Conditions: Nonalcoholic Fatty Liver Disease Nonalcoholic Steatohepatitis
Keywords: PF-05221304 NAFLD NASH features of metabolic syndrome Dose-Ranging Study
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 305
Healthy volunteers: no

Brief summary:
Phase 2a, dose-ranging Study with PF-05221304 in Nonalcoholic Fatty Liver Disease (NAFLD)

Detailed description:
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Dose-ranging, Parallel Group Study To Evaluate Safety, Tolerability, And Pharmacodynamics Of PF-05221304 Administered Daily For 16-weeks To Adult Subjects With Nonalcoholic Fatty Liver Disease

Arms:
arm 1: Double-Blind, PF-05221304-matching Placebo arm 2: PF-05221304 - 2 mg, once-daily arm 3: PF-05221304 - 10 mg, once-daily arm 4: PF-05221304 - 25 mg, once-daily arm 5: PF-05221304 - 50 mg, once-daily

Interventions: intervention 1: Placebo intervention 2: PF-05221304
Intervention descriptions: intervention 1: Placebo intervention 2: PF-05221304, Experimental Drug

Protocol document:
Prot_000.pdf: 
PF-05221304 
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
DOSE-RANGING, PARALLEL GROUP STUDY TO EVALUATE SAFETY, 
TOLERABILITY, AND PHARMACODYNAMICS OF 
PF-05221304 ADMINISTERED DAILY FOR 16-WEEKS TO ADULT SUBJECTS 
WITH NONALCOHOLIC FATTY LIVER DISEASE 
Investigational Product Number:
PF-05221304
Investigational Product Name:
Not applicable
United States (US) Investigational New Drug (IND) Number:
European Clinical Trials Database (EudraCT) Number:
2017-001156-55
Protocol Number:
C1171002
Phase:
2a
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Document History
Document
Version 
Date
Summary of Changes and Rationale
Amendment 
2
03 October
2017
This amendment is making the following substantial changes to align with 
the Pfizer Enterprise-level revision to appropriate measures to prevent 
pregnancy in the population of childbearing potential enrolled who are 
sexually active and align with the Clinical Trial Facilitation Group (CTFG) 
2014 European Guidance–
•
Section 4.4.6 revised to –
1.
Remove mandate to use highly effective contraception in female 
partners of male subjects of childbearing potential;
2.
Use of male or female condom alone is viewed as an effective 
method of contraceptive but must continue to be used with another 
highly effective method of contraceptive;
•
Language mandating use with spermicide has been removed 
since the intent is to combine use of condom with another 
highly-effective method of contraception;  
•
The following administrative changes to enhance clarity and ensure 
intended interpretation of protocol content have also been incorporated –
•
Section 4.2, exclusion criterion #9, correct inconsistency and permit 
at both Pre-Qualification and Screen 1 visits (not only Screen 1)
repeat laboratory-related assessments to assess eligibility and depict 
intent to exclude those who appear to have been cured of 
Hepatitis C viral infection by pharmacological intervention;
•
Section 5.8.5 updated to remove use of symbol and replace with 
text to delineate that list of medications taken within (not prior to)
8 weeks of Visit 1 are prohibited;
•
Section 5.8.5 updated to clarify that anti-convulsants specifically 
prescribed for management of seizures are not permitted (though 
use for other indications may be permitted); 
•
Section 5.8.5 updated to clarify that β-blockers and calcium channel 
blockers are permitted, while other antiarrhythmic agents (eg, those 
that function primarily as sodium and potassium channel blockers)
are not permitted; 
•
Typographical error in Section 7.2.1 corrected to capture that 
Visit 11 is Week 16 (not Week 11);
•
Figure 2 and Section 7.9.1 further clarified (beyond Enterprise-level 
text in Section 8.2.2) and by extension in Appendix 2, that in those 
subjects with observed platelet count below lower limit of normal 
by Week 8, additional (unplanned) visits every two weeks should 
continue while on double-blinded investigational product (ie, add 
unplanned visits at Weeks 10, and 14, in addition to already 
scheduled visits at Weeks 12, and 16) with blood samples collected 
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Document
Version 
Date
Summary of Changes and Rationale
to permit safety-related laboratory parameters including hematology 
by sponsor identified central laboratory;
•
Appendix 2 and Appendix 3 updated to reflect removal of 
“scheduled” as visits for assessment could also be unplanned.
Amendment 
1
24 July 
2017
This amendment is making the following substantial changes as requested by 
the United States Food and Drug Administration (US FDA) as part of their
review of the original protocol submitted on 11May2017 –
•
In addition to conducting standard full and brief physical examinations, 
targeted physical examinations of skin, eyes, and pulmonary system were 
added at predose at Weeks 2, 8, and 16 – refer to Table 1 and
Section 7.2.1
•
Section 3.2 updated to include explicit cross-reference to detailed 
Enterprise-level standardized management of AEs, SAEs, and cases of 
DILI;
•
Section 3.3 updated to offer instances wherein unblinded safety review by 
IRC will be triggered based on-going blinded safety reviews by selected 
members of the Sponsors’ study team;
•
Section 5.8.5 updated to exclude CYP3A4/5 substrates with narrow 
therapeutic indices
 
•
Section 7.9.3 expanded to include language expecting subjects with type 
2 diabetes mellitus to share the low blood glucose information sheet 
which delineates the symptoms of hypoglycemia along with treatment 
options with their family member(s) / roommate(s) to help in their 
management of hypoglycemia;
•
While PF-05221304 is not known to carry the potential risk of 
hypoglycemia, many of the agents used for the management of 
glycemic control in patients with T2DM carry this risk - this rationale 
this added to Section 1.3.2;
•
In addition, based on determination by the Central IRB for sites in 
Canada and USA, that informed consent must be offered by the 
participating subject only, via this amendment, at the study-level, a 
requirement is being instituted that informed consent for both 
pre-qualification and main study, be offered by the participating subject,
only
•
The provision that permits subjects’ legally acceptable representative
to offer informed consent has been deleted (in 
Sections 4.1, 8.1.2, 8.1.4, and 12.3).
•
Administrative clarifications added to Section 7.1.2 regarding 
FibroScan® operators; and Appendix 4 to capture time of onset and 
resolution of hypoglycemic event rather than time to recovery to match 
Sponsors’ new standard for capture of these events.
Original 
protocol
04 May
2017
Not applicable 
This amendment incorporates all revisions to date, including amendments made at the request of country health 
authorities and institutional review boards (IRBs)/ethics committees (ECs).  
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.......................................................................................................10
1. INTRODUCTION ...............................................................................................................16
1.1. Mechanism of Action/Indication.............................................................................16
1.2. Background .............................................................................................................16
1.2.2. Clinical Experience with PF-05221304......................................................19
1.3. Rationale for Study..................................................................................................20
1.3.1. Rationale for Design...................................................................................20
1.3.2. Rationale for Population Enrolled ..............................................................22
1.3.3. Rationale for Doses Selected......................................................................26
1.4. Summary of Benefit Risk Assessment....................................................................28
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................28
3. STUDY DESIGN.................................................................................................................30
3.1. Study Overview.......................................................................................................30
3.2. Stopping Rules for Dosing in Individual Subjects..................................................31
3.3. Considerations for Pausing or Stopping Active Dose(s) Based on Observed 
Safety.........................................................................................................................32
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................33
4.1. Inclusion Criteria.....................................................................................................33
4.2. Exclusion Criteria....................................................................................................36
4.3. Randomization Criteria ...........................................................................................40
4.4. Lifestyle Requirements ...........................................................................................41
4.4.1. Dietary Restrictions ....................................................................................41
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................42
4.4.3. Activity .......................................................................................................42
4.4.4. Confinement to Site....................................................................................42
4.4.5. Confinement at Imaging facility.................................................................43
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4.4.6. Contraception..............................................................................................43
4.5. Sponsor’s Qualified Medical Personnel..................................................................45
5. STUDY TREATMENTS.....................................................................................................45
5.1. Allocation to Treatment ..........................................................................................46
5.2. Breaking the Blind ..................................................................................................46
5.3. Subject Compliance.................................................................................................46
5.4. Investigational Product Supplies.............................................................................47
5.4.1. Dosage Form(s) and Packaging..................................................................47
5.4.2. Preparation and Dispensing........................................................................47
5.5. Administration.........................................................................................................47
5.6. Investigational Product Storage ..............................................................................48
5.7. Investigational Product Accountability...................................................................49
5.7.1. Destruction of Investigational Product Supplies ........................................49
5.8. Concomitant Treatment(s).......................................................................................49
5.8.1. Medications for Glycemic Control .............................................................49
5.8.2. Lipid-modifying medications .....................................................................50
5.8.3. Medications for Controlling Blood Pressure..............................................51
5.8.4. Other Acceptable Concomitant Medications..............................................51
5.8.5. Prohibited Medications...............................................................................52
5.9. Rescue Medication ..................................................................................................53
6. STUDY PROCEDURES .....................................................................................................53
6.1. Proposed Chronology of Procedures.......................................................................53
6.2. Pre-Qualification .....................................................................................................54
6.3. Screening (Visits 1 and 2) .......................................................................................54
6.4. Visit 3 (Run-in) through to Visit 11 (Week 16)......................................................55
6.5. Follow-up Visit .......................................................................................................55
6.6. Subject Withdrawal / Early Termination ................................................................55
7. ASSESSMENTS..................................................................................................................57
7.1. Liver Assessments using FibroScanand MRI-PDFF ...........................................57
7.1.1. Background on Liver Assessment Techniques...........................................57
7.1.2. Assessment of Liver Fat and Stiffness – using FibroScan.......................58
7.1.3. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis......58


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7.1.4. Analysis of MRI-PDFF Images Including Determination of 
Eligibility .........................................................................................................59
7.2. Safety-Related Assessments....................................................................................60
7.2.1. Physical Examination .................................................................................60
7.2.1.1. Measurement of Waist Circumference......................................61
7.2.2. Body Weight...............................................................................................61
7.2.3. 12-lead Electrocardiogram..........................................................................62
7.2.4. Blood Pressure and Pulse Rate ...................................................................62
7.3. Clinical Laboratory Tests........................................................................................63
7.3.1. Pregnancy Testing ......................................................................................65
7.4. Rater Qualifications.................................................................................................65
7.5. Pharmacokinetics – plasma for analysis of PF-05221304 ......................................65
7.6. Exploratory Biomarkers ..........................................................................................66
7.8. Blood Volume .........................................................................................................68
7.9. Specific Subject Safety Scenarios...........................................................................69
7.9.1. Potential Cases of Thrombocytopenia........................................................69
7.9.2. Potential Cases of Hypertriglyceridemia....................................................69
7.9.3. Management of Glycemic Control in Patients with T2DM........................69
7.9.3.1. Protocol-Specific Criteria for Inadequate Glycemic 
Control...............................................................................................70
8. ADVERSE EVENT REPORTING......................................................................................72
8.1. Requirements...........................................................................................................73
8.1.1. Additional Details on Recording Adverse Events on the CRF...................74
8.1.2. Eliciting Adverse Event Information..........................................................74
8.1.3. Withdrawal from the Study Due to Adverse Events (see also Section 
6.6) ...................................................................................................................74
8.1.4. Time Period for Collecting AE/SAE Information......................................74
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................75
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................75
8.1.5. Causality Assessment .................................................................................75
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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................75
8.2. Definitions...............................................................................................................76
8.2.1. Adverse Events...........................................................................................76
8.2.2. Abnormal Test Findings .............................................................................76
8.2.3. Serious Adverse Events ..............................................................................77
8.2.4. Hospitalization............................................................................................77
8.3. Severity Assessment................................................................................................79
8.4. Special Situations ....................................................................................................79
8.4.1. Protocol-Specific Serious Adverse Events.................................................79
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................79
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................81
8.4.3.1. Exposure During Pregnancy......................................................81
8.4.3.2. Exposure During Breastfeeding ................................................82
8.4.3.3. Occupational Exposure .............................................................82
8.4.4. Medication Errors .......................................................................................83
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................83
9.1. Sample Size Determination.....................................................................................84
9.2. Efficacy Analysis ....................................................................................................84
9.2.1. Analysis of the Primary Endpoint...............................................................84
9.2.2. Analysis of Secondary Endpoint ................................................................85
9.3. Analysis of Tertiary Endpoints ...............................................................................85
9.3.2. Other Tertiary Endpoints............................................................................85
9.4. Safety Analysis........................................................................................................86
9.5. Interim Analysis ......................................................................................................86
9.6. Data Monitoring Committee ...................................................................................86
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................86
11. DATA HANDLING AND RECORD KEEPING .............................................................87
11.1. Case Report Forms/Electronic Data Record .........................................................87
11.2. Record Retention...................................................................................................88
12. ETHICS..............................................................................................................................88
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12.1. Institutional Review Board/Ethics Committee......................................................88
12.2. Ethical Conduct of the Study ................................................................................88
12.3. Subject Information and Consent..........................................................................89
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................89
13. DEFINITION OF END OF TRIAL...................................................................................90
13.1. End of Trial in a Member State.............................................................................90
13.2. End of Trial in All Other Participating Countries.................................................90
14. SPONSOR DISCONTINUATION CRITERIA ................................................................90
15. PUBLICATION OF STUDY RESULTS..........................................................................90
15.1. Communication of Results by Pfizer ....................................................................90
15.2. Publications by Investigators ................................................................................91
16. REFERENCES ..................................................................................................................93
LIST OF TABLES
Table 1.
Study-Related Procedures in C1171002...............................................................14
Table 2.
Study-Related Blood and Urine Collections in C1171002...................................15
Table 3.
Randomized Regimens in Study C1171002.........................................................46
Table 4.
All Planned Safety-Related Laboratory Tests and Exploratory Biomarkers 
in Study C1171002 ...............................................................................................64
LIST OF FIGURES
Figure 1.
Overview of C1171002 Study Population............................................................23
Figure 2.
C1171002 Study Design.......................................................................................31
Figure 3.
Two-Tiered Stratification in Study C1171002 .....................................................41
APPENDICES
Appendix 1. Abbreviations......................................................................................................95
Appendix 2. Guidance to Investigators – Management of Individual Subjects With 
Decrease in Platelet Count....................................................................................99
Appendix 3. Guidance to Investigators – Management of Individual Subjects With 
Elevation in Fasting Serum Triglycerides ..........................................................100


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Appendix 4. Guidance to Investigators – Capturing Details for Episodes of 
Hypoglycemia in Patients with T2DM...............................................................101


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PROTOCOL SUMMARY
Background and Rationale: The current study is the first clinical trial proposed with 
PF-05221304 in adult subjects with NAFLD.  The investigational product will be 
administered orally, once-daily for up to 16 weeks.  It is designed as a dose-ranging trial with 
placebo and 4 active doses of PF-05221304 to assess the safety, tolerability and the effect of 
PF-05221304 on liver fat.  In addition, assessment of the effect of PF-05221304 on other 
pharmacodynamics/ exploratory parameters is planned.
Objectives and Endpoints: 
Primary Objective:
Primary Endpoint:
To evaluate the dose-response for the effect on liver 
fat with a range of PF-05221304 doses administered 
daily in adults with nonalcoholic fatty liver disease 
(entire study population)
Percent change from baseline in liver fat, as assessed 
using MRI-PDFF, at Week 16
Secondary Objective(s):
Secondary Endpoint(s):
To evaluate the dose-response for the effect on ALT 
with a range of PF-05221304 doses administered 
daily in the 1st tier stratification comprising of adults
with diagnosed/presumed nonalcoholic 
steatohepatitis, only
Percent change from baseline in ALT, at Week 16
To evaluate the safety and tolerability of a range of 
PF-05221304 doses administered daily in adults 
with nonalcoholic fatty liver disease (entire study 
population)
Assessment of TEAEs, safety-related clinical 
laboratory tests, vital signs, and 12-lead ECGs 
Tertiary Objective(s):
Tertiary Endpoint(s):
To evaluate the dose-response for the effect on liver 
fat, over time, with a range of PF-05221304 doses 
administered daily in adults with nonalcoholic fatty 
liver disease (entire study population)
Percent change from baseline in liver fat, as assessed 
using MRI-PDFF, over time up to Week 16
To evaluate the dose-response for the effect on key 
liver function tests and NASH-related biomarkers 
over time, with a range of PF-05221304 doses 
administered daily in the 1st tier stratification
comprising of adults with diagnosed/presumed 
nonalcoholic steatohepatitis, only
Percent change from baseline, over time up to 
Week 16, for:
•
ALT, AST, Alkaline Phosphatase, GGT
•
CK18-M30 and CK18-M65
•
Pro-C3 & Pro-C6
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Tertiary Objective(s):
Tertiary Endpoint(s):
To evaluate the dose-response for the effect on other 
potentially mechanism-related parameters and 
metabolic parameters, over time, with a range of 
PF-05221304 doses administered daily in adults 
with nonalcoholic fatty liver disease (entire study 
population)
Percent change from baseline, over time up to 
Week 16, for: 
•
Potentially mechanism-related parameters –
−
Serum apolipoprotein A1, B (total), C3, E
•
Metabolic parameters –
−
HbA1C
−
Fasting lipid panel (fasting total cholesterol, 
direct LDL-C, HDL-C, triglycerides, 
VLDL)
To evaluate the dose-response for the effect on 
glycemic parameters, over time, with a range of 
PF-05221304 doses administered daily in the 2nd tier 
stratification comprising of adults with T2DM, only
Change from baseline, over time up to Week 16, for: 
•
HbA1C
•
FPG
•
FPI
•
HOMA-IR
For all endpoints, baseline defined as result closest prior to dosing at Visit 5 (Day 1); for list of terms corresponding to 
the abbreviations used herein, refer to Appendix 1.
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Study Design: This is a randomized, double-blind, placebo-controlled, 5-arm (placebo, plus 
4 active doses of PF-05221304), parallel-group study.  The overall study design is 
summarized in the figure below:
Baseline
(V4)
Day 1 = Randomization
(V5)
8-weeks and 14-weeks
Stabilize
background 
medications
Treatment with double-dummy, blinded medication 
(placebo, or 1 of 4 doses PF-05221304)
PBO
only
Screen 1 
(V1)
Screen 2 
(V2)
On-site FU (V12) 
[10 ± 4 days post last dose]
Day 14 
± 4
(V6)
Day 28 
± 4
(V7)
Day 42 
± 4
(V8)
Day 56 
± 4
(V9)
Day 108 
± 4
(V11)
Continue re-stabilized background medications
[Telephone] Contact  FU 
[28 & 35 days post last dose]
Day 84 
± 4
(V10)
Pre-Qualification 
Run-in 
(V3)
Account for majority of placebo-
response related to increased 
compliance once in trial
Confirm subject can comply 
with IP dosing instructions 
prior to randomization 
(≥ 90% compliance over 
14±2 days)
Visits every 2 weeks up to V9
considering prior limited clinical experience 
Visit at Day 108 acknowledging dosing in 
16-wk tox- was upto Day 112 plus intent to 
complete V11 procedures while on IP
Each visit represents an outpatient visit to the site or Imaging facility and envisioned to last ≤ 2-hours
Liver Imaging via MRI-PDFF expected at Screen 2 [eligibility for study; centrally read], Baseline between V4 and V5, plus V7, V10, V11
Assessment using FibroScan® to occur at pre-Qualification + Screen 1 and then at Baseline between V4 and V5, plus V7, V10, V11
If at V9 platelet count is observed to be below lower limit of normal as reported by sponsor-identified central laboratory, additional 
(unplanned) visits should occur – refer to Appendix 2
6-weeks
Study Treatments: Each dose will consist of 3 tablets (1 tablet from each of the 3 bottles 
dispensed) as outlined below:
Regimen
Regimen Description 
(dosed once-daily)
Number of PF-05221304 tablets
Number of 
PF-05221304-matching 
placebo tablets
1 m
g
5 m
g
25 mg
50 m
g
1 / 5 mg
25 / 50 mg
A
Placebo
-
-
-
-
2
1
B
PF-05221304 – 2 mg
2
-
-
-
-
1
C
PF-05221304 – 10 mg
-
2
-
-
-
1
D
PF-05221304 – 25 mg
-
-
1
-
2
-
E
PF-05221304 – 50 mg
-
-
-
1
2
-
Study Population: In the Phase 2a study, the entire study population will have NAFLD 
(liver fat 8% by MRI-PDFF as part of screening assessment) and features of metabolic 
syndrome.  The population enrolled will be stratified into two sub-populations as follows:


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
Subjects with diagnosed or presumed NASH: These subjects would either have 
been diagnosed with NASH on liver biopsy (within the prior 24 months) or would 
meet imaging and clinical characteristics highly suggestive of NASH in the absence 
of a liver biopsy;

Subjects with NAFLD with likely minimal inflammation and fibrosis: These 
subjects will be classified based on evidence of ALT 1.25x upper limit of normal 
reference range (ULN) for the sponsor-identified central laboratory, and no/minimal 
evidence of liver fibrosis (as measured by Vibration-Controlled Transient 
Elastography [VCTETM] and reported as liver stiffness measure [LSM, in kilopascals, 
kPa] using FibroScan).  This population is considered a distinct, albeit related
population, to those categorized as diagnosed/presumed NASH; and included as a 
means to more broadly assess general safety (including potential mechanistic effects 
on platelets) and additional potential beneficial effects of ACC inhibition (such as 
improvement in glycemic control), then could be readily achieved via limiting the 
population to only subjects with NASH. 
In each arm, 50% of subjects randomized will be deemed to be eligible for the 
sub-population classified as diagnosed/presumed NASH; with the remaining subjects per arm 
eligible for the stratum defined as NAFLD with likely minimal inflammation and fibrosis.
Statistical Methods: The proposed sample size for this study is approximately 360 subjects
randomized (72 subjects per arm) to ensure at least 300 subjects (60 subjects per arm)
complete the study.  The sample size of a minimum of 60 completers per arm, was calculated 
to yield 80% power to detect a placebo-adjusted, percent change from baseline of 30% in 
liver fat (in entire study population and in n=30/arm in each sub-population of the 1st tier 
stratification), using a 1-sided, t-test at level 10%.  For the secondary endpoint of ALT in the 
1st tier stratification sub-population of diagnosed/presumed NASH, the sample size of a 
minimum of 30 completers per arm was calculated to yield 80% power to detect a 
placebo-adjusted, percent change from baseline in ALT of 35%, using a 1-sided, t-test at 
level 10%.
For the primary and key secondary endpoint of placebo-adjusted, percent change from 
baseline in liver fat via MRI-PDFF (in entire study population) and ALT (in the 
sub-population of diagnosed/presumed NASH) at Week 16, a mixed model repeated measure 
(MMRM) analysis will be performed with treatment, time and treatment-by-time interaction 
as fixed effects, and subject as a random effect. Descriptive summaries of the observed 
values and percent change from baseline in liver fat in each treatment group at each time 
point will be produced.  For statistical analyses, 80% confidence intervals will be produced 
for the least-square mean differences in each treatment group as compared to placebo.  One 
sided p-values will be displayed for the comparison against placebo with no multiplicity 
adjustment made.
Similar analyses will be applied to continuous secondary and tertiary endpoints, as 
appropriate to the data.  Descriptive summaries will be displayed for categorical secondary 
and tertiary endpoints. 


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SCHEDULE OF ACTIVITIES: TABLE 1 and TABLE 2 provide an overview of the protocol visits and procedures.  Refer to Section 6 and Section 7 of 
the protocol for detailed information on each procedure and assessment required for compliance with the protocol. The investigator may schedule unplanned 
visit(s) in addition to those listed in Tables 1 and 2, in order to conduct evaluations or assessments required to protect the well-being of the subject.
Table 1.
Study-Related Procedures in C1171002
Visit Identifier
[for abbreviations refer to Appendix 1]
Pre-
Qualification
Screen 1
Screen 2
Run-in
Baseline
Treatment Phase [all procedures before morning dose of 
blinded IP, except liver fat & stiffness assessments]
Follow-up
Early 
Termination
Weeks Relative to Dosing on Day 1
-2
0
2
4
6
8
12
16
17-18
20a
Days relative to Dosing on Day 1
-142
1
144
284
424
564
844
1084
--
--
Visit
1
2
3
4
5
6
7
8
9
10
11
12
--
Informed consent (x2b) & demography
x
x
(Update) Medical & Medication history
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Liver fat & stiffness (via FibroScan)c
x
x
xd
x
x
xd
Liver fat (via MRI-PDFF)e
xf
xd
x
x
xd
Physical Examg
x
x
x
x
x
x
x
x
Assess alcohol intake (AUDIT questionnaire)
x
x
xh
x
Assess correct use of contraception
x
x
x
x
x
x
x
x
x
x
x
x
Counseling on diet/exercise guidelines
x
x
Train on use and dispense glucometer & ancillary 
supplies (T2DM subjects, only)
x
Open-ended inquiry for adverse events 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Body weight (+ hula-hoop test at pre-Q)
x
x
x
x
x
x
x
x
x
x
x
Single supine 12-lead ECG
x
x
x
x
x
x
x
x
x
x
x
x
Single seated vitals (BP & pulse rate)
x
x
x
x
x
x
x
x
x
x
x
x
Registration in trial (via IRT)
x
x
Randomization in trial (via IRT)
x
Dispensationi (via IRT) of IP
x
x
x
x
x
Witnessed dosing on site of IP
x
xh
x
x
x
x
x
x
Compliance via pill count on site of returned IP
xh
x
x
x
x
Continued administration of IP
xi
xi





xj
xj
a.
To occur via telephone contact (unless local regulations dictate on-site visit); regardless, on-site visit to be considered for follow-up of open TEAEs and/or abnormal laboratory tests
b.
Subjects to provide consent for pre-qualification first; and once deemed likely eligible requested to provide separate consent for main study (V1 and on)
c.
Assessment to be performed following 4-hr fast, at site (as part of site visit) or separate visit(s) to Imaging facility; attempts to be made to stay within 2-hr window of V1 time 
d.
Assessment to be performed on any day between V4 & V5 (ie, Baseline); and while subject is taking blinded IP with previous dose 24-hr prior (at V11) 
e.
Assessment to be performed following 4-hr fast, via separate visit(s) to Imaging facility; attempts to be made to stay within 2-hr window of V2 time
f.
A single repeat assessment permitted as determined by sponsor-identified central imaging vendor; subject must not progress to V3 until results from screen-repeat confirm eligibility
g.
Includes arm circumference (at pre-Q); height plus waist circumference (at pre-Q & V1); targeted PE at V6, V9, V11 and brief PE for open AEs/abnormal tests, at investigator discretion 
h.
Review of AUDIT questionnaire responses must be deemed acceptable, and 90% compliance (with pills in each bottle), required to progress to randomization
i.
At V4, reflects single-blind placebo; from V5 onwards, reflects double-blind randomized regimen
j.
At V11 and ET visits reflects return to site of any remaining unused double-blind randomized regimen; subjects will not be offered IP post last dose in this trial 


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Table 2.
Study-Related Blood and Urine Collections in C1171002
Visit Identifier
[for abbreviations refer to Appendix 1]
Pre-
Qualification
Screen 1
Screen 2
Run-in
Baseline
Treatment Phase [all procedures before morning dose of 
blinded IP, except when specified otherwise]
Follow-up
Early 
Termination
Weeks Relative to Dosing on Day 1
-2
0
2
4
6
8
12
16
17-18
20a
Days relative to Dosing on Day 1
-14± 2
1
14±4
28±4
42±4
56±4
84±4
108±4
--
--
Visit
1
2
3
4
5
6
7
8
9
10
11
12
--
Blood collection, after ≥8-hour overnight fast, for – [refer also to Table 4 for comprehensive list of analytes]
−Hematology, chemistry, coagulation, HbA1C
xb
xb
No Blood or Urine Collections
x
x
x
x
x
x
x
x
x
xd
x
−Fasting lipid panel
xb
xb
xc
x
x
x
x
x
x
x
x
xd
x
−Pregnancy (females only)
xb
xb
xc
x
x
x
x
x
xd
x
−FSH (females only), Serology (HBsAg, 
HBcAb, HCVAb, HIV), α1-antitrypsin, 
ceruloplasmin
xb
xb
−% carbohydrate deficient transferrin
xb
xb
x
x
x
−Apolipoproteins
x
x
x
x
x
x
−CK18-M30, CK18-M65, Pro-C3, and Pro-C6
x
x
x
x
x
x
Spot urine collection for –
−Urine drug test
xb
xb
xc
−Urinalysis (and microscopy, as appropriate)
xb
xb
x
x
x
x
x
x
x
x
x
xd
x
−On-site pregnancy test (WOCBP, only)
xg
xg
xg
xg
xg
xg
x
xd
x
a.
To occur via telephone contact (unless local regulations dictate on-site visit); regardless, on-site visit to be considered for follow-up of open AEs and/or abnormal laboratory tests
b.
Test results must be reviewed by a medically qualified site staff and deemed acceptable before progression to next visit (pre-Q results prior to V1; and V1 results prior to V2)
c.
Test results must be reviewed by a medically qualified site staff and deemed acceptable before progression to randomization and first dose of double-blinded IP, at V5
d.
Collections to occur only if visit is an on-site visit; collections to be skipped if visit is via telephone contact
f.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a subject visit
g.
At each of these visits, the test result must be reviewed by a medically qualified site staff and deemed acceptable, in order to continue participation in study
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1. INTRODUCTION
Acetyl-CoA carboxylase (ACC) is a biotin carboxylase that catalyzes the adenosine 
triphosphate (ATP) dependent condensation of acetyl-CoA and carbonate to form 
malonyl-CoA.1 The malonyl-CoA produced by ACC serves two major physiologic 
functions.  It is an essential and rate-limiting substrate for de novo lipogenesis (DNL) and it 
acts as an allosteric inhibitor of the enzyme carnitine-palmitoyltransferase 1 (CPT-1).  
CPT-1 is responsible for the transport of long-chain fatty acyl-CoAs across the mitochondrial 
membrane into the mitochondria where they become available for fatty acid oxidation.  The 
transport step is rate-determining for this process.  Thus, ACC is positioned as a key 
physiologic switch regulating the transition from oxidative to lipogenic metabolism.  
Reducing malonyl-CoA production via ACC inhibition is expected to inhibit simultaneously 
the de novo synthesis of fatty acids and to increase flux through CPT-1 leading to increased 
-oxidation of long-chain fatty acids.  There are two closely related isoforms of ACC, ACC1, 
and ACC2, encoded by separate gene products that differ in tissue and cellular distribution. 
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual ACC1/2 inhibitor 
designed to have asymmetric distribution to the liver, with ≥100 fold asymmetric hepatic 
distribution demonstrated in both rats and monkeys; as such PF-05221304 is expected to 
inhibit DNL and stimulate fatty acid oxidation in the liver to a greater extent than in 
peripheral tissues.  In humans, administration of PF-05221304 has been shown to suppress 
hepatic DNL in a Phase 1 trial in healthy subjects; in addition, the drug is expected to 
stimulate hepatic fatty acid oxidation, and consequently reduce fat accumulation in the liver.  
This inhibition of hepatic DNL is postulated to result in a decrease and normalization of the 
excessive DNL observed in nonalcoholic fatty liver disease (NAFLD).  In addition, the 
inhibition of ACC via administration of PF-05221304 also has the potential for 
anti-inflammatory effects in nonalcoholic steatohepatitis (NASH). 
The current study is the first clinical trial proposed with PF-05221304 in adult subjects with 
NAFLD.  The investigational product will be administered orally, once-daily for up to 
16 weeks.  It is designed as a dose-ranging trial with placebo and 4 active doses of 
PF-05221304 to assess the safety, tolerability and the effect of PF-05221304 on liver fat.  In 
addition, assessment of the effect of PF-05221304 on other pharmacodynamics/exploratory 
parameters is planned.
1.1. Mechanism of Action/Indication
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual ACC1/2 inhibitor, 
designed to have asymmetric distribution to the liver.  It is being developed for the treatment 
of NASH with fibrosis.
1.2. Background
The World Health Organization lists NAFLD and NASH as the most important of 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 hepatocellular carcinoma 
(HCC).2 NASH is diagnosed clinically by liver biopsy demonstrating steatosis, 
inflammation, and cytological ballooning of liver hepatocytes, often with varying degrees of 


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fibrosis.  NASH progresses with increasing degrees of fibrosis, with cirrhosis developing in a 
subset of patients3 with the most common complication of cirrhosis being HCC.4 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.
NASH is a clinical and histological subset of NAFLD (defined as presence of 5% hepatic 
steatosis) that is associated with increased all-cause mortality, cirrhosis and end-stage liver 
disease, increased cardiovascular mortality, and increased incidence of both liver related and 
non-liver related cancers.3 In a recent meta-analysis, the global prevalence of NAFLD is 
estimated at 25%, with the prevalence of NASH in the subset with biopsy-proven NAFLD 
assessed at 59%.5 The majority of the population with NAFLD has simple steatosis which 
has, in general, a benign clinical course.  A proportion of patients 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 patients progress very rapidly (within 10 years) to liver cirrhosis from NAFLD.6
The 5-year (67%) and 10-year (38%) survival rates in patients with NASH is significantly 
different than in those with NAFLD.7 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.5
Alterations in lipid metabolism have been hypothesized to contribute to the molecular 
pathogenesis of NAFLD and NASH.  Elevated rates of hepatic DNL have been reported to be 
a distinctive characteristic of NAFLD (defined as liver fat 5%).8 Humans with elevated 
liver fat have a greater than 3-fold increase in the rate of hepatic DNL relative to subjects 
with normal liver fat, but differences between the groups were not detected in adipose free 
fatty acid (FFA) flux or in production of very low density lipoprotein (VLDL) from FFAs.  
Consequently, when comparing human subjects with steatosis to those with normal liver fat, 
the contribution of hepatic DNL was most significantly elevated in subjects with high liver 
fat.8 ACC inhibition is expected to suppress hepatic DNL and stimulate hepatic fatty acid 
oxidation, and consequently reduce steatosis.9 Partial inhibition of this enzyme activity 
would be expected to lead to such improvements, with 70% hepatic DNL inhibition 
normalizing the elevated flux in subjects with NAFLD to that observed in individuals with 
normal liver fat.8 Consistent with this, beneficial effects of pharmacological ACC inhibition 
on liver fat in rodent models of NAFLD/NASH have been reported.9,10,11,12
Emerging data also suggest that suppression of DNL through ACC inhibition may also 
directly reduce inflammation by restraining the formation of the inflammatory 
interleukin-17 secreting T cells of the T helper 17 lineage (Th17) cells which in turn promote 
the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells.13 Studies 
comparing patients with NASH versus those with simple steatosis or healthy liver have 
demonstrated that progression from NAFLD to NASH is marked by a higher frequency of 
Th17 cells in the liver and increase in the ratio of Th17 cells to Treg cells in peripheral blood 
and in the liver.14


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1.2.2. Clinical Experience with PF-05221304
As of May-2017, a single clinical study (C1171001) has been conducted with PF-05221304.  
A total of 96 (93 male and 3 female) healthy adult subjects were randomized in this one 
study.  Overall, 82 subjects (85%) have been exposed to at least a single oral dose of 
PF-05221304; with 56 of these subjects exposed to repeated doses of PF-05221304 for up to 
14-days.  Of these, 16 subjects received single oral doses of PF-05221304 ranging from 1 mg 
to 240 mg – with each single dose of PF-05221304 evaluated in at least 6 subjects.  An 
additional 70 subjects were exposed to up to 14-days of repeated oral dosing of 
PF-05221304 (n=56 subjects; up to 8 subjects per dose) or placebo (n=14 subjects, total) 
ranging from total daily doses of 2 mg/day to 200 mg/day – administered every 12 hours 
(Q12H) in 5 cohorts and once-daily (QD) in 2 cohorts – to assess safety, pharmacokinetics 
(PK), and steady-state effect on marker of target engagement (ie, inhibition of DNL).  Ten 
more subjects received single oral dose (100 mg) in 2 periods with and without a 
high-fat/high-caloric morning meal to assess the effect of food on plasma exposure of 
PF-05221304. 
In Study C1171001, single oral doses (up to 240 mg) and repeated total daily doses (up to 
200 mg/day) were found to be well tolerated with an acceptable safety profile.  Over this 
dose range evaluated, while the maximum tolerated dose (MTD) was not identified, higher 
doses were not assessed either because the a priori identified PK stopping limit was achieved 
(single dose) or near complete inhibition of hepatic DNL was observed (upon repeated 
dosing). 
In the clinical program to date, there have been no serious adverse events (SAEs), 
no treatment-emergent adverse events (TEAEs) of ‘severe’ intensity, and no apparent 
dose-related increase in frequency or severity of TEAEs across the 240-fold (single) and 
100-fold (repeated) dose range studied.  All of the TEAEs were ‘mild’ in intensity except 
1 TEAE of ‘platelet count decreased’ deemed to be of ‘moderate’ intensity; this resulted in 
premature withdrawal of 1 subject following 13 (of 14) days of PF-05221304 dosing at 
100 mg Q12H (200 mg/day), the highest repeated dose evaluated.  This ‘moderate’ intensity 
TEAE comprised of a gradual decline in platelet count from a baseline of 167,000/mm3 to 
114,000/mm3 at 24-hours post last dose (on Day 13).  This subject was asymptomatic with no 
signs or symptoms of platelet dysfunction and the decrease in platelet count did not meet 
criteria for thrombocytopenia (defined as < 100,000/mm3).  The platelet count increased
towards baseline by 72 hours post last dose and was back to baseline by 10 days post last 
dose.
Upon repeated dosing, the only TEAE reported by more than 2 subjects exposed to 
PF-05221304, across the entire dose range evaluated, was headache.  
 
 
  Of note, no dose related trends in venipuncture bruising-related TEAEs 
(eg, contusions) were noted despite 51 direct venipunctures (for serial blood collections) 
performed per subject during the inpatient stay phase of the repeated dosing portion of this 
study. 
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Across the other safety-related data collected, some asymptomatic, drug-related, laboratory 
parameter changes were observed.  This included a gradual increase in fasting and 
post-prandial serum triglycerides with repeated doses ≥40 mg/day with effect plateauing 
over the 14-day dosing period. 
 
 
  At the 
doses ≥60 mg/day, a gradual decrease in platelet count was observed with repeated doses 
over the 14 day dosing period. This observation was not noted at PF-05221304 doses up to 
40 mg/day and no signs or symptoms of platelet dysfunction were apparent based on the 
safety assessments performed.  There were no apparent abnormalities noted in the other 
safety-related assessments such as blood pressure, and cardiac conduction intervals [assessed 
on 12-lead electrocardiograms (ECGs)]. 
The plasma PK of PF-05221304 following oral administration suggests a moderate rate of 
absorption with a median time to maximum plasma concentration (Tmax) ranging from 3 to 
5 hours, following repeated dosing with the morning meal.  Food (high-fat/high-caloric meal) 
had no clinically relevant effect on exposure which decreased slightly (area-under-the-curve 
to infinity (AUCinf) by ~10% and Cmax by ~25%, while rate of absorption was delayed with 
Tmax of 2.5 hours (dosing in fasted state) moving out to 5 hours (when dosing occurred with 
food).  After attainment of Cmax, the disposition of PF-05221304 showed a decline with the
half-life of PF-05221304 being independent of dose, and ranging from approximately 13 to 
18 hours.  With Q12H dosing frequency, an approximate 2-fold accumulation was observed 
which reduced to approximately 1.5-fold with QD dosing frequency. Across the range of 
repeated doses evaluated (2 mg/day to 200 mg/day), the plasma exposure increased 
approximately dose-proportionally with increasing dose.  Less than 1% of the oral dose of 
PF-05221304 was excreted unchanged in the urine indicating that renal clearance is not a 
major clearance mechanism for PF-05221304. 
1.3. Rationale for Study
The current study is the first trial specifically designed to evaluate the effect of 
PF-05221304 (compared to placebo) on liver fat, as assessed via magnetic resonance imaging 
proton density fat fraction (MRI-PDFF), and other pharmacodynamic/exploratory parameters 
in adults with NAFLD.  The investigational product will be administered orally, once-daily 
for up to 16 weeks. 
1.3.1. Rationale for Design
Along with an assessment of effect of PF-05221304 on liver fat, this study is designed to 
assess the safety and tolerability of a range of oral doses of PF-05221304 compared to 
placebo.  Eligible population is defined as having liver fat ≥8% as measured by MRI-PDFF 
at Screen 2 and evidence of concomitant medical conditions, including features of metabolic 
syndrome, albeit stable with intent to stratify the population enrolled (refer to 
Section 1.3.2 and Section 4.3 for details).  While NAFLD is typically defined by liver fat 
≥5%, entry criteria at Screen 2 is proposed at ≥8% to account for a potential drift in liver fat 
during the run-in/stabilization period and negate the need for a randomization criteria related 
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to liver fat assessment between Visit 4 (Day -14) and Visit 5 (Day 1; randomization).  A 
run-in period of ≥6-weeks post confirmation of eligibility and prior to randomization (ie, 
Visit 3 to Visit 5) is specifically included to permit stabilization of background/concomitant
medications and achievement of pre-randomization baseline. 
Overall, this study includes two distinct phases to confirm eligibility before subjects are 
progressed to Screen 2 to determine eligibility based on MRI-PDFF-assessed liver fat. As 
such, two separate informed consents will be obtained – 1st limited to pre-qualification visit 
only; and 2nd for the main study only in those deemed to meet eligibility criteria based on 
pre-qualification procedures.  Between the pre-qualification visit and Visit 1 (Screen 1), 
many of the procedures and clinical laboratory tests assessed are identical – this is motivated 
by intent to confirm that the population progressed to Screen 2 is stable and consistently 
characterized in one of the two pre-specified 1st tier stratification sub-populations of 
diagnosed/presumed NASH versus NAFLD with minimal inflammation and fibrosis.  As a 
measure of additional diligence and attempt to remove variability due to differences from 
laboratory-to-laboratory, the clinical laboratory tests assessed at pre-qualification and Visit 
1 (Screen 1) are proposed to be analyzed by the sponsor-identified central laboratory.  
Furthermore, assessment of liver fat via ultrasound-based, but more quantitative FibroScan®
and reported as controlled attenuation parameter (CAPTM) is included at pre-qualification and 
Visit 1 (Screen 1), in the entire study population, with a threshold of ≥280 decibels per meter 
(dB/m), is designed to help identify the likely eligible population based on MRI-PDFF via a 
more logistically feasible, and overall more efficient approach.  
 
 
 
 
  The use of generic abdominal ultrasound to detect liver fat is not 
advocated given the limited utility of this assessment for liver fat less than 20% although 
there is high specificity for detecting ≥20-30% liver steatosis.15
For the assessment of liver fat (either via FibroScan® or MRI-PDFF), subjects will be 
required to fast (water permitted) for ≥4-hours given the ability of food to impact the results.  
As an additional measure to limit variability, attempts will be made to standardize the 
nominal time, for FibroScan® assessment and, especially related to the primary endpoint 
(MRI-PDFF).  The clock time of day when these assessments are made should fall within a 
practical window (± 2-hours) relative to clock time at Visit 1 (Screen 1) for FibroScan® and 
Visit 2 (Screen 2) for MRI-PDFF.  Serial assessments post randomization via MRI-PDFF and 
are planned to permit a mixed-model-repeated-measure analysis thereby allowing 
for evaluation of drug effect longitudinally and, at each visit, including end of dosing with 
the investigational product (IP) – ie, Visit 11 (Week 16). 
To date, the clinical experience with PF-05221304 is limited to a single Phase 1 trial in 
healthy subjects with repeated, in-patient/witnessed dosing up to 14-days.  Transitioning to 
the current study, with dominantly outpatient dosing in a patient population, increased 
variability in exposure and drug-response is plausible.  Hence, an added feature of the 
proposed study design is the frequent (every 2-week), outpatient visits during the first 
8-weeks post randomization and monthly visits thereafter.  Furthermore, at least 1 interim 
analysis (IA) is planned [refer to Section 9.5] to permit ongoing review of safety of the 
population enrolled, amongst the planned activities. 
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Plasma exposure of PF-05221304 following a high-fat/high-caloric breakfast was similar 
relative to administration of PF-05221304 following an overnight fast – suggesting that 
investigational product can be administered without regard to food.  However, in this study, 
PF-05221304 administration will be requested to occur with the morning meal – given the 
importance of a morning meal to the standard-of-care diet counselling for the planned 
population.
Total duration of dosing of investigational product in this study is proposed as up to 
16 weeks
.  This 
duration should permit an assessment of the primary pharmacology of 
PF-05221304 (ie, anti-steatosis), as well as potential improvement in liver function (as 
denoted by reduction in alanine transaminase (ALT) in the 1st tier stratification comprising of 
subjects with diagnosed or presumed NASH – a sub-population selected to have elevated
ALT at Visit 1 (Screen 1). 
A fixed, single-blind, 2-week baseline period (ie, Visit 4 to Visit 5) is included in this study 
with the explicit purpose of familiarizing the subjects with the dosing instructions for the 
blinded IP (refer to Table 3), and exclude subjects who are not compliant with the blinded 
placebo prior to randomization in an attempt to minimize medications errors post 
randomization. 
1.3.2. Rationale for Population Enrolled 
NAFLD is a condition marked by excessive (≥5%) fat accumulation in the liver with a 
subgroup progressing to having hepatocellular injury and inflammation (ie, NASH), and 
cirrhosis, and a smaller proportion of patients developing hepatic cellular carcinoma (HCC).7
In this study, while the entire study population will have evidence of liver fat ≥8% at 
Screen 2 and features of metabolic syndrome, the population enrolled will be stratified as 
denoted in Figure 1 as a means to permit an opportunity to evaluate potential for changes in 
measures of hepatic inflammation and fibrosis [refer to Figure 3 for additional detail 
regarding stratification]. 
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Figure 1.
Overview of C1171002 Study Population
Diagnosed or Presumed NASH
Biopsy-proven 
NASH in previous  
≤ 24-months
• Features of Metabolic Syndrome* 
plus
• ALT > ULN & ≤ 5x ULN
and
• Liver stiffness on FibroScan® ≥ 7.0 kPa^
NAFLD with likely minimal inflammation & fibrosis
• Features of Metabolic Syndrome* 
plus
• ALT ≤ 1.25x ULN 
and
• Liver stiffness on FibroScan® < 7.0 kPa^
Adult (≥18 and ≤ 70 yrs) patients with NAFLD defined as liver fat of ≥ 8%
Based on MRI-PDFF at Visit 2 / Screen 2 with No Additional Criteria at Randomization
*Defined by meeting ≥ 2 of 5 criteria related to fasting plasma 
glucose, fasting high-density cholesterol, fasting triglycerides, 
waist circumference, and blood pressure – refer to Section 4.1  
Plus, BMI ≥ 25 kg/m2 (Western) or 22.5 kg/m2 (Asian)
In the 1st tier stratification, the two sub-populations will be categorized as having diagnosis 
or presumed NASH versus NAFLD with likely minimal inflammation and fibrosis.  Those 
with diagnosed/presumed NASH comprise of a subset with biopsy-proven diagnosis of 
NASH or a constellation of clinical and liver imaging characteristics which are highly 
suggestive of a NASH diagnosis (in the absence of a liver biopsy).  The other sub-population 
of NAFLD with likely minimal inflammation and fibrosis will include those with alanine 
aminotransferase (ALT) ≤1.25x upper limit of reference range (ULN) for the 
sponsor-identified central laboratory, and no/minimal evidence of liver fibrosis (as measured 
by Vibration-Controlled Transient Elastography (VCTETM) and reported as liver stiffness 
measure (LSM, in kilopascals, kPa) using Fibroscan® and as such considered a distinct albeit 
related, population to those labeled as diagnosed/presumed NASH.  This NAFLD with likely 
minimal inflammation and fibrosis population is included in this Phase 2a, dose-ranging 
study, as it provides an opportunity to more broadly assess general safety (including potential 
mechanistic effect on platelet count and serum triglycerides) and additional potential 
metabolic benefits of ACC inhibition (such as improvement in glycemic control), than could 
be readily achieved via limiting the population to only subjects with NASH.  In addition, this 
study aims to permit those subjects within identified thresholds for ALT in combination with 
liver stiffness in the F0 to F3 grades of fibrosis.  In doing so, population stratification 
acknowledges that elevated ALT alone is an imperfect marker of NASH and the technology 
used (FibroScan®) to assess liver stiffness lacks the specificity to categorize F0-F2 grades of 
fibrosis with a great deal of precision.  Even with these caveats, the combination of these 
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screening parameters may aide in characterizing the population in the absence of a liver 
biopsy – the current gold standard7 despite its inherent limitations such as its invasive
assessment with procedural risks, potential for sampling errors, and inconsistency in 
interpretation of the histopathology. 
The liver stiffness cut-off for the sub-population categorized as presumed NASH was 
motivated by the intent to include those with F2-F3 grades of fibrosis though noted to permit 
likely F1 (but not F0) grades of fibrosis; similarly, the liver stiffness cut-off for the NAFLD 
with likely minimal inflammation and fibrosis reflects the intent to limit population to 
dominantly F1-F0 grades of fibrosis.  Considering that many patients diagnosed with NASH 
on liver biopsy have ALT ≤ULN, and many with elevated ALT do not have NASH on liver 
biopsy,16 it is acknowledged that the approach taken to stratify the study population is likely 
unable to definitively rule-out patients with NASH from the sub-population categorized as 
NAFLD with likely minimal inflammation and fibrosis. 
Beyond the categorization of the enrolled population into diagnosed/presumed NASH versus 
NAFLD with likely minimal inflammation and fibrosis, this study will apply a 2nd tier 
stratification to identify the population with and without a diagnosis of type 2 diabetes 
mellitus (T2DM) based on glycated hemoglobin (HbA1C) result > 6.5% and/or current use of
agents for glycemic control (Section 5.8.1).  This is to permit an assessment of whether 
PF-05221304 demonstrates insulin sensitization properties.  While PF-05221304 is not 
known to carry the potential risk of hypoglycemia, many of the agents used for the 
management of glycemic control in patients with T2DM carry this risk and hence a 
standardized approach to capture of such events will be undertaken – refer to 
Section 7.9.3.1.1 and Appendix 4. 
Together, the study is designed to understand the effect of PF-05221304 on liver fat, ALT 
and other NASH-related biomarkers, glycemic parameters, fasting lipids, and effect on other
parameters [ie, Apolipoprotein A1, B (total), C3, E, 
 
 
 as well as assess effect of
PF-05221304 on metabolic parameters.  NASH-related markers include: 
cytokeratin18-M30 (CK18-M30) and CK18-M65, markers of apoptotic activity; 
 
ProC3, the N-terminal pro-peptide of type III 
procollagen which is a potential predictor of fast progressors and responders to therapy at 
baseline; and ProC6, the C-terminal fragment of α3 chain of procollagen type VI (also known 
as Endotrophin) which is a potential predictor of responders to insulin sensitizers at baseline.  
 
 
 
In this study, based on a combination of thorough medical history (including assessment of 
ethanol intake and administration of the Alcohol Use Disorders Identification Test (AUDIT) 
10-item questionnaire, and clinical laboratory tests (including gamma glutamyl transferase 
[GGT] and percent carbohydrate deficient transferrin relative to total transferrin [%CDT]), 
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medically-qualified site-staff will be required to rule-out alcohol-based as well as other 
causes of hepatic steatosis, and ensure that the population enrolled is confirmed, as best as 
possible, to have non-alcoholic fatty liver disease.18 These assessments (AUDIT and %CDT) 
are re-assessed prior to randomization and at end of dosing to confirm that while in the study 
alcohol intake remained in moderation.  Subjects with previously confirmed genetic 
polymorphisms, for example, patatin like phospholipase domain containing protein 
3 (PNPLA3) carriers, are eligible given 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, estimated glomerular filtration rate [eGFR] ≤30 mL/min) via specific eligibility criteria 
(refer to Section 4.1 and Section 4.2).  This is in line with: (1) the clinical data to date 
obtained in a trial enrolling healthy subjects with the current trial being the first in the patient 
population; (2) the mechanism of action (ie, primarily anti-steatotic) is unlikely to display 
anti-fibrotic action in a trial with up to 16 weeks of dosing; and (3) at present, lack of Phase 
1 studies to describe the plasma PK of PF-05221304 in subjects with hepatic and/or renal 
impairment.  
 
 
 
 
 
 
 
 
 Thus, the inclusion/exclusion criteria have been defined to help 
limit pharmacokinetic variability while also capturing a population that is characteristic of 
the intended patient population. 
 
 
  In order to minimize PF-05221304 pharmacokinetic variability due to 
drug-drug interactions (DDIs), medications that have been shown to perpetrate OATP 
mediated clinically significant DDIs are excluded (notably gemfibrozil, cyclosporine).  
Furthermore, concomitant use of potent inhibitors (eg, ketoconazole or itraconazole) or 
inducers (eg, rifampin) of CYP3A4/5 is to be avoided.  
 
  
 
 
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  Amongst the 
agents for glycemic control, thiazolidinediones (TZDs) and glucagon-like peptide-1 receptor 
(GLP-1r) agonists are not permitted given their potent anti-steatotic effect18,19 and hence the 
potential to confound the primary endpoint of this study.  Refer to Section 5.8 for complete 
details regarding permitted and excluded concomitant medications. 
Given the observed effects of PF-05221304 on platelet count, and serum triglycerides (both 
fasting and post-prandial) in the Phase 1 study (C1171001), in the current study, eligibility 
criteria for platelet count and fasting triglycerides is included (refer to Section 4) along with a 
monitoring strategy for each aspect – refer to Section 7.9.1 and Appendix 2 (platelet count), 
as well as Section 7.9.2 and Appendix 3 (fasting serum triglycerides). 
For the postulated improvement in insulin sensitivity with PF-05221304 administration in 
this study, diligence will be applied via monitoring of fasting plasma glucose (FPG), fasting 
plasma insulin (FPI), HOMA-IR, HbA1C, and in patients with T2DM the standardized 
capture of any hypoglycemic events (HAEs) along with hyperglycemia (refer to 
Section 7.9.3).  To ease subjects’ burden, at Visit 3 (Run-in), the sponsor will provide all 
eligible subjects with T2DM glucometer and associated ancillary supplies to permit at-home 
self-monitoring – at least once daily. 
Both females of childbearing potential as well as those who are of non-childbearing potential 
will be enrolled 
 
 
 
refer to Schedule of Activities (Table 1 and Table 2) as well as Section 4.4.6 and
Section 7.3.1].  Measures to prevent pregnancy in female partners of male subjects are
suggested to include a simple barrier method 
 
 
 
1.3.3. Rationale for Doses Selected 
In addition, to placebo, the PF-05221304 doses selected for this study (2, 10, 25 and 50 mg 
once daily) are based on the observed safety, tolerability, pharmacokinetic, and 
pharmacodynamic data from Study C1171001 in healthy adult subjects.  In Study C1171001, 
PF-05221304 was found to be well tolerated with an acceptable safety profile with single 
doses up to 240 mg and repeated doses up to 200 mg/day) administered and the MTD not
identified.  At the three highest doses (≥ 60 mg/day), a gradual decrease in platelet count, 
was observed with repeated doses over the 14 day dosing period, though none of the values 
met the criteria for thrombocytopenia.  In addition, a gradual increase in fasting and
post-prandial triglycerides was observed with repeated doses ≥40 mg/day with effect 
plateauing over the 14-day dosing period.
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Following repeated dosing in healthy adult subjects (Study C1171001), change from baseline 
in fructose-stimulated hepatic DNL was assessed via incorporation of deuterated water tracer 
into triglyceride-palmitate over a 10-hour period where fructose doses were given every 
30-minutes to stimulate DNL.  Inhibition in DNL, a marker of target engagement, was 
observed in a dose and concentration-dependent manner with ≥90% DNL inhibition at 
PF-05221304 total daily doses ≥40 mg/day.  
 
 
 
 
 
  Given the projected degree of target engagement (ie, DNL inhibition) with 
the planned dosing frequency (ie, once-daily), PF-05221304 dosing frequency is proposed as 
once-daily (rather than Q12H evaluated on 5 of the 7 dose-levels in the Phase 1 Study 
C1171001 in healthy subjects).  The selected dose range spans a range of expected DNL 
inhibition, allowing for assessment of the relationship between DNL and the primary 
endpoint (liver fat), key secondary endpoint (ALT), as well as safety and other parameters.
 
 
 
 
 
 
 
 
 
 
 
The overall dose selection of PF-05221304 was also influenced by the aim to identify not 
only a minimally-effective dose but also characterize the dose-response using the tablet 
strengths available (1, 5, 25, and 50 mg – with the 2 lower strengths looking identical but 
different than the 2 higher strength tablets) as efficiently as possible.  As proposed, the 
dose-range planned will necessitate each subject to self-administer 3 tablets per day in order 
to maintain the double-blind design of this study. 
 
 
 
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1.4. Summary of Benefit Risk Assessment 
Study C1171002 is the first time that PF-05221304 is being administered to patients with 
NAFLD.  For the subjects participating in this study, close monitoring of their medical 
condition and safety, will occur as outlined in this protocol.  Those randomized to 
PF-05221304 may potentially derive benefit from reduction of DNL and its potential 
associated effects including reduction in hepatic steatosis, and potential reduction in liver 
inflammation.  Those randomized to placebo are not expected to obtain any specific benefit, 
beyond close monitoring of their medical condition and safety.  As of the issuance of this 
protocol, identified adverse drug reactions that may be encountered with the administration 
of PF-05221304 include elevation in blood triglycerides and reduction of platelet count.
Any adverse clinical impact of these findings are expected to depend on the severity of the 
potential reaction, and are minimized through – (1) the proposed frequent visits to site to 
permit close oversight of subjects’ safety via monitoring of a range of clinical assessments 
including laboratory tests, 12-lead ECGs, vitals, assessment of AEs; (2) inclusion of 
provisions for temporary discontinuation of dosing and permanent withdrawal from the study 
as outlined in Section 3.2; (3) institution of an Independent Review Committee (IRC) to 
undertake unblinded review of the safety data, while the study is on-going, and make 
recommendation(s) as to whether 1 or more doses should be paused/discontinued (refer to 
Section 3.3 and Section 9.5), amongst the planned activities.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:
To evaluate the dose-response for the effect on liver 
fat with a range of PF-05221304 doses administered 
daily in adults with nonalcoholic fatty liver disease 
(entire study population)
Percent change from baseline in liver fat, as assessed 
using MRI-PDFF, at Week 16
Secondary Objective(s):
Secondary Endpoint(s):
To evaluate the dose-response for the effect on ALT 
with a range of PF-05221304 doses administered 
daily in the 1st tier stratification comprising of adults 
with diagnosed/presumed nonalcoholic 
steatohepatitis, only
Percent change from baseline in ALT, at Week 16
To evaluate the safety and tolerability of a range of 
PF-05221304 doses administered daily in adults 
with nonalcoholic fatty liver disease (entire study 
population)
Assessment of TEAEs, safety-related clinical 
laboratory tests, vital signs, and 12-lead ECGs 
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Tertiary Objective(s):
Tertiary Endpoint(s):
To evaluate the dose-response for the effect on liver 
fat, over time, with a range of PF-05221304 doses 
administered daily in adults with nonalcoholic fatty 
liver disease (entire study population)
Percent change from baseline in liver fat, as assessed 
using MRI-PDFF, over time up to Week 16
To evaluate the dose-response for the effect on key 
liver function tests and NASH-related biomarkers 
over time, with a range of PF-05221304 doses 
administered daily in the 1st tier stratification
comprising of adults with diagnosed/presumed 
nonalcoholic steatohepatitis, only
Percent change from baseline, over time up to 
Week 16, for:
•
ALT, AST, Alkaline Phosphatase, GGT
•
CK18-M30 and CK18-M65
•
Pro-C3 & Pro-C6
To evaluate the dose-response for the effect on other 
potentially mechanism-related parameters and 
metabolic parameters, over time, with a range of 
PF-05221304 doses administered daily in adults 
with nonalcoholic fatty liver disease (entire study 
population)
Percent change from baseline, over time up to 
Week 16, for:
•
Potentially mechanism-related parameters –
−
Serum apolipoprotein A1, B (total), C3, E
•
Metabolic parameters –
−
HbA1C
−
Fasting lipid panel (fasting total cholesterol, 
direct LDL-C, HDL-C, triglycerides, 
VLDL)
To evaluate the dose-response for the effect on 
glycemic parameters, over time, with a range of 
PF-05221304 doses administered daily in the 2nd tier 
stratification comprising of adults with T2DM, only
Change from baseline, over time up to Week 16, for:
•
HbA1C
•
FPG
•
FPI
•
HOMA-IR
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Tertiary Objective(s):
Tertiary Endpoint(s):
For all endpoints, baseline defined as result closest prior to dosing at Visit 5 (Day 1); for list of terms corresponding to 
the abbreviations used herein, refer to Appendix 1.
3. STUDY DESIGN
3.1. Study Overview
This is a randomized, double-blind, placebo-controlled, 5-arm (placebo, plus 4 active doses
of PF-05221304), parallel-group study.
Determination of eligibility for this study will occur via a sequential, 3-step process – starting 
with pre-qualification.  Subjects identified to be eligible based on pre-qualification will then 
undergo Visit 1 (Screen 1) with only those confirmed to continue to be eligible progressing 
to Visit 2 (Screen 2).  For a given subject, this 3-step eligibility assessment (from 
pre-qualification to Screen 2, inclusive) may take up to 2-months. 
Once confirmed to be eligible based on Screen 2 procedure(s), subjects will progress to a 
run-in phase when concomitant treatment(s) will be stabilized, and baseline-related visits will 
occur.  At Visit 5 (Day 1), subjects will be randomized to receive 1 of 5 blinded regimens for 
a duration of up to 16 weeks (ie, 108±4 days).  Excluding the pre-qualification visit, this 
study includes a total of 12 scheduled outpatient visits in the morning, 
 
 and a potential for up to at least 3 visits for repeat assessments (for 
procedures/tests at Visit 1, Visit 2, or 2nd Follow-up visit).  The total participation, from 
Visit 1 (Screen 1) to 2nd Follow-up visit, will be 27-weeks (minimum) to 35-weeks 
(maximum) – refer to Figure 2. 
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Figure 2.
C1171002 Study Design
Baseline
(V4)
Day 1 = Randomization
(V5)
8-weeks and 14-weeks
Stabilize
background 
medications
Treatment with double-dummy, blinded medication 
(placebo, or 1 of 4 doses PF-05221304)
PBO
only
Screen 1 
(V1)
Screen 2 
(V2)
On-site FU (V12) 
[10 ± 4 days post last dose]
Day 14 
± 4
(V6)
Day 28 
± 4
(V7)
Day 42 
± 4
(V8)
Day 56 
± 4
(V9)
Day 108 
± 4
(V11)
Continue re-stabilized background medications
[Telephone] Contact  FU 
[28 & 35 days post last dose]
Day 84 
± 4
(V10)
Pre-Qualification 
Run-in 
(V3)
Account for majority of placebo-
response related to increased 
compliance once in trial
Confirm subject can comply 
with IP dosing instructions 
prior to randomization 
(≥ 90% compliance over 
14±2 days)
Visits every 2 weeks up to V9
considering prior limited clinical experience 
Visit at Day 108 acknowledging dosing in 
16-wk tox- was upto Day 112 plus intent to 
complete V11 procedures while on IP
Each visit represents an outpatient visit to the site or Imaging facility and envisioned to last ≤ 2-hours
Liver Imaging via MRI-PDFF expected at Screen 2 [eligibility for study; centrally read], Baseline between V4 and V5, plus V7, V10, V11
Assessment using FibroScan® to occur at pre-Qualification + Screen 1 and then at Baseline between V4 and V5, plus V7, V10, V11
If at V9 platelet count is observed to be below lower limit of normal as reported by sponsor-identified central laboratory, additional 
(unplanned) visits should occur – refer to Appendix 2
6-weeks
At least 360 subjects (72 per arm) will be randomized at approximately 120 sites to ensure a 
minimum of 300 subjects (60 per arm) complete the study.  In each arm, 50% of subjects 
randomized will be deemed to be eligible for 1st tier stratification of diagnosed/presumed 
NASH; with the remaining subjects per arm eligible for 1st tier stratification of NAFLD with 
likely minimal inflammation and fibrosis – refer to Section 4.3.
Subjects who are noted to have non-evaluable baseline MRI-PDFF, as determined by the 
sponsor-identified central imaging vendor, may be replaced, at sponsor discretion – refer to 
Section 7.1.4; otherwise, there are no plans to replace subjects who are prematurely 
withdrawn.  To ensure that the required minimum number of subjects complete the study, the 
plan is to overenroll by approximate 20% to account for premature early withdrawal. 
3.2. Stopping Rules for Dosing in Individual Subjects
At investigator discretion, for subjects’ safety, dosing with double-blinded investigational 
product (ie, post randomization), may be stopped in an individual subject – either temporarily 
or permanently.  In such cases, any open TEAEs must be followed to resolution or until such 
time that the event is viewed to have stabilized – refer to Section 8 for details – specifically, 
Section 8.1 which outlines the requirements for reporting adverse events, 
Section 8.2.3 detailing definition of serious adverse events, and Section 8.4.2 summarizing 
management of potential cases of drug-induced liver injury which are categorized as 
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An example where temporary discontinuation of dosing with investigational product, may 
be considered appropriate includes hospitalization with subsequent discharge within 7-days 
in stable medical condition, as determined by medically-qualified investigator.  Of note, in 
this study, re-challenge/re-initiation of dosing with double-blinded investigational product 
should not be attempted in subjects who meet threshold for withdrawal based on platelet 
count (Appendix 2) or fasting serum triglycerides (Appendix 3).
Examples where permanent discontinuation of dosing and withdrawal of the subject from 
the study is deemed appropriate, as determined by investigators’ medical judgment, include:

Hospitalization due to serious adverse event (SAE) resulting in clinical 
decompensation of the subject and necessitating continued inpatient stay for more 
than 7-days;

Subjects observed to have a decline over time ultimately reaching the threshold of 
< 75,000/mm3 in platelet count – refer to Section 7.9.1 and Appendix 2 for additional 
guidance;

Individual subjects with consistently increasing fasting serum triglycerides over time 
ultimately reaching the threshold of 800 mg/dL (9 mmol/L) – refer to 
Section 7.9.2 and Appendix 3 for additional guidance; 

Of note, in both the above cases of pre-identified laboratory thresholds, 1 additional 
unplanned assessment may be warranted before permanent withdrawal if the 
threshold is observed to be met as an isolated occurrence relative to all prior results 
and subject is asymptomatic.
3.3. Considerations for Pausing or Stopping Active Dose(s) Based on Observed Safety
The decision to pause or stop dosing at a study-level, for 1 or more active dose(s) of 
PF-05221304 may be considered based on recommendation from the Internal Review 
Committee (IRC) according to their review of unblinded, study-level emerging, observed
safety data – refer to Section 9.5.
In addition, during study conduct, after approximately every 20% of the total planned 
randomizations [for example: 72 subjects (20%), 145 subjects (40%), 215 subjects (60%), 
and 290 subjects (81%) of planned 360 subjects], based on blinded safety review by the 
selected members of the Sponsor’s study team, unblinded review of the safety data by the 
IRC will be triggered and a determination of the safety to continue the study documented if 
post randomization either of the below conditions are met –

More than 20% of subjects, develop a moderate or severe AE in the same system 
organ class (SOC);

More than 15 % of subjects meet the individual permanent discontinuation of dosing 
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4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects 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 subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Male or female subjects between the ages of 18 (or the minimum country-specific age of 
consent if > 18) and 70 years, inclusive, at Visit 1 (Screen 1):

Male and female subjects of childbearing potential must agree to use highly 
effective method(s) of contraception [refer to Section 4.4.6].  A subject is of 
childbearing potential if, in the opinion of the investigator, he/she is biologically 
capable of having children and is sexually active.

Female subjects of childbearing potential must not be pregnant, breastfeeding, 
or planning to become pregnant for the duration of their participation in this 
study and within 28-days following last dose of blinded investigational 
product.

Female subjects of non-childbearing potential must meet at least 1 of the 
following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level
confirming the postmenopausal state, with a single repeat assessment, via the 
sponsor-identified central laboratory, permitted to assess postmenopausal state, if 
needed;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure;
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential.

At Pre-Qualification and Visit 1 (Screen 1), in all female subjects, serum
beta human chorionic gonadotropin (-hCG) level, with a single repeat assessment, 
via the sponsor-identified central laboratory, permitted to assess non-pregnant state, if 
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2. At Pre-Qualification, pass the hula-hoop test [refer to Section 7.1.3] with a single repeat
assessment, permitted, if needed, to assess eligibility.
3. At Pre-Qualification, have an arm circumference compatible with the largest blood 
pressure cuff size available at individual sites [refer to Section 7.2.4] with a single repeat
assessment, permitted, if needed, to assess eligibility.
4. At Pre-Qualification and Visit 1 (Screen 1), total body weight of > 50 kg (110 lbs) with
BMI 25 kg/m2 (for sites in Africa, Europe, North America) or BMI 22.5 kg/m2 (for 
sites in Asia), with a single repeat assessment of body weight and/or BMI permitted to 
assess eligibility, if needed, at each of these 2 visits.
5. At Pre-Qualification and Visit 1 (Screen 1), meet the following criteria for liver fat, 
based on assessment via FibroScan, with a single repeat permitted to assess eligibility, if 
needed, at each of these 2 visits:

CAPTM 280 dB/m;

NOTE: if Pre-Qualification and Visit 1 values are discordant stratifying a given 
subject, 1 more assessment via FibroScanon a separate day is permitted, with 2 of 
the 4 assessments (at least 1 between pre-qualification and repeat pre-qualification, 
plus at least 1 between Screen 1 and repeat Screen 1) required to meet above 
threshold before progressing to Screen 2.
6. At Pre-Qualification and Visit 1 (Screen 1), meet the following criteria, as assessed by 
sponsor-identified central laboratory; with a single repeat on any of these parameters
permitted to assess eligibility, if needed, at each of these 2 visits:

International Normalized Ratio (INR) 1.3;

Albumin lower limit of normal (LLN);

Platelet count 0.95x LLN;

Fasting triglycerides 400 mg/dL (4.5 mmol/L);

HbA1C 9.5%;

Fasting plasma glucose 270 mg/dL (15.0 mmol/L);

Total bilirubin < 1.5x upper limit of normal (ULN) and direct bilirubin ULN.

NOTE: Subjects with a history of Gilbert syndrome would be eligible for this 
study provided direct bilirubin level is ULN plus ALT met criteria for 
applicable 1st tier stratification plus alkaline phosphatase, hemoglobin, and
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7. Documented liver biopsy 24-months prior to Visit 1 (Screen 1) with histological 
evidence of NASH in order to be classified in the sub-population with biopsy-proven 
NASH, only.
8. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), 
meet the following criteria for liver stiffness, based on assessment via FibroScan, with 
a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:

LSM 7.0 kPa – classified as presumed NASH;

LSM < 7.0 kPa – classified as NAFLD with likely minimal inflammation and 
fibrosis;

NOTE: if Pre-Qualification and Visit 1 values are discordant in stratifying a given 
subject, 1 more assessment via FibroScanon a separate day is permitted, with 2 of 
the 4 assessments (at least 1 between pre-qualification and repeat pre-qualification, 
plus at least 1 between Screen 1 and repeat Screen 1) required to meet above 
threshold before progressing to Screen 2.
9. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), 
meet the following criteria, as assessed by the sponsor-identified central laboratory, with 
a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:

ALT > ULN and 5x ULN – classified as presumed NASH;

ALT 1.25x ULN – classified as NAFLD with likely minimal inflammation and 
fibrosis;

NOTE: if Pre-Qualification and Visit 1 values are discordant in stratifying a given 
subject, 1 more blood collection on a separate day is permitted, with 2 of the 
4 assessments (at least 1 between pre-qualification and repeat pre-qualification, plus
at least 1 between Screen 1 and repeat Screen 1) required to meet above threshold 
before progressing to Screen 2.
10. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), 
meet 2 of the following 5 criteria for metabolic syndrome [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]:

FPG 100 mg/dL (5.6 mmol/L), or on pharmacological agents with explicit purpose
of improving glycemic control (refer to Section 5.8.1 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
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
Fasting serum triglyceride (TG) 150 mg/dL (1.7 mmol/L), or on pharmacological 
agents with explicit purpose to decrease TG (refer to Section 5.8.2 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 5.8.4 for acceptable versus prohibited 
medications);

Waist circumference 40 inches (102 cm) for males and 35 inches (89 cm) for 
females.
11. At Visit 2 (Screen 2), liver fat of 8%, using MRI-PDFF acquisition protocol at the 
sponsor-qualified Imaging facility in close proximity to the site, confirmed via a single 
repeat, if deemed necessary by the sponsor-identified central imaging vendor of 
MRI-PDFF images – refer to Section 7.1.4.
12. At Pre-Qualification, evidence of a personally signed and dated informed consent 
document indicating that the subject has been informed of all pertinent aspects of the 
pre-qualification procedures of this protocol.

NOTE: for subjects who qualify based on Pre-Qualification procedures, at 
Visit 1 (Screen 1), evidence of a separate personally signed and dated informed 
consent document indicating that the subject has been informed of all pertinent 
aspects of the main study, is required;
13. Subjects willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study-related procedures as outlined herein.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects with known prior participation (ie, randomized and received at least 1 dose of 
investigational product) in a trial involving PF-05221304.
2. Participation in other studies involving investigational drug(s) within 30-days prior to 
Visit 1 (Screen 1) and during study participation (ie, up to 2nd Follow-up).
3. At Pre-Qualification and Visit 1 (Screen 1), history of regular alcohol consumption 
exceeding 14 drinks/week for females or 21 drinks/week for males [1 drink = 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor)] 
within the previous 6 months.
4. At Pre-Qualification and Visit 1 (Screen 1), a total score of 8 on the AUDIT 
questionnaire, indicating harmful or hazardous ethanol consumption.


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5. At Pre-Qualification and Visit 1 (Screen 1), a positive urine drug test for illicit drugs.
6. At Pre-Qualification and Visit 1 (Screen 1), a persistent severe, uncontrolled 
hypertension; for example: seated systolic blood pressure (SBP) 180 mm Hg and/or 
diastolic blood pressure (DBP) 105 mm Hg after 5-minute of rest, with a single repeat 
permitted to assess eligibility, if needed, at each of these 2 visits:

For subjects with SBP 160 mm Hg or DBP 100 mm Hg, the Run-in Period must 
be used to refine the doses of the agents used for management of blood pressure (refer 
to Section 5.8.3) with the aim to have SBP 159 mm Hg and DBP 99 mm Hg at
the time of randomization [refer to Section 4.3];
7. At Pre-Qualification and Visit 1 (Screen 1), a supine 12-lead ECG demonstrating 
QTc interval >450 msec or a QRS interval >120 msec:

If QTc interval exceeds 450 msec, or QRS interval exceeds 120 msec, the ECG 
should be repeated two more times and the average of the three QTc intervals or QRS 
intervals should be used to determine the subject’s eligibility.
8. At Pre-Qualification and Visit 1 (Screen 1), clinical evidence of hepatic decompensation, 
including, but not limited to esophageal varices, ascites or hepatic encephalopathy.
9. At Pre-Qualification and Visit 1 (Screen 1), evidence of other forms of chronic liver 
disease including but not limited to the entities listed below; evidence may include 
laboratory tests, as assessed by the sponsor-identified central laboratory, with a single 
repeat permitted to assess eligibility, if needed, at each of these 2 visits:

Hepatitis B virus (HBV), defined by presence of hepatitis B surface antigen (HBsAg);

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb);

irrespective of HCV RNA result (when reflexed based on a positive result for 
HCVAb);

Human Immunodeficiency Virus (HIV) infection, defined as presence of HIV 
antibody;

Known diagnosis of primary biliary cirrhosis, primary sclerosing cholangitis, 
autoimmune hepatitis, or overlap syndrome;

Alcoholic liver disease, as evaluated via history along with laboratory tests including 
serum % carbohydrate deficient transferrin result 1.5x ULN deemed to be highly 
suggestive to alcohol abuse;

History of genetic reason for fatty liver; 

Wilson's disease, defined as ceruloplasmin level < LLN;


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
Known diagnosis of hemochromatosis;

Alpha-1-antitrypsin (A1AT) deficiency, defined as alpha-1-antitrypsin level < LLN; 

Prior known drug-induced liver injury;

Known or suspected Hepatocellular Carcinoma or other liver cancer;

History of liver transplant, current placement on a liver transplant list, or current 
model of end-stage liver disease (MELD) score >12;

Histological presence of cirrhosis on prior biopsy.
10. At Pre-Qualification and Visit 1 (Screen 1), subjects with an estimated glomerular 
filteration rate (eGFR) of < 30 mL/min using the Modification of Diet in Renal Disease 
(MDRD) equation, and serum creatinine (SCr), as assessed by the sponsor-identified 
central laboratory, with a single repeat permitted to assess eligibility, if needed, at each of 
these 2 visits.
11. At Pre-Qualification and Visit 1 (Screen 1), subjects with any of the following medical 
conditions:

Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection);

NOTE: subjects who have undergone cholecystectomy and/or appendectomy are 
eligible for this study so long as the surgery occurred more than 6 months prior to 
Screen 1;

Diagnosis of type 1 diabetes mellitus; 

In those with diagnosis of type 2 diabetes mellitus, history of:

Episodes of hypoglycemia of ‘severe’ intensity either 1 in previous 1 month or
3 in previous 3 months;

Treatment with excluded agents for glycemic control – refer to Section 5.8.1;

Subjects with prior history of pancreatitis;

Recent (ie, within the previous 6 months) history of congestive heart failure 
(New York Heart Association, NYHA, class III or IV) or unstable angina;

A history of myocardial infarction, stroke, or transient ischemic attack, in the 
previous 6 months;

5% weight loss within the previous 3 months;


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
Any malignancy not considered cured (except basal cell carcinoma and squamous cell 
carcinoma of the skin); a subject is considered cured if there has been no evidence of 
cancer recurrence in the previous 5 years;

Active placement of medical devices in/on thoracic cavity – such as pacemakers, 
defibrillators [as these interfere with use of FibroScan].
12. Subjects meeting criteria for contraindication for MRI – including the following:

History of severe claustrophobia impacting ability to perform MRI during the study 
even despite mild sedation/treatment with an anxiolytic;

Subjects with metal implants, devices, paramagnetic objects contained within the
body and excessive or metal-containing tattoos;

Subjects unable to lie still within the 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;
13. At Pre-Qualification and Visit 1 (Screen 1), subjects on any prohibited concomitant 
medication(s) or those unwilling/unable to switch to permitted concomitant
medication(s) – refer to Section 5.8.
14. Subjects with any anatomical or pathological abnormality that would either preclude or 
tend to confound the analysis of study data, including any clinically significant abnormal 
findings on MRI obtained at Visit 2 (Screen 2), by the sponsor-identified central imaging 
vendor of MRI-PDFF images [refer to Section 7.1.4].
15. Male subjects with partners who are currently pregnant, pregnant female subjects,
breastfeeding female subjects, as well as fertile male subjects and female subjects of 
childbearing potential who are unwilling or unable to use highly effective methods of 
contraception as outlined in Section 4.4.6 for the duration of the study and for 
at least 28 days after the last dose of blinded investigational product.
16. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more 
within 56 days prior to Visit 1 (Screen 1) or during the study until Visit 12 (on-site 
Follow-up).
17. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or subjects 
who are Pfizer employees, including their family members, directly involved in the 
conduct of the study.
18. At Pre-Qualification and Visit 1 (Screen 1), other acute or chronic medical or psychiatric 
condition including recent (within the past year) or active suicidal ideation or behavior or 
laboratory abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the subject inappropriate for 
entry into this study.


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4.3. Randomization Criteria

At Pre-Qualification, following completion of informed consent, subjects will be 
assigned a single 8-digit study-specific subject identification (SSID) number by the 
IRT (interactive response technology) system which will be retained throughout the 
duration of participation in the study;

At Visit 5 (Day 1), IRT will be used to assign each eligible subject a randomization 
number, with this number recorded on the electronic Case Report Form (e-CRF).

A computer-generated randomization code using the method of random permuted 
blocks will be utilized to randomize subjects 1:1:1:1:1 (across placebo or 1 of 
4 active doses of PF-05221304) at Visit 5 (Day 1) prior to the first dose of the 
double-blinded investigational product (PF-05221304 or matching placebo)
provided subjects’ satisfy all the following criteria:

Eligibility criteria outlined in Section 4.1 and Section 4.2;

A negative urine drug test for illicit drugs for sample collected at 
Visit 4 (Day -14) and results as reported by sponsor-identified central 
laboratory;

Fasting (8 hours overnight, with water permitted) serum triglyceride result 
of 400 mg/dL (4.5 mmol/L), for sample collected at Visit 4 (Day -14), as 
reported by sponsor-identified central laboratory; 

In females, serum pregnancy test at Visit 4 (Day -14) as reported by 
sponsor-identified central laboratory and urine pregnancy test on-site (in 
females of childbearing potential) at Visit 5 (Day 1) as reported on-site using 
supplies offered by sponsor-identified central laboratory, are negative for 
pregnancy – refer to Section 7.3.1;

Noted to be 90% compliant (based on pill count) with the single-blind 
placebo administered from Visit 4 (Day -14) to 1 day before Visit 5 (Day 1), 
inclusive, for a total duration of 14 2 days;

Total score of < 8 on the AUDIT questionnaire, as assessed at Visit 5 (Day 1).

Study will employ 2-tier stratification as outlined in Figure 3.


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Figure 3.
Two-Tiered Stratification in Study C1171002
Entire Study Population 
Adult (≥18 and ≤ 70 yrs) patients with NAFLD defined as liver fat of ≥ 8%
1st Tier Stratification*
2nd Tier Stratification
Diagnosed or
Presumed NASH
NAFLD with 
likely minimal inflammation and fibrosis
T2DM^
Non-T2DM
Non-T2DM
*Across planned total sample size, aim to randomize ≥ 50% in diagnosed/presumed NASH and ≤50% in NAFLD
^Those with T2DM across 1st tier stratification to be pooled for purposes of objectives/endpoints related to this sub-population
T2DM^
Via randomization, an attempt will be made to balance the number of subjects assigned to 
receive each active dose of PF-05221304 and placebo within the 1st tier stratification.  
However, an imbalance in the number of subjects assigned to receive each active dose of 
PF-05221304 versus placebo between the two-tiered stratification is allowed. 
4.4. Lifestyle Requirements
After confirmation of eligibility at Visit 2 (Screen 2), and starting at Visit 3 (Run-in), 
subjects will be instructed to maintain the guidelines described below for the duration of 
participation in the study.  These guidelines must be reiterated at Visit 5 (Day 1).
4.4.1. Dietary Restrictions 
•
Subjects must abstain from all food and drink (except water) for ≥8-hours prior to 
any blood sample collections for clinical laboratory tests, fasting glucose monitoring, 
•
Water may be consumed as desired (ad libitum);
•
Blinded investigational product must be administered every day with the morning 
meal;
•
On scheduled outpatient visits to the site, in the morning, from Visit 4 (Day -14) 
through Visit 11 (Week 16), subjects must be instructed to arrive without having 
morning meal/breakfast, self-administration of the blinded investigational product, 
and morning dose of concomitant medication for the control of glycemia, 
dyslipidemia, and BP, if applicable, for the given day;
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•
At Visit 4 (Day -14) through Visit 11 (Week 16), inclusive, the morning meal will 
be consumed with above mentioned medications at the site [with the meal either
provided by the site or the subject provided a voucher (or similar) by the site to 
purchase the meal before arriving to the site for each visit];
•
Subjects will be counseled on appropriate dietary and lifestyle guidelines, at 
Visit 3 (Run-in) and re-iterated at Visit 5 (Day 1):
•
Subjects will be asked to maintain these guidelines throughout participation in the 
study (ie, Visit 12, the on-site Follow-up);
•
Counseling on dietary guidelines should be individualized in accordance with 
local medical standards of care for these patients and appropriate for the 
concomitant medical condition(s) of each subject.
4.4.2. Alcohol, Caffeine, and Tobacco
•
Intake of alcohol is permitted in moderation [refer to Exclusion Criterion 3 for limits 
on amount of alcohol consumption];
•
Consumption of caffeinated drinks and nicotine-containing products is permitted 
during participation in the study; however, there may be a need for brief interruption 
while at the site and/or Imaging facility, depending on local policy.
4.4.3. Activity
•
Subjects 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 subject’s normal pace is
permitted.
4.4.4. Confinement to Site 
•
Each outpatient visit to the site will occur with the subject arriving at the site between 
approximately 6 AM and 10 AM with each visit envisioned to last ≤2-hours;
•
Visit to the Imaging facility for MRI-PDFF [± FibroScan®] assessment will have 
restrictions related to prior meals/food consumption and clock time of day [refer to 
Schedule of Activities (Table 1) and Section 7.1].
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4.4.5. Confinement at Imaging facility
•
Each outpatient visit to the Imaging facility (for MRI-PDFF) will occur following a 
fast (water permitted) of ≥4-hours and same time of day (± 2 hours) relative to 
MRI-PDFF completed at Visit 2 (Screen 2); refer to Section 7.1 for additional details; 
•
Visits to Imaging facility can occur on the same day as the visit to the site either
prior or after the Site visit;
•
Visit to Imaging facility is also permitted to be on days separate from visits to 
site; but in this case must still occur within the pre-defined visit window [refer to 
Schedule of Activities (Table 1)].
•
For assessment via FibroScan®, visits will occur either to the site or the Imaging 
facility – depending on where the FibroScan® device is located – however, the
location of the device must be kept consistent at individual sites throughout the study 
execution;
•
Similar to MRI-PDFF, each assessment via FibroScan® to occur following a fast 
(water permitted) of ≥4-hours and same time of day (± 2 hours) relative to 
FibroScan® assessment completed at Visit 1 (Screen 1).
4.4.6. Contraception
In this study, male subjects who are able to father children, and female subjects who are of 
childbearing potential have an 80% chance of being randomized to receive PF-05221304; 
 
Female subjects who, in the opinion of the investigator are sexually active and at risk for 
pregnancy must agree to use highly effective contraception throughout the study and 
continue use for at least 28 days after the last dose of blinded investigational product.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected the appropriate method of contraception for the individual subject from 
the list of permitted contraception methods below and instruct the subject in their consistent
and correct use.  At time points indicated in the Schedule of Activities (Table 1), the 
investigator or designee will inform the female subject of the need to use the highly effective
method of contraception consistently and correctly and document such conversation, and the 
subject’s affirmation, in the subject’s chart.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use).  
One of the below options must be used to satisfy the requirement for highly effective 
contraception in female subjects participating in this study:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, inserted, injected, implanted; and including oral, as well as transdermal
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methods unless prohibited by local regulations or ethics committee decision),
combined with either:
a.
Male or female condom;
b. Male sterilization.
2. Correctly placed copper-containing intrauterine device (IUD) or intrauterine system 
combined with either:
a.
Male or female condom;
b. Male sterilization.
3. Male sterilization with absence of sperm in the postvasectomy ejaculate in the female 
subjects’ partner combined with either:
a.
Male or female condom;
b. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive 
procedures.
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label)
combined with one of the following:
a.
IUD or intrauterine system;
b. Male or female condom;
c.
Male sterilization.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
female partner(s) to drug through ejaculate by using a condom consistently and correctly, 
beginning with the first dose of double-blinded investigational product at Visit 5 (Day 1) and 
continuing for at least 28 days after the last dose of blinded investigational product.
In female subjects, pregnancy testing will be performed at time points indicated in the 
Schedule of Activities (Table 2).  The specific contraceptive method(s) in the females of 
childbearing potential will be documented, and at every visit their consistent and correct use 
will be ascertained and documented in the subject’s source document.  For additional details, 
refer to Section 7.3.1.
In addition, the investigator or designee will instruct all subjects of childbearing potential to 
call immediately if the selected contraception method is discontinued or if pregnancy is 
known or suspected in the female subject or male subjects’ female partner.


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4.5. 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 study portal.
To facilitate access to appropriately qualified-medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study 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 
subject’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 subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are tablets for oral administration in the following 
strengths:

1 mg PF-05221304;

5 mg PF-05221304;

25 mg PF-05221304;

50 mg PF-05221304;

Placebo matching PF-05221304 tablet strengths of 1 mg and 5 mg;

Placebo matching PF-05221304 tablet strengths of 25 mg and 50 mg.
Note that the drug substance is denoted as PF-05221304-82.  All descriptions using this term 
are equivalent to PF-05221304 for the purpose of identifying the active moiety relevant to 
this study.  An investigational product manual will be provided to the sites prior to the 
initiation of randomization of subjects into the study.


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5.1. Allocation to Treatment
In this study, at least 360 subjects will be randomized to receive 1 of the regimens described 
in Table 3.  Each dose will consist of 3 tablets (1 tablet from each of the 3 bottles dispensed). 
Table 3.
Randomized Regimens in Study C1171002
Regimen
Regimen Description
(dosed once-daily)
Number of PF-05221304 tablets
Number of 
PF-05221304-matching 
placebo tablets
1 mg
5 mg
25 mg
50 mg
1 / 5 mg
25 / 50 mg
A
Placebo
-
-
-
-
2
1
B
PF-05221304 – 2 mg
2
-
-
-
-
1
C
PF-05221304 – 10 mg
-
2
-
-
-
1
D
PF-05221304 – 25 mg
-
-
1
-
2
-
E
PF-05221304 – 50 mg
-
-
-
1
2
-
Allocation of subjects to dosing regimens will occur through the use of an interactive 
response technology (IRT) system (interactive Web-based response [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 identification (ID) and password, the 
protocol number, and the subject number. The IRT system will provide a confirmation report 
containing the subject number, randomization number, and container number(s) assigned.
The confirmation report must be stored in the site’s files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Breaking the Blind
The study will be subject and investigator blinded.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject. Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary. When 
the blinding code is broken, the reason must be fully documented and entered on the case 
report form (CRF).
5.3. Subject Compliance
The number of pills returned by the subjects at Visit 5 (Day 1), Visit 7 (Week 4), 
Visit 9 (Week 8), Visit 10 (Week 12), and Visit 11 (Week 16) will be used to assess subject 
compliance.  Compliance (as assessed by pill count) will be defined as self-administration, 
by the subjects, of:


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
90% compliance with pills in each bottle of the study-supplied blinded placebo 
administered from Visit 4 (Day -14) to 1 day prior to Visit 5 (Day 1), inclusive;

80% compliance with pills in each bottle for the double-blinded IP from 
Visit 5 (Day 1) to Visit 11 (Week 16), inclusive; investigators must closely follow 
non-compliant, randomized subjects in order to enhance their adherence to IP;

Post randomization, at each dispensation visit [refer to Schedule of Activities
(Table 1)], subjects who are < 80% compliant must be re-educated on the 
importance of daily administration of investigational product, as much as 
possible; with the overall aim to maintain 80% compliance over the 16-week 
duration of dosing. 
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded investigational products (PF-05221304 and its matched placebo) will be provided as 
tablets for oral administration.  The 1-mg, 5-mg, 25-mg, and 50-mg strength tablets of 
PF-05221304 and matching placebo tablets will be supplied in separate bottles and labeled 
according to local regulatory requirements. 
PF-05221304 / matching-placebo for dispensation at the visits denoted in the Schedule of 
Activities (Table 1) will be packaged with each bottle containing a sufficient number of 
tablets to permit dosing for 14 (+2) days during single-blind period from Visit 4 (Day -14) to 
1 day prior to Visit 5 (Day 1) or 28 (+4) days from Visit 5 (Day 1) and onwards. 
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system from
Visit 4 (Day -14) to Visit 10 (Week 12) at selected visits [refer to Schedule of Activities –
Table 1]. A qualified staff member will dispense the investigational product via unique 
container numbers in the bottles provided, in quantities appropriate for the study visit 
schedule. Subjects should be instructed to maintain the IP in the bottle(s) provided 
throughout the course of dosing at the labelled storage conditions and return with the 
dispensed bottles to the site at each visit starting at Visit 5 (Day 1) and through 
Visit 11 (Week 16).  The instructions for dosing will be provided to the sites and individual 
subjects (refer to Section 5.5).  The number of bottles dispensed and the number of tablets
administered per dose will be identical for all randomized regimens.
5.5. Administration
Subjects will be instructed to take the blinded investigational product at the same time of day 
with the morning meal each day.  In addition, subjects will be instructed to delay the 
self-administration of the blinded investigational product as well as their medications for 
glycemic control, dyslipidemia, and BP control, if applicable, on the days of their outpatient 
visit to the site; on these days, these medications will be administered at the site with the 
morning meal – refer to Section 4.4.1. 


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Subjects will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing.
Subjects will be provided dosing instructions at Visit 4 (Day -14) to aide in remembering the 
correct steps to self-administer blinded investigational product.
5.6. Investigational Product Storage 
The investigator or an approved representative (eg, pharmacist, study coordinator) will 
ensure that all investigational products are stored in a secured area with controlled access 
under required storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site prior to the initiation of Visit 4 (Day -14) in 
this study.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products.  The site staff should refer to the Investigational Product Manual for 
additional guidance on storage conditions and actions to be taken when conditions are 
outside of the specified range. 


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5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
All bottles of blinded investigational product must be returned to the investigator by the 
subject at every dispensation visit and at the end of the study [refer to Schedule of 
Activities – Table 1].
5.7.1. Destruction of Investigational Product Supplies 
At the end of the study, the sponsor or designee will provide guidance on the destruction of 
unused investigational product (eg, at the site). 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, and all destruction must be adequately documented.
5.8. Concomitant Treatment(s)
Given the duration of the dosing phase in this study (ie, up to 16 weeks), whenever possible, 
attempts must be made to not alter the doses and regimens of the background/concomitant
medications after randomization [ie, Visit 5 (Day 1)], and until Visit 12 (on-site Follow-up). 
All concomitant medications taken during the study must be recorded with, at a minimum, 
the indication for use.  In addition, for diabetes, lipid-modifying, BP control medications, 
daily dose, and start and stop dates of administration must also be captured.  All subjects 
must be questioned about concomitant medication at each outpatient visit. 
Medications taken within 6-weeks before Visit 5 (Day 1) will be documented as a prior 
medication.  Medications taken after dosing of double-blind IP at Visit 5 (Day 1) and until 
the 2nd Follow-up visit (or telephone contact) will be documented as concomitant 
medications.
5.8.1. Medications for Glycemic Control
The use of the following classes of agents is not permitted within 8-weeks prior to Visit 
1 (Screen 1) and until Visit 12 (on-site Follow-up):

TZDs such as pioglitazone and rosiglitazone;

Subcutaneously administered agents for glycemic control (eg, insulin, exenatide, 
liraglutide, pramlintide).


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Subjects are permitted to be on stable doses of up to a maximum of 3 oral agents for 
glycemic control, starting at 8-weeks prior to Visit 1 (Screen 1) and until Visit 12 (on-site 
Follow-up), across the country-specific, approved classes of agents including (but not limited 
to) the following:

Biguanide such as metformin; 

Sulphonylureas such as acetohexamide, chlorpropamide, tolazamide, tolbutamine, 
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.
5.8.2. Lipid-modifying medications 
The use of monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin 
type 9 (PCSK9) such as alirocumab, evolocumab is not permitted within 12-weeks prior to 
Visit 1 (Screen 1) and until Visit 12 (on-site Follow-up). 
Subjects are permitted to be on stable doses of up to a maximum of 3 lipid-modifying 
agents, starting at 8-weeks prior to Visit 1 (Screen 1) and until Visit 12 (on-site 
Follow-up), across the country-specific, approved classes of agents including (but not limited 
to) the following –

Statins such as atorvastatin, simvastatin, rosuvastatin, pravastatin;

Bile acid sequestrants such as cholestyramine, colestipol;

Fenofibrate , a fibric acid derivative;

Nicotinic acid / niacin;

Ezetimibe;

Doses and agent(s) are permitted to be adjusted at Visit 3 (Run-in), with stable doses 
for 6-weeks before Visit 5 (Day 1) required for continuing participation in this 
study.


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
The use of the following selected agents is not permitted starting at Visit 3 (Run-in)
and until Visit 12 (on-site Follow-up):

Gemfibrozil (a potent OATP inhibitor);

Colesevalam. 

Subjects on either of the above two oral agents, at Visit 3 (Run-in), must be 
willing to switch to other acceptable agents and on stable doses of the 
acceptable agents for 6-weeks before Visit 5 (Day 1) in order to participate 
in this study.
5.8.3. Medications for Controlling Blood Pressure 
Across the many classes of agents for management of hypertension, subjects are permitted to 
be on stable doses of up to a maximum of 3 agents, starting at 8-weeks prior to Visit 
1 (Screen 1) and until Visit 12 (on-site Follow-up), across the country-specific, approved 
classes of agents; 

Starting at Visit 3 (Run-in), doses of medications (and additional medications can be 
added to a maximum of 3) in order to control BP and meet criteria needed to progress 
to randomization [refer to Section 4.2, Exclusion Criterion 6].
5.8.4. Other Acceptable Concomitant Medications
Any subject on the following list of medications must be on stable doses [ie, 8-weeks 
prior to Visit 1 (Screen 1) and until Visit 12 (on-site Follow-up), where possible]:

Non-steroidal anti-inflammatory medications (NSAIDs) such as ibuprofen, 
ketoprofen, diclofenac, naproxen, indomethacin, meloxicam; and celecoxib; 

Also permitted is intermittent use of acetaminophen/paracetamol at doses of 
up to 1 gram per day and intermittent use of NSAIDs (for example: for 
short-term pain management);

Inhaled and topical corticosteroids:

NOTE: Intercurrent treatment with systemic steroids, during participation in 
the study, may be permitted if treatment does/will not exceed 14-days;

Thyroid replacement therapy, as well as acceptable contraception medication and 
hormone replacement therapy (in eligible female subjects), etc;

Anti-psychotic medications such as olanzapine, risperidone;

Antidepressant medications such as tricyclic agents, selective serotonin reuptake 
inhibitors, and serotonin/norepinephrine reuptake inhibitors;


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•
Vitamin E, including high doses so long as regimen is stable;
•
Certain herbal supplements but only following consultation with sponsor.
5.8.5. Prohibited Medications 
Across the agents used for glycemic control, lipid-modification, and BP control, certain 
medications are not permitted – refer above to Section 5.8.1 to Section 5.8.3.
Also, use of drugs historically associated with fatty liver are prohibited within any ≥4-week
interval in the previous 12 months prior to Visit 1 (Screen 1) –
•
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;
In addition, subjects using the following medications within 8-weeks prior to 
Visit 1 (Screen 1) or needing them at any time until Visit 12 (on-site Follow-up) should not
participate in this study –
•
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; 
•
(Medical-grade) marijuana, regardless of medical indication;
•
Specific classes of agents given current study is 1st study in patient population –
•
Coumadin-type anticoagulants or other anticoagulants (eg, dabigatran); 
though aspirin at doses ≤ 325 mg/day is permitted
•
Anticonvulsants – specifically when prescribed for the explicit management 
of seizures (though use of some agents for other indications may be permitted; 
for example: use of benzodiazepines for management of anxiety);
•
Antiarrhythmics – specifically those agents whose primary mechanism of 
action is sodium or potassium channel blockade (eg, procainamide, phenytoin, 
quinidine, propafenone; as well as amiodarone, dofetilide, sotalol);
•
NOTE: β-adrenergic receptor blocking agents (eg, atenolol, metoprolol) 
and calcium channel blockers (eg, diltiazem, amlodipine, nifedipine) are 
permitted;
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Use of chronic agents which are clinically significant OATP inhibitors (eg, 
cyclosporine, gemfibrozil, rifampin).
5.9. Rescue Medication
There is no rescue therapy to reverse any adverse events (AEs) observed with administration 
of investigational product; standard medical supportive care must be provided to manage the 
AEs including administration of carbohydrates to treat hypoglycemic events.
Subjects with T2DM with repeated fasting glucose values > 270 mg/dL (15.0 mmol/L), as 
reported by the sponsor-identified central laboratory or self-checking conducted by subjects 
via sponsor-provided glucometers, must be withdrawn.
6. STUDY PROCEDURES
Prior to the conduct of any study-specific procedures – at the Pre-Qualification Visit and 
separately at Visit 1 (Screen 1) – each subject must provide informed consent.
•
Request for the subjects to arrive at the site following an overnight fast of ≥ 8-hours 
for either the Pre-Qualification or Screen 1 visit will not be considered 
study-specific; such instruction is classified as routine standard-of-care for the 
targeted population for this study. 
6.1. Proposed Chronology of Procedures 
For the procedures described below, where multiple procedures are scheduled at the same 
timepoint(s) relative to dosing, the following chronology of events should be adhered to, 
where possible:
•
12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing [refer to Section 7.2.3];
•
Vital Signs (blood pressure, pulse rate): obtain after 12-lead ECG collection but prior 
to obtaining blood samples and prior to dosing [refer to Section 7.2.4];
•
Fasting blood samples [for safety (Section 7.3), 
 
after assessment of 
12-lead ECG and vital signs but prior to dosing;
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Other pre-dose procedures: should be obtained/performed as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection;
•
Dosing: must occur with the morning meal; and where applicable, after any predose 
blood sample collection(s).
6.2. Pre-Qualification
Refer to the Schedule of Activities (Table 1 and Table 2) for the study procedures to be 
completed at the pre-qualification visit.  Subjects can only proceed to Visit 1 (Screen 1) of 
the main study when deemed to meet eligibility criteria [refer to Section 4.1 and Section 4.2] 
for the selected procedures completed as part of pre-qualification. 
6.3. Screening (Visits 1 and 2)
Refer to the Schedule of Activities (Table 1 and Table 2) for the study procedures to be 
completed at the 1st and 2nd Screening visits.  The two screening visits are to be performed 
sequentially. 
•
At Visit 1 (Screen 1), all screening procedures except assessment of liver fat by 
MRI-PDFF, will be undertaken to determine eligibility – refer to Section 4.1 and
Section 4.2;  
•
Only after subjects are identified to be otherwise eligible, should they proceed with 
the Visit 2 (Screen 2) to the Imaging facility to undergo liver fat assessment via 
MRI-PDFF acquisition to assess whether they meet Inclusion Criterion #11.
Subjects will be screened within 8-weeks (minimum) and 14-weeks (maximum) prior to
the first dose of the blinded investigational product to confirm that they meet the subject 
selection criteria for the study.  The investigator (or an appropriate delegate at the 
investigator site) will obtain informed consent from each subject. 
In rare cases, subjects may be re-screened; however, this is permitted only when, due to 
logistical constraints, the maximum period between Visit 1 to Visit 5 (ie, Screen 1 to Day 1),
of 14 weeks, is exceeded.  In such cases, all pre-screening and screening procedures must be 
repeated and the subject assigned a new 8-digit SSID number.  Subjects must be deemed to 
meet all the eligibility criteria including assessment of liver fat via MRI-PDFF at Screen 
2 visit, under the new 8-digit SSID.
To prepare for study participation, subjects will be instructed on the Lifestyle Requirements 
(Section 4.4) and Concomitant Treatments (Section 5.8).
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6.4. Visit 3 (Run-in) through to Visit 11 (Week 16) 
Refer to the Schedule of Activities (Table 1 and Table 2) for the study procedures to be 
completed starting at Visit 3 (Run-in) through Visit 11 (Week 16). 
6.5. Follow-up Visit
In this study, there are two Follow-up visits –

1st is an on-site visit where the subjects will return to the site 10 4 days post last 
dose of blinded investigational product – Visit 12;

2nd is a telephone contact visit (unless local regulations dictate on-site visit) to occur
28- to 35-days, inclusive, following the last dose of blinded investigational 
product

NOTE: this visit can be considered as on-site in order to permit follow-up of open 
TEAEs and/or abnormal laboratory tests from prior visit(s), as needed.

Refer to the Schedule of Activities (Table 1 and Table 2) for the study procedures to 
be completed at each of the two Follow-up visits.
6.6. Subject Withdrawal / Early Termination
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (refer to 
Section 8.1.3) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given study site. 
In this study, any subject who discontinues participation in the trial post the pre-qualification 
visit (eg, viewed as ineligible based on procedures completed), or discontinues based on 
Screen 1 or Screen 2 procedures (ie, Screen Fail) will have no additional procedures 
completed.  However, an early termination visit is to be considered for all subjects who 
were randomized and received at least 1 dose of the investigational product, and then are 
prematurely withdrawn from the study.  Subjects should return to the site for final safety 
assessments to be scheduled as early as practically feasible following the decision to 
withdraw but 14-days after last dose of blinded investigational product.  Subjects 
should be questioned regarding their reason for withdrawal.  At the early withdrawal visit, 
every effort must be made to complete the assessments outlined in the Schedule of Activities
(Table 1 and Table 2).  Lack of completion of all or any of the early termination procedures 
will not be viewed as protocol deviations so long as the subject’s safety was preserved.
Withdrawal of consent:
Subjects who request to discontinue receipt of study treatment 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 subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.


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Subjects 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 investigational product 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 subject 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.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product(s), request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects withdrawn from the study, after receiving at least 1 dose of the double-blinded IP 
(ie, after dosing at Visit 5 [Day 1]), will not be replaced – except those with non-evaluable 
baseline MRI-PDFF assessment – refer to Section 7.1.4. 


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will 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.
7.1. Liver Assessments using FibroScanand MRI-PDFF
7.1.1. Background on Liver Assessment Techniques
FibroScanis an ultrasound based technique permitting an assessment of liver fat (via 
controlled attenuation parameter - CAPTM) and liver stiffness (via vibration controlled 
transient elastography - VCTETM and reported as liver stiffness measure – LSM), developed 
by EchoSens.  These measurements are performed on the right lobe of the liver through 
intercostal spaces with the subject lying in dorsal decubitus with the right arm in maximal 
abduction.  A transducer probe delivers a painless, mechanical impulse to the liver and 
measures the resulting shear wave.  The LSM is directly proportional to the velocity of the 
shear wave.  Simultaneously, the CAPTM measures the ultrasonic attenuation coefficient in 
the forward and return path of the radio-frequency pulse through the liver.  To account for 
varying subcutaneous fat layers, the device is equipped with at least two probes; the 
M+ probe for lean/overweight adult subjects, and the XL+ probe for overweight/obese 
adults.  After a total of 10 valid, serial measures are acquired per assessment, the device 
calculates the median LSM and CAPTM values and reports these values simultaneously.
MRI-PDFF technique further improved upon the conventional Dixon in- and out-of-phase 
(IOP) method to give a quantitative, standardized, and objective MRI measurement of fat 
content.  MRI-PDFF utilizes a gradient echo sequence with low flip angle (FA) to minimize 
T1 bias, corrects T2* decay (due to iron overload) via modeling of the fat signal as a 
superposition of multiple frequency components from five different lipid types, and is 
applied in each of the 9 Couinaud segments.  This technique improves fat quantification 
accuracy for the entire liver permitting quantification of small differences/changes following 
pharmacological intervention.  Relative to the reference standard of magnetic resonance
spectroscopy (MRS), MRI-PDFF has the advantages of permitting fat mapping for the entire 
liver via an imaging-based technique versus a biochemical-based technique that provides 
data on liver fat content in a small region of interest in the liver. 


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7.1.2. Assessment of Liver Fat and Stiffness – using FibroScan
In this study, assessment of liver fat and liver stiffness using FibroScanwill occur at 
scheduled visits outlined in the Schedule of Activities (Table 1) and Section 4.4.5.  The 
results for liver fat (via CAPTM) in decibels per meter (dB/m) and liver stiffness (via LSM) in 
kilopascals (kPa) to determine whether an individual subject qualifies at pre-qualification to 
progress to Screen 1 (or at Screen 1 to progress to Screen 2) will be displayed on the 
FibroScandevice at the end of each assessment.  These results do not need independent 
over-read but steps to ensure that acquisition was complete and accurate are required – per 
training to be offered to at least 2 site staff (who must 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 
subjects’ assessment is performed by the same site staff.
Each acquisition will require the subjects to be in a supine position with the right arm placed 
flat above the head and will take approximately 10 minutes.  Each assessment must be 
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 Visit 1 (Screen 1). 
Complete details regarding acquisitions using FibroScanto assess CAPTM and LSM will be 
offered by EchoSens before the initiation of pre-qualification portion of this study.  All 
images acquired must be saved by the site until the conclusion of the study; the summary of 
numerical results (including quality-related outputs) must be printed and saved by the site 
(or Imaging facility, as applicable) as part of each subject’s source documents. 
7.1.3. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis
In this study, at scheduled visits [refer to the Schedule of Activities (Table 1) and 
Section 4.4.5] liver fat will be assessed via MRI, using the PDFF acquisition protocol.  In 
order to ensure that the population identified for this trial can be appropriately imaged via an 
MRI machine, at the pre-qualification visit, subjects will undergo a hula-hoop test –

Subject will be asked to be in the standing position with arms either to the side or
vertically up above the head, feet positioned close together, and weight evenly 
distributed across both feet;

NOTE: as much as practically possible, the same position of the arms must be 
used for all MRI-PDFF assessments in this trial;

Using a sponsor-approved hula-hoop, an attempt will be made to slide the hoop over 
the subjects head and determine if the hoop can pass over the subjects’ trunk and 
hips;

Hula-hoop will be passed while the subject is at the end of a normal expiration (when 
lungs are at their residual capacity); 

If the hula-hoop slides easily from the head down to the feet, the subject is eligible 
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
If the hula-hoop cannot slide down to the feet (eg, fits snug at the waist or hips), the
subject is deemed ineligible for this study;

Additional details on steps for identification of the appropriate hula-hoop 
circumference, which depends on the individual Imaging facility’s MRI machine 
opening (ie, bore diameter) along with bed thickness, and coils selected, will be 
provided in an Imaging Manual offered to the sites prior to the start of the study. 
Transportation of the subjects to the Imaging facility does not need to be supervised by the 
site staff.  Each assessment will require the subjects 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 Visit 2 (Screen 2). 
Across the sites selected for this study, the sponsor-identified central imaging vendor will 
train the staff at the Imaging facility on the MRI-PDFF acquisition protocol, on just-in-time 
review of the acquired images for assessment of images being deemed evaluable, and on 
transfer (preferably electronically) of the images to the sponsor-identified central imaging 
vendor for analysis and quantification of liver fat.  Only the staff members at the Imaging 
site who are trained by the sponsor-identified central imaging vendor are permitted to 
acquire images in the subjects who consent for this study; 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 offered 
to the sites prior to the start of the study.
As much as practically possible, analysis of the MRI-PDFF images acquired from baseline 
(ie, between Visit 4 and Visit 5) to Visit 11 (Week 16) will be undertaken by a single 
colleague at the sponsor-identified central imaging vendor who will be blinded to individual 
subjects’ clinical data, as well as randomization and stratification assignment.  However, this 
colleague will be unblinded to Visit of each assessment (ie, Screen 2, Baseline, etc). 
7.1.4. Analysis of MRI-PDFF Images Including Determination of Eligibility 
Subjects’ eligibility for this study based on liver fat as assessed via MRI-PDFF at 
Screen 2 will be made by the sponsor-identified central imaging vendor, only.  The individual 
subjects’ liver fat result will not be communicated to the site [though results from 
Screen 2 and Baseline may be known to the sponsor].  In the case of the Screen 2 MRI, sites 
will only be informed whether the subjects meet eligibility criteria or if the screening MRI 
should be repeated once – as determined by the sponsor-identified central imaging vendor.  
For all subsequently scheduled MRI-PDFF assessments, sites will only be informed whether 
the images are deemed evaluable (or not); of note, subjects with non-evaluable baseline 
images [as determined by the sponsor-identified central imaging vendor] may be withdrawn 
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Management of incidental findings 
An incidental finding is one unknown to the subject 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 MR images will be reviewed by the sponsor-identified central imaging vendor. 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 subject. 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 principal investigator. 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-patient relationship. The principal investigator will be responsible 
for reporting any AEs identified from incidental findings as described in the Adverse Event 
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. 
7.2. Safety-Related Assessments
7.2.1. Physical Examination
In this study, physical examinations are to be performed at nominal time points specified in 
the Schedule of Activities (Table 1). 
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination
will include head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, and neurological systems.  A targeted physical 
examination specifically covering visual examination of skin, examination of the eyes using 
an ophthalmoscope, as well as auscultation of the pulmonary system, will be conducted at 
Visit 6 (Week 2), Visit 9 (Week 8) and Visit 11 (Week 16).  In addition, this targeted 
physical examination will be incorporated into the full physical examinations prior to the first 
dose of the investigational product.  The brief physical examination will be focused on 
general appearance, the respiratory and cardiovascular systems, as well as towards subject 
reported symptoms.
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7.2.1.1. Measurement of Waist Circumference
Waist circumference will be measured at the nominal time points specified in the Schedule of 
Activities (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:

Either before or after the assessment of body weight;

While subject is in a standing position with arms resting comfortably at the side;

Under standard conditions including post-void, with the tape touching the skin (not 
clothing);

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.
7.2.2. Body Weight
In this study, assessment of body weight will occur at the nominal time points specified in 
the Schedule of Activities (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:

At approximately the same time of the day at each nominal time point;

After the subject has been asked to void (ie, forced void);

Under standard conditions (eg, subjects 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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
With subjects remaining still while on the weighing scale.
7.2.3. 12-lead Electrocardiogram
In this study, assessment of cardiac conduction via 12-lead ECGs will occur at the nominal 
time points specified in the Schedule of Activities (Table 1) per the following specifications:

All scheduled 12-lead ECGs should be performed after the subject has rested quietly 
for 10-minutes in a supine position;

Single supine 12-lead ECGs will be obtained; the ECG collected at Visit 5 (Day 1) 
will serve as each subject’s baseline;  

Refer to Section 6.1 for proposed chronology of procedures for nominal time points 
when 12-lead ECG assessments coincide with other procedures.
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.  It is important that leads are placed 
in the same positions each time in order to achieve precise ECG recordings.  If a 
machine-read QTc value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTc values are in the 
acceptable range.
7.2.4. Blood Pressure and Pulse Rate
In this study, assessment of vital signs (including seated blood pressure, and pulse rate) will 
occur at the nominal time points specified in the Schedule of Activities (Table 1) per the 
following specifications –

At the pre-qualification visit, the subjects’ arm circumference [eg, using a flexible 
anthropometric tape] should be measured 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):

Subjects 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 subject’s arm 
supported at the level of the heart, and recorded to the nearest mm Hg, following a 
rest of 5-minutes; the assessment at Visit 5 (Day 1) will serve as each subject’s 
baseline;

Same arm (preferably the dominant arm) will be used for blood pressure/pulse rate 
assessment throughout the study;


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
Blood pressure/pulse rate assessment should not be taken from the arm with an 
intravenous catheter, if placed;

Subjects should be instructed not to speak during blood pressure/pulse rate 
measurements;

Refer to Section 6.1 for proposed chronology of procedures for nominal time points 
when vital sign assessments coincide with other procedures.
Additional collection times, or changes to collection times of blood pressure /pulse rate will 
be permitted, as necessary, to ensure appropriate collection of safety data.
7.3. Clinical Laboratory Tests
The blood/urine samples for the clinical laboratory tests [summarized in Table 4] related to 
safety and exploratory biomarkers will be collected at the nominal time points specified in 
the Schedule of Activities (Table 2). 


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Table 4.
All Planned Safety-Related Laboratory Tests and Exploratory Biomarkers 
in Study C1171002
Hematology
Chemistry
Urinalysis
Other
−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 [and eGFR using 
MDRD]
−Plasma glucose (fasting)
−Calcium
−Sodium
−Potassium
−Chloride
−Total CO2 (Bicarbonate)
−AST (SGOT)
−ALT (SGPT)
−Alkaline phosphatase
−GGT
−Total Bilirubin
−Direct (conjugated) bilirubina
−Indirect (unconjugated) 
bilirubina
−Total bile acids
−Creatine Kinaseb
−Uric acid
−Albumin
−Total protein
−pH
−Glucose (qual)
−Protein (qual)
−Blood (qual)
−Ketones
−Nitrites
−Leukocyte 
esterase
−Urobilinogen
−Urine bilirubin
−Microscopyc
−Plasma aPTT, PT, INR
−Serum FSHd
−Serum and urine 
pregnancy test [refer to
Section 7.3.1]
−Urine drug teste
−Serologyf: HBsAg, 
HBcAb, HCVAb (and if 
positive, reflex HCV 
RNA), HIV
−α1-antitrypsinf
−Ceruloplasminf
−Serum % carbohydrate 
deficient transferrinf
−HbA1Cg
−Fasting Lipid Panelh
Additional exploratory biomarker 
assessmentsi include:
−Serum apolipoproteins A1, B(total), C3, E
−Plasma Insulin (fasting)  
−Calculate HOMA-IR using fasting glucose & 
insulin
−CK18-M30, CK18-M65
−ProC3 & ProC6
Additional Tests (Needed for instances of suspected Hy’s law)
−AST, ALT
−Total bilirubin
−Albumin
−Alkaline phosphatase
−Direct bilirubin
−Indirect bilirubin
−Creatine kinase
−GGT
−PT/INR
−Total bile acids
−Acetaminophen drug levels and/or protein adduct level
a. Direct + indirect bilirubin measured at Pre-qualification, Screen 1, V4, and V5; after initiation of investigational 
product, direct + indirect bilirubin measured only when total bilirubin is >ULN
b. Test to be assessed at Pre-qualification, Screen 1, V4, and V5; after initiation of investigational product, this test 
measured only when ALT or AST is >ULN
c. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase
d. At Pre-qualification, Screen 1, ONLY; and in females, only
e. At Pre-qualification, Screen 1, V4, ONLY; minimum requirement for urine drug test include cocaine, 
tetrahydrocannabinol (THC), opiates/opioids, benzodiazepines and amphetamines
f. At Pre-qualification, Screen 1, ONLY [in addition, %CDT also assessed at V4, V5, and V11]
g. HbA1C = glycosylated hemoglobin (NGSP certified method)
h. Includes total cholesterol, triglycerides, VLDL, HDL-C, and direct LDL-C
i.
As part of clinical laboratory tests collected at V4 though V11, only – refer to Table 2
For list of terms corresponding to the abbreviations used herein, refer to Appendix 1
•
All blood samples for scheduled clinical laboratory tests must be obtained following 
an overnight fast (except water) of ≥8-hours. 
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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 sponsor-identified central laboratory or 
secondary laboratory; or as derived from calculated values.  These additional tests would not
require additional collection of blood. 
Unscheduled clinical laboratory tests for subject safety may be obtained at any time during 
the study to assess any perceived safety concerns and shipped to the sponsor-identified 
central laboratory for analysis.
Additional details regarding sample collection, processing, and shipment will be offered in 
the study-specific central laboratory manual to be provided prior to the start of the study.
7.3.1. Pregnancy Testing
All pregnancy tests (serum and urine) used in this study must have a sensitivity of 
at least 25 mIU/mL, and must be performed using supplied offered by the sponsor-identified 
central laboratory certified laboratory. 
For female subjects of childbearing potential, following a negative pregnancy test result 
and after confirmed eligibility based on Visit 2 (Screen 2) tests(s), appropriate contraception 
must be commenced and the second negative pregnancy test result will then be required prior 
to randomization.  In addition, at a minimum, 2 negative serum pregnancy tests (ie, negative 
pregnancy test at Visit 1 and Visit 4) plus a negative urine at Visit 4 (Day -14) and Visit 
5 (Day 1; randomization) are required before receiving double-blind IP – starting on Day 1.  
In the absence of regular menstrual bleeding, the female subject should have used highly 
effective method of contraception (refer to Section 4.4.6) for at least 28-days before 
Visit 4 (Day -14).
Pregnancy tests will be performed at times defined in the Schedule of Activities (Table 2) to 
confirm that the subject has not become pregnant during the study.  Pregnancy tests will also 
be done whenever 1 menstrual cycle is missed during the active treatment period (ie, Day 
1 through Week 16, inclusive) and when potential pregnancy is otherwise suspected, and 
may be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs)
or if required by local regulations.  In the case of a positive confirmed pregnancy, the subject 
will be withdrawn from administration of investigational product and from the study.
7.4. Rater Qualifications
In this study, the AUDIT questionnaire will be completed by the site staff based on responses 
offered by the subjects – at the visits outlined in the Schedule of Activities (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. 
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7.6. Exploratory Biomarkers
Blood samples for exploratory biomarkers – including NASH-related biomarkers, potential 
mechanism-related parameters, metabolic parameters, and exploratory markers of liver 
function – will be collected at the nominal time points defined in the Schedule of Activities
(Table 2).  Refer to list of endpoints outlined in Section 2 that encompass these exploratory 
biomarkers.
•
These samples must be processed and shipped as indicated in the study-specific 
laboratory manual provided to the investigator 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 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 scheduled collection prior to next dose of blinded investigational product, if 
undertaken post dose, will be captured as a protocol deviation even if results are 
deemed evaluable;
•
Refer to Section 6.1 for proposed chronology of procedures for nominal time points 
when these collections coincide with other procedures;
•
Samples will be analyzed using a validated analytical method (which need not meet 
Good Laboratory Practice (GLP) standards, especially for these exploratory
endpoints) but in all cases, the method will be in compliance with Pfizer standard 
operating procedures.
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7.8. Blood Volume
In this study, the total blood sampling volume for individual subjects will be approximately 
400 mL.  This includes approximately 40 mL blood drawn across the clinical laboratory tests 
at the pre-Qualification; and the remaining approximately 360 mL blood drawn from Visit 
1 (Screen 1) through the On-site Follow-up visit, inclusive. 
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Additional blood samples may be taken for safety assessments, only, provided the total 
volume taken during the study does not exceed 550 mL.
7.9. Specific Subject Safety Scenarios
7.9.1. Potential Cases of Thrombocytopenia
While thrombocytopenia (defined as platelet count below 100,000/mm3) has not been 
observed in the completed Study C1171001, 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 2 every two 
weeks post randomization (on Day 1 / Visit 5) up to Visit 9 (Week 8) and monthly thereafter 
(Visit 10 / Week 12 and Visit 11 / Week 16).

In subjects observed to have platelet count below the LLN at Visit 9 (Week 8), unplanned 
visits at Week 10 and Week 14 (in addition to the scheduled Visit 10 [Week 12] and 
Visit 11 [Week 16]) should be used 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.
Subjects observed to have a decline over time ultimately reaching the threshold of 
< 75,000/mm3 in platelet count as outlined in Appendix 2 should be withdrawn with the 
primary reason for withdrawal captured as an adverse event of thrombocytopenia. 
7.9.2. Potential Cases of Hypertriglyceridemia
In Study C1171001, gradual increases in fasting and post-prandial serum triglycerides have 
been observed – refer to Section 1.2.2.  Hence, 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 3. 
Individual subjects with consistently increasing fasting serum triglycerides over time 
ultimately reaching the threshold of 800 mg/dL (9 mmol/L) as outlined in 
Appendix 3 should be withdrawn with have the primary reason for withdrawal captured as an 
adverse event of hypertriglyceridemia.
7.9.3. Management of Glycemic Control in Patients with T2DM
Events of hypoglycemia (HAE) and fasting plasma glucose will be routinely monitored 
during participation in the study, in subjects with T2DM.  At Visit 3 / Run-in, subjects will 
be given the following instructions/guidance to be complied with for the duration of 
participation in the study:

Subjects will be provided the following (as provided to the sites by the sponsor).

To aide in management of their T2DM the following (or similar) items:


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
Home glucose monitoring supplies including a sponsor-provided, 
plasma-referenced, home glucometer and accompanying supplies;

Diary to be completed at home for any symptomatic episodes and brought to each
visit to the site along with the glucometers;

Instructions on use and documentation of home glucose monitoring results;

Low blood glucose information sheet which delineates the symptoms of 
hypoglycemia along with treatment options and instructions to share with their 
family member(s) / roommate(s) to help in their management of hypoglycemia;

Recommended frequency for routine home glucose monitoring will be determined 
for each subject by the investigator, however, a frequency of at least once per 
day should be emphasized;

Home glucose monitoring must be undertaken in the event subjects’ experience 
symptoms of HAE, whenever possible; these symptoms must be captured in the 
diary.

Routine safety monitoring (eg, liver function monitoring) for any background 
medications, including anti-diabetic agents, is the responsibility of the investigator 
and should be consistent with guidelines found in prescribing information for the 
respective agents;

Wherever possible, new agents for glycemic control or change in doses of 
concomitant agents for glycemic control (refer to Section 5.8.1) should be avoided 
during participation in the study unless protocol-specific criteria for inadequate 
glycemic control are met – refer to Section 7.9.3.1.
7.9.3.1. Protocol-Specific Criteria for Inadequate Glycemic Control
Investigators must review the diary completed by the subjects and the readings stored in the 
glucometer devices at each visit after the Run-in Visit.  Based on this information, as well as 
review of the results reported by the central laboratory, an assessment of any symptomatic 
and asymptomatic occurrence of hypo- or hyper- glycemia must be undertaken. 
7.9.3.1.1. Management of Hypoglycemia (HAE)
Any episode of HAE must be captured with sufficient detail as outlined in Appendix 4.  For 
definition of HAE and severity categorization, refer to Section 7.9.3.1.2, below. 
7.9.3.1.2. Definition and Severity Categorization of HAE
Based on review of the subject completed diary at each visit to the site as well as results 
reported by the central laboratory, the investigator must assess the glucose values as well as 
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HAE is defined as one of the following:
1. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a plasma glucose reading of 49 mg/dL (2.7 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or sponsor-identified 
central laboratory);
2. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose reading of < 70 mg/dL (3.9 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or sponsor-identified 
central laboratory) and the clinical picture includes prompt resolution with food 
intake, subcutaneous glucagon, or intravenous glucose;
3. Probable symptomatic hypoglycemia: An event during which symptoms of HAE
are not accompanied by a plasma glucose determination, but was presumably caused 
by a plasma glucose concentration of < 70 mg/dL (3.9 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or sponsor-identified 
central laboratory) and the clinical picture includes prompt resolution with food 
intake, subcutaneous glucagon, or intravenous glucose.
NOTE: Pseudo-hypoglycemia: An event during which symptoms consistent with HAE are 
reported along with a plasma glucose reading 70 mg/dL (3.9 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or sponsor-identified central 
laboratory) may be reported as an adverse event (AE) of HAE but will not be considered as 
having met the protocol definition of HAE offered above.
Each episode of HAE must be characterized with respect to severity.  In order to characterize 
the event as ‘severe’, all three (3) criteria below must be met:
1. The subject was unable to treat him/herself.  Neurologic impairment, and not the age 
of the subject, is the explanation for why the subject could not treat him/herself and 
required the assistance of another person.
2. The subject exhibited at least one of the following neurological symptoms:

Memory Loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;

Unusual difficulty in awakening;

Suspected seizure;


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
Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was 49 mg/dL (2.7 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or central laboratory) or

If blood glucose was not measured, the clinical manifestations were reversed by oral 
carbohydrates, subcutaneous glucagon, or intravenous glucose.
Events that do not meet all the criteria above for ‘severe’ HAE are characterized as ‘mild’ or 
‘moderate’ in severity. 
7.9.3.1.3. Management of Hyperglycemia
Hyperglycemia is defined as a glucose reading of > 270 mg/dL (15 mmol/L) using 
sponsor-provided, plasma-referenced, home glucometers (or sponsor-identified central 
laboratory).
Subjects noted to have a fasting plasma glucose value (during home glucose monitoring 
using sponsor-provided, plasma-referenced, home glucometers or as reported by the 
sponsor-identified central laboratory) meeting the above definition of hyperglycemia must be 
instructed to repeat the measurement the next day (following 8-hour fast except water).  If 
the second measurement also meets the above definition, subjects must be asked to return to 
the site in the next 5 2 days, following 8-hour fast except water, and have blood 
collected for fasting plasma glucose (and shipped to sponsor-identified central laboratory for 
analysis).
If the results from the sponsor-identified central laboratory confirm the readings using 
sponsor-provided, plasma-referenced, home glucometers or a previous result reported by the 
sponsor-identified central laboratory, the subject must be withdrawn from the study – with 
the reason for withdrawal captured as an adverse event of hyperglycemia.
8. ADVERSE EVENT REPORTING
In this study, the active collection period for adverse events (serious and non-serious) will 
start at the time individual subjects’ consent to pre-Qualification and continue through to a 
minimum of 28 calendar days after the last dose of the investigational product.  
Treatment-emergent adverse events will be defined as those noted to have an onset or
increase in severity after first dose of double-blinded investigational product (at 
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8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or breastfeeding, 
and occupational exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see Section 8.2.3 below).  In addition, the investigator may be requested by Pfizer Safety to 
obtain specific follow-up information in an expedited fashion.  This information is more 
detailed than that recorded on the CRF.  In general, this 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 subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer 
Safety.  Any pertinent additional information must be reported on the CT SAE Report Form; 
additional source documents (eg, medical records, CRF, laboratory data) are to be sent to 
Pfizer Safety ONLY upon request.


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also Section 6.6) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with 
Section 8.1 above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who fail during the pre-qualification phase or after Screen 1, the active 
collection period ends when the subject is deemed to be not suitable / eligible for this study 
(ie, screen failure status).
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including the 
2nd Follow-up Visit.  At the 2nd Follow-up Visit, the subject will be contacted by telephone 
(unless local regulations dictate on-site visit) to inquire about SAEs, including 
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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result 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; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject, or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are 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.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specific Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.
8.4.2. 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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (xULN) should be monitored more frequently to determine if they are an “adaptor” or 
are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2x ULN) by several days 
or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated above 
3x ULN (ie, AST/ALT and TBili values will be elevated within the same lab 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.


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The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects 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:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST or ALT values >3x ULN and a TBili value >2x ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 xULN or not 
available;

For subjects 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 > 3x ULN or >8x ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least > ULN or if the value reaches >3x ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The subject 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, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels – refer to
Table 4.  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 (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) may be warranted. 


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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 liver function test (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.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, 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.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
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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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
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 includes 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 investigational product.
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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using 
the CT SAE Report Form.  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’s administration, the SAE is reported together with the exposure 
during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject 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.
8.4.4. Medication Errors 
Other exposures to the investigational product 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 may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
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 non-serious, are recorded on an 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.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (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 
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9.1. Sample Size Determination
The sample size for this study was based on interest to assess a dose-response for effect of 
PF-05221304 on percent change from baseline in liver fat (entire study population as well as 
separately in each sub-population in 1st tier stratification) and percent change from baseline 
in ALT in the 1st tier stratification sub-population of diagnosed/presumed NASH. 
The proposed sample size for this study is approximately 360 subjects randomized 
(72 subjects per arm) to ensure at least 300 subjects (60 subjects per arm) complete the study. 
The sample size of a minimum of 60 completers per arm, was calculated to yield 
80% power to detect a placebo-adjusted, percent change from baseline of 30% in liver fat 
(in entire study population and in n=30/arm in each sub-population of the 1st tier 
stratification), using a 1-sided, t-test at level 10%.  The calculation assumes that the standard 
deviation for liver fat is 7.8% (between-subject) and 6.2% (within-subject).
For the secondary endpoint of ALT in the 1st tier stratification sub-population of 
diagnosed/presumed NASH, the sample size of a minimum of 30 completers per arm was 
calculated to yield 80% power to detect a placebo-adjusted, percent change from baseline 
in ALT of 35%, using a 1-sided, t-test at level 10%.  The calculation assumes that the 
standard deviation for the parameter of placebo-adjusted, percent change from baseline in 
ALT is 55% (between-subject).
Overall, via the planned interim analysis (refer to Section 9.5), if the observed standard 
deviation for the liver fat (MRI-PDFF) and ALT data, based on unblinded review, is greater 
than the assumptions above, the sample size for this study may be adjusted upward, at 
sponsor discretion, to a maximum of 500 subjects randomized (ie, 100 subjects per arm).
9.2. Efficacy Analysis
9.2.1. Analysis of the Primary Endpoint
The primary endpoint is placebo-adjusted, percent change from baseline in liver fat (via 
MRI-PDFF) at Week 16, for the entire study population.  A mixed model repeated measure 
(MMRM) analysis will be performed with treatment, time and treatment-by-time interaction 
as fixed effects, and subject as a random effect. 
Descriptive summaries of the observed values and percent change from baseline in liver fat 
in each treatment group at each time point will be produced. 
For statistical analyses, 80% confidence intervals will be produced for the least-square mean 
differences in each treatment group as compared to placebo.  One sided p-values will be 
displayed for the comparison against placebo with no multiplicity adjustment made.
Dose-response modeling of the percent change from baseline in liver fat will be explored 
with total daily dose and time as a continuous variable to characterize and evaluate the 
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9.2.2. Analysis of Secondary Endpoint
One of the key secondary endpoint is percent change from baseline in ALT at Week 16 in the 
1st tier stratification sub-population of diagnosed/presumed NASH.  An MMRM analysis will 
be performed with treatment, time and treatment-by-time interaction as fixed effects, and 
subject as a random effect. 
Descriptive summaries of the observed values and percent change from baseline in ALT in 
each treatment group at each time point will be produced. 
For statistical analyses, 80% confidence intervals will be produced for the least-square mean 
differences in each treatment group as compared to placebo.  One sided p-values will be 
displayed for the comparison against placebo with no multiplicity adjustment made.
Dose-response modeling of the percent change from baseline in ALT, the 1st tier stratification 
sub-population of diagnosed/presumed NASH, will be explored with total daily dose and 
time as a continuous variable to characterize and evaluate the dose-response relationship; 
assessment of dose-response for effect on ALT for the entire entire study population, may be 
considered, depending on the data. 
9.3. Analysis of Tertiary Endpoints
9.3.2. Other Tertiary Endpoints
For continuous endpoints, a MMRM analysis will be performed with treatment, time and 
treatment-by-time interaction as fixed effects, and subject as a random effect.  Two-sided 
p-values and 80% confidence intervals will be displayed for the least-square mean difference 
or ratio (for natural log-transformed endpoints) against placebo.  Descriptive summaries of 
the observed values and change from baseline in each treatment group at each time point will 
also be produced. 
Depending on the observed data at the end of the study and when applicable, dose-response 
modeling of the tertiary endpoints may be explored with total daily dose as a continuous 
variable to characterize and evaluate the dose-response relationship. 
Descriptive summary (number and percentages) will be displayed for categorical endpoints.
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9.4. Safety Analysis
Treatment-emergent AEs, as well as SAEs/deaths, clinical safety-related laboratory tests, 
12-lead ECG data, as well as vital signs will be summarized descriptively as appropriate for 
Pfizer data standards.  Statistical inference may be determined for safety measures of clinical 
concern.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, as appropriate to Pfizer standards.
Physical exam information collected during the course of the study will not be captured for 
inclusion into the study database, unless otherwise noted.  However, any untoward findings 
identified on physical exams conducted after the administration of the first dose of blinded 
investigational product will be captured as an adverse event, if those findings meet the 
definition of an adverse event as defined in Section 8.
9.5. Interim Analysis
Interim analysis (IA) will be performed at least once while the study is on-going.  This 
review will include an assessment of the observed safety, and observed (versus assumed) 
variability for the primary endpoint (liver fat via MRI-PDFF) as well as key secondary 
endpoint (ALT).  The 1 planned IA is proposed after at least one-third of the total planned 
randomized subjects (ie, approximately 120 subjects), complete through at least one-third of 
the total dosing duration (ie, Visit 8 [Week 6]) of the study. Interim analysis results may be 
used for conducting a sample size re-estimation, stopping a dose-level for observed safety, 
facilitate 
 and internal business decisions regarding planning of future trials 
with PF-05221304. Before any interim analysis is instigated, the details of the objectives, 
decision criteria, dissemination plan, and method of maintaining the study blind as per 
Pfizer’s standard operating procedures (SOPs) will be documented and approved in an IRC 
charter. In addition, the analysis details will be documented and approved in an interim
analysis SAP or final SAP.
9.6. Data Monitoring Committee 
This study will not use a data monitoring committee. 
An IRC to undertake unblinded review of the safety data and unblinded review of the 
observed standard deviation for the liver fat (MRI-PDFF) and ALT data, is planned while the 
study is on-going – refer to Section 9.5.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
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During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
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11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
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12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
At the end of the study, the investigational product in this study will not be provided to the 
subjects who participated.
12.4. 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 investigational 
product, 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 subjects against any immediate hazard, and of 
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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV)
reflected by completion of the 2nd Follow-up visit for the last subject randomized in the 
study. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-05221304 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 28 calendar days.  As directed by Pfizer, all study materials must be 
collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
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PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.


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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev 
Nutr 2008, 28, 253-72.
2.
LaBrecque D, Abbas Z, Anania F, et al. Nonalcoholic fatty liver disease and 
nonalcoholic steatohepatitis. In: WGO Global Guidelines NAFLD/NASH (long 
version). Milwaukee, WI: World Gastroenterology Organisation; 2012: 29 pages.
3.
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):1392-405.
4.
Khan F, Perumpail R, Wong R, et al. Advances in hepatocellular carcinoma: 
Nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 
2015; 7(18):2155-61.
5.
Younossi Z, Koenig A, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty 
liver disease – meta-analytic assessment of prevalence, incidence, and outcomes.  
Hepatology 2016;64(1):73-84.
6.
Noureddin M, Anstee Q, Loomba R.  Review article: emerging anti-fibrotic therapies in 
the treatment of non-alcoholic steatohepatitis.  Aliment Pharmacol Ther 
2016;43(11):1109-23.
7.
LaBrecque D, Abbas Z, Anania F, et al. Nonalcoholic fatty liver disease and
nonalcoholic steatohepatitis. In: WGO Global Guidelines NAFLD/NASH (long 
version). Milwaukee, WI: World Gastroenterology Organisation; 2012: 29 pages.
8.
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):726-35.
9.
Savage DB, Choi CS, Samuel VT, et al. Reversal of diet-induced hepatic steatosis and 
hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA 
carboxylases 1 and 2. J Clinical Invest 2006; 116(3):817-24. 
10.
Schreurs M, van Dijk TH, Gerding A, et al. Soraphen, an inhibitor of the acetyl-CoA 
carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. 
Diabetes Obes Metab 2009; 11(10):987-91.
11.
Esler WP, Turner, SM, Amor PA, et al. Effects of acetyl-CoA carboxylase inhibition on 
lipid metabolism in rodents and human subjects. In: American Diabetes Association 
75th Scientific Session; 5-9 Jun 2015; Boston, MA, 2015. Abstr.


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12.
Harriman G; Greenwood J, Bhat S, et al. ND-630, a potent and liver-directed 
acetyl-CoA carboxylase inhibitor, reduces hepatic steatosis and improves dyslipidemia 
in diet-induced obese and diabetic rat models of non-alcoholic fatty liver disease. In:
Keystone Symposia; 01-06 Mar 2015; British Columbia, Canada. 2015: Abstr.
13.
Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate 
between regulatory T and T helper 17 cells. Nat Med 2014; 20(11):1327–33.
14.
Rau M, Schilling AK, Meertens J, et al. Progression from nonalcoholic fatty liver to 
nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver 
and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. 
J Immunol 2016; 196(1):97–105.
15.
Hernaez R, Lazo M, Bonekamp S, et al.  Diagnostic accuracy and reliability of 
ultrasonography for the detection of fatty liver: A meta-analysis.  Hepatology 
2011;54:1082-90. 
16.
Neuschwander-Tetri BA, Clark JM, Bass NM, et al.  Clinical, Laboratory and 
Histological Association in Adults with Nonalcoholic Fatty Liver Disease.  Hepatology 
2010;52:913-24. 
17.
Schomaker S, Warner R, Bock J, et al.  Assessment of emerging biomarkers of liver 
injury in human subjects. Toxicol Sci 2013;132(2):276-83.
18.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of 
non-alcoholic fatty liver disease: practice Guideline by the American Association for 
the Study of Liver Diseases, American College of Gastroenterology, and the American 
Gastroenterological Association. Hepatology. 2012; 55(6):2005-23.
19.
Petit JM, Cercueil JP, Loffroy R, et al.  Effect of liraglutide therapy on liver fat content 
in patients with inadequately controlled type 2 diabetes. The Lira-NAFLD study.  J Clin 
Endocrinol Metab 2017; doi:10.1210/jc.2016-2775.


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Appendix 1. Abbreviations 
This following is a list of the abbreviations that may be used in this document.
Abbreviation
Term
%CDT
Percent Carbohydrate deficient transferrin relative to total transferrin
β-hCG
Beta-human chorionic gonadotropin
A1AT
Alpha-1-antitrypsin
Abs
absolute
ACC
acetyl-CoA carboxylase
AE
adverse event
ALT / SGPT
alanine aminotransferase / serum glutamic pyruvic transaminase
AST / SGOT
aspartate aminotransferase / serum glutamic oxalo-acetic transaminase
ATP
adenosine triphosphate
AUC
area under the curve (used when referring to PK)
AUC24
area under the concentration-time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last quantifiable concentration
AUCtau
area under the concentration-time curve from time 0 to time t
AUDIT
Alcohol use disorders identification test
AUEC
Area under effect curve (used when referring to drug response)
BID
bis in die
BLQ
below the limit of quantification
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CAPTM
Controlled attenuation parameter
CK
creatine kinase
CK18-M30
cytokeratin-18-M30 sub-species
CK18-M65
cytokeratin-18-M65 sub-species
Cmax
peak or maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CPT-1
carnitine-palmitoyl transferase 1
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CYP3A
Cytochrome P-450 3A
D2O / 2H2O
deuterium oxide / deuterated water 
dB/m
decibels per meter
DBP
diastolic blood pressure
DCT
data collection tool
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
DPP-IVi
Dipeptidyl peptidase-IV inhibitors
DU
Dispensing Unit
EC
ethics committee
ECG
electrocardiogram
e-CRF
Electronic case report form
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
CCI
CCI


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Abbreviation
Term
eGFR
Estimated glomerular filtration rate 
EIU
exposure in utero
ET
Early Termination
EU
European Union
EudraCT
European Clinical Trials Database
FA
flip angle
FDA
Food and Drug Administration
FFA
free fatty acid
FIH
first-in-human
FPG
Fasting plasma glucose 
FPI
Fasting plasma insulin
FSH
follicle-stimulating hormone
FU
Follow-up
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
GLP
Good Laboratory Practice
GLP-1r
glucagon-like peptide-1 receptor
HAE
Hypoglycemia
HbA1C
Glycated hemoglobin
HBsAg
hepatitis B surface antigen
HBV
Hepatitis B virus 
HCC
Hepatic Cellular Carcinoma
HCV
Hepatitis C virus
HCV RNA
Hepatitis C virus genetic material (ie, Ribonucleic acid)
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol
HIV
human immunodeficiency virus
HOMA-IR
Homeostatic model assessment of insulin resistance
hr
hour
ht
height
IA
Interim Analysis
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IOP
in- and out-of-phase
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IWR
interactive web response
kPa
kilopascals
LDL-C
low density lipoprotein-cholesterol
LFT
liver function test
LLN
lower limit of normal
LSLV
last subject last visit 
LSM
Liver stiffness measure
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
CCI
CCI
CCI
CCI
CCI


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Abbreviation
Term
MCV
mean corpuscular volume
MDR1
multi-drug resistance protein-1
MDRD
Modification of Diet in Renal Disease
MEC
molar extinction coefficient
MedDRA
medical Dictionary for Regulatory Activities
MELD
model of end-stage liver disease
min
minute
MMRM
Mixed model repeated measure 
MRI-PDFF
Magnetic resonance imaging using proton density fat fraction acquisition
MRS
Magnetic resonance spectroscopy
MSDS
material safety data sheets
MTD
Maximum tolerated dose 
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NASH
Nonalcoholic steatohepatitis
NGSP
National Glycohemoglobin Standardization Program 
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NSAIDS
Non-steroidal anti-inflammatory medications
NYHA
New York Heart Association
OATP
organic anion-transporting polypeptide
OEB5
occupational exposure banding 5
PBPK
physiologically based pharmacokinetic
PCD
primary completion date
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
Pharmacodynamics(s)
PE
physical exam
PI
Principal investigator
PK
pharmacokinetics
PNPLA3
Patatin like phospholipase domain containing protein 3
pre-Q
Pre-qualification visit 
ProC3
N-terminal pro-peptide of type III procollagen
ProC6
C-terminal fragment of α3 chain of procollagen type VI  (also known as Endotrophin)
PT
prothrombin time
PTR
peak to trough ratio
Q12H
Every 12 hours (eg, dosing)
QC
quality control
QD
quaque die
QTc
corrected QT
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous
SCr
serum creatinine
SEM
standard error of mean
SOP
standard operating procedure
SRSD
single reference safety document
SSID
Study-specific Subject identification
SUSAR
suspected unexpected serious adverse reaction
CCI
CCI
CCI
CCI
CCI


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Abbreviation
Term
T1/2
terminal half-life
T2DM
type 2 diabetes mellitus
TBili
total bilirubin
TEAE
Treatment-emergent adverse event
TG
triglycerides
Th17
T helper 17
THC
tetrahydrocannabinol
Tmax
time to reach maximum concentration
Treg
regulatory T
TZDs
thiazolidinediones
ULN
upper limit of normal
US
United States
V
Visit
VCTE
Vibration-Controlled Transient Elastography 
VLDL
very low density lipoprotein
Vz/F
apparent oral volume of distribution
w/v
weight per volume
WBC
white blood cell
WOCBP
Women of childbearing potential
wt
Weight
CCI


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Appendix 2. Guidance to Investigators – Management of Individual Subjects With 
Decrease in Platelet Count
Platelet Count result at Visits starting at Visit 5 / Day 1 to Visit 11 / Week 16, 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 / mm3
And < 100,000 / mm3
< 75,000 / mm3
Subject 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 / mm3 And < 100,000 / mm3
• Subject to return for next scheduled visit 
• At Investigator discretion, additional unplanned visit(s) before next Scheduled Visit permitted
• < 75,000 / mm3
• Subject should be withdrawn
Subject should 
be withdrawn
NOTE: If at Week 8 (V9) platelet count is observed to be below lower limit of normal as reported by sponsor-identified central 
laboratory, visits should occur at Week 10 ± 4 days (unplanned), Week 12 ± 4 days (V10), Week 14 ± 4 days (unplanned), and 
Week 16 ± 4-days (V11) relative to Day 1 (V5), in order to follow this parameter, closely


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Appendix 3. Guidance to Investigators – Management of Individual Subjects With 
Elevation in Fasting Serum Triglycerides
Serum Triglyceride result at Visits starting at Visit 5 / Day 1 to Visit 11 / Week 16, 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]
Subject 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]
• Subject 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]
• Subject should be withdrawn
Subject should 
be withdrawn


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Appendix 4. Guidance to Investigators – Capturing Details for Episodes of 
Hypoglycemia in Patients with T2DM
The following checklist must be completed by the site staff during each outpatient visit to 
the site based on responses provided by the subject and where applicable, the adequate 
medical care provided to treat episodes of hypoglycemia.
Did the subject have any symptoms of hypoglycemia since their last visit to the site?
 YES  NO
If yes, did the subject require assistance of another person to actively administer treatment 
for the event?  YES  NO
Did the subject exhibit any of the CNS symptoms of severe hypoglycemia? These include: 
memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in 
awakening, suspected seizure, seizure, loss of consciousness.   YES  NO
Was blood glucose measured?  NO  YES
If yes, what was the result? ____  mmol/L  mg/dL; and did the result meet threshold for 
severe hypoglycemia?  YES  NO
Severe hypoglycemia is defined as subject was unable to treat him/her self AND subject 
exhibited CNS symptoms of severe hypoglycemia mentioned above AND either blood 
glucose when measured was 49 mg/dL (or 2.7 mmol/L) or blood glucose was not measured 
by clinical manifestation reversed by oral carbohydrates, subcutaneous glucagon or 
intravenous glucose.
If no, did symptoms resolve when treated with carbohydrates, or glucagon?  YES  NO
Did the event awaken the subject while asleep for the night?  YES  NO
What time did the hypoglycemic event start?  What time did it resolve?  
When was the last meal (of 400 kcals) consumed?  ____ Date; ____ Time
When was the last dose of concomitant medication for glycemic control taken?  
____ Date; ____ Time
Were any actions taken?  YES  NO
If yes, dosing with investigational product – choose only one and enter details in 
concomitant treatment section.
 No action taken  Trial drug stopped temporarily  Trial drug stopped permanently


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Concomitant treatment dosing – choose only one and enter details in concomitant treatment
section.
 No action taken  Dose increased  Dose reduced
 Drug stopped temporarily  Drug stopped permanently
Subject was: choose all relevant options and enter details in concomitant treatment section 
if applicable.
 Withdrawn from Trial
 Treatment given (specify details in concomitant treatment section
 Other (specify):
 No Action
Does Serious Criteria apply? Serious is defined as fatal, life-threatening, inpatient 
hospitalization or prolongation of existing hospitalization, persistent or significant 
diability/incapability, congenital anomaly/birth defect, important medical event (ie, may 
jeopardize subject and may require medical/surgical intervention to prevent above listed 
outcomes).  YES  NO
Was the event a result of a study medication error?   YES / UNKNOWN  NO
If yes, complete Medication Error Log.
The following elements must be completed at the time the event resolves or at the end of the 
trial:
Causality: Is there a reasonable possibility the adverse event is related to trial treatment?
 YES / UNKNOWN  NO
If no, what is the most likely cause of the hypoglycemic adverse event? Choose one of the 
following:
 Concomitant treatment – drug or nondrug (specify);
 Other (specify).
If subject experienced symptoms of hypoglycemia, choose all that apply:
 Hunger  Palpitations  Blurred Vision  Headache  Tachycardia  Disorientation
 Dizziness  Tremulousness  Loss of Consciousness  Light Headedness  Irritability 


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 Seizures  Sweats  Other (specify)
What type of treatment was administered? 
Oral carbohydrates  YES  NO
Parenteral  YES  NO
Was a precipitating event identified?  YES  NO
If yes, choose all relevant options from the list below:
 Missed Meal/missed snack  Diabetes Medication Error – wrong dose
 Delayed Meal/delayed snack  Diabetes Medication Error – wrong time
 Exercise  Other precipitating event (specify)
 Comments

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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 5 of 83 
 
 
TABLE OF CONTENTS  
LIST OF TABLES ...................................................................................................... 7 
LIST OF FIGURES .................................................................................................... 7 
1 
VERSION HISTORY ..................................................................................... 10 
2 
INTRODUCTION ........................................................................................... 11 
2.1 
Study Objectives .................................................................................... 12 
2.2 
Study Design .......................................................................................... 13 
3 
ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ............................................................................................ 15 
3.1 
Primary Endpoint(s) ............................................................................... 15 
3.2 
Secondary Endpoint(s) ........................................................................... 15 
3.3 
Tertiary Endpoints ................................................................................. 15 
3.4 
Safety Endpoints .................................................................................... 16 
3.4.1 
Adverse Events ........................................................................ 16 
3.4.2 
Laboratory Data ....................................................................... 17 
3.4.3 
Standard Safety Other than AEs .............................................. 19 
3.5 
Baseline Variables ................................................................................. 20 
4 
ANALYSIS SETS ........................................................................................... 20 
4.1 
Full Analysis Set .................................................................................... 20 
4.2 
Per Protocol Analysis Set ...................................................................... 21 
4.3 
Safety Analysis Set ................................................................................ 21 
4.4 
Treatment Misallocations ...................................................................... 21 
4.5 
Stratum Reassignment ........................................................................... 22 
4.6 
Protocol Deviations ............................................................................... 22 
4.6.1 
Deviations Assessed Prior to Randomization ......................... 22 
4.6.2 
Deviations Assessed Post-Randomization .............................. 22 
4.7 
Other Analysis Sets ................................................................................ 23 
4.7.1 
Concentration Analysis Set ..................................................... 23 
5 
GENERAL METHODOLOGY AND CONVENTIONS ............................... 23 
5.1 
Hypotheses ............................................................................................. 23 
5.2 
General Methods .................................................................................... 23 
5.2.1 
Analyses for Continuous Data ................................................. 23 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 9 of 83 
 
 
Appendix 2.3.4. % Carbohydrate-Deficient Transferrin (%CDT) ........................... 75 
Appendix 2.4. Compliance ....................................................................................... 75 
Appendix 3. GRAPHICAL REPRESENTATIONS ................................................. 77 
Appendix 3.1. Box and Whisker Plot Representation for Changes/Percent Changes 
from Baseline at Week 16 by Randomized Arm ...................................... 77 
Appendix 3.2. Box and Whisker Plot for Changes/ Percent Changes From Baseline 
by Randomized Arm and Week ............................................................... 78 
Appendix 3.3. Figure for MMRM LS Mean vs Time by Randomized Arm for 
Changes/ Percent Changes From Baseline Over Time ............................ 79 
Appendix 3.4. Figure for MMRM LS Mean vs Time by Randomized Arm for 
Changes/ Percent Changes From Baseline Placebo-Adjusted Over Time 80 
Appendix 3.5. Figure for MMRM LS means for Changes/ Percent Changes From 
Baseline by Randomized Arm at Week16 overlaid with Emax Estimates 
(and 80%CI) ............................................................................................. 81 
Appendix 3.6. Figure for MMRM LS means for Placebo-Adjusted  Changes/ 
Percent Changes From Baseline by Randomized Arm at Week16 .......... 82 
Appendix 3.7. Additional Figure requested .............................................................. 83 
 
 
 


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Acetyl-CoA carboxylase (ACC) is a biotin carboxylase that catalyzes the adenosine 
triphosphate (ATP) dependent condensation of acetyl-CoA and carbonate to form 
malonyl-CoA. The malonyl-CoA produced by ACC serves two major physiologic 
functions. It is an essential and rate-limiting substrate for de novo lipogenesis (DNL) and 
it acts as an allosteric inhibitor of the enzyme carnitine-palmitoyltransferase 1 (CPT-1). 
CPT-1 is responsible for the transport of long-chain fatty acyl-CoAs across the 
mitochondrial membrane into the mitochondria where they become available for fatty acid 
oxidation. The transport step is rate-determining for this process. Thus, ACC is positioned 
as a key physiologic switch regulating the transition from oxidative to lipogenic 
metabolism. Reducing malonyl-CoA production via ACC inhibition is expected to inhibit 
simultaneously the de novo synthesis of fatty acids and to increase flux through CPT-1 
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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 12 of 83 
 
 
leading to increased β-oxidation of long-chain fatty acids. There are two closely related 
isoforms of ACC, ACC1, and ACC2, encoded by separate gene products that differ in 
tissue and cellular distribution.  
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual ACC1/2 
inhibitor designed to have asymmetric distribution to the liver, with ≥ 100 fold asymmetric 
hepatic distribution demonstrated in both rats and monkeys; as such PF-05221304 is 
expected to inhibit DNL and stimulate fatty acid oxidation in the liver to a greater extent 
than in peripheral tissues. In humans, administration of PF-05221304 has been shown to 
suppress hepatic DNL in a Phase 1 trial in healthy subjects; in addition, the drug is 
expected to stimulate hepatic fatty acid oxidation, and consequently reduce fat 
accumulation in the liver. This inhibition of hepatic DNL is postulated to result in a 
decrease and normalization of the excessive DNL observed in nonalcoholic fatty liver 
disease (NAFLD). In addition, the inhibition of ACC via administration of PF-05221304 
also has the potential for anti-inflammatory effects in nonalcoholic steatohepatitis 
(NASH).  
The current study is the first clinical trial proposed with PF-05221304 in adult subjects 
with NAFLD. The investigational product will be administered orally, once-daily for up to 
16 weeks. It is designed as a dose-ranging trial with placebo and 4 active doses of 
PF-05221304 to assess the safety, tolerability and the effect of PF-05221304 on liver fat. 
In addition, assessment of the effect of PF-05221304 on other 
pharmacodynamics/exploratory parameters is planned. 
This SAP provides the detailed methodology for summary and statistical analyses of the 
data collected in study C1171002. This document may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoint definition or its 
analysis will also be reflected in a protocol amendment. 
2.1 Study Objectives 
Primary Objective: 
• 
To evaluate the dose-response for the effect on liver fat, as assessed via MRI-PDFF, with a 
range of PF-05221304 doses administered daily in adults with nonalcoholic fatty liver 
disease (entire study population)  
Secondary Objective(s): 
• 
To evaluate the dose-response for the effect on ALT with a range of PF-05221304 doses 
administered daily in the 1st tier stratification comprising of adults with diagnosed/presumed 
nonalcoholic steatohepatitis, only  
• 
To evaluate the safety and tolerability of a range of PF-05221304 doses administered daily 
in adults with nonalcoholic fatty liver disease (entire study population) 
Tertiary Objective(s): 
• 
To evaluate the dose-response for the effect on liver fat, over time, with a range of 
PF-05221304 doses administered daily in adults with nonalcoholic fatty liver disease 
(entire study population)  


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To evaluate the dose-response for the effect on key liver function tests and NASH-related 
biomarkers over time, with a range of PF-05221304 doses administered daily in the 1st tier 
stratification comprising of adults with diagnosed/presumed nonalcoholic steatohepatitis, 
only 
•
To evaluate the dose-response for the effect on other potentially mechanism-related 
parameters and metabolic parameters, over time, with a range of PF-05221304 doses 
administered daily in adults with nonalcoholic fatty liver disease (entire study population)
•
To evaluate the dose-response for the effect on glycemic parameters, over time, with a range 
of PF-05221304 doses administered daily in the 2nd tier stratification comprising of adults 
with T2DM, only 

 6WXG\'HVLJQ
This is a randomized, double-blind, placebo-controlled, 5-arm (placebo, plus 4 active 
doses of PF-05221304), parallel-group study. 
Determination of eligibility for this study will occur via a sequential, 3-step process – 
starting with pre-qualification. Subjects identified to be eligible based on pre-qualification 
will then undergo Visit 1 (Screen 1) with only those confirmed to continue to be eligible 
progressing to Visit 2 (Screen 2). For a given subject, this 3-step eligibility assessment 
(from pre-qualification to Screen 2, inclusive) may take up to 2-months.  
Once confirmed to be eligible based on Screen 2 procedure(s), subjects will progress to a 
run-in phase when concomitant treatment(s) will be stabilized, and baseline-related visits 
will occur. At Visit 5 (Day 1), subjects will be randomized to receive 1 of 5 blinded 
regimens for a duration of up to 16 weeks (ie, 108±4 days). Excluding the 
pre-qualification visit, this study includes a total of 12 scheduled outpatient visits in the 
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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
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Final 
Page 14 of 83 
 
 
morning, 3 random visits for PK blood draws, and a potential for up to at least 3 visits for 
repeat assessments (for procedures/tests at Visit 1, Visit 2, or 2nd Follow-up visit). The 
total participation, from Visit 1 (Screen 1) to 2nd Follow-up visit, will be 27-weeks 
(minimum) to 35-weeks (maximum) – refer to Figure 1.  
At least 360 subjects (72 per arm) will be randomized at approximately 120 sites to ensure 
a minimum of 300 subjects (60 per arm) complete the study. In each arm, ≥ 50% of 
subjects randomized will be deemed to be eligible for 1st tier stratification of 
diagnosed/presumed NASH; with the remaining subjects per arm eligible for 1st tier 
stratification of NAFLD with likely minimal inflammation and fibrosis (refer to Section 4.3 
of the protocol for more details).  
 
Figure 1. C1171002 Study Design 
 
Subjects who are noted to have non-evaluable baseline MRI-PDFF, as determined by the 
sponsor-identified central imaging vendor, may be replaced, at sponsor discretion (refer 
to Section 7.1.4 of the protocol for more details); otherwise, there are no plans to replace 
subjects who are prematurely withdrawn. To ensure that the required minimum number of 
subjects complete the study, the plan is to overenroll by approximate 20% to account for 
premature early withdrawal.  
Baseline
(V4)
Day 1 = Randomization
(V5)
≥8-weeks and ≤14-weeks
Stabilize
background 
medications
Treatment with double-dummy, blinded medication 
(placebo, or 1 of 4 doses PF-05221304)
PBO
only
Screen 1 
(V1)
Screen 2 
(V2)
On-site FU (V12) 
[10 ± 4 days post last dose]
Day 14 
± 4
(V6)
Day 28 
± 4
(V7)
Day 42 
± 4
(V8)
Day 56 
± 4
(V9)
Day 108 
± 4
(V11)
Continue re-stabilized background medications
[Telephone] Contact  FU 
[≥28 & ≤35 days post last dose]
Day 84 
± 4
(V10)
Pre-Qualification 
Run-in 
(V3)
Account for majority of placebo-
response related to increased 
compliance once in trial
Confirm subject can comply 
with IP dosing instructions 
prior to randomization 
(≥ 90% compliance over 
14±2 days)
Visits every 2 weeks up to V9
considering prior limited clinical experience 
Visit at Day 108 acknowledging dosing in 
16-wk tox- was upto Day 112 plus intent to 
complete V11 procedures while on IP
Each visit represents an outpatient visit to the site or Imaging facility and envisioned to last ≤ 2-hours
Liver Imaging via MRI-PDFF expected at Screen 2 [eligibility for study; centrally read], Baseline between V4 and V5, plus V7, V10, V11
Assessment using FibroScan® to occur at pre-Qualification + Screen 1 and then at Baseline between V4 and V5, plus V7, V10, V11
If at V9 platelet count is observed to be below lower limit of normal as reported by sponsor-identified central laboratory, additional 
(unplanned) visits should occur – refer to Appendix 2
≥6-weeks


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• Percent change from baseline in liver fat, as assessed using MRI-PDFF, at Week 
16 in subjects with nonalcoholic fatty liver disease (entire study population)  
 6HFRQGDU\(QGSRLQWV
• Percent change from baseline in ALT, at Week 16 in adults with 
diagnosed/presumed nonalcoholic steatohepatitis, only  
• Assessment of TEAEs, safety-related clinical laboratory tests, vital signs, and 
12-lead ECGs in adults with nonalcoholic fatty liver disease (entire study 
population)±UHIHUWR6HFWLRQEHORZ
 7HUWLDU\(QGSRLQWV
• Percent change from baseline in liver fat, as assessed using MRI-PDFF, over time 
up to Week 16in adults with nonalcoholic fatty liver disease (entire study 
population)
• In adults with diagnosed/presumed nonalcoholic steatohepatitis onlySercent 
change from baseline, over time up to Week 16, for
9 ALT, AST, Alkaline Phosphatase (ALKP), GGT7RWDO%LOLUXELQ7%,/, 
9 CK18-M30 and CK18-M65 
9 Pro-C3 & Pro-C6 

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• In adults with nonalcoholic fatty liver disease (entire study population)percent 
change from baseline, over time up to Week 16, for:
• 3RWHQWLDOO\PHFKDQLVPUHODWHGSDUDPHWHUV±
9 Serum apolipoprotein A1, B (total), C3, E 
 
• Metabolic parameters  
9 Fasting lipid panel (fasting total cholesterol, direct LDL-C, HDL-C, 
triglycerides, VLDL) 
• &KDQJHIURPEDVHOLQHQRWSHUFHQWFKDQJHIURPEDVHOLQHDVPHQWLRQHGLQ
SURWRFROover time up to Week 16 for*O\FDWHGKHPRJORELQHbA1c
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• In adults with T2DM, only
• Change from baseline, over time up to Week 16 for 
9 *O\FDWHGKHPRJORELQHbA1c
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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 17 of 83 
 
 
severity post dosing on Day 1 will be listed and summarized under the category 
of “Run-In”.  
 
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 list in the product’s Safety Review Plan (version dated 
01Sep2017 [GDMS link - http://gdms.pfizer.com/gdms/drl/objectId/090177e18cd3d394 ]) 
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 subjects 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 
3.4.2 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, week 8, 
week 12, week 16, and Follow-up. 
• Number of occurrences of these abnormalities defined as “Flag Level” or “Alert 
Level” 
• Number of subjects with these abnormalities defined as “Flag Level” or “Alert 
Level” 
 
Table 2 Clinical Laboratory Parameters of Interest  
Parameter 
Flag Level 
Alert Level 
Conventiona
l Units 
Fasting Serum Triglycerides 
≥ 400  
≥ 600 
mg/dL 
-- 
≥ 800 
mg/dL 
Platelet Count  
< 100 
< 75 
x 10^3 
/mm^3
Fasting Plasma Glucose  
< 70 
≤ 49 
mg/dL 
≥140
>270 
mg/dL 
Alanine aminotransferase 
≥ 2x ULN
Pfizer std flag for PCC 
IU/L 
Aspartate aminotransferase 
≥ 2x ULN
Pfizer std flag for PCC 
IU/L 


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Alkaline Phosphatase 
 2x ULN
Pfizer std flag for PCC 
IU/L 
Gamma Glutamyl Transferase 
> ULN
Pfizer std flag for PCC 
IU/L 
Total Bilirubin 
> 1.5x ULN
Pfizer std flag for PCC 
mg/dL
Direct (Conjugated) Bilirubin
> ULN
Pfizer std flag for PCC 
mg/dL
*All flag level changes are cumulative from baseline (defined as result closest prior to dosing at Visit 5 (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 5 (Day 1); 
values when noted during the study, by central laboratory necessitates rapid notification (via fax/e-mail) to site 
and Study Clinician  
PCC – potential clinical concern 
ULN – upper limit of normal as determined by the central laboratory
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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 5 
(Day 1) 
bpm – beats per minute 
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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 24 of 83 
 
 
5.2.1.2 Longitudinal Analysis 
The over time effect of PF-05221304 on primary, secondary, and tertiary endpoints (see 
list in section 3) will be analyzed using the MMRM approach with randomized arm, time 
and randomized arm by-time interaction as fixed effects, subject as random effect using 
unstructured (UN) covariance structure. Baseline (in raw scale or log scale depending on 
the endpoint) will be included as covariate in the model. 
Other covariance structures (eg Compound Symmetry (CS), Autoregressive(1) [AR(1)], 
Heterogeneous CS (CSH), and Heterogeneous AR(1) [ARH(1)]) will be considered if 
convergence in the previous model is not met.  
 
The effect of PF-05221304 doses at all post-randomization visits will be estimated by the 
least-square (LS) means as well as LS mean differences against placebo respectively from 
the model described above.  
 
For all analyses performed on log-transformed relative change from baseline (RCBL), 
the LS mean estimates and their corresponding confidence intervals (CIs) will be 
obtained for each randomized arm and week. Differences (and corresponding 
confidence intervals) between LS mean estimates will be obtained comparing 
randomized arms for each week. All LS means and LS mean differences (including 
CI’s) will be back transformed to provide adjusted geometric LS means and ratios of 
adjusted geometric LS means. Then, percent change from baseline will be calculated 
as follows: 
 
            Percent change = 100* (RCBL - 1)  
 
where RCBL is either the adjusted geometric LS means estimate or the ratio of 
adjusted geometric means coming from the statistical model. The corresponding 80% 
CIs will be calculated as well.  
 
For all analyses performed on raw scale, the LS means estimates and their 
corresponding confidence intervals (CIs) will be obtained for each randomized arm and 
week. Differences (and corresponding confidence intervals) between LS means will be 
obtained comparing randomized arms for each week.  
 
Regardless if the data are analyzed in raw scale or after log-transformation, the inter- 
and intra-subject variability from the statistical model will be available and reported.  
 
For % liver fat assessed by MRI-PDFF analyzed on log-scale, 80% confidence intervals 
will be presented for the LS geometric mean ratio.  
 
For endpoints which are on raw scale, 80% confidence intervals will be presented for the 
LS mean differences along with the corresponding two-sided p-values when changes from 
baseline is the primary parameter.  
 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 28 of 83 
 
 
Parameters: % Liver fat assessed with MRI-PDFF: 
o Analysis time points: all applicable post Day 1/Visit 5 time points where 
scheduled assessment of specific continuous parameter is outlined in protocol 
o Analysis population: FAS and PPAS (as sensitivity analysis). 
o Analysis methodology: Log transformed relative change from baseline will be 
analyzed using MMRM model with log(baseline) as a covariate (specified in 
section 5.2.1.2). 
 
Reporting results: 
• Raw data and percent changes from baseline: Randomized subject, number of 
subject contributing to summary, sample size, mean, standard deviation, median, 
minimum, maximum, Q1 and Q3 at baseline and post-baseline visits will be 
presented for each randomized arm (see Appendix 2 for further detail). 
• MMRM Outputs:  
 Adjusted geometric LS mean estimates with 80% confidence interval for each 
randomized arm along with the translation in percent change over time, 
 Ratio of adjusted geometric LS mean estimates for each active randomized arm 
against placebo and the corresponding 80% confidence interval along with the 
translation in percent difference over time. 
 
Figures from MMRM outputs: 
1. Line plot of percent change from baseline after back transformation of adjusted 
geometric LS means with 80% confidence interval over time (see Appendix 3.3),  
2. Line plot of percent change from baseline placebo-adjusted after back 
transformation of adjusted geometric LS means ratios with 80% confidence 
interval over time (see Appendix 3.4), 
3. Percent change from baseline after back transformation of adjusted geometric LS 
means with 80% confidence interval at Week 16 (see Appendix 3.5), 
4. Percent change from baseline placebo-adjusted after back transformation of 
adjusted geometric LS means ratios with 80% confidence at Week 16 (see 
Appendix 3.6). 
 
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 16 and left 
panel for placebo adjusted response at Week 16) should be produced. 
 
Note regarding MRI windowing; 
Subjects with MRI assessment up to a maximum of 48Hrs post last dose on Week 16 
instead of 24Hrs post last dose on Week 16 as currently stated will be included in FAS and 
PPAS.  This is to permit assessment of the primary endpoint while on drug.  


Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 29 of 83 
 
 
6.1.2 Supportive Analyses on % Liver Fat Assessed using MRI-PDFF 
6.1.2.1 Dose-Response Model 
For % Liver Fat assessed by MRI-PDFF at Week 16, the analysis will be performed on the 
FAS without covariates in subject with nonalcoholic fatty liver disease (entire study 
population). The primary endpoint is the log transformed relative change from baseline in 
liver fat at Week 16 using the dose response model as described in section 5.2.1.3. 
 
Endpoint: Relative change from baseline 
Parameter: % Liver fat assessed by MRI-PDFF 
o Analysis time points Week 16  
o Analysis population: FAS in subject with nonalcoholic fatty liver disease 
(entire study population) 
o Analysis methodology: Natural log-transformed relative change from baseline 
in % liver fat will be analyzed using the Dose-Response model (specified in 
section 5.2.1.3).  
o Supporting objective: Primary Objective 
 
Reporting results for model: 
• The three parameters of the Emax model (E0, ED50, and Emax) along with their 
respective 80% confidence interval if non-linear model. .  
 
6.1.2.2 Covariate-by-treatment interaction 
Covariate-by-Treatment interaction will be performed on % Liver Fat at Week 16 on 
FAS and PPAS (observed cases) as described in section 5.2.1.4. 
 
6.2 
Secondary Endpoint(s) 
The secondary endpoint will be analyzed on the FAS. All analyses will be based on 
observed cases. 
6.2.1 Alanine Aminotransferase (ALT) 
Population: Subjects with diagnosed/presumed nonalcoholic steatohepatitis, only 
Endpoint: Relative change from baseline  
Parameters: ALT: 
o Analysis time points: all applicable post Day 1/Visit 5 time points where 
scheduled assessment of specific continuous parameter is outlined in protocol) 
o Analysis population: FAS. 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 38 of 83 
 
 
increased) by randomized arm. For subjects who did not complete the study, the 
reasons for withdrawal from the study will be presented. 
• Baseline Characteristics: Demographic characteristics such as subject age, gender, 
height, weight, body mass index (BMI), race, by 1st tier stratification and total per 
arm, by treatment group will be tabulated. 
• For each PD endpoint (ie primary, secondary or tertiary endpoint) and, as detailed 
in Appendix 2, baseline values will be listed and summarized by randomized arm 
and/or stratum and/or metabolic status (ie Type 2 Diabetes subjects vs non Type 2 
Diabetes subjects). Descriptive statistics for these endpoints and derived endpoints 
will be also tabulated as detailed in Appendix 2. 
• Overall compliance (Day 1 to Week 16 or premature termination during treatment 
phase) will be summarized by frequency (%) in the following two categories by 
randomized arm. Formula to compute compliance is defined in Appendix 2.4.  
o < 80% 
o ≥ 80% (and up to 110%) 
 
6.5.2 Baseline Summaries 
For each endpoint (ie primary, secondary or tertiary endpoint) and, as detailed in 
Appendix 2, baseline values will be listed and summarized by randomized arm and/or 
stratum and/or metabolic status (ie subjects with versus those without Type 2 Diabetes 
Mellitus). 
6.5.3 Concomitant Medications and Non-Drug Treatments 
Number of subjects taking, at any time post randomization, medication affecting % liver 
fat (eg Vitamin E) will be tabulated by randomized arm. 
 
Number of subjects under T2DM medication (T2DM), lipid medication, hypertension 
medication (HTN) will be tabulated by randomized arm. 
 
For each category of medication (ie T2DM, lipid and HTN), the number of subjects 
receiving 0, 1, 2, or 3 medications will also be tabulated by randomized arm. 
 
List of remaining concomitant drugs not part of the above list will only be listed. 
 
6.6 Safety Summaries and Analyses 
6.6.1 Adverse Events 
Unless otherwise noted, all safety data, including the following, will be summarized 
descriptively by randomized dose group through appropriate data tabulations and 
descriptive statistics: 


Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 39 of 83 
 
 
• 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 
randomized 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 section 
3.4 in relation to randomized treatment).  
• Vital signs will be summarized according to Pfizer standards (note that baseline is 
defined as in Appendix 2. in relation to randomized treatment).  
• For the safety endpoints of special clinical concern other than AEs as defined in 
section 3.4.2, they will be presented with descriptive statistics as appropriate for 
continuous or categorical data as defined in section 5.2. 
• Hypoglycemic Adverse Event (HAE) for T2DM subjects will be characterized for 
each randomized arm of subjects with T2DM only, as follows: 
• The number and percent of subjects reporting at least one hypoglycemic 
event 
• The hypoglycemic event rate, defined as the number of events reported per 
subject-month of treatment (per 100 subject months for severe events). 
Risk ratio of each active randomized arm against placebo will be displayed 
along with 80% CI and p-value.  
• The number of subjects with 0 event, 1 event, 2 events, 3 events, 4 events, 
and >=5 events.  
• The median number of events per subject. P-value of each active 
randomized arm as compared to placebo using rank-sum test will be 
displayed. 
• 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 
tier-2 events, point estimates and 95% confidence intervals for the risk 
difference will be presented.  


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Interim analysis (IA) will be performed at least once while the study is on-going. This 
review will include an assessment of the observed safety, and observed (versus assumed) 
variability for the primary endpoint (liver fat via MRI-PDFF) as well as key secondary 
endpoint (ALT). The 1 planned IA is proposed after at least one-third of the total planned 
randomized subjects (ie, approximately 120 subjects), complete through at least one-third 
of the total dosing duration (ie, Visit 8 [Week 6]) of the study. Interim analysis results may 
be used for conducting a sample size re-estimation, stopping a dose-level for observed 
safety, 
 and internal business decisions regarding planning of 
future trials with PF-05221304.  
In addition, during study conduct, after approximately every 20% of the total planned 
randomizations [for example: 72 subjects (20%), 145 subjects (40%), 215 subjects (60%), 
and 290 subjects (81%) of planned 360 subjects], based on blinded safety review by the 
selected members of the Sponsor’s study team, unblinded review of the safety data by the 
IRC will be triggered and a determination of the safety to continue the study documented 
if post randomization either of the below conditions are met – 
• More than 20% of subjects, develop a moderate or severe AE in the same system 
organ class (SOC);  
• More than 15 % of subjects meet the individual permanent discontinuation of 
dosing rules DVGHVFULEHGLQVHFWLRQVRIWKHSURWRFRO. 
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No formal statistical analyses (eg MMRM, rank test) will be performed on safety data. 
Intra- and Inter-Subject Variability Determination of  % Liver Fat Using MRI-
PDFF and ALT variability determination:  
At the time of a planned interim analysis, MRI-PDFF data up to and including Day 1 
(Visit 5) for all randomized subjects will be analyzed using a mixed model with week as 
fixed factor and subject as random factor to permit an assessment of the observed intra- 
and inter-subject variability in order to benchmark the results against the assumed 
standard deviations utilized to derive the sample size for the study.  
At the time of a planned interim analysis, all data available for ALT parameter in all 
randomized subjects in placebo arm will be included as part of the formal internal analysis 
and analyzed using a mixed model with subject as random factor to permit an assessment 
of the observed percent change from baseline variability in the placebo arm in order to 
permit an assessment of whether the observed standard deviation utilized to derive the 
sample size for the study are in line with the assumed standard deviation for 
this parameter.  
8 REFERENCES  
1. 
Siddiqui, Hung and O’Neil, “MMRM vs. LOCF: A Comprehensive Comparison 
Based on Simulation Study and 25 NDA Datasets”, Journal of Biopharm. Stats, 19: 
227-246, 2009. 
2. 
Westfall and Krishen, “Optimally weighted, fixed sequence, and gatekeeping 
multiple testing procedures”, Journal of Statistical Planning and Inference. 99, 25-40, 
2001. 
3. 
Hoeting, J.A, Davis R.A Merton A.A and Thompson S. E, “Model selection for 
Geostatistical Models”, Ecological Applications, 16(1), 87–98, 2006. 
4. 
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. 
5. 
Wagenknecht L.E., Palmer N.D., Bowden D.W., Rotter J.I., Norris J.M., Ziegler J., 
Chen Yii-Der I., Haffner S., Scherzinger A., and Langefeld C.D., “Association of 
PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin 
Resistance Atherosclerosis Family Study”, Liver Int., 31(3), 412-416, 2011. 
 


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9 
APPENDICES  
Appendix 1. SUMMARY OF EFFICACY ANALYSES 
Endpoint 
Analysis 
Set 
Statistical 
Method 
Model/ Covariates/ Strata 
Missing 
Data 
Interpretation 
Percent change from 
Baseline in % Liver 
Fat assessed by MRI-
PDFF Over Time 
FAS and 
PPAS 
MMRM on log-
transformed 
relative change 
Treatment, time and treatment-
by-week interaction as fixed 
effects, subject as random effect 
with log(baseline) as covariate. 
No Imputation 
Primary Analysis  
Percent Change from 
Baseline in % Liver 
Fat  assessed by MRI-
PDFF at Week 16 
FAS and 
PPAS 
ANCOVA on 
log-transformed 
relative change 
Treatment, Weight and treatment-
by-Weight interaction as fixed 
effects, subject as random effect 
with log(baseline) as additional 
covariate.
No Imputation 
Sensitivity analysis with 
two covariates on primary 
endpoint. 
Percent Change from 
Baseline in % Liver 
Fat assessed by MRI-
PDFF at Week 16 
FAS and 
PPAS 
ANCOVA on 
log-transformed 
relative change 
Treatment, concomitant drug and 
treatment-by-concomitant drug 
interaction as fixed effects, 
subject as random effect with 
log(baseline) as additional 
covariate.
No Imputation 
Sensitivity analysis with 
two covariates on primary 
endpoint. 
Percent Change from 
Baseline in % Liver 
Fat assessed by MRI-
PDFF at Week 16 
FAS 
Dose-Response 
model 
See section 5.2.1.3 
No Imputation 
Supportive analysis on 
primary endpoint 
Percent change from 
Baseline in ALT Over 
Time 
FAS  
MMRM on log-
transformed 
relative change 
Treatment, time and treatment-
by-week interaction as fixed 
effects, subject as random effect 
with log(baseline) as covariate. 
No Imputation 
Secondary analysis  


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Endpoint 
Analysis 
Set 
Statistical 
Method 
Model/ Covariates/ Strata 
Missing 
Data 
Interpretation 
Percent Change from 
Baseline in ALT at 
Week 16 
FAS 
Dose-Response 
model 
See section 5.2.1.3 
No Imputation 
Supportive Analysis on 
secondary endpoint 
Tertiary endpoints: 
Change from Baseline 
over time 
FAS 
MMRM on 
change from 
baseline 
Treatment, time and treatment-
by-week interaction as fixed 
effects, subject as random effect 
and baseline as covariate  
No Imputation 
Tertiary analysis 
Tertiary endpoints: 
Percent change from 
Baseline over time 
other than % Liver Fat 
using MRI-PDFF  
FAS  
MMRM on log-
transformed 
relative change 
Treatment, time and treatment-
by-week interaction as fixed 
effects, subject as random effect 
and log(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 
Each collected assessment will be mapped to their actual visit window according the 
following algorithm described in Table A2.1-1. 
Table A2.1-1. 
Algorithm to Map Collected assessment to Actual Visit 
Visit label 
Protocol 
defined 
Window 
Visit
Visit window as part of final reporting* 
For efficacy, PD, PK and  
safety endpoints 
Pre-Qualification 
NA 
1 
NA
Screen 1 
NA 
2
NA
Screen 2 
NA 
3
NA
Run-In 
NA 
3
NA
Week -2 
-14 ± 2 
4
• 
Between Week 0 and Week -2, data are used to 
define baseline 
• 
Intent is for baseline to be result closest prior to 
dosing on randomized regimen on Day 1 [Visit 5]  
• 
Window for baseline measurements is from Day -20 
to Day 1 [Visit 5] pre-dose
Week 0 
1 
5 
Week 2 
14 ± 4 
6 
‘Date of assessment’ – ‘Baseline date’ + 1 = [8; 20];  
ie, ±6 days
Week 4 
28 ± 4 
7 
‘Date of assessment’ – ‘Baseline date’ + 1 = [22 ; 34]; 
ie, ±6 days  
Week 6 
42 ± 4 
8 
‘Date of assessment’ – ‘Baseline date’ + 1 = [36 ; 48]; 
ie, ±6 days
Week 8 
56 ± 4 
9 
‘Date of assessment’ – ‘Baseline date’ + 1 = [50 ; 62]; 
ie, ±6 days
Week 12 
84 ± 4 
10 
‘Date of assessment’ – ‘Baseline date’ + 1 = [77 ; 91]; 
ie, ±7 days
Week 16 
108 ± 4 
11 
‘Date of assessment’ – ‘Baseline date’ + 1 = [101; 115]; 
ie, ±7 days
1st Follow-up 
visit 
10 ± 4 days 
post last dose 
12 
At least 5 days post last dose and up to days 27 post last 
dose
2nd Follow-up 
visit 
28 + 7 days 
post last dose 
13 
 
Note: * permitted to be wider than window defined in protocol for purposes of reporting data by nominal 
visit. 
 
Special consideration: 
• For subject 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. 
 


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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)’  
 
Appendix 2.2. Data Derivation for Primary, Secondary, and Tertiary Endpoints 
Appendix 2.2.1. % Liver Fat using MRI-PDFF  
For each subject with nonalcoholic fatty liver disease (entire study population), the 
Whole Liver PDFF (WLPDFF in %) will be calculated from the pre-defined individual 
segmental PDFF (SPDFF in %) measured in Segment 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 4, Week 12, and Week 16). 
Note: If any negative value 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 4, Week 12, and Week 16.  
For instance, 
 
if results are reported for all segments at Baseline, and on Week 4, Week 12, 
and Week 16 (see below), The number of segments assessed is equal to 9 . 
 
 
 
 
If at Baseline, all segment data are available but, on Week 4, or Week 12, or 
Week 16, only 7 segments have results reported, WLPDFF will be calculated at 
Baseline, and on Week 4, Week 12, and Week 16 and using the matching 
individual segments providing values on all weeks. For instance, based on the 
schema below, segment II and Segment V will not be used to calculate 
Baseline 
Week 4 


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WLPDFF on any of the time points reported. In this case, WLPDFF will be 
calculated using data in the 7 segments reported at all visits. 
 
 
 
 
WLPDFF and individual % liver fat measured in each individual segment will be listed. 
WLPDFF will be summarized by randomized arm, and Week as described in Table  
A2.2-1.  
Note: If baseline at the individual segment level is zero by itself or after imputation, % 
change from baseline at individual segment level will be reported as “.” (because not 
calculable) with a footnote explaining that the value at baseline was zero or imputed to 
zero.  
Table A2.2-1: Summary Statistics for % Liver Fat (WLPDFF) assessed by MRI-
PDFF 
Weeks 
Summary Statistics 
Screen2, Baseline, 
and 4, 12, 16 
N, arithmetic mean, median, %CV, standard 
deviation, minimum, maximum, Q1, Q3
 
 
Derived Parameters 
Individual change from baseline, percent change from baseline and relative change from 
baseline for WLPDFF will be calculated and listed. Percent change from baseline will be 
summarized by randomized arm as described in Table A2.2-2.  
 
Table A2.2-2: Summary Statistics for Percent Change From Baseline in % Liver 
Fat (WLPDFF) using MRI-PDFF 
Weeks 
Derived parameter 
Summary Statistics 
4, 12, 16 
Percent Change from 
Baseline  
N, arithmetic mean, median, standard 
deviation, minimum, maximum, Q1, 
Q3
 
Figures: 
• Median response versus week will be presented against randomized arm. Q1 and Q3 
values will be added. 
Baseline 
Week 4 


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Page 56 of 83 
 
 
Box and whisker plots by randomized arm and by week will also be displayed to 
characterize the distribution of percent changes from baseline over time (see 
Appendix 3.2). Only box, whiskers, arithmetic mean, and outliers should be reported 
in this graphic. 
Figure for triglycerides only (should be included in the safety set of figures) 
• For subjects with any after Day 1 (ie post-randomization) where fasting  
TG ≥ 600 mg/dL and up to Week 16 (include unplanned in chronological/continuous 
order – not categorical), graph fasting TG, FPI, ApoC3, and FPG data together. To do 
so, real date reported in eCRFe-data loads received from Covance will be used 
 
• If possible, this figure containing 4x4 panels (1 panel per subject) by treatment will 
be created with LEFT Y-axis reporting TG and FPG levels and RIGHT Y-axis 
reporting FPI and ApoC3 levels. 
 
Appendix 2.2.7.  Glycated Hemoglobin  
Glycated hemoglobin (HbA1c) values will be assessed at timepoints described in the 
Schedule of Activity of the protocol. 
HbA1c values will be listed and summarized by randomized arm, and week as described 
in Table A2.2-14 
 
Table A2.2-14: Summary Statistics for HbA1c Over Time 
Weeks 
Parameter 
Population 
Summary Statistics 
Baseline, 
2, 4, 6, 8, 
12, 16, 
FU  
HbA1c 
 
Subjects with 
nonalcoholic fatty liver 
disease (ie entire study 
population)
N, arithmetic mean, median, 
%CV, standard deviation, 
minimum, maximum, Q1, Q3
Baseline, 
2, 4, 6, 8, 
12, 16, 
FU  
HbA1c 
 
T2DM subjects 
N, arithmetic mean, median, 
%CV, standard deviation, 
minimum, maximum, Q1, Q3
Note: FU = 1st Follow-up as defined in Tables 1 and 2 of the protocol 
 
Derived Parameter 
Individual change from baseline over time on HbA1c will be calculated, listed, and 
summarized by randomized arm, and week as described in Table A2.2-15.  
Table A2.2-15: Summary Statistics for Change From Baseline in HbA1c Over Time 
Weeks 
Derived 
parameter 
Population 
Summary Statistics 
Baseline, 
2, 4, 6, 
Change 
from 
Baseline  
Subjects with nonalcoholic 
fatty liver disease (ie entire 
N, arithmetic mean, 
median, standard deviation, 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 59 of 83 
 
 
Table A2.2-19: Summary Statistics for Change From Baseline in Fasting Plasma 
Glucose and Fasting Plasma Insulin Over Time 
Weeks 
Derived parameter 
Summary Statistics 
2, 4, 6, 8, 
12, 16, FU 
FPG - change from baseline 
in subject with T2DM only 
N, arithmetic mean, median, standard 
deviation, minimum, maximum, Q1, 
Q3
2, 4, 6, 8, 
12, 16 
FPI - change from baseline 
in subject with T2DM only 
N, arithmetic mean, median, standard 
deviation, minimum, maximum, Q1, 
Q3
Note: FU = 1st Follow-up as defined in Tables 1 and 2 of the protocol 
 
Figure (1 set for each parameter): 
• Median response versus week will be presented against randomized arm. Q1 and Q3 
values will be added. 
• Median change from baseline versus week will be presented against randomized arm. 
A reference line cutting the Y-Axis at 0 will be overlaid. Q1 and Q3 values will be 
added. 
 
Appendix 2.2.10.  Homeostatic Model Assessment for Insulin Resistance (T2DM 
Subjects Only) 
The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) will be derived 
using fasting plasma glucose values and fasting plasma insulin values at timepoints 
described in the Schedule of Activity of the protocol. 
 
The formula used to derive HOMA-IR is as follow: 
 
HOMA-IR = (GlucoseFasting Concentration x InsulinFasting Concentration) / 405 
 
where plasma glucose concentrations is reported in mg/dL and plasma insulin is reported 
in mU/L. As such, HOMA-IR is unit-less. 
HOMA-IR values will be listed and summarized by randomized arm, and week as 
described in Table A2.2-20. 
Table A2.2-20: Summary Statistics for HOMA-IR Over Time 
Weeks 
Parameter 
Summary Statistics 
Baseline, 2, 4, 
6, 8, 12, 16  
HOMA-IR in subjects 
with T2DM only 
N, arithmetic mean, median, %CV, 
standard deviation, minimum, maximum, 
Q1, Q3
 
Derived Parameters 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 76 of 83 
 
 
#ExpectedTabUsedOverall = 3*(last dose date – first dose date + 1) 
 
NOTE: Data entered on Drug Accountability CRF page (which only captures details 
regarding pill count returned) will not be used to calculate and report out subject-level 
compliance. 


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Protocol C1171002 (PF-05221304) 
Statistical Analysis Plan 
 
 
Version control: C1171002 
Final 
Page 83 of 83 
 
. 
 
Appendix 3.7.  
Additional Figure requested  
In order to apprehend the dose –effect relationship between different endpoints, please provide the following additional figures: 
• 
% change in liver fat at Wk16 (X-axis) versus % change in fasting TG (Y-axis) with 5 colored dots/squares/circles representing 5 arms (red = placebo) 
to permit either an assessment of whether increase in TG is related to dose or individual-subject sensitivity to drug. 
• 
Change in fasting TG at Wk16 (X-axis) versus change in fasting ApoC3 (Y-axis) with 5 colored dots/squares/circles representing 5 arms (red = placebo) 
to permit either an assessment of whether increase in ApoC3 is related to Dose or individual-subject sensitivity to drug.