected at approximately 50%, and 100% of total study data from
Part 1. These data are expected to include the primary endpoint (MRI-PDFF), plasma PK for 
DGAT2i and ACCi, fasting serum lipid parameters including fasted serum triglycerides (and 
fasted serum apolipoproteins, if available).  Other data outlined in Table 5, may also be 
considered. The PK/PD analysis output at the completion of Part 1 (ie, achievement of 
LPLV in Part 1) will be shared as part of the planned Interim Analysis with selected 
members of the Sponsors’ study team to enable decision to conduct Part 2 and if so, the 
dose(s) and dosing regimen(s) of DGAT2i + ACCi evaluated in Part 2.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use an IRC. The IRC will undertake periodic unblinded review of the safety 
data while the study is on-going. These reviews are envisioned, at a minimum, after 
approximately 33%, and 66%, of planned total sample size in Part 1 (and separately if 
conducted, Part 2), has been randomized. The IRC is independent of the study team and 


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includes 3 senior Sponsor colleagues members with no direct involvement in the conduct of 
the study. The IRC charter describes the role of the IRC in more detail.

Across the IRC members, there will be at least 1 medically-qualified individual, and 
1 statistician.

The IRC will be responsible for ongoing monitoring of the safety of participants in 
the study according to the charter. The recommendations made by the IRC to alter 
the conduct of the study will be forwarded to the appropriate Pfizer personnel for 
final decision.  Pfizer will forward such decisions, which may include summaries of 
aggregate analyses of safety data, to regulatory authorities, as appropriate.


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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 sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  The participant should be given 
sufficient time and opportunity to ask questions and to decide whether or not to participate in 
the trial.
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.  Participants who are rescreened
are required to sign new ICD(s).


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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 study 
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.
The investigator must maintain accurate documentation (source data) that supports the
information entered in the CRF.
Definition of what constitutes source data can be found in the clinical 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 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 from Part 1 and Part 2 are envisioned to be presented as a single pooled dataset at 
the end of the trial at a scientific meeting.  Beyond this, 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 


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authorship requirements. If publication is addressed in the clinical study agreement, the 
publication policy set out in this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or
problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  The contact number is not intended for use by the participant directly, 
and if a participant calls that number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
Table 6 delineates the protocol mandated safety related laboratory tests and exploratory 
biomarkers to be collected following an overnight fast of ≥8 hours. The required blood and 
urine collections will be performed at times defined in SoA - Table 2. 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.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigator 
sites or other blinded personnel until the study has been unblinded.
Table 6.
All Planned Protocol Required Safety-Related Laboratory Tests and 
Exploratory Biomarkers in Study C3711005
Hematology
Chemistry
Urinalysis
Hemoglobin
Hematocrit
RBC count
Reticulocyte count (Abs)
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
Cystatin-C (and eGFR using 
CKD-Epi-Cystatin-C)
Plasma Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST (SGOT)
ALT (SGPT)
Total bilirubin
Alkaline phosphatase
GGT
Direct (conjugated) bilirubin
Indirect (unconjugated) bilirubin
Total bile acids
Creatine Kinase
Uric acid
Albumin
Total protein
−pH
−Glucose (qual)
−Protein (qual)
−Blood (qual)
−Ketones
−Nitrites
−Leukocyte esterase
−Urobilinogen
−Urine bilirubin
−Microscopya


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Other 

HbA1C

Coagulation (Plasma aPTT, PT, INR)

Serum FSHb

Serum and urine pregnancy test (refer to Section 8.2.6)

Urine drug testc

1-antitrypsind

ceruloplasmind

Serology:d HBsAg, HCVAb (and if positive, reflex HCV RNA), HIV

%CDTe

Fasting serum Lipid Panelf
Additional exploratory biomarker
assessmentsg include:
Serum apolipoproteins A1, Btotal, B100, B48,
C3, E, and direct VLDL
−Plasma Insulin
−hs-CRP
CK18-M30, CK18-M65
ProC3 and ProC6
Plasma PCSK9
Adiponectin
Pre-Specified PGx and Prep D1 (DNA)
Prep B1.5 (plasma) and B2.5 (serum) for 
mechanistic/disease-related biomarkers 
Additional Testsfor instances of suspected Hy’s Law [refer to 
Appendix 10.6]: 
ALT, AST (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase (repeat)
Direct bilirubin
Indirect bilirubin
Creatinine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or protein adduct levels
a.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b.
Only in females, at PreQ, and SCR, only.
c.
At PreQ, SCR, and Baseline/Visit 3, only; minimum requirement for urine drug test include cocaine,
opiates/opioids, benzodiazepines and amphetamines.
d.
At PreQ, and SCR, only.
e.
At PreQ, SCR, Day 1/Visit 4, and Week 6/Visit 7.
f.
Includes triglycerides, HDL-C, direct LDL-C, and total cholesterol.
g.
At Baseline/Visit 3 and onwards, as per SoA - Table 2.
For list of terms corresponding to the abbreviations used herein, refer to Appendix 10.12.


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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 


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sequelae.
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 


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should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  These
requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse events 
(AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 


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


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


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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 make attempts to locate, where applicable, 
and 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 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 
with DGAT2i and ACCi.
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 a contraceptive method that is highly effective (with a failure
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 28 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate any reproductive 
safety risk of the study intervention(s). 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;


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
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
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 of age and not using hormonal 
contraception or HRT. 

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen 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.
In addition, one of the following effective barrier methods must also be used when 
option 6 or 7 are chosen above:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).


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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors
involved in the response to the study intervention or study interventions of this class 
to understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in CSR or in a separate study 
summary or may be used for internal decision making without being included in a 
study report.

The Sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7.1) will be stored for up to 
3 years after regulatory approval or other period as per local requirements.

Samples for banking will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.

Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.


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


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as Serious Adverse Events

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node;

In awake, symptom-free patients with atrial fibrillation and bradycardia with 
1 or more pauses of at least 5 seconds or longer;

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to 


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<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR >100 bpm 
(such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications 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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10.8. Appendix 8: Strong CYP3A Inhibitors and Inducers
This list is not considered as exhaustive. Any questions regarding use of CYP3A inhibitors 
and inducers should be directed to the Sponsor study team.
CYP3A Inhibitors
CYP3A Inducers
HIV antivirals
HIV antivirals
Indinavir
Nevirapine
Nelfinavir
Miscellaneous
Ritonavir
Barbiturates
Saquinavir
Carbamazepine
Boceprevir
Glucocorticoids(systemic)
Lopinavir/ritonavir
Oxcarbazepine
Amprenavir
Phenobarbital
Atazanavir
Phenytoin
Telaprevir
Rifabutin
Darunavir/ritonavir
Rifampin
Fosamprenavir
St. John's wort3
Tiprinavir/ritonavir
Troglitazone
Antibiotics
Nafcillin
Clarithromycin
Avasimibe4
Troleandomycin
Enzalutamide
Telithromycin
Mitotane
Anti-infective
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Miscellaneous
Nefazodone
Grapefruit juice1
Conivaptan
Mibefradil2
Idelalisib
1.
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another
preparation was used (eg, low dose, single strength).
2.
Withdrawn from the United States market.
3.
The effect of St. John’s wort varies widely and is preparation-dependent.
4.
Not a marketed drug.
Reference: U.S. Food and Drug Administration. Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers, available at:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm.


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10.9. Appendix 9: Guidance to Investigators – Management of Individual Participants 
Glycemic Control – including Metformin Dose Starting at Run-In/Visit 2  
Is Participant with T2DM 
on Metformin at SCR? 
Is TDD > 1 gm per day?
No
Yes
Starting at Run-In/Visit 2, participant must 
agree to drop TDD by one-third or one-
half, guided by available tablet strengths
Is Fasting Plasma Glucose > 270 mg/dL [15 mmol/L] at any visit between Week 2/Visit 5
and Week 6/Visit 7, inclusive, as assessed via Sponsor-identified central laboratory?
No
Yes
Participant to be Screen Failed 
And metformin dose returned to 
be same as prior to Run-In/Visit 2
At Baseline/Visit 3 (or repeat, if done), is FPG result 
≤ 270 mg/dL (15 mmol/L)?
Yes
No
No
Yes
Continue to next 
Scheduled Visit
Arrange for an unplanned visit 
within 5 ± 2 days of receipt of 
results from scheduled visit 
and re-assess FPG
Is Participant on 
Metformin? 
Increase dose to match 
TDD prior to Run-In/Visit 2
Yes
No
If unplanned visit fasting result is 
> 270 mg/dL [15 mmol/L], withdraw participant from study
≤270 mg/dL [15 mmol/L], continue to next Scheduled Visit [though, at investigator 
discretion, additional unplanned visit(s) before next Scheduled Visit permitted]  


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10.10. Appendix 10: Guidance to Investigators – Management of Individual 
Participants with Elevation in Fasting Serum Triglycerides
Serum Triglyceride result at Visits starting at Day 1/Visit 4 to Week 6/Visit 7, inclusive, 
as assessed via Sponsor-identified central laboratory is…
Was Scheduled Visit collection post ≥ 8-hr overnight fast?
Yes
No
Arrange for an unplanned visit within 5 ± 2 days 
of receipt of results from scheduled visit
Collect lipid panel post ≥ 8-hr overnight fast
≥ 600 and < 800 mg/dL
[≥ 6.8 and < 9.0 mmol/L]
≥ 800 mg/dL
[≥ 9.0 mmol/L]
Participant to return for next 
Scheduled Visit post ≥ 8-hr
overnight fast
Was Scheduled Visit collection post ≥ 8-hr overnight fast?
Yes
No
If unplanned visit result is…
• ≥ 600 and < 800 mg/dL [≥ 6.8 and < 9.0 mmol/L]
• Participant to return for next scheduled visit post ≥ 8-hr overnight fast
• At Investigator discretion, additional unplanned visit(s) before next Scheduled Visit permitted
• ≥ 800 mg/dL [≥ 9.0 mmol/L]
• Participant should be withdrawn from study 
Participant should be 
withdrawn from study


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10.11. Appendix 11: Guidance to Investigators – Management of Individual 
Participants With Decrease in Platelet Count
Platelet Count result at Visits starting on Day 1/Visit 4 to Week 6/Visit 7, inclusive, 
as assessed via Sponsor-identified central laboratory is…
Was Scheduled Visit result representing 
a continued decline relative to result(s) 
from prior visit(s)?
Yes
No
Arrange for an unplanned visit within 5 ± 2 days 
of receipt of results from scheduled visit
Collect hematology panel
≥ 75,000 per mm3
And < 100,000 per mm3
< 75,000 per mm3
Participant to return for 
next Scheduled Visit
Was Scheduled Visit result representing 
a continued decline relative to result(s) 
from prior visit(s)?
Yes
No
If unplanned visit result is…
• ≥ 75,000 and < 100,000, per mm3
• Participant to return for next Scheduled Visit 
• At Investigator discretion, additional unplanned visit(s) before next Scheduled Visit permitted
• < 75,000 per mm3
• Withdraw participant from study 
Withdraw participant from study


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10.12. Appendix 12: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%CDT
percent carbohydrate deficient transferrin relative to total transferrin
A1AT
Alpha-1-antitrypsin
ABCG2
constitutively expressed ATP-binding cassette transporter
Abs
Absolute
ACC
acetyl-CoA carboxylase
ACCi
acetyl-CoA carboxylase inhibitor (PF-05221304)
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
ANCOVA
Analysis of Covariance 
Apo
Apolipoprotein
aPTT
activated partial thromboplastin time
AST 
aspartate aminotransferase 
ATP
adenosine triphosphate
AUC0-24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUCtau
area under the concentration-time curve from time 0 to end of dosing period
AUDIT
Alcohol use disorders identification test
AV
Atrioventricular
BBS
Biospecimen Banking System
BCRP
breast cancer resistant protein
BID
bis in die (twice-a-day)
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CAPTM
Controlled attenuation parameter
CDT
Carbohydrate deficient transferrin
CFR
code of federal regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatinine kinase
CK18-M30
cytokeratin-18-M30 fragment
CK18-M65
cytokeratin-18-M65 fragment
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration equation
Cmax
peak or maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CoA
coenzyme A
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form


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Abbreviation
Term
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
Ctrough
plasma concentration before next dose
CYP
Cytochrome P-450 (3A, 2B6, 2C9, 2C19)
D/C
Discontinue
DAG
Diacylglycerol
dB/m
decibels per meter
DCCT
Diabetes Control and Complications Trial
DDI
drug drug interaction
DGAT1
diacylglycerol acyltransferase 1
DGAT2
diacylglycerol acyltransferase 2
DGAT2i
diacylglycerol acyltransferase 2 inhibitor (PF-06865571)
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
DPP-IVi
dipeptidyl peptidase-IV 
DU
dispensing Unit
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form 
ED50
dose that produces half maximum drug effect 
EDP
exposure during pregnancy
EFD
embryo-fetal developmental
eGFR
estimated glomerular filtration rate
EMA
European Medical Agency
EU
European Union
EudraCT
European Clinical Trials Database
F/U
follow-up
FFA
free fatty acid
FPG
fasting plasma glucose
FPI
fasting plasma insulin
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HbA1C
glycated hemoglobin
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV RNA
hepatitis C virus genetic material (ie, Ribonucleic acid)
HCVAb
hepatitis C virus antibody
HDL-C
high density lipoprotein cholesterol 
HIPPA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-IR
homeostatic model assessment of insulin resistance


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Abbreviation
Term
HR
heart rate
HRT
hormone replacement therapy
hs-CRP
high-sensitive C-reactive protein
HSD17b13
17-Hydroxysteroid dehydrogenase type 13
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IPAL
Integrated Path to Architectural Licensure
IRB
Institutional Review Board
IRC
internal review committee
IRT
interactive response technology
IWR
interactive web response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kPa
kilopascals
LDL-C
low density lipoprotein-cholesterol
LFTs
liver function tests
LLN
lower limit of normal
LPLV
last participant last visit
LS
least square
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MELD-Na
model of end-stage liver disease including serum sodium (in addition to serum creatinine, 
bilirubin, and INR)
MMRM
mixed model repeated measure
MR
magnetic resonance
MRI
magnetic resonance imaging
MRI-PDFF
magnetic resonance imaging using proton density fat fraction acquisition 
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NASH
Nonalcoholic steatohepatitis
NGSP
National Glycohemoglobin Standardization Program
NOAEL
no observed adverse effect level
non-HDL
non-high density lipoprotein cholesterol
NSAIDs
non-steroidal anti-inflammatory drugs 
NTCP
sodium-dependent uptake transporter
NYHA
New York Heart Association
OAT
organic anion transporter (P1B1, P1B3, P2B1) 
OATP
organic anion-transporting polypeptide


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Abbreviation
Term
OCT2
organic cation transporter 2
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
Pharmacodynamics
PE
physical exam
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PI
principal investigator
PK
Pharmacokinetics
PK/PD
pharmacokinetic-pharmacodynamic
PNPLA3
patatin like phospholipase domain containing protein 3
PreQ
prequalification visit
ProC3
N-terminal propeptide of type III procollagen
ProC6
C-terminal fragment of α3 chain of procollagen type VI  
PT
prothrombin time
PVC
premature ventricular contraction
Q12H
every 12 hours (eg, dosing)
Q8H
every 8 hours
QD
quaque die (once-a-day)
QRS
combination of Q-, R- and S- wave on an electrocardiogram representing ventricular
depolarization
QTc
QT interval corrected for heart rate 
QTcF
Fridericia’s formula, a correction formula for the QC interval
RBC
red blood cell
RNA
ribonucleic acid
RR
interval between 2 successive R waves in a QRS complex
SAE
serious adverse event
SAP
statistical analysis plan
SCR
Screen/Visit 1
SD
standard deviation
SGOT
serum glutamic oxalo-acetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLC10A1
solute carrier Family 10 Member 1
SLCO
solute carrier organic transporter family member (1B1, 1B3, 2B1)
SoA
Schedule of Activities
SOP
standard operating procedure
SREBPs
sterol regulatory-element binding proteins
SRSD
single reference safety document
SSID
service set identifier
SUSAR
suspected unexpected serious adverse reaction
SWE
Sheer wave elastography
t1/2
terminal half-life 
T1D
type 1 diabetes
T2DM
type 2 diabetes mellitus
TBili
total bilirubin
TEAE
treatment-emergent adverse event


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Abbreviation
Term
TI
therapeutic index
TZD
Thiazolidinediones
UDFF™
ultrasound-derived fat fraction
ULN
upper limit of normal
US
United States
VCTETM
Vibration-Controlled Transient Elastography
VLDL
very low-density lipoprotein
WBC
white blood cell
WOCBP
women of childbearing potential


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11. REFERENCES
                                                
1
Yen CL, Stone SJ, Koliwad S, et al. Thematic review series: glycerolipids. DGAT 
enzymes and triacylglycerol biosynthesis. J Lipid Res 2008;49(11)(Nov):2283-301.
2
Buhman KK, Smith SJ, Stone SJ, et al. DGAT1 is not essential for intestinal
triacylglycerol absorption or chylomicron synthesis. J Biol Chem
2002;277(28)(12 Jul):25474-9.
3
Cases S, Stone SJ, Zhou P, et al. Cloning of DGAT2, a second mammalian 
diacylglycerol acyltransferase, and related family members. J Biol Chem
2001;276(42)(Oct):38870-6.
4
Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev
Nutr 2008;28:253-72.
5
Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic 
steatosis but elevated plasma triglycerides in mice and humans: a bedside to bench 
investigation. Cell Metab 2017;26(2)(Aug):394-406e6.
6
Sanyal AJ, Friedman SL, McCullough AJ, et al. Challenges and opportunities in drug 
and biomarker development for nonalcoholic steatohepatitis: findings and 
recommendations from an American Association for the Study of Liver Diseases-U.S. 
Food and Drug Administration Joint Workshop. Hepatology 2015;61(4)(Apr):1392-405.
7
Khan FZ, Perumpail RB, Wong RJ, et al. Advances in hepatocellular carcinoma:
Nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 
2015;7(18)(Aug):2155-61.
8
Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic 
fatty liver disease – meta-analytic assessment of prevalence, incidence, and outcomes.
Hepatology 2016;64(1)(Jul):73-84.
9
Lambert JE, Ramos-Roman MA, Browning JD, et al. Increased de novo lipogenesis is a 
distinct characteristic of individuals with nonalcoholic fatty liver disease. 
Gastroenterology 2014;146(3)(Mar):726-35.
10
Regev A, Palmer M, Avigan MI, et al. Consensus: guidelines: best practices for 
detection, assessment and management of suspected acute drug-induced liver injury 
during clinical trials in patients with nonalcoholic steatohepatitis. Aliment Pharmacol 
Ther 2019;49(6)(03):702-13.


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11
Babor TF, Higgins-Biddle JC, Saunders JB, et. al. AUDIT. The alcohol use disorders 
identification test. Guidelines for use in primary care. WHO/MSD/MSB/01.6a. Geneva, 
Switzerland: World Health Organization; 2001: 40 pages.
12
Younossi ZM, Loomba R, Anstee QM, et al. Diagnostic modalities for nonalcoholic 
fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology
2018;68(1)(07):349-60.
13
Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from 
serum creatinine and cystatin C. N Engl J Med 2012; 367(1)(Jul):20-9.
14
Wong VW, Adams LA, de Ledinghen V, et al. Noninvasive biomarkers in NAFLD and 
NASH – current progress and future promise. Nat Rev Gastroenterol Hepatol
2018;15(8)(08):461-78.
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)(Dec):23.
16
Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients 
on the liver-transplant waiting list. N Engl J Med 2008;359(10)(Sep):1081-26.

SAP_001.pdf: 
Protocol C3711005 (PF-06865571 + PF-05221304) 
Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3711005
A PHASE 2A, 2-PART, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY 
PLACEBO-CONTROLLED, PARALLEL-GROUP (SPONSOR OPEN) STUDY TO 
ASSESS PHARMACODYNAMICS AND SAFETY OF PF-06865571 (DGAT2I)
COADMINISTERED WITH PF-05221304 (ACCI) IN ADULT PARTICIPANTS
WITH PRESUMED NONALCOHOLIC STEATOHEPATITIS (NASH)
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
16-Jun-2021


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Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives, Endpoints, and Estimands............................................................8
2.1.1. Estimand 1 ..................................................................................................10
2.1.2. Estimand 2 ..................................................................................................10
2.1.3. Estimand 3 ..................................................................................................11
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoint(s) ................................................................................................13
3.1.1. Liver Fat Assessed Using MRI-PDFF at Week 6.......................................13
3.2. Secondary Endpoint(s) ............................................................................................13
3.2.1. Fasting Serum Triglycerides Over Time ....................................................13
3.2.2. Safety and Tolerability ...............................................................................13
3.3. Other Endpoint(s)....................................................................................................13
3.3.1. Liver Fat determined by Quantitative Ultrasound Using FibroScan®........13
3.3.2. Liver Stiffness Determined by Quantitative Ultrasound Using 
FibroScan®.......................................................................................................13
3.3.3. Liver Function Tests Over Time.................................................................14
3.3.3.1. Alanine Aminotransferase (ALT) .............................................14
3.3.3.2. Aspartate Aminotransferase (AST)...........................................14
3.3.3.3. Alkaline Phosphatase (ALKP) ..................................................14
3.3.3.4. Total Bilirubin (TBIL) ..............................................................14
3.3.3.5. Gamma Glutamyl Transferase (GGT).......................................14
3.3.4. Metabolic Parameters Over Time...............................................................15
3.3.4.1. Total Cholesterol.......................................................................15
3.3.4.2. Direct Low Density Lipoprotein (Direct LDL).........................15
3.3.4.3. High Density Lipoprotein Cholesterol (HDL-C) ......................15
3.3.4.4. Direct Very Low Density Lipoprotein (Direct VLDL).............15


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3.3.4.5. Apolipoproteins.........................................................................15
3.3.4.6. Derived non-High-Density Lipoprotein Cholesterol (Non-
HDL-C)..............................................................................................16
3.3.4.7. Glycated Hemoglobin A1C (HbA1C).......................................16
3.3.4.8. Fasting Plasma Glucose (FPG) .................................................16
3.3.4.9. Fasting Plasma Insulin (FPI).....................................................16
3.3.4.10. Homeostatic Model Assessment for Insulin Resistance
(HOMA-IR).......................................................................................16
3.3.5. Biomarkers..................................................................................................17
3.3.5.1. Markers of Apoptotic Activity (CK18-M30 and CK18-
M65) ..................................................................................................17
3.3.5.2. Markers of fibrinogenesis (ProC3 and ProC6)..........................17
3.3.5.3. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)........17
3.3.5.4. Adiponectin ...............................................................................17
3.3.5.5. High Sensitive C-Reactive Protein (hsCRP).............................18
3.4. Baseline Variables...................................................................................................18
3.5. Safety Endpoints .....................................................................................................18
3.5.1. Adverse Events...........................................................................................18
3.5.2. Laboratory Data..........................................................................................19
3.5.3. Standard Safety Other than AEs.................................................................21
3.5.3.1. Vital Signs of Special Clinical Concerns ..................................21
3.5.3.2. ECG of Special Clinical Concerns............................................21
3.5.3.3. Background Medications of Special Interest ............................22
3.5.3.4. Platelet Count ............................................................................22
3.5.3.5. Estimated Glomerular Filtration Rate .......................................23
3.5.3.6. Alcohol Intake...........................................................................23
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................23
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................24
5.1. Hypotheses and Decision Rules ..............................................................................24
5.2. General Methods .....................................................................................................24
5.2.1. Analyses for Binary Endpoints...................................................................24
5.2.2. Analyses for Continuous Endpoints ...........................................................24
5.2.3. Analyses for Categorical Endpoints ...........................................................25


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5.2.4. Analysis of Covariance (ANCOVA)..........................................................25
5.2.5. Longitudinal Analysis.................................................................................26
5.3. Methods to Manage Missing Data ..........................................................................27
5.3.1. Deviations, Missing Concentrations and Anomalous Values.....................27
5.3.2. Pharmacokinetic Parameters.......................................................................27
5.3.3. Pharmacodynamic Parameters....................................................................27
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoint ....................................................................................................28
6.1.1. Liver Fat Content Assessed Using MRI-PDFF at Week 6.........................28
6.2. Secondary Endpoint(s) ............................................................................................29
6.2.1. Fasting Serum Triglycerides Over Time ....................................................29
6.2.2. Safety and tolerability.................................................................................30
6.3. Other Endpoint(s)....................................................................................................30
6.3.1. Liver Fat Content Using CAP® by FibroScan®..........................................30
6.3.2. Liver Stiffness Assessed Using by FibroScan®..........................................31
6.3.3. Liver Function Tests Over Time.................................................................31
6.3.4. Other Fasting Serum Lipids Over Time .....................................................32
6.3.5. Apolipoproteins Over Time........................................................................33
6.3.6. HbA1C, FPG, FPI and HOMA-IR Over Time...........................................34
6.3.7. Mechanism/Disease-Related Biomarkers Over Time ................................35
6.3.8. Body Weight...............................................................................................36
6.3.9. Pharmacokinetic Analysis ..........................................................................36
6.4. Subset Analyses.......................................................................................................36
6.5. Baseline and Other Summaries and Analyses.........................................................36
6.5.1. Physical Examination .................................................................................36
6.5.2. Standard Analyses ......................................................................................37
6.5.3. Baseline Summaries....................................................................................37
6.5.4. Concomitant Medications and Non-Drug Treatments................................37
6.5.5. Alcohol Intake ............................................................................................38
6.5.5.1. AUDIT Questionnaire...............................................................38
6.5.5.2. % Carbohydrate-Deficient Transferrin (%CDT).......................38
6.5.6. Other Analyses............................................................................................38


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6.6. Safety Summaries and Analyses .............................................................................38
6.6.1. Adverse Events...........................................................................................38
6.6.2. Vital Signs Analyses...................................................................................39
6.6.3. Electrocardiogram Analyses.......................................................................39
6.6.4. Other Safety Data .......................................................................................40
6.6.4.1. Platelet count.............................................................................40
6.6.4.2. Estimated Glomerular Filtration Rate .......................................41
6.6.4.3. Additional Graphical Representation........................................41
7. IRC REVIEW OF UNBLINDED SAFETY DATA (DURING STUDY CONDUCT)......41
7.1.1. Analyses and Summaries............................................................................42
7.2. Planned Interim Analysis Post Part 1 (and before start of Part 2)...........................43
8. REFERENCES ....................................................................................................................43
9. APPENDICES .....................................................................................................................44
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................7
Table 2.
Clinical Laboratory Parameters of Interest in Study C3711005..............19
Table 3
Vital Signs to be Monitored.....................................................................21
Table 4
ECG QT and QTc Interval Criteria to be Monitored...............................21
LIST OF FIGURES
Figure 1.
Overall Study Design................................................................................11
Figure 2.
Study Design for Part 1 and Optional Part 2...........................................12
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................44
Appendix 2. Data Derivation Details.......................................................................................45
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................45
Appendix 2.2. Endpoint Derivations .......................................................................................46
Appendix 2.2.1. % Liver Fat using MRI-PDFF.......................................................................46
Appendix 2.2.2. Compliance ...................................................................................................47


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Appendix 3. Statistical Methodology Details..........................................................................48
Appendix 3.1.1. MMRM for Safety Analysis and PD analysis:..............................................48
Appendix 3.1.2. ANCOVA for Safety Analysis and PD Analysis:.........................................48
Appendix 4. List of Abbreviations...........................................................................................49
Appendix 5. Graphical Representations ..................................................................................52
Appendix 5.1. Box and Whisker Plot Representation for Changes/Percent Changes 
from Baseline at Week 6 by Treatment ....................................................52
Appendix 5.2. Box and Whisker Plot for Changes/ Percent Changes From Baseline by 
Treatment and Week.................................................................................53
Appendix 5.3. LS Means and Placebo Adjusted LS Means with 80% CI from MMRM 
Analysis Over Time Versus Week per Treatment (to be adapted for 
C3711005 Design)....................................................................................54
Appendix 5.4. Example for LS Means and Placebo Adjusted LS Means with 80% CI 
from ANCOVA Analysis at Week 6 per Treatment (to be adapted 
for C3711005 Design) ..............................................................................55
Appendix 5.5. Example for Figure Reporting Multiple Laboratory Parameters Over 
Time Simultaneously (to be adapted for C3711005 Design) ...................56


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol Amendment
Rationale
Specific Changes
1 / 11-Aug-2020
Original protocol dated 27-Mar-2020 + 
associated PACL dated 01-Jul-2020
N/A
N/A
2 / 16-Jun-2021
Original protocol dated 27-Mar-2020 + 
associated PACL dated 01-Jul-2020 + 
associated PACL dated 22-Jan-2021
Per request from IRC as 
part of 1st safety review 
(May2021) to include
derived non-HDL-C 

Sections 2.1, 3.3.4, 6.3.4, and 7.1.1 were modified 
to include derived non-HDL-C as endpoint along 
with summarization, and analysis.

Appendix 4 was modified to include non-HDL-C 
acronym definition.


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2. INTRODUCTION
The current study is to evaluate the effect of coadministration of a range of doses of DGAT2i 
(ie, PF-06865571) with 1 (and potentially 2) doses of ACCi (ie, PF-05221304), on the 
primary pharmacology (effect on liver steatosis) and evaluate the ability of a range of doses 
of DGAT2i to mitigate ACCi-induced elevations in serum triglycerides.  This is the first 
clinical study specifically designed to identify the lowest dose of DGAT2i which, when 
coadministered with ACCi, results in reduction in hepatic steatosis while mitigating the 
identified adverse reaction (ie, elevation in serum triglycerides) observed with 
administration of ACCi alone.
This study has a 2-part design with sequential conduct of Part 1 and Part 2 with each part 
conducted in distinct/separate cohorts of participants.  While the overall study design, 
objectives/endpoints, eligibility criteria for both parts are envisioned to remain identical, 
data from Part 1 will be used to determine whether to conduct Part 2.  Observed data from 
Part 1 will guide the selection of doses and dosing regimens (ie, QD vs BID) of DGAT2i + 
ACCi coadministration evaluated in optional Part 2.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary:
To evaluate effect on liver fat, 
determined by MRI-PDFF, of a 
range of DGAT2i doses 
coadministered with a fixed 
dose of ACCi compared to 
placebo in participants with 
presumed NASH.
Percent change from baseline in liver fat as 
assessed via MRI-PDFF, at Week 6. 
Estimand 1
Secondary:
To evaluate effect on fasting 
serum triglyceride levels of a 
range of DGAT2i doses 
coadministered with a fixed 
dose of ACCi compared to 
placebo in participants with 
presumed NASH.
Percent change from baseline in fasting 
serum triglyceride levels over time. 
Estimand 2
To assess safety and 
tolerability with a range of 
DGAT2i doses coadministered
with fixed dose of ACCi 
compared to placebo in 
participants with presumed 
NASH. 
Proportion of participants with 
treatment-emergent adverse events (TEAEs) 
and clinically significant, abnormal clinical 
laboratory tests, vital signs, and 12-lead 
ECGs.
Not applicable for 
safety and tolerability
endpoints
Tertiary/Exploratory: 


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Objectives
Endpoints
Estimands
To evaluate effect on liver fat
determined by quantitative 
ultrasound (FibroScan®) of a 
range of DGAT2i doses 
coadministered with fixed dose 
of ACCi, compared to placebo 
in participants with presumed 
NASH. 
Percent change from baseline in liver fat at 
Week 6, as assessed by CAP™ via 
FibroScan®.
Estimand 1
To evaluate effect on liver 
function tests of a range of 
DGAT2i doses coadministered 
with fixed dose of ACCi, compared 
to placebo in participants with 
presumed NASH
Percent change from baseline, over time, in: 
ALT
AST
Alkaline Phosphatase
Total Bilirubin and
GGT
Estimand 2
To evaluate effect on metabolic 
parameters of a range of DGAT2i 
doses coadministered with fixed 
dose of ACCi, compared to 
placebo in participants with 
presumed NASH
Percent change from baseline, over time, in: 
Total cholesterol
Direct LDL
HDL-C
Direct VLDL
Apolipoprotein A1, Btotal, B100, B48, C3, and E
Derived non-HDL-C
Change from baseline, overtime, in:
HbA1C
FPG
FPI
HOMA-IR
Estimand 2
Estimand 3
To evaluate the effect on 
mechanism/disease-related
biomarkers of a range of DGAT2i 
doses coadministered with fixed 
dose of ACCi, compared to 
placebo in participants with 
presumed NASH
Percent change over time in: 
CK 18-M30, -M65
Pro-C3, and Pro-C6
PCSK9
Adiponectin
hsCRP
Estimand 2
To summarize plasma PK of 
DGAT2i and ACCi, across the 
active doses of DGAT2i + ACCi 
evaluated in participants with 
presumed NASH 
Predose DGAT2i and ACCi plasma concentrations 
(ie, Ctrough) 
Not Applicable for 
this analysis
To enable the exploratory research 
through collection of banked 
biospecimens, unless prohibited by 
local regulations or ethics 
committee decision
Biobanking of blood-based specimens (including 
Prep D1, B1.5, and B2.5 collections to permit 
retrospective analysis of yet-to-be identified 
biomarkers) 
These results may or may not be generated in the 
context of the present study
Not Applicable for 
this analysis


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2.1.1. Estimand 1
For a given endpoint, the estimand will be the estimated population based average treatment 
effect on natural log-transformed relative change from baseline for DGAT2i + ACCi 
relative to placebo at Week 6 for all randomized/evaluable participants.
Intercurrent Events: 

Non evaluable baseline – All data collected post-randomization will be excluded.

Withdrawal from study intervention after randomization – All data collected after a 
participant stops taking study intervention will be excluded. 

Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the primary endpoint will be omitted from the 
analysis. The list of concomitant medications would be reviewed prior to database 
lock to determine which would be classed as “prohibited” for this estimand.

Inadequate compliance – All randomized/evaluable participants with compliance 
<80%, over the entire duration of dosing with double-blind, double-dummy study 
intervention, will not have their endpoint measurement used as recorded in the 
analysis.  
Population level summary: 

The population level summary will be the mean difference in natural log-transformed 
relative change from baseline between DGAT2i + ACCi groups and placebo groups 
for the endpoint of interest at Week 6.
2.1.2. Estimand 2
For a given endpoint, the estimand will be the estimated population based average treatment 
effect on natural log-transformed relative change from baseline for DGAT2i + ACCi 
relative to placebo over time for all randomized/evaluable participants.
Intercurrent Events: 

Non evaluable baseline – All data collected post-randomization will be excluded.

Withdrawal from study intervention after randomization – All data collected after a 
participant stops taking study intervention will be included.

Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the endpoint will be omitted from the analysis. The 
list of concomitant medications would be reviewed prior to database lock to 
determine which would be classed as “prohibited” for this estimand.


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
Inadequate compliance – All randomized/evaluable participants, regardless of the 
level of compliance, will have their endpoint measurement used as recorded in the 
analysis.
Population level summary: 

The population level summary will be the mean difference in natural log-transformed 
relative change from baseline between DGAT2i + ACCi groups and placebo groups 
for the endpoint of interest over time.
2.1.3. Estimand 3
For a given endpoint, the estimand will be the estimated population based average treatment 
effect on change from baseline for DGAT2i + ACCi relative to placebo over time for all 
randomized/evaluable participants.
Intercurrent Events: 

Same as Estimand 2.
Population level summary: 

Same as Estimand 2 but with the mean difference in change from baseline between 
DGAT2i + ACCi groups and placebo groups for the endpoint of interest over time.
2.2. Study Design
This is a multicenter, 2-part, sequentially conducted, randomized, double-blind, 
double-dummy, placebo-controlled, parallel-group evaluation of DGAT2i + ACCi as 
summarized in Figure 1.
Figure 1.
Overall Study Design


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Determination of eligibility will occur via a sequential, 2-step process starting with 
Prequalification visit (PreQ).  Participants identified to be eligible at PreQ will transition to 
the main study, starting with Screening (SCR) visit.  The double-confirmation (at PreQ and 
SCR) will permit progression of only a selected subset of participants confirmed to meet 
Sponsor-defined presumed NASH criteria (along with other eligibility criteria) to the 
Run-In/Visit 2.  At the Run-In/Visit 2, stabilization of concomitant medicines may occur, as 
needed/appropriate (refer to Section Section 6.5 of the protocol).  All eligible participants 
must complete the Run-In/Visit 2, followed by Baseline/Visit 3.  On Day 1/Visit 4, 
participants who meet the randomization criteria (refer to Section 5.3 of the protocol) will be 
assigned to receive 1 of pre-defined double-blind, double-dummy regimens (refer to 
Section 4.1.1 [for Part 1] and Section 4.1.2 [for Part 2] of the protocol) for a duration of up to 
6 weeks, refer to Figure 2 [updated to reflect the PACL that removed Acuson Sequoia®
assessments].
Figure 2.
Study Design for Part 1 and Optional Part 2
In Part 1, approximately 90 participants (18 per group) with Sponsor-defined presumed 
NASH will be randomly assigned to the study intervention to ensure approximately 
75 evaluable participants (15 per group) offer evaluable data.  In Part 2, a maximum of 
4 active doses (plus placebo) will be evaluated in Part 2; furthermore, the total number of 
participants will not exceed 90 (with no more than approximately 27 participants per each 
active dose).


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
3.1.1. Liver Fat Assessed Using MRI-PDFF at Week 6
Percent change from baseline in liver fat content measured at Week 6 using MRI-PDFF 
constitutes the primary endpoint. The analysis will be performed using the natural-
logarithmic transformation of relative change from baseline as described in Section 5.2.4.
Baseline is defined as described in Section 3.4.
Note: Relative Change from Baseline = Post-dose timepoint Value / Baseline Value
3.2. Secondary Endpoint(s)
3.2.1. Fasting Serum Triglycerides Over Time
Percent change from baseline in fasting serum triglycerides over time constitutes one of the 
secondary endpoints. The analysis will be performed using the natural-logarithmic 
transformation of relative change from baseline over time as described in Section 5.2.5.
Baseline is defined as described in Section 3.4.
3.2.2. Safety and Tolerability
The proportion of participants with treatment-emergent adverse events (TEAEs) and 
clinically significant, abnormal clinical laboratory tests, vital signs, and 12-lead ECGs
constitute the other secondary endpoint.
Baseline is defined as described in Section 3.4.
3.3. Other Endpoint(s)
3.3.1. Liver Fat determined by Quantitative Ultrasound Using FibroScan®
Liver fat, as obtained by controlled attenuation parameter (CAP®) measurement using 
FibroScan, will be assessed at timepoints described in the Schedule of Activities of the 
protocol. The analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.4.
Baseline is defined as described in Section 3.4.
Note: Relative Change from Baseline = Post-dose timepoint Value / Baseline Value
3.3.2. Liver Stiffness Determined by Quantitative Ultrasound Using FibroScan®
Liver stiffness, as obtained by vibration-controlled transient elastography (VCTETM) 
measurement using FibroScanwill be assessed at timepoints described in the Schedule of 
Activities of the protocol.


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Baseline is defined as described in Section 3.4.
3.3.3. Liver Function Tests Over Time
Liver function tests include ALT, AST, ALKP, GGT, and Total Bilirubin.  For all these 
laboratory parameters, baseline is defined as described in Section 3.4.
3.3.3.1. Alanine Aminotransferase (ALT)
Alanine Aminotransferase (ALT) levels will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
Percent change from baseline in ALT over time will be the endpoint of interest. The analysis 
will be performed using the natural-logarithmic transformation of relative change from 
baseline as described in Section 5.2.5.
3.3.3.2. Aspartate Aminotransferase (AST)
Aspartate Aminotransferase (AST) levels will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
Percent change from baseline in AST over time will be the endpoint of interest. The analysis 
will be performed using the natural-logarithmic transformation of relative change from 
baseline as described in Section 5.2.5.
3.3.3.3. Alkaline Phosphatase (ALKP)
Alkaline Phosphatase (ALKP) levels will be assessed at timepoints described in the Schedule 
of Activities of the protocol.
Percent change from baseline in alkaline phosphatase over time will be the endpoint of 
interest. The analysis will be performed using the natural-logarithmic transformation of 
Relative change from baseline as described in Section 5.2.5.
3.3.3.4. Total Bilirubin (TBIL)
Total Bilirubin (TBIL) levels will be assessed at timepoints described in the Schedule of 
Activities of the protocol.
Percent change from baseline in total bilirubin over time will be the endpoint of interest. The 
analysis will be performed using the natural-logarithmic transformation of relative change 
from baseline as described in Section 5.2.5.
3.3.3.5. Gamma Glutamyl Transferase (GGT)
Gamma Glutamyl Transferase (GGT) levels will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
Percent change from baseline in GGT over time will be the endpoint of interest. The analysis 
will be performed using the natural-logarithmic transformation of relative change from 
baseline as described in Section 5.2.5.


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3.3.4. Metabolic Parameters Over Time
All of the following parameters, assessed following a fast of at least 8 hours (except HbA1C 
which is deemed evaluable even when assessed in a non-fasted state), will have baseline 
defined as described in Section 3.4.
3.3.4.1. Total Cholesterol
Total Cholesterol levels will be assessed at timepoints described in the Schedule of Activities
of the protocol.
Percent change from baseline in total cholesterol over time will be the endpoint of interest. 
The analysis will be performed using the natural-logarithmic transformation of relative 
change from baseline as described in Section 5.2.5.
3.3.4.2. Direct Low Density Lipoprotein (Direct LDL)
Direct Low Density Lipoprotein (Direct LDL) levels will be assessed at timepoints described 
in the Schedule of Activities of the protocol.
Percent change from baseline in direct LDL over time will be the endpoint of interest. The 
analysis will be performed using the natural-logarithmic transformation of relative change 
from baseline as described in Section 5.2.5.
3.3.4.3. High Density Lipoprotein Cholesterol (HDL-C)
High Density Lipoprotein cholesterol (HDL-C) levels will be assessed at timepoints 
described in the Schedule of Activities of the protocol.
Percent change from baseline in HDL-C over time will be the endpoint of interest. The 
analysis will be performed using the natural-logarithmic transformation of relative change 
from baseline as described in Section 5.2.5.
3.3.4.4. Direct Very Low Density Lipoprotein (Direct VLDL)
Direct Very Low Density Lipoprotein (Direct VLDL) levels will be assessed at timepoints 
described in the Schedule of Activities of the protocol.
The analysis will be performed using the natural-logarithmic transformation of relative 
change from baseline as described in Section 5.2.5.
3.3.4.5. Apolipoproteins
The apolipoproteins of interest are apolipoprotein A1 (ApoA1), apolipoprotein B Total 
(ApoBTotal), apolipoprotein B100 (ApoB100), apolipoprotein B48 (ApoB48), apolipoprotein C3 
(ApoC3), and apolipoprotein E (ApoE) and their levels will be assessed at timepoints 
described in the Schedule of Activities of the protocol.


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For each apolipoprotein described above, percent change from baseline over time will be the 
endpoint of interest. The analysis will be performed using the natural-logarithmic 
transformation of relative change from baseline as described in Section 5.2.5.
3.3.4.6. Derived non-High-Density Lipoprotein Cholesterol (Non-HDL-C)
Non High-Density Lipoprotein cholesterol (Non-HDL-C) levels will be derived, as follows,
at timepoints described in the Schedule of Activities of the protocol for fasting TG, direct 
LDL-C, HDL-C, total cholesterol -
Derived non-HDL-C = total cholesterol minus HDL-C
where all parameters are reported in mg/dL.
Percent change from baseline over time will be the endpoint of interest. The analysis will be 
performed using the natural-logarithmic transformation of relative change from baseline as 
described in Section 5.2.5.
3.3.4.7. Glycated Hemoglobin A1C (HbA1C)
Glycated Hemoglobin A1C (HbA1C) levels will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
The change from baseline in HbA1C over time will be the endpoint of interest and will be 
analyzed as described in Section 5.2.5.
3.3.4.8. Fasting Plasma Glucose (FPG)
Fasting Plasma Glucose (FPG) levels will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
The change from baseline in FPG over time will be the endpoint of interest. and will be 
analyzed as described in Section 5.2.5.
3.3.4.9. Fasting Plasma Insulin (FPI)
Fasting Plasma Insulin (FPI) levels will be assessed at timepoints described in the Schedule 
of Activities of the protocol.
The change from baseline in FPI over time will be the endpoint of interest and will be 
analyzed as described in Section 5.2.5.
3.3.4.10. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
The change from baseline in HOMA-IR over time will be the endpoint of interest. The 
change from baseline in HOMA-IR over time will be the endpoint of interest and will be 
analyzed as described in Section 5.2.5.
As described in the Schedule of Activities of the protocol, HOMA-IR values will be derived 
at each timepoint as follows:


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HOMA-IR = (GlucoseFasting Concentration x InsulinFasting Concentration) / 405
where fasting plasma glucose concentrations is reported in mg/dL and fasting plasma insulin 
is reported in mU/L. As such, HOMA-IR is unit-less.
3.3.5. Biomarkers
Baseline for all the following endpoints is defined as described in Section 3.4 .
3.3.5.1. Markers of Apoptotic Activity (CK18-M30 and CK18-M65)
Markers of apoptotic activity will be assessed at timepoints described in the Schedule of 
Activities of the protocol.  These include the caspase-cleaved cytokeratin-18-M30 (ie CK18-
M30) produced during apoptosis or the caspase-cleaved and intact cytokeratin-18-M65 (ie 
CK18-M65) usually released from cells undergoing necrosis.
The percent change from baseline in CK18-M30 and CK18-M65 over time will be the 
endpoints of interest. The analysis will be performed using the natural-logarithmic 
transformation of relative change from baseline as described in Section 5.2.5.
3.3.5.2. Markers of fibrinogenesis (ProC3 and ProC6)
Markers of collagen/fibrin formation will be assessed at timepoints described in the Schedule 
of Activities of the protocol.  These include N-terminal pro-peptide of type III procollagen 
(ie ProC3) or C-terminal fragment of the α3 chain of procollagen type VI (ie ProC6).
The percent change from baseline in ProC3 and ProC6 over time will be the endpoints of 
interest. The analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.
3.3.5.3. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels will be assessed at timepoints 
described in the Schedule of Activities of the protocol.
The percent change from baseline in PCSK9 over time will be the endpoints of interest. The 
analysis will be performed using the natural-logarithmic transformation of relative change 
from baseline as described in Section 5.2.5.
3.3.5.4. Adiponectin
Adiponectin levels will be assessed at timepoints described in the Schedule of Activities of 
the protocol.
The percent change from baseline in adiponectin over time will be the endpoints of interest. 
The analysis will be performed using the natural-logarithmic transformation of relative 
change from baseline as described in Section 5.2.5.


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3.3.5.5. High Sensitive C-Reactive Protein (hsCRP)
High Sensitive C-Reactive Protein (hsCRP) will be assessed at timepoints described in the 
Schedule of Activities of the protocol.
The percent change from baseline in hsCRP over time will be the endpoints of interest. The 
analysis will be performed using the natural-logarithmic transformation of relative change 
from baseline as described in Section 5.2.5.
3.4. Baseline Variables
Baseline for all endpoints described in section 2, section 3, section 5 and section 6 is defined 
as the evaluable result closest prior to dosing on Day 1 0H (ie pre-dose).
In Particular, for each participant, for each of the following parameters, baseline will be 
defined as:

Liver fat content, via MRI-PDFF, defined as the value of WLPDFF (see Appendix 
2.2.1) obtained between Visit 3 and Visit 4 (ie, labeled as baseline)

Liver fat assessment via CAP® using FibroScan® obtained between Visit 3 and Visit 4 
(ie, labeled as baseline)

Liver stiffness assessment via VCTE® using FibroScan® obtained between Visit 3 and 
Visit 4 (ie, labeled as baseline)

Result closest prior to dosing on Day 1 [Visit 4] for the remaining pharmacodynamic 
endpoints and all safety-related continuous endpoints
o
As such would be results as reported on Day 1 [ Visit 4], and if these are not 
reported would be the results reported on Day -14 [Visit 3]
o
If results on Day 1 [Visit 4] and on Day -14 [Visit 3] are missing the baseline 
will be considered as missing.

For Adverse events, refer to definition of treatment-emergent outlined in Section 
3.5.1.
Change from baseline (CBL), relative change from baseline (RCBL) and percent change 
from baseline (PBL) will be calculated as follows:

CBL = Observed Value – Baseline Value

RCBL = Observed Value / Baseline Value

PBL = 100 (Observed Value – Baseline Value) / Baseline Value
3.5. Safety Endpoints
3.5.1. Adverse Events
Any adverse event included in the adverse CRF page will be considered as treatment 
emergent.


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In fact, an adverse event will be considered treatment emergent (ie, TEAEs) relative to a 
given treatment if:

event occurs for the first time during the effective duration of treatment and was not 
seen prior to 1st dose of double-blinded study medication on Day 1 [Visit 4], for 
example, during the internal between when participants offered informed consent 
for pre-qualification up to the day prior to 1st dose

NOTE: Adverse events deemed non-treatment emergent observed during the 
interval between when participants offering informed consent for pre-qualification 
up to 1st dose on Day 1 (Visit 4) but resolved before 1st dose on Day 1). 
The effective duration of treatment is determined by the lag time defined as the Pfizer 
Standard of 999 days post last dose of double-blinded study medication. Any treatment-
emergent event occurring within the lag time, whether it occurs during a break in treatment 
or at the end of treatment, will be attributed to the assigned randomized regimen.
A 3-tier approach will be used to summarize TEAEs. Under this approach, TEAEs will be
classified into 1 of 3 tiers. Different analyses will be performed for different tiers (See 
Section 6.6.1). 
Tier-1 events: These are pre-specified events of clinical importance (TMEs, DMEs, and 
CPTs) and are maintained in a program level list in CATEList.
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA preferred 
term (PT) is defined as a tier-2 event if there are at least 4 participants with at least one 
occurrence in any treatment group, per Pfizer Standard to distinguish Tier-2 events from 
Tier-3 events.
Tier-3 events: These are events that do not meet criteria for either tier-1 nor tier-2 events
3.5.2. Laboratory Data
For the specific laboratory parameters listed in Table 2 below, the following endpoints will 
be evaluated using CaPS: 

Absolute value and change from baseline at week 2, week 4, week 6, and 1st Follow-
up visit.

Number of occurrences of these abnormalities defined as “Flag Level” or “Alert 
Level”

Number of participants with these abnormalities defined as “Flag Level” or “Alert 
Level”
Table 2.
Clinical Laboratory Parameters of Interest in Study C3711005
Parameter
Flag Level
Alert Level
Conventional Units
Fasting Serum Triglycerides
400 
600
mg/dL
--
800
mg/dL
Platelet Count 
< 100,000
< 75,000
/mm3
Fasting Plasma Glucose 
< 70
49
mg/dL


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Table 2.
Clinical Laboratory Parameters of Interest in Study C3711005
Parameter
Flag Level
Alert Level
Conventional Units
140
> 270
mg/dL
Alanine aminotransferase
≥ 2x ULN
--
U/L
> 3x ULN
--
U/L
> 5x ULN
>8x ULN
U/L
Aspartate aminotransferase
≥ 2x ULN
--
U/L
> 3x ULN
--
U/L
> 5x ULN
>8x ULN
U/L
Alkaline Phosphatase
≥ 2x ULN
--
U/L
> 3x ULN
--
U/L
>5x ULN
--
U/L
Gamma Glutamyl Transferase 
> ULN
--
U/L
Total Bilirubin
> 1.5x ULN
>3x ULN
mg/dL
Direct (Conjugated) Bilirubin
> ULN
--
mg/dL
*All flag level changes are cumulative from baseline (defined as result closest prior to dosing at Visit 4 (Day 1); 
reflect either threshold for entry criteria into study or clinically significant thresholds
^All alert changes are cumulative from baseline (defined as result closest prior to dosing at Visit 4 (Day 1); values 
when noted during the study, by central laboratory necessitates rapid notification (via fax/e-mail) to site and Study 
Clinician, Pfizer Medical Monitor, and Global Clinical Lead, in parallel
ULN – upper limit of normal as determined by the central laboratory
Across all the laboratory-related analytes (for safety and pharmacodynamics/biomarker), 
inclusion of results when assessed at scheduled nominal visits meet the following criteria:-
1. Collection must be prior to AM dose of double-blinded study medication
2. Collection permitted to be nonfasted for the following analytes and will be permitted 
to be grouped with fasted results given that nonfasted state is not known to impact 
results
Chemistry panel
Hematology
Other
Urinalysis
Direct bilirubin
Indirect bilirubin
Urea Nitrogen
Creatinine
Uric acid
Calcium
Total protein
Albumin
Creatine kinase
Sodium
Potassium
Bicarbonate
Chloride
Hemoglobin
Hematocrit
RBC
MCV
MCH
MCHC
WBC
Neutrophils (abs)
Lymphocytes (abs)
Monocytes (abs)
Eosinophils (abs)
Basophils (abs)
Platelets
Reticulocyte count%
Reticulocyte count
aPTT
PT
INR
Urine-drug-testing
Serology testing 
[hepatitis B, 
hepatitis C, HIV]
Alpha-1-antitrypsin
Ceruloplasmin
β-hCG
FSH
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Nitrite
Leukocyte esterase
Microscopic UA
3. But, the following analytes will only be included in summary outputs if collections 
are confirmed to be following an overnight fast of at least 8 hours as it is well known 
that fasting status impacts numerical results (or there is insufficient data regarding 
effect of meals on results)


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Biomarkers
Lipid-related
Other Blood-related
% CDT
Plasma Glucose
Plasma Insulin
Total Bile Acids
Plasma PCSK9
CK18-M30
CK18-M65
ProC3 
ProC6
Total cholesterol
HDL-C
Direct LDL-C
Triglycerides
VLDL
Apolipoprotein A1
Apolipoprotein BTotal
Apolipoprotein B48
Apolipoprotein B100
Apolipoprotein C3
Apolipoprotein E
Prep B1.5 (plasma) and 
B2.5 (serum) related 
mechanistic/disease-related 
biomarkers
Note: Prep samples (ie Prep B1.5 (plasma) and B2.5 (serum)) if analyzed will consider the fasted collection and 
will be reported in a supplemental CSR.
3.5.3. Standard Safety Other than AEs
3.5.3.1. Vital Signs of Special Clinical Concerns
Individual participants’ vital signs outlined in Table 3 of special clinical concern, which align 
with the Pfizer standard criteria, will be summarized by treatment, as part of standard safety-
related outputs.
Table 3 Vital Signs to be Monitored
Parameter
Flag Level*
Conventional Units
Systolic Blood Pressure (seated)
< 90 
mm Hg
30 change from baseline 
mm Hg
Diastolic Blood Pressure (seated)
< 50
mm Hg
20 change from baseline
mm Hg
Pulse rate (seated)
<40
Bpm
> 120
Bpm
*All flag level changes are cumulative from baseline (defined as result closest prior to dosing at Visit 4 
(Day 1)
bpm – beats per minute
In addition Pfizer standard criteria for reporting of cardiac conduction intervals will be
summarized by treatment. 
3.5.3.2. ECG of Special Clinical Concerns
Individual participants’ ECG outlined in Table 4 of special clinical concern, which align with 
the Pfizer standard criteria, will be summarized by treatment, as part of standard safety-
related outputs.
Table 4
ECG QT and QTc Interval Criteria to be Monitored
Degree of 
Prolongation
QTcF Interval Prolongation (msec)
Uncorrected QT 
Interval (msec)
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
450-480
480-500
500
500


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Table 4
ECG QT and QTc Interval Criteria to be Monitored
Degree of 
Prolongation
QTcF Interval Prolongation (msec)
Uncorrected QT 
Interval (msec)
Mild (msec)
Moderate (msec)
Severe (msec)
Increase from baseline
30-60
60
Note: For purposes of reporting study-level results, QTcF interval will be derived using Fridericia’s heart rate 
correction formula (see below) applied to databased QT interval, and RR interval.
QTc not otherwise specified as captured in CRF will be only listed. Summary outputs will 
summarize only programmatically derived QTcF.
QTcF (ie, Fridericia’s heart rate correction formula) is:
QTcF (msec) = QT(msec) / (RR, in msec)^(1/3)
3.5.3.3. Background Medications of Special Interest
Across the many background medications being taken by the population enrolled, the 
number/proportion of participants using (and proportion needing changes in) selected 
medications of special interest will be summarized.  These include 

Agents for glycemic control (see list in Protocol section 6.5.1)

Agents for lipid control (see list in Protocol section 6.5.2)

Agents for blood pressure control (see list in Protocol section 6.5.3)
The number of participants using glycemic control agents, lipid-modifying agents
medication, and agents for BP control will be summarized by treatment as well.
For each category of medication (ie Glycemic, Lipid, and BP), the number of participants 
receiving 0, 1, 2, or 3 medications will also be tabulated by treatment.
Given the relatively short duration of the double-blind, double-dummy dosing in this study, if
changes in background medications related to glycemic control, lipid control, or blood 
pressure are reported/observed, they will be summarized as follows, at any time after Day 1
and up to the last dose of study drug (ie, Week 6 or premature discontinuation) whichever is 
first –

Dose increase and decrease in concomitant medication for glycemic control (see list 
in Protocol section 6.5.1),

Dose increase and decrease in concomitant lipid-modifying medications (see list in 
Protocol section 6.5.2),

Dose increase and decrease in concomitant blood pressure management medications 
(see list in Protocol section 6.5.3).
3.5.3.4. Platelet Count
Percent and absolute change from baseline in platelet count over time will be the endpoint of 
interest. Both endpoints will be analyzed as described in Section 5.2.5.


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Baseline is defined as described in Section 3.4 .
3.5.3.5. Estimated Glomerular Filtration Rate
The estimated glomerular filtration rate (eGFR) at each time point defined in the Schedule of 
Activities will be calculated using cystatin-C as follows:
If cystatin-C > 0.8 mg/L:
eGFR ൌ133 ∗ሾሺcystatin െCሻ/0.8ሿିଵ.ଷଶ଼∗0.996୅୥ୣ∗0.932ሺif Femaleሻ
If cystatin-C ≤ 0.8 mg/L:
eGFR ൌ133 ∗ሾሺcystatin െCሻ/0.8ሿି଴.ସଽଽ∗0.996୅୥ୣ∗0.932ሺif Femaleሻ
Where 
eGFR unit is mL/min/1.73 m2,
Age is subject’s age at screening in years, 
(cystatin-C) is cystatin-C concentration in mg/dL.
The change from baseline in eGFR over time will be the endpoint of interest and will be 
analyzed as described in Section 5.2.5.
Baseline is defined as described in Section 3.4.
3.5.3.6. Alcohol Intake 
For the entire study population, alcohol intake will be assessed 1 of 3 ways; with only 2 of 
these being databased and reported –
1. %CDT – reported using descriptive summary statistics over time 
2. Total score on interview-based AUDIT questionnaire – reported using description 
summary statistics over time 
3. Participants’ self-reported intake of alcohol-containing drinks [not databased]
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are randomized but not treated.
If a participant takes a treatment that is not consistent with the treatment they are randomized 
to, for example, error in dispensation of blister cards relative to assigned made by IRT, then 
they will be reported under the treatment that they actually receive (so called actual 
treatment) for all safety, PK and PD analyses, where applicable.


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A full list of protocol deviations will be compiled and reviewed to identify major deviations, 
which may potentially impact inclusion in the applicable estimand, prior to database lock and 
release.
For purposes of analysis, the following analysis sets are defined:
Participants Analysis Set
Description
Enrolled 
All participants who sign the preQ ICD.
Randomly assigned to 
investigational product
All participants randomly assigned to IP, on Day 1/Visit 4, regardless of 
whether or not study intervention was administered.
Evaluable
All participants randomly assigned to IP and who take at least 1 dose of IP.  
Participants will be analyzed according to the randomized intervention.
Safety
All participants randomly assigned to IP and who take at least 1 dose of IP.  
Participants will be analyzed according to the treatment arm they actually 
received.
Defined Population for 
Analysis
Description
PK Concentration Set
All participants randomly assigned to study intervention and who take at least 
1 dose of DGAT2i + ACCi and in whom at least 1 concentration value is 
reported.
Note: Analysis set for Part 2 is envisioned to be identical to Part 1.
5. GENERAL METHODOLOGY AND CONVENTIONS
Data from Parts 1 and 2 will be pooled for purposes of summarizing/analyzing end-of-study 
results and will be reported from placebo followed by ascending order of the DGAT2i to 
ACCi total daily dose (TDD) ratio (mg:mg).
In case the same co-administration ratio for BID and QD dosing regimen is evaluated, data 
will be reported 1st for BID and then QD while still in the ascending order for DGAT2i to 
ACCi TDD ratio (mg:mg).
5.1. Hypotheses and Decision Rules
Not applicable
5.2. General Methods
5.2.1. Analyses for Binary Endpoints
Not applicable
5.2.2. Analyses for Continuous Endpoints
Continuous endpoints and relevant safety endpoints will be presented using summary 
statistics: number of randomized participants, number of participants contributing to 
summary, arithmetic mean, standard deviation, median, minimum and maximum values.


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5.2.3. Analyses for Categorical Endpoints
Categorical endpoints and relevant safety endpoints will be presented using summary statistics: 
number of randomized participants, number of observations, counts and percentages.
5.2.4. Analysis of Covariance (ANCOVA)
The effect of DGAT2i + ACCi on primary, secondary, and tertiary endpoints at Week 6 will 
be analyzed using ANCOVA approach.
Analysis of change from baseline:
The ANCOVA model will include the change from baseline of the relevant endpoint as 
specified in Section 6  as the dependent variable and will include treatment as a fixed effect 
and baseline as a covariate.
Missing values will not be imputed.
The Least Squares Means (LSMeans) together with 80% confidence intervals and standard 
errors will be obtained for each treatment.  Differences in LSMeans between each treatment 
and placebo, together with 80% confidence intervals and standard errors, will also be 
obtained.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in Appendix 3.
Analysis of percent change from baseline:
The ANCOVA model will include the natural logarithmic transformed of relative change 
from baseline of the relevant endpoint as specified in Section 6  as the dependent variable 
and will include treatment as a fixed effect and baseline as a covariate.
Missing values will not be imputed.
The adjusted geometric Least Squares Means (LSMeans) together with 80% confidence 
intervals and standard errors will be obtained for each treatment.  Differences in adjusted 
geometric LSMeans between each treatment and placebo, together with 80% confidence 
intervals and standard errors, will also be obtained. All LSMeans and LSMeans differences 
(including CI’s) will be back transformed to provide adjusted geometric LSMeans and ratios 
of adjusted geometric LSMeans. Then, percent change from baseline will be calculated as 
follows:
Percent change = 100* (RCBL - 1)
where RCBL is either the adjusted geometric LSMeans estimate or the ratio of adjusted 
geometric means coming from the statistical model. The corresponding 80% CIs will be 
calculated as well.


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Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in Appendix 3.
5.2.5. Longitudinal Analysis
The effect over time of DGAT2i + ACCi on secondary, and tertiary endpoints (see list in 
Section 3) will be analyzed using a Mixed-Model Repeated Measures (MMRM) approach 
with treatment, week and treatment by-week interaction as fixed effects, participant as 
random effect. An unstructured covariance matrix will be used to estimate the variances and 
covariance within participants across time points.  If convergence is not obtained or model fit 
is not adequate, other covariance structures will be investigated as necessary.  The Kenward-
Roger approximation will be used for estimating degrees of freedom for the model 
parameters.  Missing values will not be imputed as part of the MMRM model assumptions.
Baseline (in raw scale or log scale depending on the endpoint) will be included as covariate 
in the model.
Analysis to report percent change from baseline: 
MMRM models will include the natural log transformed of relative change from baseline 
(RCBL) of the relevant endpoints as specified in Section 6.
The adjusted geometric Least Squares Means (LSMeans) together with 80% confidence 
intervals and standard errors will be obtained for each treatment and week.  Differences (and 
corresponding confidence intervals) between LSMeans estimates will be obtained comparing 
treatments for each week. All LSMeans and LSMeans differences (including CI’s) will be 
back transformed to provide adjusted geometric LSMeans and ratios of adjusted geometric 
LSMeans. Then, percent change from baseline will be calculated as follows:
Percent change = 100* (RCBL - 1)
where RCBL is either the adjusted geometric LSMeans estimate or the ratio of adjusted 
geometric means coming from the statistical model. The corresponding 80% CIs will be 
calculated as well.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in Appendix 3.
Analysis of change from baseline: 
MMRM models will include change from baseline (CFB) of the relevant endpoints as 
specified in Section 6.
The Least Squares Means (LSMeans) together with 80% confidence intervals and standard 
errors will be obtained for each treatment and week.  Differences (and corresponding 


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confidence intervals) between LSMeans estimates will be obtained comparing treatments for 
each week.
Standard SAS output will be provided to support the main statistical summary table for the 
models.
Example SAS code is provided in Appendix 3.
5.3. Methods to Manage Missing Data
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
5.3.1. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
5.3.2. Pharmacokinetic Parameters

Missing pharmacokinetic data will be treated as such and no imputed values will be 
derived when presenting descriptive statistics at scheduled assessments.

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.
5.3.3. Pharmacodynamic Parameters

Missing data for all the pharmacodynamic parameters will be treated as such and no 
imputed values will be derived when presenting descriptive statistics at scheduled
assessments.

Concentrations below Lower Limit of Quantification (LLQ) will be set to half-LLQ (ie 
LLQ/2) for summary outputs; in listings BLQ values will be reported as “<LLQ”. 

Derived data by calculation (eg indirect bilirubin) will not follow the rule described 
above and will be reported as <LLQ (in listings) with a derived value of (<negative 
value> minus 0.0001 = positive value) when generating summary statistics, as required.

Any values above the Upper Limit of Quantification (ULQ) will be assigned to the ULQ 
for display purposes in Figures and for computation of summary statistics; in listings 
ULQ values will be reported as “>ULQ”.

Observed cases will be used when analyzing continuous variables using Mixed-Model 
Repeated Measures (MMRM), analysis of covariance (ANCOVA) and nonlinear models.


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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Liver Fat Content Assessed Using MRI-PDFF at Week 6

Estimand strategy: Estimand 1
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.

Figures for summary Outputs: 
Box and whisker plots for individual percent change from baseline at Week 6 versus 
treatment will be presented and overlaid with arithmetic means. Only box, whiskers, 
median, arithmetic mean, and outliers should be reported in this graphic.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.4.

Statistical outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval),
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval). P-values for the ratio 
of adjusted geometric LSMeans estimates for each active treatment against placebo 
will be reported as well,
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs
Plot of percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval over time, 
Plot of percent change from baseline placebo-adjusted after back transformation of 
adjusted geometric LSMeans ratios with 80% confidence interval over time.
Note regarding the figures;
Instead of producing 2 independent figures, and in order to having a better understanding 
of the placebo effect, 1 figure containing side-by-side two panels presenting bullet 1 and 
2 outputs (right panel for response per treatment and left panel for placebo adjusted 
response)


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6.2. Secondary Endpoint(s)
6.2.1. Fasting Serum Triglycerides Over Time

Estimand strategy: Estimand 2
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.

Figure for summary Outputs: 

Box and whisker plots by treatment and by week will be displayed to characterize 
the distribution of percent changes from baseline over time. Only box, whiskers, 
median, arithmetic mean, and outliers should be reported in this graphic.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.

Statistical outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time. P-values for 
the ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo at each time point will be reported as well,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs
Line plot of percent change from baseline after back transformation of adjusted 
geometric LSMeans with 80% confidence interval over time, 
Line plot of percent change from baseline placebo-adjusted after back transformation 
of adjusted geometric LSMeans ratios with 80% confidence interval over time,
Percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval at Week 6,
Percent change from baseline placebo-adjusted after back transformation of adjusted 
geometric LSMeans ratios with 80% confidence at Week 6.
Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 
placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline.  


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6.2.2. Safety and tolerability
Unless otherwise noted, all safety data, including the following, will be summarized 
descriptively by actual dose group through appropriate data tabulations and descriptive 
statistics:

Tier-3 adverse events will be summarized according to Pfizer standards. Tier-1 and 
tier 2 events will also be included in these standard summary. 

Safety laboratory tests will be summarized according to Pfizer standards (note that 
actual visit window will be applied as defined in Appendix 2.1 in relation to actual
treatment). 

ECGs will be summarized by visits. Categorical summary of ECGs will be presented 
according to Pfizer standards (note that baseline is defined as in Appendix 2 in 
relation to actual treatment).

Vital signs will be summarized according to Pfizer standards (note that baseline is 
defined as in Appendix 2. in relation to actual treatment).

For the safety endpoints of special clinical concern other than AEs as defined in 
Section 3.5.3, they will be presented with descriptive statistics as appropriate for 
continuous or categorical data as defined in section 5.2.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for
further investigation. The 3-tier approach facilitates this exploratory analysis.
6.3. Other Endpoint(s) 
6.3.1. Liver Fat Content Using CAP® by FibroScan®

Estimand strategy:  Estimand 1
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.4.

Statistical outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval),
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval),


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Summary tables reporting MMRM outputs will included the number of participants 
included in the analysis.

Figures from statistical outputs
Plot of percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval over time, 
Plot of percent change from baseline placebo-adjusted after back transformation of 
adjusted geometric LSMeans ratios with 80% confidence interval over time.
Note regarding the figures;
Instead of producing 2 independent figures, and in order to having a better understanding 
of the placebo effect, 1 figure containing side-by-side two panels presenting bullet 1 and 
2 outputs (right panel for response per treatment and left panel for placebo adjusted 
response)
6.3.2. Liver Stiffness Assessed Using by FibroScan®

Estimand strategy:  Estimand 1
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.
6.3.3. Liver Function Tests Over Time

Estimand strategy: Estimand 2
For each liver Function test, ALT, AST, Alkaline Phosphatase, Total Bilirubin, and GGT
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.

Statistical outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs


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Line plot of percent change from baseline after back transformation of adjusted 
geometric LSMeans with 80% confidence interval over time, 
Line plot of percent change from baseline placebo-adjusted after back transformation 
of adjusted geometric LSMeans ratios with 80% confidence interval over time,
Percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval at Week 6,
Percent change from baseline placebo-adjusted after back transformation of adjusted 
geometric LSMeans ratios with 80% confidence at Week 6.
Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 
placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline. 
6.3.4. Other Fasting Serum Lipids Over Time

Estimand strategy:  Estimand 2
For each of the following fasting serum lipids, Total Cholesterol, Direct LDL-C, HDL-C, 
Non-HDL-C, and Direct VLDL
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.

Figures for summary Outputs: 

Box and whisker plots by treatment and by week will be displayed to characterize 
the distribution of percent changes from baseline over time. Only box, whiskers, 
median, arithmetic mean, and outliers should be reported in this graphic.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.

Statistical Outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.


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
Figures from statistical outputs
Line plot of percent change from baseline after back transformation of adjusted 
geometric LSMeans with 80% confidence interval over time, 
Line plot of percent change from baseline placebo-adjusted after back transformation 
of adjusted geometric LSMeans ratios with 80% confidence interval over time,
Percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval at Week 6,
Percent change from baseline placebo-adjusted after back transformation of adjusted 
geometric LSMeans ratios with 80% confidence at Week 6.
Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 
placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline.  
6.3.5. Apolipoproteins Over Time

Estimand strategy:  Estimand 2
For each of the following apolipoprotein, ApoA1, ApoBtotal, ApoB100, ApoB48, ApoC3 
and ApoE:
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.

Figures for summary Outputs: 

Box and whisker plots by treatment and by week will be displayed to characterize 
the distribution of percent changes from baseline over time. Only box, whiskers, 
median, arithmetic mean, and outliers should be reported in this graphic.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.

Statistical Outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.


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
Figures from statistical outputs
Line plot of percent change from baseline after back transformation of adjusted 
geometric LSMeans with 80% confidence interval over time, 
Line plot of percent change from baseline placebo-adjusted after back transformation 
of adjusted geometric LSMeans ratios with 80% confidence interval over time,
Percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval at Week 6,
Percent change from baseline placebo-adjusted after back transformation of adjusted 
geometric LSMeans ratios with 80% confidence at Week 6.
Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 
placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline.  
6.3.6. HbA1C, FPG, FPI and HOMA-IR Over Time

Estimand strategy: Estimand 3
For each parameter:
Raw data, and changes from baseline will be summarized by treatment, and week as 
described in Section 5.2.2.
The statistical analysis will be performed using the change from baseline as described in
Section 5.2.5.

Statistical outputs: 
The LSMeans estimates, and 80% confidence interval for each treatment at each 
time-point, 
Difference between the LSMeans for active treatment against placebo and the 
corresponding 80% confidence interval will be presented at each time point.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs
Line Plot of LSMeans estimates and 80% confidence interval over time,
Line Plot of placebo adjusted LSMeans and 80% confidence interval over time.
Change from baseline of adjusted-LSMeans with 80% confidence at Week 6.
Change from baseline placebo-adjusted of adjusted-LSMeans with 80% confidence
at Week 6.


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Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 
placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline.  
6.3.7. Mechanism/Disease-Related Biomarkers Over Time

Estimand strategy: Estimand 2
For each of the following biomarker: CK18-M30, CK18-M65, ProC3, ProC6, PCSK9, 
Adiponectin, and hsCRP:
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.
The statistical analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline as described in Section 5.2.5.

Statistical Outputs: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs
Line plot of percent change from baseline after back transformation of adjusted 
geometric LSMeans with 80% confidence interval over time, 
Line plot of percent change from baseline placebo-adjusted after back transformation 
of adjusted geometric LSMeans ratios with 80% confidence interval over time,
Percent change from baseline after back transformation of adjusted geometric 
LSMeans with 80% confidence interval at Week 6,
Percent change from baseline placebo-adjusted after back transformation of adjusted 
geometric LSMeans ratios with 80% confidence at Week 6.
Note regarding the figures;
Instead of producing 4 independent figures, and in order to having a better 
understanding of the placebo effect, 1 figure containing side-by-side two panels 
presenting bullet 1 and 2 outputs (right panel for response over time and left panel for 
placebo adjusted response over time), and 1 figure with two panels presenting side-
by-side bullet 3 and 4 outputs (right panel for response at Week 6 and left panel for 


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placebo adjusted response at Week 6) should be produced. Both sets of figures should 
start X-axis at Day 1/Baseline.  
6.3.8. Body Weight

Estimand strategy:  Estimand 2
Raw data, changes from baseline, and percent changes from baseline will be summarized at 
each time point with statistics as described in Section 5.2.2 and will be presented per
treatment and week.

Figures for summary Outputs: 
Box and whisker plots by treatment and by week will be displayed to characterize
the distribution of changes from baseline over time. Only box, whiskers, median, 
arithmetic mean, and outliers should be reported in this graphic.
6.3.9. Pharmacokinetic Analysis
All pharmacokinetic analyses will be performed on the PK concentration set. 
Plasma concentration data for DGAT2i and ACCi will be listed and summarized (Ctrough
only) by actual Treatment.
In addition, as permitted by data and determined by the Sponsor, exposure-response 
relationships between plasma concentrations of DGAT2i and/or ACCi and effect on primary, 
secondary and tertiary endpoints may be characterized using a population PK/PD approach.  
The objectives of such an analysis, if conducted, would aim to characterize  
exposure-response relationships and explore potential covariates (eg, age, race, gender, and 
body weight, etc.) influencing the observed PK and/or response to DGAT2i and/or ACCi.  
The population PK and/or PK/PD analyses, if conducted, will be reported separately from 
the main clinical study report.
6.4. Subset Analyses
Not applicable. 
6.5. Baseline and Other Summaries and Analyses
6.5.1. Physical Examination
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted.  However, any untoward findings identified on physical and/or 
neurological examinations conducted during the active collection period will be captured as 
AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data (unless noted below), ECGs, and vital signs, will be required to be reported for 


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randomized participants.  Amount of information databased for participants who screen fail 
will be limited and not summarized.  Demographic data collected at screening will be 
reported. 
6.5.2. Standard Analyses

Listings that account for all participants who offered at least consent for pre-
qualification and whether screen failed (at any point after the consent offered at the 
prequalification visit and before randomization on Day 1/Week 0/Visit 4 will be
presented.

Study Conduct and Participant Disposition: The number of participants randomized, 
treated, completing and discontinuing from the study. For participants who did not 
complete the study, the reasons for withdrawal from the study will be presented.

Baseline Characteristics: Demographic characteristics such as participant age, gender, 
height, weight, body mass index (BMI), race, and total per arm, by treatment group 
will be tabulated. In addition,
o
The number of participants randomized and treated will be summarized per 
arm, by treatment group, with each of the pre-defined medical history terms 
(ie, T2DM, Hyperglycemia, HDL increased, TG increased, hypertension, 
waist circumference increased).
o
The number of participants in each analysis population will be included in 
each summarized output (for safety set, PK concentration set, and for each 
estimand strategy) by actual treatment.

Overall compliance (Day 1 to Week 6 or premature termination during treatment 
phase) will be summarized by frequency (%) in the following two categories by 
treatment. Formula to compute compliance is defined in Appendix 2.4. 
o
< 80%
o
≥ 80% (and up to 110%)
6.5.3. Baseline Summaries
For each PD endpoint (ie primary, secondary or tertiary endpoint), baseline values will be 
listed and summarized by treatment). Descriptive statistics for these endpoints and derived 
endpoints will be also tabulated.
6.5.4. Concomitant Medications and Non-Drug Treatments
The concomitant medications of special interest (see Section 3.5.3.3) will be summarized by 
treatment. However, all remaining concomitant drugs and non-drug treatments will only be 
listed.
Dose increases, dose decreases, or no changes in dose of concomitant medications of special 
interest observed at Week 6 (ie, end of dosing of study drug) or premature discontinuation 
relative to 1st dose of study drug will be summarized by treatment arm.


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6.5.5. Alcohol Intake 
6.5.5.1. AUDIT Questionnaire
AUDIT questionnaire results will be listed and summarized by treatment, and Week as 
described in Section 5.2.2.
6.5.5.2. % Carbohydrate-Deficient Transferrin (%CDT)
%CDT values reported at PreQ, and Screen visits when available plus for randomized 
participants at Week 1 and Week 6 will be summarized as described in Section 5.2.2.
6.5.6. Other Analyses
Pharmacogenomic or biomarker data from Banked Biospecimens may be collected during or 
after the trial and retained for future analyses; the results of such analyses are not planned 
to be included in the CSR.
6.6. Safety Summaries and Analyses
All safety analyses will be performed on the safety population.
The safety data will be summarized in accordance with Pfizer Data Standards.  All 
participants who receive study intervention (safety population) will be included in the safety 
analyses. 
All safety data will be summarized descriptively through appropriate data tabulation, 
descriptive statistics, categorical summaries, and graphical presentations.
6.6.1. Adverse Events
The MedDRA dictionary will be used to classify all AEs with respect to system organ class 
and preferred term. Summaries of AEs will include treatment-emergent AEs according to 
treatment group.
The primary analyses will be on the incidence and severity of all treatment emergent adverse 
events (TEAE), that will be reported by treatment group.  The number of participants and 
percent will be presented.

Analysis of Tier-1 and Tier-2 TEAEs:
Unconditional exact test will be utilized. Risk difference will be used for the 
comparison. 
No multiplicity adjustment will be made. 
Tables and graphs will be generated. For tier-1 events, point estimates, 95% 
confidence intervals for the risk difference and p-values will be presented; for 


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tier-2 events, point estimates and 95% confidence intervals for the risk difference 
will be presented. 
TEAEs, by preferred term, will be sorted in descending point estimate of risk 
difference.
Pair-wise comparison will be made for each active treatment (each dose of 
DGAT2i+ACCi) against placebo. 
For table/graphic output, include the following footnotes to provide proper 
interpretation of p-values and/or confidence intervals, describe how comparison is 
conducted. E.g. P-values and confidence intervals are not adjusted for multiplicity 
and should be used for screening purpose only. 95% Confidence intervals are 
provided to help gauge the precision of the estimates for Risk Difference. Risk 
Difference is computed as < PF-06865571 xx mg + PF-05221304 xx mg, <dosing 
frequency>, versus Placebo>.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory analysis.
6.6.2. Vital Signs Analyses
Vital signs will be summarized according to Pfizer standards (note that baseline is defined as 
in Section 3.4 in relation to actual treatment).
Changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate will 
be summarized by treatment and time. The number (%) of participants with maximum 
increases from baseline will be tabulated by treatment as defined in Section 5.2.3. Numbers 
and percentages of participants meeting the categorical criteria will be provided and 
individual values listed in the study report. 
No formal inferential statistics will be applied to the vital signs data.
6.6.3. Electrocardiogram Analyses
ECGs will be summarized by visits. Categorical summary of ECGs will be presented 
according to Pfizer standards (note that baseline is defined as in Section 3.4 in relation to 
actual treatment).


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Changes from baseline for the ECG parameters QT interval, RR interval, calculated QTcF 
interval (using QT and RR interval), PR interval, and QRS interval will be summarized by 
treatment and time. QTcF will be derived using Fridericia’s correction formula. The number 
(%) of participants with maximum increases from baseline will be tabulated by treatment as 
defined in the Section 5.2.3. Numbers and percentages of participants meeting the 
categorical criteria will be provided and individual values listed in the study report.
No formal inferential statistics will be applied to the ECG data.
6.6.4. Other Safety Data
6.6.4.1. Platelet count
Raw data, changes from baseline, and percent changes from baseline will be summarized by 
treatment, and week as described in Section 5.2.2.

Figures from summary outputs
Box and whisker plots by treatment and by week will also be displayed to 
characterize the distribution of changes from baseline over time. Only box, whiskers, 
median, arithmetic mean, and outliers should be reported in this graphic.
Box and whisker plots by treatment and by week will also be displayed to 
characterize the distribution of percent changes from baseline over time. Only box, 
whiskers, median, arithmetic mean, and outliers should be reported in this graphic.
For participants with any after Day 1 (ie post-randomization) platelet count result of 
< 100,000/mm3, individual plots with overlay of platelet count, aPTT, and INR up to 
Week 6 (include unplanned in chronological/continuous order – not categorical) will 
be generated, by treatment. To do so, real date as reported in e-data load from 
Covance will be used.

If possible, a figure containing 4x4 panels (1 panel per participant) by 
treatment will be created with LEFT Y-axis reporting platelet count and aPTT 
levels and RIGHT Y-axis reporting INR levels.
Two statistical analyses will be performed on platelets levels. 
The first statistical analysis will be performed using change from baseline over time. 
The second analysis will be performed using the natural-logarithmic transformation of 
relative change from baseline in order to report percent change from baseline. 
Both analyses will be performed and reported as described in Section 5.2.5.

Statistical Outputs for changes from Baseline: 
The LSMeans estimates, and 80% confidence interval for each treatment at each 
time-point, 
Difference between the LSMeans for active treatment against placebo and the 
corresponding 80% confidence interval will be presented at each time point.


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Summary tables reporting MMRM outputs will included the number of participants 
included in the analysis.

Statistical Outputs for Percent Changes from Baseline: 
Adjusted geometric LSMeans estimates with 80% confidence interval for each 
treatment along with the translation in percent change (with their associated 
confidence interval) over time,
Ratio of adjusted geometric LSMeans estimates for each active treatment against 
placebo and the corresponding 80% confidence interval along with the translation in 
percent difference (with their associated confidence interval) over time.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.
6.6.4.2. Estimated Glomerular Filtration Rate
Raw data, and changes from baseline will be summarized by treatment, and week as 
described in Section 5.2.2.
The statistical analysis will be performed using the change from baseline as described in
Section 5.2.5_Ref41484348.

Statistical Outputs: 
The LSMeans estimates, and 80% confidence interval for each treatment at each 
time-point, 
Difference between the LSMeans for active treatment against placebo and the 
corresponding 80% confidence interval will be presented at each time point.
Summary tables reporting MMRM outputs will include the number of participants 
included in the analysis.

Figures from statistical outputs
Line Plot of LSMeans estimates and 80% confidence interval over time,
Line Plot of placebo adjusted LSMeans and 80% confidence interval over time.
6.6.4.3. Additional Graphical Representation
A figure containing 4x4 panels (1 panel per participant) by treatment will be created with 
LEFT Y-axis reporting TG and FPG levels and RIGHT Y-axis reporting FPI and ApoC3
levels when triglycerides levels ≥ 600 mg/dL post dosing.
7. IRC REVIEW OF UNBLINDED SAFETY DATA (DURING STUDY CONDUCT)
This study will use an IRC.  The IRC will undertake periodic unblinded review of the safety 
data while the study is on-going.  These reviews are envisioned, at a minimum, after 
approximately 33%, and 66%, of planned total sample size in Part 1 (and separately if 
conducted, Part 2), has been randomized. The IRC is independent of the study team.


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These reviews will include an assessment of the observed safety – using unblinded outputs. 
7.1.1. Analyses and Summaries
For the planned unblinded safety reviews, IRC members will receive the following data 
summarized/analyzed by treatment along with the relevant data listings. 
Study conduct and Baselined characteristics of Population Randomized:

Study conduct issues (e.g., enrollment status, currentness of the database, time between 
randomization and first treatment, eligibility violations)

Participant evaluation groups

Demographic and other baseline characteristics
Safety Data: The Committee will monitor certain specific safety-related laboratory 
parameters, vital sign parameters, and treatment-emergent adverse events (TEAEs) as well as 
serious adverse events (SAEs including death) listings in an unblinded manner for overall 
frequency of events. To do so, the listings which will be provided include: 

TEAEs (and SAEs) leading to temporary discontinuation of dosing;

TEAEs (and SAEs) leading to permanent discontinuation and withdrawal;

The listing of individual TEAEs and SAEs;

All instances of hyperglycemia, or platelet reduction, or hypertriglyceridemia leading to 
permanent withdrawal;

Listing of Treatment emergent adverse events (TEAEs) as defined in section 6.6 of this 
SAP;

Listings of SAEs/deaths and narratives requested from the safety database (ie, ARGUS or 
similar)

eGFR values and laboratory parameters outlined in Table 2 of this SAP represent the 
minimum list of parameters which will be listed and provided to the committee. 

This list may be expanded depending on team blinded review.
The Committee will receive the distribution of participants over time whose values cross the 
boundaries (ie Flag and Alert levels separately) for each of the parameters included in Table 
2 of this SAP.
Percent change from baseline in fasting lipid parameters (ie triglycerides, total cholesterol, 
direct LDL-C, VLDL, HDL-C, and derived non-HDL-C), fasting apolipoproteins (ie ApoA1, 
ApoBtotal, ApoB100, ApoB48, ApoC3, and ApoE), liver function parameters (ie ALT, AST, 
Total Bilirubin, GGT, and Alkaline Phosphatase), eGFR, and will be provided for review.


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Change from baseline in glycemic parameters (ie HbA1c, FPI and FPG) will be provided for 
review as well.
The following graphical representations will be provided:

Box and whiskers plots of percent change from baseline for  parameters in Table 2, 
eGFR, fasting lipid parameters (see list above), fasting apolipoproteins  (see list 
above), and liver function test.

Box and whiskers plots of changes from baseline for glycemic parameters (see lest 
above):
Individual vital signs (blood pressure and pulse rate) via a listing of the raw data as well as 
values meeting the criteria outlined in Table 3 of this SAP will be provided. 
No formal statistical analyses (eg MMRM) will be performed on safety data, for purposes of 
IRC review of unblinded safety data.
7.2. Planned Interim Analysis Post Part 1 (and before start of Part 2)
Interim analyses will be performed after completion of Part 1 to determine whether to 
conduct Part 2 and if so, guide selection of doses of DGAT2i and/or ACCi to evaluate in 
Part 2.  Interim analysis results may be used to conduct a sample size re-estimation (eg, 
observed variability in Part 1 is higher than assumed for derivation of sample size for Part 
1), facilitate PK/PD modeling, and internal business decisions regarding planning of future 
trials with DGAT2i and/or DGAT2i+ACCi.
A limited number of individuals not on the study team will be unblinded according to 
Sponsor SOPs with the purpose of composing PK/PD analysis sets and conducting PK/PD 
analysis.  Data draws are expected at approximately 50%, and 100% of total study data from 
Part 1.  These data are expected to include the primary endpoint (MRI-PDFF), plasma PK 
for DGAT2i and ACCi, fasting serum lipid parameters including fasted serum triglycerides 
(and fasted serum apolipoproteins, if available).  Other data outlined in Section 3 may also 
be considered.  The PK/PD analysis output at the completion of Part 1 (ie, achievement of 
LPLV in Part 1) will be shared as part of the planned Interim Analysis with selected 
members of the Sponsors’ study team to enable decision to conduct Part 2 and if so, the 
dose(s) and dosing regimen(s) of DGAT2i + ACCi evaluated in Part 2.
8. REFERENCES
1.
Westfall and Krishen, “Optimally weighted, fixed sequence, and gatekeeping multiple 
testing procedures”, Journal of Statistical Planning and Inference 2001; 99, 25-40.
2.
Littell, R.C, Milliken, G A., Stroup, WW, and Wolfinger, R D., “SAS System for 
Mixed Models (second edition)” , Cary, NC: SAS Institute Inc, 2006.
3.
Inker LA, Schmid CH, Tighiouart H et al. Estimating Glomerular Filtration Rate from 
Serum Creatinine and Cystatin C. N Engl J Med 2012; 367: 20-29.


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9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Estimand
Strategy
Statistical 
Method
Model/ Covariates/ Strata
Missing 
Data
Interpretation
Percent Change from 
Baseline in % Liver 
Fat assessed by MRI-
PDFF at Week 6
Estimand 1
ANCOVA on 
log-transformed 
relative change
Treatment as fixed effects with
log(baseline) as covariate.
No 
Imputation
Primary Analysis
Percent change from 
Baseline in Fasting 
Serum Triglycerides 
Over Time
Estimand 2
MMRM on log-
transformed 
relative change
Treatment, week and 
treatment-by-week interaction 
as fixed effects, participant as 
random effect with 
log(baseline) as covariate. 
No 
Imputation
Secondary Analysis
Tertiary endpoints: 
Percent change from 
Baseline over time 
Estimand 2
MMRM on log-
transformed 
relative change
Treatment, Week and 
Treatment-by-Week
interaction as fixed effects, 
participant as random effect 
and log(baseline) as covariate. 
No 
Imputation
Tertiary Analysis
Tertiary endpoints 
Percent Change from 
Baseline at Week 6
Estimand 1
ANCOVA on 
log-transformed 
relative change
Treatment as fixed effects with
log(baseline) as covariate.
No 
Imputation
Tertiary analysis
Tertiary endpoints: 
Change from Baseline 
over time
Estimand 3
MMRM on 
change from 
baseline
Treatment, Week and 
Treatment-by-Week
interaction as fixed effects, 
participant as random effect 
and baseline as covariate 
No 
Imputation
Tertiary analysis


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Visit label
Protocol 
defined 
Window
Visit
Visit window as part of final reporting*
For efficacy, PD, PK and 
safety endpoints
Pre-Qualification
NA
0
NA
Screening
NA
1
NA
Run-In
NA
2
NA
Week -2
-14 ± 2
3

Intent is for baseline to be the result closest prior to
dosing on randomized regimen on Day 1 [Visit 4] 

Window for baseline measurements is from Day -20 to 
Day 1 [Visit 4] pre-dose
Week 0
Day 1
1
4
Week 2
14 ± 2
5
‘Date of assessment’ – ‘Baseline date’ + 1 = [8; 20]; 
ie, ±6 days
Week 4
28 ± 2
6
‘Date of assessment’ – ‘Baseline date’ + 1 = [22 ; 34];
ie, ±6 days 
Week 6
42 ± 2
7
‘Date of assessment’ – ‘Baseline date’ + 1 = [36 ; 48];
ie, ±6 days with all assessments within 72 hours of last dose
1st Follow-up
visit
14 ± 2 days 
post last dose
8
‘Date of assessment’ – ‘Last Dose date’ + 1 = [8  ; 20];
ie, ±6 days
2nd Follow-up 
visit
30 ± 2 days 
post last dose
9
‘Date of assessment’ – ‘Last Dose date’ + 1 = [24 ; 36];
ie, ±6 days
Note: * permitted to be wider than window defined in protocol for purposes of reporting data by nominal 
visit.
Special consideration:

For participants withdrawn early, the follow-up visit window (F/U) should be 
excluded from windowing algorithm, and the visit label is defined in accordance with 
the nominal label as recorded on the “E_TERM/FOLLOW_UP” Administration CRF.

If 2 or more observations fall within the visit window for Week N, the observation 
used will be the one closest to Day 7N (randomization day is Day 1). If the 2 closest 
observations are equidistant from Day 7N, the earlier observation will be used.
An assessment is considered ‘on treatment’ if the following is true:

‘Date (time when databased) of assessment’ > ‘Baseline date (time)’ and ≤‘Last dose 
date (time)’ 
All PD endpoints defined in section 6.1, 6.2.1, 6.3.1-6.3.9, 6.6.4.1, 6.6.4.2 are applied for 
visit window. For safety data (including laboratory analytes), there are no summary outputs 
planned by visit window; and for Vitals/12-lead ECG data as well as PK data, summaries 
will be generated based on reported nominal visit (and not use above visit windowing).  


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Appendix 2.2. Endpoint Derivations
Appendix 2.2.1. % Liver Fat using MRI-PDFF 
For each participant in the study, the Whole Liver PDFF (WLPDFF in %) will be calculated 
from the pre-defined individual segmental PDFF (SPDFF in %) measured in Segments I, II, 
III, IVa, IVb, V, VI, VII and VIII as follows:
WLPDFF= (SPDFF Segment I + SPDFF Segment II + SPDFFSegment III + SPDFF Segment IVa
+ SPDFFSegment IVb + SPDFF Segment V + SPDFF Segment VI + SPDFFSegment VII 
+ SPDFFSegment VIII) / (number of segments assessed and no missing/mapping at   
                   Baseline, and on Week 6)
Note: If any negative values is reported by the central vendor for an individual segment, the 
value of this segment will be imputed to “0” before inclusion into derivation of whole liver 
PDFF. However, the negative value, as offered by the central vendor, will be included in the 
listing.
Calculation Rule for % Liver Fat when Assessed with MRI-PDFF:
WLPDFF will be calculated on mapping no missing segments at Baseline, and on 
Week 6. 
For instance,
if results are reported for all segments at Baseline, and on Week 6 (see below), 
The number of segments assessed is equal to 9.
If at Baseline, all segment data are available, but, on Week 6 only 7 segments have results 
reported, WLPDFF will be calculated at Baseline, and on Week 6 and using the matching 
individual segments providing values on both weeks. For instance, based on the schema 
below, Segment II and Segment V will not be used to calculate WLPDFF on any of the time 
points reported. In this case, WLPDFF will be calculated using data in the 7 segments
reported at both imaging visits.
Baseline
Week 6


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WLPDFF and individual % liver fat measured in each individual segment will be listed. 
WLPDFF will be summarized by actual treatment, and Week as described in Section 5.2.2. 
Appendix 2.2.2. Compliance
Compliance with double-blinded study medication will be calculated using data entry 
exclusively from the Double Blinded treatment CRF pages on Week 2, Week 4 and 
Week 6.
Compliance between any two visits in the study will be calculated as:
% Compliance   = 
100 x (# of pills actually taken since the previous visit ) /
(# of pills expected to be taken since the previous visit)
The # of pills actually taken since the previous visit will be taken directly from the “Actual
Dose” field in the Double Blinded treatment CRFs (sites will be instructed to enter the total
number of tablets that the participant has consumed since the last on-site visit).
The # of pills expected to be taken since the previous visit = (Date of current visit – Date
of previous visit )* (Expected Tablets per day in each part1)
Compliance across the overall study treatment period will be calculated as:
% Compliance =100 x ( # of pills actually taken during the double-blind treatment phase ) /
(# of pills expected to be taken during the double-blind treatment phase)
The # of pills actually taken during the double-blind treatment phase = sum of all
“Actual dose” fields for all visits during the double-blind treatment phase (ie, the sum of the
total number of tablets that the participant has consumed during the double-blind treatment
phase).
The # of pills expected to be taken during the double-blind treatment phase = (Week 6
(V7) or Early Term visit date – Baseline visit date (V4))* (Expected Tablets per day in each 
part1)
1 To be determined for part 2. For instance in Part 1 the total daily dose will be administered using 6 tablets
Baseline
Week 6


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Appendix 3. Statistical Methodology Details
Appendix 3.1.1. MMRM for Safety Analysis and PD analysis:
On raw scale:
    proc mixed data = dataset method = reml;
class subjid treatment day;
model cfb = treatment base day base*day day*treatment/ ddfm = kr
residual;
repeated day / subject = subjid type = un;
lsmeans treatment*day / diff cl alpha = 0.1;
     run;
On natural logarithmic scale:
    proc mixed data = dataset method = reml;
class subjid treatment day;
model log(RCBL) = treatment log(base) day log(base)*day day*treatment/ ddfm = kr
residual;
repeated day / subject = subjid type = un;
lsmeans treatment*day / diff cl alpha = 0.1;
     run;
Appendix 3.1.2. ANCOVA for Safety Analysis and PD Analysis:
On raw scale:
    proc mixed data = dataset method = reml;
class treatment;
model CFB = treatment base /residual;
lsmeans treatment / diff cl alpha = 0.1;
     run;
On natural logarithmic scale:
proc mixed data = dataset method = ml;
class treatment;
model log(RCBL) = treatment log(base) /residual;
lsmeans treatment / diff cl alpha = 0.1;
    run;


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Appendix 4. List of Abbreviations
Abbreviation
Term
Abs
absolute
AE
adverse event
ALKP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
ApoA1
Apolipoprotein A1
ApoB100
Apolipoprotein B100
ApoB48
Apolipoprotein B48
ApoBTotal
Apolipoprotein B Total
ApoC3
Apolipoprotein C3
ApoE
Apolipoprotein E
AST
Aspartate Aminotransferase
ATC
Anatomic Therapeutic Chemical
AUC
area under the curve
AUDIT
alcohol use disorders identification test
BA
bioavailability
BE
bioequivalence
BLQ
below the limit of quantitation
BOCF
baseline observation carried forward
BP
blood pressure
CAP®
Controlled Attenuation Parameter
CBL
Change from baseline
CDARS
Clinical Data Analysis and Reporting System (of US Food and Drug 
Administration)
CI
confidence interval
CK18-M30
Cytokeratin-18-M30
CK18-M65
Cytokeratin-18-M65
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
EAC
event adjudication committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FPG
Fasting Plasma Glucose
FPI
Fasting Plasma Insulin
GCP
Good Clinical Practice


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Abbreviation
Term
GGT
Gamma Glutamyl Transferase
GLIMMIX
generalized linear mixed-effects model with repeated measures
GMC
geometric mean concentration
GMFR
geometric mean fold rise
GMR
geometric mean ratio
GMT
geometric mean titer
HbA1C
Glycated Hemoglobin A1C
HDL-C
High Density Lipoprotein Cholesterol
HOMA-IR
Homeostatic Model Assessment for Insulin Resistance
hsCRP
High Sensitive C-Reactive Protein
ICD
informed consent document
ICH
International Council for Harmonisation
IRC
internal review committee
IST
independent statistical team
ITT
intent-to-treat
LDL
Low Density Lipoprotein
LLOQ
lower limit of quantitation
LOCF
last observation carried forward
LOD
limit of detection
LS
least-squares
LSM
least-squares mean
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
MMRM
mixed-effects model with repeated measures
MMTT
mixed meal tolerance test
MNAR
missing not at random
N/A
not applicable
NNB
number needed to benefit
NNH
number needed to harm
NNT
number needed to treat
NOAEL
no-observed-adverse-effect level
Non-HDL-C
Non High-Density Lipoprotein Cholesterol
PBL
Percent change from baseline
PCSK9
Proprotein convertase subtilisin/kexin type 9
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PP
per-protocol
PPAS
per-protocol analysis set
PRO
patient-reported outcome
ProC3
N-terminal pro-peptide of type III procollagen
ProC6
C-terminal fragment of the α3 chain of procollagen type VI
PT
preferred term


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Abbreviation
Term
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
RCBL
Relative change from baseline
RCDC
reverse cumulative distribution curve
RR
relative risk
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SGS
Statistical Guidance Standards
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TA
therapeutic area
TBIL
Total bilirubin
TEAE
Treatment emergent adverse event
ULN
upper limit of normal
VCTETM
Vibration-Controlled Transient Elastography
VLDL
Very Low Density Lipoprotein cholesterol
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary
%CDT
% Carbohydrate-Deficient Transferrin 


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Appendix 5. Graphical Representations
Appendix 5.1.
Box and Whisker Plot Representation for Changes/Percent Changes from Baseline at Week 6 by Treatment
Note: To be adapted for C3711005 design with correct total daily dose and orderd by ratio then by dosing regimen (eg BID vs QD). 
Only box, whiskers, median, arithmetic mean and outliers should be reported in this graphic (individual participant data [open circles 
within 5th and 95th whisker should not be included] only the individual values which are outliers/outside whiskers).


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Appendix 5.2.
Box and Whisker Plot for Changes/ Percent Changes From Baseline by Treatment and Week 
Note:
To be adapted for C3711005 design (eg weeks as legend) with correct total daily dose. Only box, whiskers, median, arithmetic 
mean and outliers should be reported in this graphic (individual participant data [open circles within 5th and 95th whisker should 
not be included] only the individual values which are outliers/outside whiskers).


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Appendix 5.3. LS Means and Placebo Adjusted LS Means with 80% CI from MMRM Analysis Over Time Versus Week per 
Treatment (to be adapted for C3711005 Design) 


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Appendix 5.4. Example for LS Means and Placebo Adjusted LS Means with 80% CI from ANCOVA Analysis at Week 6 per 
Treatment (to be adapted for C3711005 Design)


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Appendix 5.5. Example for Figure Reporting Multiple Laboratory Parameters Over Time Simultaneously (to be adapted for 
C3711005 Design)