Conditions: Non-Alcoholic Fatty Liver Disease (NAFLD)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 99
Healthy volunteers: no

Brief summary:
This study is to assess the effect of PF 05221304 alone, PF 06865571 alone, the co administration of PF 05221304 and PF 06865571, or placebo on whole liver fat in subjects with NAFLD. In addition, this study will evaluate the safety and tolerability of co administration of PF 05221304 and PF 06865571 along with the effects on selected pharmacodynamics (PD)/exploratory parameters, compared to administration of PF 05221304 alone, PF 06865571 alone, and placebo in adults with NAFLD.

Detailed description:

Arms:
arm 1: Placebo (PF 05221304) BID Placebo (PF 06865571) BID arm 2: 15 mg PF-05221304 BID Placebo (PF-06865571) BID arm 3: Placebo (PF-05221304) BID 300 mg PF-06865571 BID arm 4: 15 mg PF-05221304 BID 300 mg PF-06865571 BID

Interventions: intervention 1: PF-05221304 Monotherapy intervention 2: PF-06865571 Monotherapy intervention 3: Placebo intervention 4: PF-05221304 and PF-06865571 Combination
Intervention descriptions: intervention 1: Participants enrolled in this Arm will receive 15 mg dose of PF-05221304 (3 tablets of 5 mg each) and 3 tablets of Placebo for PF-06865571, each to be taken twice daily for 41 days and once on Day 42. intervention 2: Participants enrolled in this Arm will receive 300 mg dose of PF-06865571 (3 tablets of 100 mg each) and 3 tablets of Placebo for PF-05221304, all to be taken twice daily for 41 days and once on Day 42. intervention 3: Participants enrolled in this Arm will receive 3 tablets for Placebo of PF-05221304 and 3 tablets of Placebo of PF-06865571, to be taken twice daily for 41 days and once on Day 42. intervention 4: Participants enrolled in this Arm will receive 15 mg dose of PF-05221304 (3 tablets of 5 mg each) and 3 tablets of PF-06865571 (3 tablets of 100 mg each), each to be taken twice daily for 41 days and once on Day 42.

Protocol document:
Prot_000.pdf: 
PF-05221304 and PF-06865571
C3711001
Final Protocol Amendment 1, 02 October 2018
Page 1
A PHASE 2A, RANDOMIZED, DOUBLE BLIND (SPONSOR-OPEN), PLACEBO 
CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE 
PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-05221304 AND 
PF-06865571 CO-ADMINISTERED FOR 6 WEEKS IN ADULTS WITH 
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Investigational Product Number:
PF-05221304 and PF-06865571
Investigational Product Name:
Not Applicable
United States (US) Investigational New 
Drug (IND) Number:
Protocol Number:
C3711001
Phase:
2a
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
02 October 2018
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 
15 August 2018.
1. In response to agency’s request to remove the 
term “metabolic syndrome” from Inclusion 
Criterion #5 (Section 4.1), the text was modified 
to reflect that the 2 out of 5 criteria listed should 
be met; the criteria being “commonly associated”
with metabolic syndrome instead of original text, 
which reflected that 5 criteria may be indicative 
of metabolic syndrome.
2. In response to agency’s request to add trial 
stopping criteria, an additional sub-section was 
added in Study Design ie, Section 3.3: 
“Considerations for Pausing or Stopping 
Treatment Arm or Trial Based on Observed 
Safety”. The sub-section outlines the rules for 
pausing or stopping a treatment arm or Trial.
Modifications in text were also made in related 
Section 9.8.
3. In response to agency’s request to establish 
baseline values for liver enzymes by at least two 
samples obtained at least 4 weeks apart to 
account for disease related changes in liver 
enzymes and bilirubin, text was added to the 
Exclusion Criterion #2 (Section 4.2) to clarify 
that subjects meeting the exclusion criterion for
liver enzymes and bilirubin laboratory values in 
either Visit 1 or Visit 4 will be excluded from the 
study. The study design Figure 1: C3711001 
Study Design was revised to reflect that the time 
duration between Screen 1 (Visit 1) and Visit 4 
(start of Run-In) is expected to be at least 
4 weeks, but not to exceed 6 weeks, thereby, 
fulfilling a minimum 4 week time period 
requirement between 2 visits. Schedule of 
Activities and text in Section 3.1 and Section 6.1


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was modified to reflect changes to Figure 
schematic. 
In addition to the FDA requested changes, following 
revisions have been made to the protocol in this 
Amendment: 
4. Schedule of Activities:
In Table 1, text in column header “Treatment 
Phase” was modified to include the 
phrase “ ….unless otherwise noted” to 
accommodate post-dose PK collections which 
will be conducted 2 hours post dosing. 
5. Schedule of Activities:
For Visit 10, instead of allowed 2 days from 
Day 42 visit, the allowable window has been 
changed to ‘42(-3)’ ie, subjects are allowed to 
make Visit 10 up to 3 days in advance of Day 42 
visit, but not beyond Day 42. This change was 
made to ensure to limit potential medication 
errors of dosing beyond 42 days specified by the 
protocol. Additional footnote “b” was added to 
clarify the visit window.
6. Schedule of Activities, Section 5.4.2, and 
Section 5.5:
Text was added in foot note “k” of Table 1, in 
Section 5.4.2 and Section 5.5 to clarify that on 
Visit 10, there will not be any evening dose.
7. Section 1.4.2
Text was modified to clarify the language 
regarding potential effect of PF-06865571 in
inhibiting OCT2/MATE.
8. Section 1.5.1: 
A typographical error was made in the dose 
rationale text. The error was rectified as below:
“The anticipated exposures of PF-05221304 at 
15 mg BID in this study are 122-fold and 29-fold 


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higher lower (Cmax and AUC24, respectively) than 
the NOAEL (30 mg/kg (QD) PF-05221304 + 
300 mg/kg (BID) PF-0686557) in the 6-week 
combination toxicology study in monkeys.  
Similarly, the anticipated exposures of 
PF-06865571 at 300 mg BID in this study are 
3.7 and 6.2-fold higher lower than the 6-week 
monkey NOAEL.”
 
 
 
 
 
 
10. Section 1.5.2:
Under heading ‘Clinical Experience with 
Combination of PF-05221304 and PF-06865571’, 
a brief summary was added regarding trends of 
fasting triglyceride levels observed in C3711002 
Cohort 2. This summary was unintentionally 
excluded in the original version.
11. Section 4.1, Inclusion Criterion #6:
Divided text from a single inclusion criterion
(#6 in Original Protocol) into 2 individual 
inclusion criteria. Instead of Inclusion Criterion 
#6 in the Original protocol which stated that “At 
Screen 1 and Screen 2 both ….” Inclusion 
Criterion #6 in this Amendment states “At Screen 
1…”. In addition, Criterion #7 has been added 
which states “At Screen 2…”. This change was 
made to properly capture protocol deviations 
associated with each criterion in the eCRFs
(electronic case report forms).
12. Section 4.2, Exclusion criterion #3:
Language modified to clarify that subject has to 
be negative for urine drug test at Screen 1 
(Visit 1), start of Run-in (Visit 4) and at Baseline 
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(Visit 6) visit in order to enroll and remain in the 
study, not just Screen 1 (Visit 1) as implied in the 
Original Protocol.
13. Section 6.4.4 and Footnote “g” in Schedule of 
Activities
Added text to clarify that if MRI-PDFF 
assessment for Visit 10 is completed on the day of 
the site visit for Visit 10, subjects should refrain 
from taking IP until blood draw for laboratory 
assessments is completed.  
Original 
protocol
09 August 2018
Not applicable (N/A)
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...................................................................................................................10
LIST OF FIGURES .................................................................................................................11
APPENDICES .........................................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................12
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................16
1.2. Background and Rationale ......................................................................................16
1.3. Background Information for PF-05221304.............................................................17
1.3.1. Nonclinical Experience with PF-05221304................................................17
1.3.2. Clinical Experience with PF-05221304......................................................18
1.4. Background Information for PF-06865571.............................................................20
1.4.1. Nonclinical Experience with PF-06865571................................................20
1.4.2. Clinical Experience with PF-06865571......................................................20
1.5. Background Information on PF-05221304 and PF-06865571 Combination..........23
1.5.1. Non-Clinical Experience with Combination of PF-05221304 and 
PF-06865571....................................................................................................23
1.5.2. Clinical Experience with Combination of PF-05221304 and 
PF-06865571....................................................................................................24
1.6. Study Rationale .......................................................................................................27
1.6.1. Design Rationale.........................................................................................28
1.6.2. Rationale for Population Enrolled ..............................................................29
1.6.3. Dose Rationale............................................................................................30
1.6.4. Rationale for Banked Biospecimen Collection...........................................31
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................31
3. STUDY DESIGN.................................................................................................................33
3.1. Study Overview.......................................................................................................33
3.2. Stopping Rules in Individual Subjects ....................................................................34
3.3. Considerations for Pausing or Stopping Treatment Arm or Trial Based on 
Observed Safety.........................................................................................................35
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................35
4.1. Inclusion Criteria.....................................................................................................35
4.2. Exclusion Criteria....................................................................................................37


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4.3. Randomization Criteria ...........................................................................................41
4.4. Lifestyle Requirements ...........................................................................................41
4.4.1. Meals and Dietary Restrictions...................................................................41
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................41
4.4.3. Physical Activity.........................................................................................42
4.4.4. Contraception..............................................................................................42
4.5. Sponsor’s Qualified Medical Personnel..................................................................43
5. STUDY TREATMENTS.....................................................................................................43
5.1. Allocation to Treatment ..........................................................................................44
5.2. Breaking the Blind ..................................................................................................45
5.3. Subject Compliance.................................................................................................45
5.4. Investigational Product Supplies.............................................................................45
5.4.1. Dosage Form(s) and Packaging..................................................................45
5.4.2. Preparation and Dispensing........................................................................45
5.5. Administration.........................................................................................................46
5.6. Investigational Product Storage ..............................................................................46
5.7. Investigational Product Accountability...................................................................47
5.7.1. Destruction of Investigational Product Supplies ........................................47
5.8. Concomitant Treatment(s).......................................................................................48
5.8.1. Medications for Glycemic Control.............................................................48
5.8.2. Anti-Hypertensive Medications..................................................................48
5.8.3. Lipid-Modifying Medications ....................................................................49
5.8.4. Other Acceptable Concomitant Medications..............................................49
5.8.5. Prohibited Concomitant Medications .........................................................50
5.9. Rescue Medication ..................................................................................................51
6. STUDY PROCEDURES .....................................................................................................51
6.1. Screening.................................................................................................................51
6.2. Run-in Period (Visit 4)............................................................................................52
6.3. Baseline MRI-PDFF (Visit 5) .................................................................................53
6.4. Study Period ............................................................................................................53
6.4.1. Day 1 (Visit 6) ............................................................................................53
6.4.2. Day 5 (Visit 7) ............................................................................................53


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6.4.3. Day 14 (Visit 8) and Day 28 (Visit 9) ........................................................54
6.4.4. Day 42 (Visit 10) ........................................................................................54
6.4.5. Follow-up....................................................................................................54
6.4.6. Follow-up Contact ......................................................................................55
6.5. Subject Withdrawal/Early Termination ..................................................................55
7. ASSESSMENTS..................................................................................................................56
7.1. Imaging Assessments ..............................................................................................57
7.1.2. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis......57
7.1.3. Analysis of MRI-PDFF Images Including Determination of 
Eligibility .........................................................................................................58
7.2. Safety.......................................................................................................................59
7.2.1. Physical Examinations................................................................................59
7.2.2. Body Weight and Hula-hoop Test ..............................................................59
7.2.3. Blood Pressure and Pulse Rate ...................................................................60
7.2.4. Electrocardiogram.......................................................................................60
7.3. Clinical Laboratory Tests........................................................................................61
7.3.1. Serum for Cystatin C ..................................................................................62
7.5. Pharmacodynamics Parameters...............................................................................64
7.5.1. Serum for Lipid Panel.................................................................................65
7.5.3. Apolipoprotein A1, B100 and Apolipoprotein C3 .....................................65
7.5.8. Plasma PCSK9............................................................................................66
7.6. Pharmacogenomics..................................................................................................66
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7.6.1. Genotyping Analysis ..................................................................................66
7.7. Banked Biospecimens .............................................................................................66
7.7.1. Additional Research....................................................................................67
8. ADVERSE EVENT REPORTING......................................................................................68
8.1. Requirements...........................................................................................................68
8.1.1. Additional Details On Recording Adverse Events on the CRF..................69
8.1.2. Eliciting Adverse Event Information..........................................................69
8.1.3. Withdrawal From the Study Due to Adverse Events (See also the 
Subject Withdrawal 6.5) ..................................................................................69
8.1.4. Time Period for Collecting AE/SAE Information......................................70
8.1.5. Causality Assessment .................................................................................70
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................71
8.2. Definitions...............................................................................................................71
8.2.1. Adverse Events...........................................................................................71
8.2.2. Abnormal Test Findings .............................................................................72
8.2.3. Serious Adverse Events ..............................................................................72
8.2.4. Hospitalization............................................................................................73
8.3. Severity Assessment................................................................................................74
8.4. Special Situations ....................................................................................................74
8.4.1. Protocol-Specified Serious Adverse Events...............................................74
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................74
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................76
8.4.4. Medication Errors .......................................................................................78
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................79
9.1. Sample Size Determination.....................................................................................79
9.2. Analysis of the Primary Endpoint ...........................................................................79
9.3. Analysis of Secondary Endpoints ...........................................................................80
9.4. Analysis of Tertiary/Exploratory Endpoints ...........................................................80
9.6. Analysis of Other Endpoints ...................................................................................80
9.7. Safety Analysis........................................................................................................80
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9.8. Interim Analysis ......................................................................................................81
9.9. Data Monitoring Committee ...................................................................................81
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................82
11. DATA HANDLING AND RECORD KEEPING .............................................................82
11.1. Case Report Forms/Electronic Data Record .........................................................82
11.2. Record Retention...................................................................................................83
12. ETHICS..............................................................................................................................83
12.1. Institutional Review Board/Ethics Committee......................................................83
12.2. Ethical Conduct of the Study ................................................................................84
12.3. Subject Information and Consent..........................................................................84
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................85
13. DEFINITION OF END OF TRIAL...................................................................................85
13.1. End of Trial in All Participating Countries ...........................................................85
14. SPONSOR DISCONTINUATION CRITERIA ................................................................85
15. PUBLICATION OF STUDY RESULTS..........................................................................85
15.1. Communication of Results by Pfizer ....................................................................85
15.2. Publications by Investigators ................................................................................86
16. REFERENCES ..................................................................................................................88
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................12
Table 2.
Summary of Plasma PF-06865571 PK Parameters Following Single Oral 
Doses in C2541001...............................................................................................21
Table 3.
Summary of Preliminary Steady State (Day 14) Plasma PF-06865571 PK 
Parameters Following Multiple Oral Doses in C2541002....................................22
Table 4.
PF-05221304 PK Parameters following Administration of PF-05221304 
Alone (15 mg BID) or with PF-06865571 (300 mg BID) in C3711002 ..............27
Table 5.
PF-06865571 PK Parameters following Administration of PF-06865571 
Alone (300 mg BID) or with PF 05221304 (15 mg BID) in C3711002...............27
Table 6.
Study Treatment Regimen and Dispensing Schedule...........................................44
Table 7.
Clinical Laboratory Tests .....................................................................................61


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LIST OF FIGURES
Figure 1.
C3711001 Study Design.......................................................................................33
APPENDICES
Appendix 1. Abbreviations......................................................................................................90
Appendix 2. Strong CYP3A Inhibitors and Inducers* ............................................................95
Appendix 3. Guidance to Investigators –Management of Individual Subjects With 
Decrease in Platelet Count....................................................................................96
Appendix 4. Guidance to Investigators –Management of Individual Subjects With 
Elevation in Fasting Serum Triglycerides ............................................................97


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SCHEDULE OF ACTIVITIES
The schedule of activities table below provides an overview of the protocol visits and procedures.  Refer to Section 7 of the protocol 
for detailed information on each procedure and assessment required for compliance with the protocol.  The investigator may schedule 
visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to conduct evaluations or assessments 
required to protect the well-being of the subject.
Table 1.
Schedule of Activities
Visit Identifier
Screen 1
Screen 2 Screen 3 Run-In Baselinea Treatment Phase [all procedures before
morning dose of blinded IP, unless 
otherwise noted]
Follow-up
Early
Termi
nation 
(ET)
Week Relative to Dosing on Day 1
Visit 1 to Visit 4 should be 
≥4 and ≤6 weeks
-2
-1
0
1
2
4
6
7-14 days 
post last 
dose
28-35 
days post 
last dosec
Days Relative to Dosing on Day 1
-14±2
-4±2
1
5±1
14±2
28±2
42(-3)b
Visit to Site or Imaging Facility 
1
2
3
4
5
6
7
8
9
10
11
--
Informed consent & demography
X
Medical history
X
Medication history (update)d
X
X
X
X
X
X
X
X
X
X
 FibroScan®)e
X
X
X
X
X
X
Liver fat (via MRI-PDFF)e,f
X
X
Xg
Xh
Physical examination (PE)i
X
X
X
X
X
X
Body weight (+ hula-hoop test at Screen 1 only)
X
X
X
X
X
X
Single, supine 12-lead ECG
X
X
X
X
X
X
X
X
X
Single, seated vitals assessment (BP & pulse rate)
X
X
X
X
X
X
X
X
X
Serious and non-serious adverse event (AE) 
monitoring
X
→
→
→
→
→
→
→
→
→
→
X
X
Randomization in trial (via IRT)
X
Dispense Investigational Product (IP) (via IRT)j
X
X
X
X
Administration of IPk
X
→
X
X
X
X
X
Compliance via pill count of returned IP
X
X
X
X
X
X
Confirm contraceptive method
X
X
X
X
X
X
X
X
Instructions on Dosing of IP
X
X
X
X
X
Counseling on diet/exercise guidelines
X
X
X
X
X
X
Blood Collections after ≥8-hour, preferably 10-hour fast; refer to Table 7 for additional details
Clinical laboratory tests 
X
X
X
X
X
X
X
X
X
Cystatin Cl
X
X
X
X
X
X
X
X
X
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Visit Identifier
Screen 1
Screen 2 Screen 3 Run-In Baselinea Treatment Phase [all procedures before
morning dose of blinded IP, unless 
otherwise noted]
Follow-up
Early
Termi
nation 
(ET)
Week Relative to Dosing on Day 1
Visit 1 to Visit 4 should be 
≥4 and ≤6 weeks
-2
-1
0
1
2
4
6
7-14 days 
post last 
dose
28-35 
days post 
last dosec
Days Relative to Dosing on Day 1
-14±2
-4±2
1
5±1
14±2
28±2
42(-3)b
Visit to Site or Imaging Facility 
1
2
3
4
5
6
7
8
9
10
11
--
Serology (HepBsAg, HepBcAb, HCVAb, HCV RNA, 
HIV), Serum FSH (females only)
X
Ceruloplasmin, Coagulation (aPTT, PT, PT/INR), 
α1-antitrypsin (A1AT)
X
 
Fasting Lipid Panel
X
X
X
X
X
X
X
X
X
 
Apolipoproteins (A1, B100 and C3)
X
X
Plasma PCSK9
X
X
OATP Pharmacogenomics blood sampleo
X
Banked bio-specimen: Prep D1.5o
X
Banked bio-specimen: Prep B1.5 and B2.5
X
X
Urine Collections
Urine drug testp
X
X
X
Urinalysis (and microscopy, as appropriate)
X
X
X
X
X
X
X
X
X
Abbreviations: →= ongoing/continuous event; A1AT = α1-antitrypsin; AE = Adverse Event; aPTT = activated Partial Thromboplastin Time; BP = Blood Pressure; 
 ECG = electrocardiogram; ET = Early Termination; FSH = Follicle Stimulating Hormone; 
 
HCVAb = Hepatitis C Virus Antibody; HCV RNA = Hepatitis C Virus Ribonucleic Acid; HepBcAb = Hepatitis B Core Antibody; HepBsAg = Hepatitis B Surface Antigen; 
HIV = Human Immunodeficiency Virus; 
; IP = Investigational Product; IRT = Interactive Response Technology; 
MRI-PDFF = Magnetic Resonance Imaging – Proton Density Fat Fraction; OATP = Organic Anion Transporter Polypeptide; PCSK9 = Proprotein Convertase Subtilisin/kexin 
type 9; PE = Physical Examination; 
; 
 PT = Prothrombin Time; 
PT/INR = Prothrombin Time/International Normalized Ratio
a.
baseline for liver fat assessments by MRI-PDFF is Day -4±2; baseline for all other assessments is Day 1, prior to first dose.
b.
The Day 42 visit can occur up to 3 days prior ie, Day 39 to Day 42, but no later than Day 42. 
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c.
To occur via telephone contact and must occur within 28-35 days from administration of the final dose of double-blind IP; this contact can be considered as on-site in order to 
permit follow-up of open AEs and/or abnormal laboratory tests from prior visit(s), as needed.
d.
Update at post-screening visits.
e.
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 perform baseline visit for each 
assessment (Visit 6 for FibroScan® and Visit 5 for MRI-PDFF) within ±2-hr window of initial screen time (Visit 1 for FibroScan® and Visit 3 for MRI-PDFF).  
Post-randomization assessments should be within ±2-hr window of baseline visit time (Visit 6 for FibroScan® and Visit 5 for MRI-PDFF).
f.
A single repeat assessment is permitted at screening as determined by sponsor-identified central imaging vendor; at baseline (Visit 5) and at Visit 10, single repeat is 
permitted only after consultation with the Sponsor.
g.
MRI-PDFF assessment to be performed within approximately 24 hours prior to Visit 10, or on the same day as Visit 10. If subjects perform MRI-PDFF in the morning of 
same day as Visit 10 visit, they should wait for blood collections before administration of morning dose at the site. Subjects will not take evening dose on Day 42. 
h.
MRI-PDFF will be obtained only for those subjects who receive at least 4 weeks of double-blind IP ie for subjects who drop out after Visit 9.  
i.
Includes arm and waist circumference, and height at Visit 1 only; targeted PE at Visit 4, Visit 6, Visit 10, Visit 11 and Early Termination; limited PE for follow-up on open 
AEs/abnormal tests, at investigator discretion.
j.
Visit 4 and Visit 5 reflect single-blind placebo regimen; from Visit 6 onwards, reflects double-blind randomized regimen.
k.
Administration of single or double-blind IP is twice daily; administration of witnessed dosing at site is on the mornings of Visit 4 for single-blind IP and on the mornings of 
Visit 6, Visit 7, Visit 8, Visit 9, and Visit 10 for double-blind IP, with meal.  On these visits, evening dose to be administered as outpatient, with evening meal, except for 
Visit 10 for which, subjects will not take evening dose.
l.
Review of Cystatin C results not required for dosing or discharge.
o.
If not collected on the designated collection day, collect at the next available time point when bio-specimens are being collected in conjunction with a subject visit.
p.
A dipstick, provided by Sponsor-identified central lab, will be used.
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1. INTRODUCTION
The dual acetyl-CoA (coenzyme A) carboxylase 1 and 2 (ACC1/2) inhibitor PF-05221304 
and the diacylglycerol acyltransferase 2 (DGAT2) inhibitor PF-06865571 are each currently 
in clinical development as monotherapy agents for the treatment of non-alcoholic 
steatohepatitis (NASH) with liver fibrosis.  Nevertheless, as exemplified by other metabolic 
disorders (eg, type 2 diabetes, dyslipidemias, etc), it is possible that a single drug may be 
insufficient to successfully treat NASH and therefore, combination therapy is being 
considered as an early intervention strategy.  Inhibition of ACC1/2 by PF-05221304 and 
inhibition of DGAT2 by PF-06865571 are anticipated to modulate lipid metabolism in 
distinct and complementary ways, suggesting that co-administration of the two 
investigational agents may lead to greater efficacy than either agent administered alone.
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual acetyl-CoA 
(coenzyme A) carboxylase 1 and 2 (ACC1/2) inhibitor (ACCi) designed to have asymmetric 
distribution to the liver, with 100 fold asymmetric hepatic distribution demonstrated in both 
rats and monkeys.  ACC inhibition stimulates fatty acid oxidation, suppresses hepatic 
de novo lipogenesis (DNL), and reduces steatosis in animal models1 and in humans.2  As a 
result of its asymmetric distribution favoring the liver, 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 study in healthy adult subjects.  This inhibition of hepatic DNL is postulated to 
result in a decrease and normalization of the excessive DNL observed in non-alcoholic fatty 
liver disease (NAFLD), and consequently reduce fat accumulation in the liver.  Emerging 
data also suggest that suppression of DNL through reduction in ACC activity restrains the 
formation of the inflammatory interleukin-17 secreting T cells of the T helper 17 lineage 
(Th17) cells which in turn promotes the development of anti-inflammatory Foxp3(+) 
regulatory T (Treg) cells.3  Based on these observations, it is hypothesized that ACC1/2 
inhibition by PF-05221304 may lead concurrently to reductions in liver fat content and
anti-inflammatory effects, thus mitigating two key pathophysiologic drivers of NAFLD. 
PF-06865571 is an oral, small molecule diacylglycerol acyltransferase 2 (DGAT2) inhibitor 
that is postulated to decrease hepatic triglyceride (TG) synthesis and hepatic lipid burden in 
NAFLD and NASH.  Diacylglycerol acyltransferases (DGATs) catalyze the terminal step in 
TG synthesis; specifically, the esterification of a fatty acid with diacylglycerol (DAG) 
resulting in the formation of TG.4  In mammals, two structurally unrelated DGAT enzymes 
(DGAT1 and DGAT2) have been characterized.  DGAT1 is highly expressed in the intestine 
and plays a central role in fat absorption.5  DGAT2 is highly expressed in the liver and 
adipose tissue.6  In preclinical models, blockade of hepatic DGAT2 using antisense 
oligonucleotides results in both down-regulation of the expression of multiple genes 
encoding proteins involved in lipogenesis and parallel induction in oxidative pathways.7,8  
The net result of these changes is a decrease in the levels of hepatic DAG and TG lipid 
which, in turn, reduces hepatocyte lipid burden and decreases hepatic very low density 
lipoprotein (VLDL) TG secretion.8,9


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The purpose of this study is to assess if the liver fat lowering effect of co-administration of 
PF-05221304 and PF-06865571 is greater than the effect of PF-05221304 or PF-06865571, 
when administered alone.  The study will also assess the safety and tolerability of 
co-administration of PF-05221304 and PF-06865571 and effects on selected 
pharmacodynamics/exploratory parameters eg triglycerides, in subjects with NAFLD. 
1.1. Mechanism of Action/Indication
PF-05221304 is a potent, selective, orally bioavailable, and reversible dual ACC1/2 small 
molecule inhibitor, designed to have asymmetric distribution to the liver.  It is being 
developed for the treatment of NASH with fibrosis.
PF-06865571 is an oral, small molecule DGAT2 inhibitor that is currently being developed 
for the treatment of NASH with fibrosis.
1.2. Background and Rationale
The World Health Organization lists NAFLD and NASH as the most important conditions 
contributing to the global health burden due to liver diseases, with NASH acknowledged as a 
potentially fatal condition leading to cirrhosis, liver failure, and hepatocellular carcinoma 
(HCC).10 NASH is a clinical and histological subset of NAFLD (defined as presence of 
5% hepatic steatosis in the absence of other liver disease etiologies) that is associated with 
increased all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular 
mortality, and increased incidence of both liver related and non-liver related cancers.11  It is 
diagnosed clinically by liver biopsy demonstrating steatosis, inflammation, and cytological 
ballooning of liver hepatocytes, often with varying degrees of fibrosis.  NASH progresses 
with increasing severity of fibrosis, with cirrhosis developing in a subset of patients11 and a
common complication of cirrhosis being HCC.12
In a recent meta-analysis, the global prevalence of NAFLD was estimated at 25%, with the 
prevalence of NASH in the subset with biopsy-proven NAFLD assessed at 59%.13  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.14  Patients with NASH may be 
asymptomatic or have non-specific symptoms such as fatigue, despite having significant 
disease on liver biopsy and associated risk for progression to cirrhosis and liver-related 
mortality.  The 5-year (67%) and 10-year (38%) survival rates in patients with NASH is 
significantly different than in those with NAFLD.10 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.13  


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Elevated rates of hepatic DNL have been reported to be a distinctive characteristic of 
NAFLD.15 Human subjects with elevated liver fat showed a more than 3-fold increase in the 
rate of hepatic DNL relative to subjects with normal liver fat, but no differences between the 
groups were detected in adipose free fatty acid (FFA) flux or in production of VLDL from 
FFAs. 
As described above, inhibition of ACC1/2 by PF-05221304 and inhibition of DGAT2 by 
PF-06865571 are anticipated to modulate lipid metabolism in distinct and complementary 
ways, suggesting that co-administration of both agents may provide greater efficacy than 
either agent alone.
1.3. Background Information for PF-05221304
1.3.1. Nonclinical Experience with PF-05221304
PF-05221304 has been orally administered once-daily for up to 16 weeks in toxicity studies 
conducted in rats and monkeys.  In addition, PF-05221304 has been evaluated in genetic 
toxicity studies, central nervous system (CNS) and cardiovascular safety pharmacology
studies, dose range-finding and definitive embryo-fetal development (EFD) studies in rats 
and rabbits, fertility and early embryonic study in rats, and in vitro and in vivo phototoxicity 
studies.  The no observed adverse effect level (NOAEL) in the 16-week study in rats was 
15 mg/kg/day (in males) and 5 mg/kg/day (in females).  These doses were associated with 
total maximum plasma concentration (Cmax) of 6300 ng/mL (247 ng/mL, unbound) and total 
area-under-the-curve over dosing interval of 24-hours (AUC24) of 40,300 ng•h/mL 
(1580 ng•h/mL, unbound) and total Cmax of 1250 ng/mL (49 ng/mL, unbound) and AUC24 of 
10,100 ng•h/mL (396 ng•h/mL, unbound) for males and females, respectively.  The NOAEL 
in the 16-week study in monkeys was 30 mg/kg/day for both sexes with associated total Cmax
of 30,600 ng/mL (293 ng/mL, unbound) and total AUC24 of 218,000 ng•h/mL 
(2080 ng•h/mL, unbound). 
In the rat CNS Safety Pharmacology study, higher numbers of vertical movements were 
noted in all dose groups (in a non-dose-dependent manner) compared with control animals.  
There were no other findings noted in that study on other measures of CNS activity 
(horizontal movements and functional observational battery), and there were no CNS-related 
findings in monkey or rat toxicology studies of up to 16 weeks in duration.  From the above, 
it is suggested that these findings are not likely to lead to adverse events of concern in 
clinical trials.
Based on the nonclinical toxicity studies conducted, the kidney is considered a potential 
target based on moderate degeneration/regeneration of renal tubules in a single female 
monkey at 90 mg/kg/day in the 2 week toxicity study in monkeys with the finding associated 
with minimal increase in blood urea nitrogen (BUN); however, these findings were not seen 
in the 16 week toxicity study in monkeys at the same dose (90 mg/kg/day).  Additionally, 
observed adverse microscopic findings in the lung, skin, nonglandular gastric mucosa (rats) 
and non-adverse findings in the Harderian (rats) and Meibomian glands (monkeys), and in 
platelet production (monkeys), were likely the result of exaggerated pharmacology and fatty 
acid deficiency. 


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In embryo-fetal development (EFD) studies, PF-05221304 resulted in fetal skeletal variations 
(rats and rabbits) plus fetal external and skeletal malformations (rabbits).  In a fertility and 
early embryonic study in rats, all mating and fertility parameters were similar for dose groups 
up to the highest dose of 30 mg/kg/day, and there were no effects on estrous cycling or 
ovarian or uterine parameters in females, although female rats had lower weight gain before 
mating and during gestation, which was considered adverse.  There were no effects on early 
embryonic survival, or reproductive organ weights or sperm parameters in the males. 
In a phototoxicity study in pigmented rats, there were no clinical signs or skin reactions 
indicative of phototoxicity in the pigmented or non-pigmented skin sites; as well as no 
changes in ophthalmology parameters or light microscopic findings in the eye (cornea, lens, 
and retina), at all of the PF-05221304 doses tested.
1.3.2. Clinical Experience with PF-05221304 
As of issuance of this protocol, a single clinical study (C1171001) has been completed with 
PF-05221304.  Four additional studies are ongoing: a 16-week clinical study (C1171002) in 
subjects with NAFLD, a single dose study evaluating the effect of hepatic impairment on 
pharmacokinetics (PK) (C1171006), a single dose absorption, metabolism and excretion 
study (C1171010) and a fixed sequence combination study to evaluate pharmacokinetic 
drug-drug interaction between PF-05221304 and PF-06865571 in healthy subjects 
(C3711002; Section 1.5.2).  In C1171001, a total of 96 (93 male and 3 female) healthy adult 
subjects were randomized.  Overall, 82 subjects (85%) were 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.  Single oral doses (from 1 mg to 240 mg) and repeated total daily doses 
(from 2 mg/day to 200 mg/day administered once-daily or every 12 hours) 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 pharmacokinetic (PK) stopping limit was achieved (single 
dose) or near complete inhibition of hepatic DNL was observed (with repeated dosing 
regimens evaluated). 
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 every 12 hours (Q12hr) (200 mg/day), the highest repeated dose evaluated.  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.


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Upon single dose administration, the only TEAE reported by more than 1 subject was upper 
respiratory tract infection (1 subject while on placebo and 2 subjects while receiving 
100 mg).  Furthermore, with repeated dosing, the only TEAE reported by more than 
2 subjects exposed to PF-05221304, across the entire dose range evaluated, was headache.  
All TEAEs were self-limiting requiring isolated use of concomitant medications and/or 
non-drug treatments to manage them.
Across the other safety-related data collected, drug-related, laboratory parameter changes 
were observed although none were remarkable following single dose administration of 
PF-05221304.  Upon repeated dose administration of PF-05221304, identified adverse drug 
reactions (ADRs) included elevation in blood triglycerides and reduction of platelet count.  
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 
steady-state, the increase in mean fasting serum triglycerides (placebo-adjusted change from 
baseline) ranged from 35%-50% at doses 40 mg/day; while increases in weighted-mean 
(AUC24/24) serum triglycerides (placebo-adjusted change from baseline) ranged from 
20%-60%, at these same doses.  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.  These ADRs have 
not been observed with administration of single oral doses as high as 240 mg.  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.  Following single oral doses, the plasma PK parameters showed 
low-to-moderate variability with % Coefficient of Variation (CV) for AUCinf ranged from 
16% to 36% and from 17 to 25% for Cmax.  Following single and multiple oral doses, mean 
apparent clearance (CL/F) ranged from 15 to 26 mL/min and mean volume of distribution 
(Vz/F) ranged from 20 to 31 L.  PF-05221304 has been determined to be highly bound to 
plasma protein in humans.  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. 
Preliminary assessment of circulating metabolites suggests no concern of metabolites 
reaching exposures where Metabolites in Safety Testing (MIST) criteria need to be 
considered.


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1.4. Background Information for PF-06865571
1.4.1. Nonclinical Experience with PF-06865571
PF-06865571 was evaluated in vitro and in vivo in genetic toxicity studies and safety 
pharmacology studies, in vivo in oral repeat-dose rat and monkey toxicity studies up to 
6 weeks duration, and in an in vitro phototoxicity assessment.  PF-06865571 was not 
mutagenic or clastogenic in in vitro studies and was negative in in vivo rat micronucleus 
studies.  No significant findings were noted in safety pharmacology in vitro or in vivo in 
neuro-pulmonary and cardiovascular studies in rats and monkeys, respectively.  No adverse 
toxicity and no target organs or systems were identified in Wistar Han rats or cynomolgus 
monkeys following single or repeat doses (up to 6 weeks) of PF-06865571 via oral gavage 
administration at doses up to 1000 (500 twice daily [BID]) mg/kg/day.  These were 
maximum feasible doses based on dose volume and formulation limitations.  PF-06865571 
did not demonstrate phototoxic potential in the neutral red uptake phototoxicity assay in 
mouse fibroblasts.  At this time, it is not known whether PF-06865571 can cause fetal harm 
when administered to pregnant women.  Animal reproductive studies have not been 
conducted with PF-06865571.  It is also not known whether PF-06865571 can affect male or 
female fertility, or whether PF-06865571 is secreted in human milk. 
The NOAELs in the 6-week studies were the highest dose levels tested, 1000 (500 BID) 
mg/kg/day with associated unbound Cmax and area under the curve over 24 hours (AUC24) of 
2450/7880 ng/mL and 25300/103000 ng•h/mL (males/females), respectively, in rats, and 
4790 ng/mL and 56900 ng•h/mL, respectively, in monkeys.  After correction for species 
differences in protein binding, the stopping criteria in humans are set to a Cmax of 
6940 ng/mL and AUC24 of 71670 ng•h/mL (ie, NOAEL exposures observed in rats). 
1.4.2. Clinical Experience with PF-06865571
As of issuance of this protocol, three clinical studies have completed dosing with 
PF-06865571: C2541001, C2541002, and C2541003.  C2541001 was the first study in 
which PF-06865571 was administered to human subjects and was an investigator- and 
subject-blind, sponsor-open, randomized, placebo-controlled, single ascending, oral dose, 
2-cohort, interleaving design with placebo substitution, 4-period crossover study in which 
17 healthy adult subjects were exposed to at least one dose of PF-06865571 ranging from 
5 mg to 1500 mg.  C2541002 was the first clinical trial designed to administer repeated (up to 
14 days) oral doses of PF-06865571 in the fed state to human subjects.  In C2541003, 
PF-06865571 pharmacokinetics (PK) of immediate release (IR) and modified release (MR) 
tablets of PF-06865571 was being compared to IR oral suspension under fed conditions.  
C2541005 is ongoing and is a Phase 1b, randomized double-blind (sponsor-open), 
placebo-controlled parallel group study designed to assess the safety, tolerability 
pharmacodynamics and pharmacokinetics of multiple oral doses of PF-06865571 for 2 weeks 
in adults with NAFLD. 
In C2541001, PF-06865571 was administered as an immediate release suspension.  PK data 
for 7 dose levels ranging from 5 mg to 1500 mg are presented below in Table 2.
PF-06865571 was well tolerated with an acceptable safety profile, and there were no serious 
adverse events (SAEs) reported.  A total of 16 adverse events (AEs) which were deemed 


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mild, were reported in C2541001, for subjects receiving active drug or placebo.  No 
clinically significant trends in safety laboratory parameters, creatinine levels, ECGs, and vital 
signs were observed over the range of doses administered in C2541001.  The maximum 
tolerated dose was not identified. 
Following administration of single oral doses of PF-06865571 under fed conditions, median 
time for Cmax (Tmax) ranged from 1.5 to 4 hours across the dose groups.  Approximate 
dose-proportional increases in Cmax and AUC24 were observed between the 5 mg and 
1500 mg doses.  Under fed conditions, the mean terminal t½ ranged from 1.5 to 5.2 hours.  At 
the 1000 mg dose level, exposures under fasted condition were approximately 2-fold lower 
than those in the fed state.  Median PF-06865571 Tmax occurred earlier in the fasted state, 
compared to dosing under fed conditions (1 hour versus 4 hours).  In addition, the terminal 
elimination half-life (t½) under fasted conditions was more variable than under fed 
conditions.
Table 2.
Summary of Plasma PF-06865571 PK Parameters Following Single Oral 
Doses in C2541001
Parameter Summary Statisticsa for PF-06865571 by Treatment
Parameter 
(units)
5 mg
Fed
15 mg
Fed
50 mg
Fed
150 mg
Fed
500 mg
Fed
1000 mg
Fed
1500 mg
Fed
1000 mg
Fasted
N
6
6
6
5
6
6
5
6
AUCinf
(ng•hr/mL)
64.69
(20)
281.7
(31)
742.3
(21)
3354
(29)
9738
(21)
33160 
(25)
39040 (17)
20120 (13)
AUClast
(ng•hr/mL)
63.92 (21)
279.3
(30)
738.3
(21)
3354
(29)
9736
(21)
33120 (25)
38970 (17)
19470 (11)
Cmax
(ng/mL)
17.87 (25)
73.01
(27)
193.2
(29)
785.7
(30)
1820
(26)
5257
(24)
5356
(19)
3470
(20)
Tmax
(hr)
2.00 
(0.500-4.00)
1.50 
(0.500-3.00)
2.00 
(1.00-4.00)
3.00 
(2.00-4.00)
3.00 
(2.00-4.00)
4.00 
(3.00-6.00)
4.00 
(3.00-6.00)
1.00 
(1.00-2.02)
t½
(hr)
1.450 
0.222
1.638 
0.129
1.630 
0.552
2.552 
0.401
3.365 
1.126
4.693 
1.681
5.220 
3.137
10.32 
6.95
Abbreviations: %CV = percent coefficient of variation; hr = hour; N = number of subjects in the treatment group and 
contributing to summary statistics; PK = pharmacokinetic(s); SD = standard deviation.
a.
Geometric mean (geometric %CV) for all except: median (range) for Tmax and arithmetic mean SD for t1/2.
Clinical data from the C2541002 study are available. Following 14 days of dosing of 
PF-06865571 up to 600 mg every 8 hours (Q8hr) or placebo to healthy subjects (n=60), there 
were a total of 112 AEs, a majority (103/112) of which were mild in intensity.  Of the AEs of 
moderate intensity, 2 AEs were due to venipuncture, and other moderate AEs were isolated 
occurrences and included nausea, vomiting, headache, penile discharge, generalized pruritus
without visible skin changes and presence of white blood cells in the urine.  There was no 
evidence of increasing incidence or severity of AE with increasing dose.


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There was one serious adverse event (SAE) in C2541002.  One subject who was assigned to 
receive 600 mg PF-06865571 Q8hr in Cohort 4 was noted to have atrial fibrillation detected 
by ECG on Day 7.  This episode of atrial fibrillation was not associated with any symptoms 
or adverse changes in blood pressure and resolved spontaneously within 24 hours.  This 
episode prompted a brief hospitalization for less than 24 hours and was determined to be a 
SAE, and the subject discontinued dosing on Day 7.  The investigator considered the event to 
be possibly related to study treatment, and the subject was withdrawn from the study.  
Dosing for the remainder of subjects in this cohort was halted on Day 8, per protocol.  After 
investigator and Sponsor’s review of clinical data, dosing was resumed in a subsequent 
cohort (Cohort 5) at 400 mg Q8hr for 14 days.  After review of the clinical data of Cohort 5, 
Cohort 6 was administered 600 mg Q8hr for 14 days.  This cohort completed dosing for the 
planned period of 14 days.
No clinically-significant trends in safety laboratory parameters, ECGs, or vital signs have 
been observed in clinical studies to date.  However, preliminary data indicate that creatinine 
levels increased slightly with dose.  At doses of 100 mg Q8hr and above, median creatinine 
levels increased by approximately 0.15 to 0.2 mg/dL compared to baseline, but returned to 
baseline levels at follow-up.  The organic cation transporter 2 (OCT2) and/or multi-drug and 
toxin extrusion protein (MATE) inhibition by DGAT2 has been shown to affect creatinine 
levels.16 Therefore, these changes are not necessarily reflective of changes in glomerular 
filtration rate (GFR) and instead may be due to OCT2 and/or MATE inhibition.  Cystatin C 
levels, a marker of kidney function whose levels are not affected by OCT2/MATE inhibition, 
were measured in C2541002 and review of these data demonstrated no clear changes. 
Based on overall AE and safety laboratory assessment, PF-06865571 was generally safe and 
well tolerated at the doses tested in study C2541002.
Steady state (Day 14) PK revealed an approximately dose proportional increase in 
PF-06865571 exposure.  Steady state appeared to be attained by Day 1 due to the short 
elimination half-life.  The median peak to trough ratio (PTR) was approximately 10-fold 
across the cohorts.  A summary of multiple-dose PK data in C2541002 is presented in 
Table 3.  Less than 2% of the total dose was eliminated renally across the dose range 
evaluated.
Table 3.
Summary of Preliminary Steady State (Day 14) Plasma PF-06865571 PK 
Parameters Following Multiple Oral Doses in C2541002
Parameter (units)
30 mg Q8hr
100 mg Q8hr
240 mg Q8hr
400 mg Q8hr
600 mg Q8hr
Cmax (ng/mL)
171.5 (38)
665.6 (43)
1520 (29)
2598 (22)
3527 (36)
Tmax (hr)
2.03 (1-3.02)
2.01 (1-3)
2.5 (1-3)
2 (2-3)
3.0 (1.05-4)
AUCtau (ng•hr/mL)
652.5 (36)
2619 (47)
5717 (32)
10,830 (15)
17010 (38)
t1/2 (hr)
3.294 (46)
4.365 (48)
4.096 (13)
3.840 (27)
6.916 (33)
PTR
10.85 (58)
10.15 (62)
9.693 (65)
8.988 (53)
5.178 (49)
Geometric mean (%CV) for Cmax and AUC.  Median (range) for Tmax and arithmetic mean (%CV) for t1/2; NA- not 
available; All values reported as below limit of detection (BLQ) have been replaced with zero for all calculations.


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Biomarker data used to assess potential for cytochrome P450 (CYP)3A induction (plasma 
4-hydroxycholesterol/cholesterol and urinary 6-hydroxycortisol/cortisol ratios) indicate no 
clinically meaningful changes from baseline relative to placebo.  Additionally, PF-06865571 
Day 14 exposure was approximately dose proportional in C2541002, indicating no 
auto-induction of metabolism of PF-06865571 with multiple oral doses.  Together, these data 
suggest that PF-06865571 is not a clinically meaningful inducer of CYP3A.
In addition, the potential of PF-06865571 to inhibit OCT2/MATE was assessed in C2541002 
by evaluation of renal clearance of N-methylnicotinamide (NMN), an endogenous substrate 
for OCT2 and MATE transporters.  PF-06865571 doses of 400 mg and 600 mg Q8hr, but not 
lower doses, appeared to have numerically greater reductions from baseline in renal 
clearance of NMN compared with placebo suggesting potential inhibition of OCT2/MATE 
transporters. These changes are consistent with the in vitro data indicating that PF-06865571 
may be an OCT2/MATE1 inhibitor.
Study C2541003 was a Phase 1, open-label study in healthy subjects to investigate the PK of 
PF-06865571 following single oral administration of IR and MR tablets compared to oral 
suspension under fed conditions.  A single oral dose of 150 mg PF-06865571 was 
administered as IR suspension, IR tablets, and slow and fast release MR tablets under fed 
conditions in order to mimic the anticipated conditions of actual clinical use.  In this study, 
PF-06865571 demonstrated an acceptable safety and tolerability profile.  PF-06865571 Cmax
and AUC values from IR suspension and tablets were similar to each other and met the 
bioequivalence (BE) criteria.
1.5. Background Information on PF-05221304 and PF-06865571 Combination
1.5.1. Non-Clinical Experience with Combination of PF-05221304 and PF-06865571 
Platelet lowering is thought to be a class effect of ACC inhibition resulting from significant 
inhibition of DNL in the bone marrow leading to impaired megakaryocyte (MK) maturation. 
Consistent with this information, reductions in platelets have been observed as a non-adverse 
event in monkeys with PF-05221304.  However, reductions in platelet counts were not 
observed in cynomolgus monkey toxicology studies with the DGAT2 inhibitor PF-06865571, 
or in clinical studies with that compound.  Monkeys were selected for combination toxicity 
testing because monkeys are sensitive to the effects of PF-05221304 on platelets, whereas, 
rats are not.  In addition, monkeys are also a relevant species to test any impact of DGAT2 
inhibition on PF-05221304 platelet lowering. 
A pivotal 6-week repeat-dose toxicity study was conducted in cynomolgus monkeys with 
PF-05221304 and PF-06865571, alone and in combination.  In this study, monkeys were 
administered 30 or 60 QD (quodque die, (once daily)) mg/kg/day PF-05221304 alone, 30 or 
60 (QD) mg/kg/day PF-05221304 in combination with 300 (150 BID) mg/kg/day 
PF-06865571, or 300 (150 BID) mg/kg/day PF-06865571 alone.  Test-article-related findings 
in the 60 (QD) mg/kg/day PF-05221304 alone and 60 (QD) mg/kg/day PF-05221304 in 
combination with 300 (150 BID) mg/kg/day PF-06865571 consisted of adverse body weight 


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loss and dehydration, and non-adverse changes in hematology and clinical chemistry 
parameters. 
Co-administration of 300 (150 BID) mg/kg/day PF-06865571 did not alter the toxicity 
associated with 60 (QD) mg/kg/day PF-05221304.  The toxicokinetics of PF-06865571 and 
PF-05221304 were not affected by co-administration.  The oral administration of up to 
60 (QD) mg/kg/day PF-05221304 and/or 300 (150 BID) mg/kg/day PF-06865571 alone or in 
combination to cynomolgus monkeys for 6 weeks did not result in mortality or any test 
article-related changes in mean body weights or mean body weight changes, ECG 
parameters, mean organ weight ratios, coagulation or urinalysis test results, and no test 
article-related macroscopic or microscopic observations were noted.  The few test 
article-related clinical pathology findings noted on Day 43 were all considered non-adverse 
due to their small magnitude and lack of correlative clinical or microscopic findings. The 
non-adverse test article-related hematology finding was mildly to moderately decreased 
platelet count (0.37x-0.55x baseline) in 1 male and 1 female administered 
60 (QD) mg/kg/day PF-05221304 alone and 1 male (Animal P0503) administered 
60 (QD) mg/kg/day PF-05221304 with 300 (150 BID) mg/kg/day PF-06865571.  The 
non-adverse, test article-related clinical chemistry findings were minimally decreased 
albumin (0.81x-0.85x baseline) in animals administered 60 (QD) mg/kg/day PF-05221304 
alone or with 300 (150 BID) mg/kg/day PF-06865571 and mildly decreased cholesterol 
(0.55x-0.61x baseline) in animals administered 30 (QD) or 60 (QD) mg/kg/day PF-05221304 
with 300 (150 BID) mg/kg/day PF-06865571. 
In monkeys, doses of 30 (QD) mg/kg/day PF-05221304 and 300 (150 BID) mg/kg/day 
PF-06885571, alone or in combination, were considered the no observed adverse effect levels 
(NOAEL) for each respective and combined test articles based on a lack of adverse findings.  
The anticipated exposures of PF-05221304 at 15 mg BID in this study are 122-fold and 
29-fold lower (Cmax and AUC24, respectively) than the NOAEL (30 mg/kg (QD) 
PF-05221304 + 300 mg/kg (BID) PF-06865571) in the 6-week combination toxicology study 
in monkeys.  Similarly, the anticipated exposures of PF-06865571 at 300 mg BID in this 
study are 3.7 and 6.2-fold lower than the 6-week monkey NOAEL.  The dose of 
60 (QD) mg/kg/day PF-05221304, alone or with 300 (150 BID) mg/kg/day PF-06865571, 
was adverse due to the severity of body weight loss and/or dehydration with concomitant 
fecal abnormalities for 1 male in each group that required supportive fluid therapy and dose 
suspension for 1 male. 
1.5.2. Clinical Experience with Combination of PF-05221304 and PF-06865571
At the issuance of this protocol, C3711002, the first clinical study testing co-administration 
of PF-05221304 and PF-06865571, is underway.  C3711002 is designed as a Phase 1, open 
label, multiple dose, 2-cohort, non-randomized, fixed-sequence study to evaluate the 
pharmacokinetic drug-drug interaction (DDI) between PF-05221304 and PF-06865571, and 
safety and tolerability of in healthy adult subjects.  Each of the Investigational Products (IPs)
is being administered orally twice daily. 


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A total of 16 subjects were enrolled in this study (N=7 in Cohort 1, N=9 in Cohort 2).  In 
Cohort 1, subjects received PF-05221304 15 mg Q12hr (every 12 hours) on Days 1-7 and 
PF-05221304 15 mg Q12hr plus PF-06865571 300 mg Q12hr on Days 8-13.  On Day 14, 
subjects received PF-05221304 15 mg plus PF-06865571 300 mg once (AM only).  In 
Cohort 2, subjects received PF-06865571 300 mg Q12hr on Days 1-7 and PF-05221304 
15 mg Q12hr plus PF-06865571 300 mg Q12hr on Days 8-13.  On Day 14, subjects received 
PF-05221304 15 mg plus PF-06865571 300 mg once (AM only).  All doses in this study 
were administered with food.  Pharmacokinetic parameters were compared on Day 14 
(combination) versus Day 7 (each agent administered alone).  Additionally, safety and 
tolerability were assessed for each subject.  C3711002’s dosing period is completed and a 
summary of the available preliminary data is provided below. 
Safety Summary
In Cohort 1, after 7 days of dosing PF-05221304, followed by 7 days of combined dosing of 
PF-05221304 and PF-06865571, a total of 9 AEs were reported in 5 subjects, with 6 AEs 
categorized as mild and 3 as moderate in severity. 
The 3 AEs of moderate severity were reported in one subject and corresponded to concurrent 
elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and 
gamma-glutamyl transferase (GGT).  The subject started the study with a minor elevation in 
baseline ALT (59 Units/Liter (U/L)).  Asymptomatic increases in ALT and AST were 
detected on scheduled safety labs on Day 7 while dosing PF-05221304 alone.  ALT peaked at 
187 U/L (3.8x upper limit of normal (ULN)) and AST peaked at 116 U/L (2.9x ULN) on 
Day 8, prompting precautionary discontinuation of the subject from the study on Day 9, after 
completing one full day of dosing of the PF-05221304 and PF-06865571 combination.  Total 
bilirubin and alkaline phosphatase remained normal.  Upon further review of the 
pre-randomization labs, it was found that the subject had high GGT at baseline (123 U/L; 
Normal Limit Range=0-73 U/L).  The subject’s liver function tests returned to baseline 
values on Day 22 of the study.  The subject remained asymptomatic throughout the entire 
period.
Preliminary analysis of safety laboratory data from Cohort 1 was notable for the following 
observations.  A mild elevation in ALT (~1.4x ULN) was observed in 2 other subjects on 
Day 7 of the monotherapy dosing period with PF-05221304.  In both cases ALT returned 
within normal range with continued dosing, which included completion of the 7-day period 
of combined dosing with PF-05221304 and PF-06865571.  These elevations were not 
considered as AEs.
Two subjects had increases in triglycerides exceeding ULN with peak values at Day 10 of 
212 mg/dL and 255 mg/dL respectively.  Both subjects trended down on Day 14, one subject 
with continued dosing. The second subject is the same one that was discontinued as a 
precautionary measure due to ALT elevation >3 x ULN (see above). 


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One subject with a baseline platelet count of 156,000/mm3 (lower limit of normal 
(LLN)=150,000/mm3) had platelet count dip slightly below normal with a nadir of 
138,000/mm3 and remained stable at approximately that level throughout the study.  Platelet 
values for all other subjects remained within normal limits. 
A slight trend for increase in serum creatinine was observed after Day 7, which remained 
stable at Day 14, returning towards baseline at follow-up.  All values remained within the 
normal range for the whole period of observation.  Cystatin C remained within the normal 
range with minor fluctuations during this period.  Thus, these observations are interpreted as 
consistent with an effect of PF-06865571 to inhibit OCT2/MATE and not necessarily 
reflective of changes in glomerular filtration rate or renal function.  No clinically significant 
trends in other safety laboratory parameters, ECGs or vital signs were observed in Cohort 1. 
In Cohort 2, after 7 days of dosing PF-06865571, followed by 7 days of combined dosing of 
PF-06865571 and PF-05221304, a total of 17 AEs were reported in 7 subjects, with 13 AEs 
categorized as mild and 4 as moderate in severity.  Two of the 4 moderate severity AEs 
corresponded to a concurrent episode of, respectively, nausea and vomiting in one subject.  
The other 2 moderate severity AEs corresponded to left back pain and headache in another 
subject.  All AEs resolved without sequelae. 
Preliminary analysis of safety laboratory data from Cohort 2 was notable for the following 
observations.  One subject had a mild elevation in ALT to 58 U/L (ULN<49 U/L), detected 
on scheduled safety laboratories in Day 7 while receiving PF-06865571.  ALT increased 
slowly with peak value of 99 U/L on Day 10, then decreasing towards baseline with 
continued dosing, which included completion of the 7-day period of combined dosing with 
PF-06865571 and PF-05221304.  ALT values reached baseline by Day 21. 
A slight trend for increase in creatinine was observed from baseline to Day 7 with dosing of 
PF-06865571 alone, with average increase in creatinine of approximately 0.05 mg/dL and 
remaining stable through the rest of the dosing period.  All creatinine values remained within 
normal limits and values were trending back to baseline by Day 22 (follow up visit).  
Cystatin C trended slightly up with all values remaining well within normal limits.  These 
observations are again interpreted as consistent with an effect of PF-06865571 to inhibit 
OCT2/MATE and not necessarily reflective of changes in glomerular filtration rate.  Three 
subjects in this cohort had increases in fasting triglycerides exceeding ULN with peak values 
at Day 14 of 166 mg/dL, 196 mg/dL and 223 mg/dL respectively.  All subjects trended down 
on Day 22 with continued dosing. 
No clinically significant trends in other safety laboratory parameters, ECGs or vital signs 
were observed in Cohort 2. 
No SAEs have been reported in the study, to date. 


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PK Summary
Preliminary PF-05221304 plasma PK parameters when administered alone (Day 7) or with 
PF-06865571 (Day 14) have been summarized below in Table 4.  PF-05221304 AUC12 was 
modestly lower (~19%) when administered with PF-06865571 versus alone.
Table 4.
PF-05221304 PK Parameters following Administration of PF-05221304 
Alone (15 mg BID) or with PF-06865571 (300 mg BID) in C3711002
Parameter (units)
PF-05221304 
Alone (Day 7)
PF-05221304 + 
PF-06865571 (Day 14)
GMR (90%CI)
AUCtau (ng•hr/mL)
12130.35 (25.80%)
9482.76 (23.03%)
0.81(0.74,0.88)
Cmax (ng/mL)
1337.03 (25.08%)
1128.14 (19.94%)
0.88(0.80,0.98)
Tmax (hr)
4.00 (2.00-6.00)
2.00 (1.50-4.00)
NA
Geometric mean (%CV) for Cmax and AUC.  Median (range) for Tmax; NA = not applicable; 
GMR=Geometric Mean Ratio (Day 14/Day 7); CI= confidence interval.
Preliminary PF-06865571 plasma PK parameters of administered alone (Day 7) or with 
PF-05221304 (Day 14) have been summarized in Table 5.  PF-06865571 pharmacokinetics 
are essentially unchanged when administered with PF-05221304 versus alone.
Table 5.
PF-06865571 PK Parameters following Administration of PF-06865571 
Alone (300 mg BID) or with PF 05221304 (15 mg BID) in C3711002
Parameter (units)
PF-06865571 
Alone (Day 7)
PF-06865571 + 
PF-05221304 (Day 14)
GMR (90%CI)
AUCtau (ng•hr/mL)
8716.33 (18.73%)
9436.24 (33.88%)
1.08(0.97,1.21)
Cmax (ng/mL)
2385.54 (9.56%)
2579.70 (20.71%)
1.08(0.98,1.19)
Tmax (hr)
2.00 (1.00-4.00)
2.00 (1.00-2.00)
NA
Geometric mean (%CV) for Cmax and AUC.  Median (range) for Tmax; NA = not applicable; 
GMR=Geometric Mean Ratio (Day 14/Day 7); CI= confidence interval; 
Additional information for PF-05221304 and PF-06865571 may be found in the single 
reference safety document (SRSD) for each compound, which are the Investigators’ 
Brochures (IBs) for PF-05221304 and PF-06865571, respectively. 
1.6. Study Rationale
The objective of this study is to assess the effect of PF-05221304 alone, PF-06865571 alone, 
the co-administration of PF-05221304 and PF-06865571, or placebo on whole liver fat in 
subjects with NAFLD.  In addition, this study will evaluate the safety and tolerability of 
co-administration of PF-05221304 and PF-06865571 along with the effects on selected 
pharmacodynamics (PD)/exploratory parameters, compared to administration of 
PF-05221304 alone, PF-06865571 alone, and placebo in adults with NAFLD.


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1.6.1. Design Rationale
To address the potential effect of PF-05221304 and PF-06865571 co-administration on liver 
fat, the eligible population for study enrollment is subjects with NAFLD, defined as having 
liver fat 8%, as assessed by magnetic resonance imaging-proton density fat fraction 
(MRI-PDFF) at Screening Visit 3.  In an effort to help identify these subjects, evidence of 
concomitant medical conditions known to predispose subjects to NAFLD, including features 
of metabolic syndrome or T2DM will be utilized.  FibroScanassessments will be done at 
Visit 1 (Screen 1) and Visit 2 (Screen 2) to help initially estimate liver fat using a more 
scalable and cost-efficient approach than MRI-PDFF.  Subjects who meet all eligibility 
criteria for the study during Screen 1 will proceed to Screen 2 for an additional liver fat 
approximation by FibroScan.  Two assessments using FibroScan will be used because of the 
variability in fat determination with Controlled Attenuation Parameter (CAP), measure of 
liver fat content.  These assessments will provide a more accurate initial estimate of liver fat 
prior to MRI-PDFF.  Subjects will then undergo liver fat assessment by MRI-PDFF
(Screen 3) for confirmatory purposes.
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.  
In order to limit measurement variability, the nominal time for FibroScanand MRI-PDFF 
assessments will be standardized.  Baseline assessments for MRI-PDFF and FibroScan
(Visits 5 and 6, respectively) should fall within a practical window (2 hours) relative to 
clock time of the initial screening visit for each assessment.  All post-randomization 
assessments for both MRI-PDFF and FibroScanshould occur within a practical window 
(2 hours) relative to clock time of the baseline visit for each assessment (ie, Visit 5 and 6, 
respectively).
A fixed, single-blind placebo run-in period of approximately 14 days (from Visit 4 to Visit 6) 
following confirmation of eligibility and prior to randomization is included to familiarize 
subjects with the study treatment regimen and to exclude subjects who are not compliant with 
single-blinded placebo administration prior to randomization at Visit 6.  To date, clinical 
experience with PF-05221304 and PF-06865571 co-administration is limited to a PK 
drug-drug interaction (DDI) study (C3711002) with a total of 1 week duration of combined 
drug exposure in an inpatient setting.  In this study, with longer and predominantly outpatient 
dosing in a patient population, close safety monitoring will be implemented with frequent 
(every 2 weeks) outpatient visits post randomization, including an additional, early visit at 
Day 5 (Visit 7). 
Total duration of PF-05221304 and PF-06865571 co-administration in this study will be 
approximately 6 weeks, supported by a completed 6-week non-clinical combination toxicity 
study in monkeys.  This duration is expected to allow assessment of effects of 
co-administration of PF-05221304 and PF-06865571 on liver fat content, as well as on safety 
and tolerability of these agents. 
In this study PF-05221304 and PF-06865571 co-administration will be required to occur 
twice daily with food (breakfast and dinner). 


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This study is designed to assess the effect of PF-05221304 and PF-06865571 on liver fat and 
other PD biomarkers that are intended to provide insight into metabolic pathways related to 
ACC and DGAT2 inhibition.  Specifically, the study will evaluate the effect of PF-05221304 
and PF-06865571 combination on liver fat and liver function [ie, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase and gamma-glutamyl 
transferase (GGT)], glycemic parameters, and fasting lipids including total cholesterol, 
low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) 
and triglycerides (TGs).  In addition, effect on other PD parameters [ie apolipoproteins A1, 
B (total), C3, 
, proprotein convertase subtilisin/kexin type 9 (PCSK9)
 
 and certain NASH-related biomarkers] will be 
assessed. 
 
 
 
 
 
 
 
Creatinine is actively secreted by OCT2/MATE in kidney.  In the setting of OCT2/MATE 
inhibition, serum creatinine levels have been reported to increase slightly.  In accordance 
with reported literature on OCT2/MATE inhibition, minor increases in serum creatinine have 
been observed in C2541002, a 2-week multiple dose ascending study for PF-06865571, with 
very limited change in cystatin.  In order to better assess renal function in the setting of 
possible PF-06865571-induced OCT2/MATE inhibition resulting in spurious serum 
creatinine increases, serum cystatin C will be assessed as part of the standard safety labs, in 
addition to serum creatinine, in order to accurately interpret potential changes in glomerular 
filtration rate (GFR).
Interim analysis (IA) may be performed [refer to Section 9.8] to permit a review of safety 
and pharmacodynamics of the population enrolled, amongst the planned activities. 
1.6.2. Rationale for Population Enrolled
The study population included in this study will be overweight or obese subjects (body mass 
index [BMI] ≥25 kg/m2) with clinical indicators of metabolic syndrome and/or T2DM. 
Although NAFLD is a condition with excessive fat accumulation in the liver defined as ≥5%, 
this study will enroll subjects with liver fat values ≥8% at screening to allow for potential 
measurement variability and help ensure baseline liver fat values are likely to be ≥5%.  As it 
is unknown whether subjects with lower versus higher baseline liver fat values may respond 
differently to therapy, subjects will be stratified at randomization (Visit 6) based on 
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MRI-PDFF (Screen 3) liver fat ranges of 8% to <15%; and 15% as a means of balancing 
liver fat content between dosing cohorts.  A second-tier stratification will also be applied at 
randomization based on the presence or absence of T2DM (refer to Section 4.3 for additional 
details regarding stratification).
T2DM subjects will be permitted to be on a stable dose of up to 1 acceptable oral drug for 
glycemic control.  These may include sulphonylureas, dipeptidyl peptidase-IV inhibitors 
(DPP-IVi) and meglitinides.  However, thiazolidinediones (TZDs), glucagon-like peptide-1 
receptor (GLP-1r) agonists and sodium-glucose co-transporter 2 (SGLT2) antagonists are not 
permitted given their reported anti-steatotic effect that may potentially confound the effect of 
study drugs on primary endpoint of this study.  Metformin is not permitted due to the 
potential risk for OCT2/MATE inhibition by PF-06865571 resulting in a drug-drug 
interaction (DDI) potentially increasing metformin exposure.  Refer to Section 5.8 for 
complete details regarding permitted and excluded concomitant medications.
Eligible women will be confirmed to be of non-childbearing potential since at the present 
time embryo-fetal developmental toxicology studies with PF-06865571 have not yet been 
conducted and exposure to PF-05221304 in embryo-fetal developmental toxicology studies 
has been shown to result in fetal skeletal variations (rats and rabbits) plus fetal external and 
skeletal malformations (rabbits).  In eligible men, appropriate measures to minimize potential 
transfer of PF-05221304 or PF-06865571 via semen to a woman of childbearing potential are
expected to be followed [refer to Section 4.4.4]. 
1.6.3. Dose Rationale
This study is planned as a 2x2 factorial, 4-arm, parallel group study with 1 placebo arm, 
1 active dose arm of PF-05221304 (15 mg, Q12hr), 1 active dose arm of PF-06865571 
(300 mg, Q12hr) and 1 active dose arm for co-administration of PF-05221304 (15 mg, 
Q12hr) and PF-06865571 (300 mg, Q12hr).
The objective of this study is to assess the effect of PF-05221304 alone, PF-06865571 alone, 
the co-administration of PF-05221304 and PF-06865571, or placebo on whole liver fat in 
subjects with NAFLD.  Additionally, the study is designed to further characterize the safety 
and tolerability of PF-05221304 and PF-06865571 when co-administered versus each agent 
given alone.  Lastly, the ability of PF-06865571 to mitigate possible increases in plasma 
triglycerides that are associated with PF-05221304 dosing when high levels of hepatic DNL 
inhibition are achieved will be explored. 
As data are not available at this time regarding the effect of PF-06865571 on liver fat in 
patients with NAFLD, a dose was selected (300 mg BID) that is projected to achieve average 
daily concentration 4-fold higher than the projected unbound human efficacious 
concentration (Ceff) [120 nM (48.9 ng/mL)].  This dose is also the highest dose being 
examined in an ongoing 2-week study assessing the effect of PF-06865571 on liver TG in 
subjects with elevations in liver fat.  A total daily dose 2 fold higher than the PF-06865571 
dose proposed for this study has been well tolerated with an acceptable safety profile in the 
multiple ascending dose study (C2541002).


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A dose of 15 mg BID was selected for PF-05221304 in this study.  Although PF-05221304 
has a pharmacokinetic half-life conducive to once daily dosing, a Q12hr dosing regimen was 
selected to match the profile of a combination product (Q12hr dosing likely needed due to 
short half-life of PF-06865571).  The 15 mg Q12hr dose is expected to yield similar average 
daily hepatic de novo lipogenesis inhibition (88%) as the top dose of 50 mg QD in the 
ongoing 16 week Phase 2a study (C1171002) in subjects with elevated liver fat (90%).  The 
dose of 15 mg Q12hr is approximately 6 fold less than the highest dose tested in C1171001 
(100 mg Q12hr).
1.6.4. Rationale for Banked Biospecimen Collection
In this study, subject to regulatory and ethics approval/favorable opinion, an additional 
research component includes collection of blood for Prep D1.5, Prep B1.5, and Prep B2.5
(see Section 7.7) for possible exploratory analyses.  These retained pharmacogenomic and 
biomarker collections will be undertaken as a means to enable the exploration of the 
contribution of genomic and other biomarker variations to the observed variability in PK of, 
and for response to, PF-05221304 and PF-06865571 and wider research investigation, as 
permitted by subject consent.
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who 
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) makes it possible to better understand the 
investigational product’s (IP) mechanism of action and to seek explanations for differences 
in, for example, exposure, tolerability, safety, and/or efficacy not anticipated prior to the 
beginning of the study. 
Banked biospecimens retained in the BBS can also be used in research on non-alcoholic fatty 
liver disease or related metabolic disorders.
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s): 
Primary Endpoint(s): 
To determine the effect of co-administration of 
PF-05221304 and PF-06865571 on whole liver fat 
compared to placebo, PF-05221304 administered 
alone, and PF-06865571 administered alone in 
subjects with NAFLD.
Relative change from baseline in whole liver fat at 
Day 42, as assessed by magnetic resonance imaging 
proton density fat fraction (MRI-PDFF).
Secondary Objective(s): 
Secondary Endpoint(s): 
To evaluate safety and tolerability of PF-05221304 
and PF-06865571 co-administration compared to 
Assessment of treatment-emergent adverse events 
(and serious adverse events), clinical laboratory tests 


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placebo, PF-05221304 administered alone, and 
PF-06865571 administered alone in subjects with 
NAFLD.
including lipids, vital signs, and 12-lead 
electrocardiograms.
Tertiary/Exploratory Objective(s): 
Tertiary/Exploratory Endpoint(s): 
To evaluate the effect of co-administration of 
PF-05221304 and PF-06865571, on liver function 
tests (LFTs) compared to placebo, PF-05221304 
administered alone, and PF-06865571 administered 
alone in subjects with NAFLD.
Percent change from baseline at all time points for:
•
ALT, AST.
•
Alkaline Phosphatase.
•
Gamma-glutamyl transferase (GGT).
To evaluate effects of co-administration of 
PF-05221304 and PF-06865571 on lipids compared 
to placebo, PF-05221304 administered alone, and 
PF-06865571 administered alone in subjects with 
NAFLD.
Percent change from baseline at all time points for:
•
Triglycerides.
•
Total cholesterol, HDL-C, direct LDL-C, Total 
cholesterol/HDL-C ratio, and non-HDL-C.
 
 
 
 
 
 
 
 
 
 
To evaluate the PD effects of co-administration of 
PF-05221304 and PF-06865571 compared to 
placebo, PF-05221304 administered alone, and 
PF-06865571 administered alone, in adults with 
NAFLD.
Analyses for PD parameters: 
•
% Change from baseline to Day 42 in 
Apolipoproteins (A1, B100 and C3).
 
•
% Change from baseline to Day 42 in plasma 
PCSK9.
 
 
 
 
To collect banked biospecimen for exploratory
research, unless prohibited by local regulation or 
ethics committee decision.
Collection of banked bio-specimens unless prohibited 
by local regulations or ethics committee decision.  
Additional information on collection and potential 
use is provided in Section 7.7
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3. STUDY DESIGN
3.1. Study Overview
This is a randomized, double-blind (sponsor-open), placebo-controlled, 2x2 factorial, 4-arm 
(placebo, monotherapy of PF-05221304, monotherapy of PF-06865571 and combination of 
PF-05221304 and PF-06865571), parallel group study (Figure 1).
Figure 1.
C3711001 Study Design
Determination of eligibility for this study will occur via a sequential, 3-step process, starting 
at the first screening visit (Screen 1).  Subjects identified to be eligible based on Screen 1
AND Screen 2 procedures will proceed to Screen 3 to measure liver fat by MRI-PDFF.  For a 
given subject, this 3-step eligibility assessment may take up to 6 weeks.
Once confirmed to be eligible based on results of Screen 3, subjects will progress to a Run-in 
period (Visit 4), at which time subjects will receive single-blind placebo for approximately 
14 days to ensure compliance with the administration of IP.  Approximately 4 days prior to 
randomization, subjects will report to the imaging center (Visit 5) to have a baseline 
MRI-PDFF scan performed.  At Visit 6 (Day 1), subjects will be randomized to receive 1 of 
4 blinded IP regimens (placebo, PF-05221304 monotherapy, PF-06865571 monotherapy, or 
PF-05221304 plus PF-06865571 combination) for a duration of up to 6 weeks (ie, 42 days).  
This study includes a total of 11 scheduled outpatient visits to the study site, including 
4 visits to the imaging center, and a safety Follow-up telephone contact.  The total 
participation, from Visit 1 (Screen 1) to Follow-up telephone phone call will be up to 
approximately 19 weeks. 
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Approximately 98 subjects (14 for the placebo group, 28 for each of the monotherapy groups 
and 28 for the combination group) will be randomized at approximately 30 sites (refer to 
Section 9.1). 
Subjects who are noted to have non-evaluable baseline MRI-PDFF, as determined by the 
sponsor-identified central imaging vendor, should have their MRI-PDFF repeated once; if the 
images are still non-evaluable on single-repeat, the subject will be considered as screen 
failed; otherwise, there are no plans to replace subjects who are prematurely withdrawn.
3.2. Stopping Rules in Individual Subjects
At investigator discretion, for subjects’ safety, dosing with any of the double-blinded 
investigational product(s) (ie, post randomization), may be stopped in an individual 
subject-either temporarily or permanently.  Any treatment-related SAE will result in 
permanent discontinuation of the subject.  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.  Of 
note, subjects who meet threshold for withdrawal based on platelet count (see Appendix 3) or 
fasting serum triglycerides (see Appendix 4), should not be re-challenged with 
investigational product.  Additionally, a subject may not cross-over to another group, once 
randomized to a particular group.
An example where temporary discontinuation of dosing with investigational product(s) may 
be considered includes hospitalization with subsequent discharge within 7-days in stable 
medical condition, as determined by medically-qualified investigator.  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 Appendix 3 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 Appendix 4 for 
additional guidance.

Note: In both cases of pre-identified laboratory thresholds listed above, 
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. 


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3.3. Considerations for Pausing or Stopping Treatment Arm or Trial Based on 
Observed Safety
A monthly blinded safety review, including laboratory values, vital signs, adverse events and 
SAEs will be conducted throughout the study. When approximately 50% of the planned 
number of subjects are randomized, the subsequent monthly safety review will assess 
whether either of the below conditions are met.

More than 25% of subjects, develop a moderate or severe AE in the same system 
organ class (SOC); 

More than 25% of subjects meet the individual permanent discontinuation of dosing 
rules (Section 3.2).
If neither of these criteria is met the study will continue as planned, while continuing 
monthly blinded safety monitoring. If either criterion is met, an unblinded review by a 
pre-specified Internal Review Committee (IRC), independent from the study team, will be 
triggered. Based on their unblinded safety review the IRC will make a recommendation to 
the team to either continue the trial as designed, discontinue one or more of the active arms 
of the study, or stop the trial altogether.
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. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
3. Male subjects or female subjects of non-childbearing potential between the ages of 
18 and 70 years, inclusive, at Screen 1.


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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; status should be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
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. 
4. At Screen 1 (Visit 1), total body weight of >50 kg (110 lbs) and a BMI 25 kg/m2.
5. Subjects at Screen 1 (Visit 1), with a medical diagnosis of Type 2 Diabetes Mellitus 
(T2DM) being treated with no more than 1 acceptable oral antidiabetic drug (see
Section 5.8.1 for acceptable versus prohibited medications); 
OR
Subjects without a diagnosis of T2DM that meet 2 of the following 5 criteria 
commonly associated with metabolic syndrome:

Fasting Plasma Glucose (FPG) 100 mg/dL (5.6 mmol/L);

Documentation of at least stage 1 hypertension as demonstrated by a seated blood 
pressure (BP) 130/80 mmHg or medical history of hypertension actively treated 
with pharmacological agents;

Fasting serum HDL-C <40 mg/dL (1 mmol/L) for males and <50 mg/dL 
(1.3 mmol/L) for females, or on pharmacological agents with explicit purpose to 
increase HDL-C (refer to Section 5.8.3 for acceptable versus prohibited 
medications);

Fasting serum triglyceride (TG) 150 mg/dL (1.7 mmol/L), or on 
pharmacological agents with explicit purpose to decrease TG (refer to
Section 5.8.3 for acceptable versus prohibited medications);

Waist circumference 40 inches (102 cm) for males and 35 inches (89 cm) for 
females.

Note: 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.


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6. At Screen 1 (Visit 1), a CAP280 dB/m via FibroScanassessment.
7. At Screen 2 (Visit 2), a CAP280 dB/m via FibroScanassessment:

Note (for #6 and #7): if the CAPvalue is in the range of 260-279 dB/m during 
Screen 1 or Screen 2, the FibroScanassessment may be repeated on a different 
day following at least a 4-hour fast; thus 2 assessments (at least 1 of Screen 1 and 
repeat Screen 1, plus at least 1 of Screen 2 and repeat Screen 2) are required to be 
met above threshold before progressing to Screen 3.
8. At Screen 3 (Visit 3), liver fat 8% measured by MRI-PDFF acquisition protocol at 
the Sponsor-qualified Imaging facility, confirmed via a single repeat, if deemed 
necessary by the Sponsor-identified central imaging vendor.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included (or 
randomized) in the study:
1. Subjects with 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.
2. Subjects with any of the following clinical laboratory abnormalities at Screen 1
(Visit 1), as assessed by sponsor-identified central laboratory and confirmed by a 
single repeat, if deemed necessary:

Fasting TG >400 mg/dL;

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma 
glutamyl transferase (GGT) >2.0x upper limit of normal (ULN);

Hemoglobin A1c (HbA1c) >7.0%;

Fasting plasma glucose >270 mg/dL (15.0 mmol/L);

Total bilirubin >1.5x ULN with a direct bilirubin ULN;

Note: Subjects with a history of Gilbert syndrome will be eligible for this 
study provided direct bilirubin level is ULN plus ALT meets inclusion 
criteria and alkaline phosphatase, hemoglobin, and reticulocyte count are 
ULN.

Albumin < lower limit of normal (LLN);


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
Platelet count <0.95 x LLN;

International normalized ratio (INR) 1.3.

Note: For ALT, AST, total bilirubin and INR, laboratory values should not 
meet exclusion criteria at both Screen 1 and at Visit 4. 
3. A positive urine test for illicit drugs at Screen 1 (Visit 1), start of Run-in (Visit 4), or 
baseline (Visit 6).

Note: Subjects who have been medically prescribed opiates/opioids or 
benzodiazepines and report the use of these drugs to the investigator at Screen 1 
may be allowed to participate if approved by the sponsor.
4. History of regular alcohol consumption exceeding 14 drinks/week for female subjects 
or 21 drinks/week for male subjects (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 from Screen 1 (Visit 1).
5. At Screen 1 (Visit 1), seated systolic blood pressure (BP) 160 mmHg and/or 
diastolic BP 100 mmHg after 5 minutes of rest.

If needed, the BP may be repeated 2 more times and the average of the 3 BP 
values will be used to determine the subject’s eligibility.
6. At Screen 1 (Visit 1), supine 12-lead ECG demonstrating a corrected QT (QTcF) 
interval >450 msec or a QRS interval >120 msec.

If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be 
repeated 2 more times and the average of the 3 QTcF or QRS values should be 
used to determine the subject’s eligibility. 
7. At Screen 1 (Visit 1), subjects with an estimated GFR <60 mL/min/1.73m2 as 
calculated by the modification of diet in renal disease equation (MDRD), and 
confirmed via a single repeat, if necessary.
8. Evidence or diagnosis 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 prior to Screen 3, 
permitted to assess eligibility, if needed.

Hepatitis B virus (HBV), defined by presence of hepatitis B surface antigen 
(HepBsAg) or hepatitis B core Antibody (HepBcAb);

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb);


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
irrespective of HCV RNA (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;

History of esophageal varices, ascites, or hepatic encephalopathy;

Alcoholic liver disease;

Wilson’s disease, defined as ceruloplasmin level < LLN;

Known diagnosis of hemochromatosis;

-1-antitrypsin (A1AT) deficiency, defined as A1AT 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.
9. Subjects with any of the following medical conditions:

Any condition possibly affecting drug absorption (eg prior bariatric surgery, 
gastrectomy, ileal resection);

Diagnosis of type 1 diabetes mellitus;

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 of Screen 1;

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 or abdominal cavities such as 
pacemakers, defibrillators as these could interfere with the use of FibroScan.


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10. 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-PDFF obtained at Screen 3 (Visit 3), by the 
Sponsor-identified central imaging vendor or subjects meeting criteria for 
contraindication for MRI-PDFF, including the following:

History of severe claustrophobia impacting ability to perform MRI-PDFF during 
the study 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 despite mild 
sedation/treatment with an anxiolytic;

Subjects with abdominal girth greater than the bore size of the site’s MRI system, 
as measured by the Hula-hoop test.
11. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing and until the on-site Follow up visit.
12. Subjects taking prohibited concomitant medication(s) or those unwilling/unable to 
switch to permitted concomitant medication(s) (refer to Section 5.8.).
13. Weight loss of 5% within 1 month prior to Screen 1.
14. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
15. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential; fertile male subjects who are unwilling or unable to use highly 
effective method(s) of contraception as outlined in this protocol (Section 4.4.4) for 
the duration of the study and for at least 28 days after the last dose of investigational 
product.
16. 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.
17. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of IP (whichever is longer).
18. Subjects with known prior participation in a clinical trial involving PF-05221304 
and/or PF-06865571 (ie received at least 1 dose of IP).


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4.3. Randomization Criteria
On Day 1, interactive response technology (IRT) will be used to assign each eligible subject 
a randomization number, with this number recorded on the electronic Case Report Form 
(CRF).  A computer-generated randomization code using the method of random permuted 
blocks will be utilized to randomize subjects in 1:2:2:2 ratio
(placebo:PF-05221304:PF-06865571:PF-05221304 plus PF-06865571 combination) prior to 
the first dose of IP, provided subjects satisfy all of the eligibility criteria outlined in
Section 4.1 and Section 4.2.

An attempt will be made to equally balance the number of subjects assigned to each 
treatment arm within stratum by utilizing a stratification scheme as follows.  Subjects 
will be stratified at randomization (Day 1) by the MRI-PDFF liver fat measurement 
determined by the Sponsor-identified central imaging vendor of images obtained 
during Screen 3:

Screening liver fat 8% and <15%;

Screening liver fat 15%;

Subjects will then be stratified by the presence or absence of T2DM.
4.4. Lifestyle Requirements
After confirmation of eligibility at Screen 3 (Visit 3) and starting at Run-in (Visit 4), subjects 
will be instructed to maintain the guidelines described below for the duration of participation 
in the study.  These guidelines must be reiterated on Day 1 (Visit 6) and during site visits 
thereafter.  The following guidelines are provided.
4.4.1. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) for at least 8, but 
preferably 10 hours, prior to any blood sample collections for clinical laboratory tests.

Note: Subjects must abstain from all food and drink (except water) for 4 hours 
prior to ALL liver fat assessments, including Screen 1 and Screen 2.

Blinded IPs should be administered twice daily with morning and evening meals and 
should be separated by at least 8 hours.

Subjects will be instructed to maintain their normal diet throughout participation in 
the study (ie through Visit 11).
4.4.2. Alcohol, Caffeine, and Tobacco

Intake of alcohol is permitted in moderation as defined in Section 4.2.


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
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. Physical Activity

Subjects will be asked to not engage in physically strenuous exercise (for example: 
heavy lifting, weight training, calisthenics, and aerobics) within 48 hours before 
blood sample collections for clinical laboratory tests.
4.4.4. Contraception
All fertile male subjects who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of investigational product.  The investigator or his or 
her designee, in consultation with the subject, will confirm that the subject has selected an 
appropriate method of contraception for the individual subject and his partner(s) from the 
permitted list of contraception methods (see below) and will confirm that the subject has 
been instructed in its consistent and correct use.  At time points indicated in the Schedule of 
Activities, the investigator or designee will inform the subject of the need to use highly 
effective contraception consistently and correctly and document the conversation and the 
subject’s affirmation in the subject’s chart (subjects need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the
investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
partner. 
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) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness;
2. Correctly placed copper-containing intrauterine device (IUD);
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository). For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate;
4. Male sterilization with absence of sperm in the post vasectomy ejaculate;


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5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
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 dose of investigational product (Day 1) and continuing for at least 28 days 
after the dose of IP(s).
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 supporting study documentation. 
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 product(s) are PF-05221304 and PF-06865571 and their 
matching placebo.  These will be administered as oral tablets.


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5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system.  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 
site personnel will then be provided with a randomization number and dispensable unit (DU) 
or container number.  The IRT system will provide a confirmation report containing the 
subject number, randomization number, and DU or container number 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. 
Table 6.
Study Treatment Regimen and Dispensing Schedule
Treatment 
Group
Treatment Regimen
Dosagea
AM and PM
A
Placebo (PF-05221304) BID
Placebo (PF-06865571) BID
3 x Placebo (PF-05221304) tablets
PLUS
3 x Placebo (PF-06865571) tablets
B
15 mg PF-05221304 BID
Placebo (PF-06865571) BID
3 x 5 mg PF-05221304 tablets
PLUS
3 x Placebo (PF-06865571) tablets
C
Placebo (PF-05221304) BID
300 mg PF-06865571 BID
3 x Placebo (PF-05221304) tablets
PLUS
3 x 100 mg PF-06865571 tablets
D
15 mg PF-05221304 BID
300 mg PF-06865571 BID
3 x 5 mg PF-05221304 tablets
PLUS
3 x 100 mg PF-06865571 tablets
a: Dosing in AM (with breakfast) and PM (with dinner) will be same
A computer generated randomization schedule will be used to assign approximately 
98 subjects to one of the 4 treatment groups described in Table 6 in a randomization ratio of 
1:2:2:2 for treatment groups A, B, C, and D respectively.  The randomization number will be 
recorded in the case report form (CRF).  The subject will receive the appropriate IP assigned 
by the IRT system.
In order to maintain the double-blind design:

5 mg PF-05221304 and matching placebo tablets will be the same size and shape; 
similarly, 100 mg PF-06865571 and matching placebo tablets will be the same size 
and shape.

Each dose will consist of 6 white to off-white tablets representing 
PF-05221304/PF-06865571/placebo.

Note: For Visit 4 (Day -14) drug product dispensed will only consist of 
single-blind placebo to match PF-05221304 and PF-06865571 tablets.


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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
Compliance of single-blind placebo administration during the Run-in period will be assessed
by pill count on Day 1 (Visit 6) for the purposes of inclusion into the study.  Acceptable 
compliance will be defined as self-administration by the subjects of:

85% of the study-supplied blinded placebo taken by the subject during the Run-In 
period (ie, Visit 4 to Visit 6) – up to 4 single doses are permitted to be missed.
Compliance of IP administration will be assessed during the treatment phase of the study by 
the number of tablets returned by the subjects at Visits 7, 8, 9 and 10.

A compliance rate of 80% with self-administration of the IP is expected from Day 1 
(Visit 6) to Day 42 (Visit 10); investigators must closely monitor non-compliant 
subjects in order to enhance their adherence to the study treatment.  Subjects having 
missed more than 2-4 doses of IP during a one week treatment period will be 
re-educated on the importance of compliance on their site visit.  If similar 
non-compliance is noted on their next site visit also, the subject may be discontinued 
from the study, upon discussion with the Sponsor. 
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded investigational products (5 mg PF-05221304, 100 mg PF-06865571 or their 
matching placebos) will be provided as white to off-white tablets for oral administration.  All 
investigational products will be provided in blister packs and labeled according to local 
regulatory requirements.  PF-05221304, PF-06865571, and their matching placebos for 
dispensation at the visits denoted in the Schedule of Activities will be packaged with blister 
packs containing a sufficient number of tablets to permit dosing for 14 (+2) days.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system from 
Visit 4 to Visit 9 [refer to Schedule of Activities].  A qualified staff member will dispense the 
investigational product via unique container numbers on the blister packs provided, in
quantities appropriate for the study visit schedule.  Subjects should be instructed to 


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maintain the IP in the blister pack(s) provided throughout the course of dosing at the 
labelled storage conditions and return with the dispensed blister pack(s) to the site at each 
visit starting at Visit 6 (Day 1) and through morning of Visit 10 (Day 42).  The instructions 
for dosing will be provided to the sites and individual subjects.  The number of blister packs 
dispensed and the number of tablets administered per dose will be identical for all 
randomized arms.
5.5. Administration
Subjects will be instructed to take the blinded investigational product at the same time of day, 
twice a day, with the morning and evening meals each day except for Day 42 dose, for which 
subjects would not take evening dose.  In addition, subjects will be instructed to delay the 
self-administration of the blinded investigational product as well as other allowed, 
concomitant medication, 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.
Subjects will swallow the investigational product whole with approximately 240 mL of 
non-carbonated water, and will not manipulate or chew the investigational product prior to 
swallowing.
Subjects will be provided dosing instructions starting at Visit 4 (Day -14) to aid in 
remembering the correct steps to self-administer blinded investigational product.
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, 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. 


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Any excursions from the product label(s) 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(s) must be quarantined and not 
used until Pfizer provides permission to use the investigational product(s).  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.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
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.
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product(s) supplies.  All investigational products will 
be accounted for using a drug accountability form/record.
All blister packs of study drug must be returned to the investigator by the subject at every 
visit and at the end of the trial, except on Day 5 visit (Visit 7), when the subject will bring the 
un-used study drug to the site for compliance check, but will take it back with them to 
complete dosing for remainder of the days, until their next site visit. 
5.7.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product(s) (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.
For all blister packs returned to the investigator by the subject, the investigator will maintain 
the returned supply until destruction is authorized. Pfizer will provide instructions as to the 
disposition of any unused investigational product.


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5.8. Concomitant Treatment(s)
Subjects in this study will be allowed to take certain concomitant medications to treat 
coexisting conditions such as type 2 diabetes, hyperlipidemia and hypertension.  All 
concomitant treatments taken during the study must be recorded with indication, daily dose, 
and start and stop dates of administration.  Attempts must be made to not alter the doses and 
regimens of chronic background medications after randomization and for the duration of 
participation in this study.  Any changes made to background medications must be captured 
in the CRF.  All subjects will be questioned about concomitant treatment at each study visit.
Treatments taken within 42 days before the first dose of IP(s) on Day 1 will be documented 
as a prior treatment.  Treatments taken after the first dose of IP(s) will be documented as 
concomitant treatments.
5.8.1. Medications for Glycemic Control
Subjects with a diagnosis of T2DM are permitted to be on stable doses of 1 oral agent for 
glycemic control, starting at 8 weeks prior to Visit 1 (Screen 1) and until Visit 11 (on-site 
Follow-up), including (but not limited to) the following approved classes of agents:

Sulphonylureas such as glimepiride, glipizide, glyburide;

Dipeptidyl peptidase-4 inhibitors (DPP-4i) such as sitagliptin, saxagliptin, 
vildagliptin;

Meglitinides such as repaglinide, nateglinide.
The use of the following classes of agents is NOT permitted starting at 8 weeks prior to 
Visit 1 and until Visit 11 (on-site Follow-up):

Metformin;

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone;

Subcutaneously administered agents for glycemic control (eg, insulin, exenatide, 
liraglutide, pramlintide);

Sodium-glucose co-transporter 2 (SGLT2) inhibitors such as canagliflozin, 
dapagliflozin, empagliflozin.
5.8.2. Anti-Hypertensive Medications
Use of background antihypertensive agent(s) is permitted.  Doses of antihypertensive agents 
should be stable for at least 8 weeks prior to Screen 1 and throughout the study (until on-site 
Follow-up visit, Visit 11). 


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5.8.3. Lipid-Modifying Medications
Subjects are permitted to be on stable doses of the following lipid-modifying agents, starting 
at 8 weeks prior to Screen 1 and until on-site Follow-up visit, including (but not limited to) 
the following: 

Statins such as atorvastatin, simvastatin, pitavastatin, pravastatin;

Note: Rosuvastatin, gemfibrozil and fluvastatin are not permitted within 4 weeks
prior to Screen 1 and until on-site Follow-up visit;

Bile acid sequestrants such as cholestyramine, colestipol, colesevalam;

Fenofibrate;

Nicotinic acid/niacin.
5.8.4. Other Acceptable Concomitant Medications
Subjects on the following list of medications must be on stable doses (ie, at least 8 weeks 
prior to Screen 1) and for the duration of participation in the study through on-site Follow-up 
visit:

Inhaled and topical corticosteroids;

Thyroid replacement therapy;

Postmenopausal hormone therapy;

Non-steroidal anti-inflammatory medications (NSAIDs) such as ibuprofen, 
ketoprofen, naproxen, indomethacin, and meloxicam.  Intermittent use of these 
medications is also permitted;

Intermittent use of acetaminophen/paracetamol at doses 1 gram per day;

Aspirin at doses 325 mg per day;

Antidepressant medications such as tricyclic agents, selective serotonin reuptake 
inhibitors, and serotonin/norepinephrine reuptake inhibitors;

Certain herbal supplements but only following consultation with Sponsor;

Limited use of nonprescription medications that are not believed to affect subject 
safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor.


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5.8.5. Prohibited Concomitant Medications
Subjects must abstain from using the following medications for 4 weeks prior to Screen 1
and until on-site Follow-up visit:

Chronic use of systemic glucocorticoids such as prednisone, dexamethasone, 
triamcinolone, budesonide, betamethasone; and immunosuppressants such as 
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 that the current study is the first study for 
administration of combination IPs, in a patient population:

Coumadin-type anticoagulants or other anticoagulants (eg, dabigatran); 

Anticonvulsants;

Antiarrhythmics, except for beta blockers or calcium channel blockers if used for 
the management of conditions other than arrhythmias.

Medications historically associated with fatty liver are prohibited if used for 
4 weeks of continuous use in the previous 12 months prior to Screen 1, examples 
include: 

Amiodarone, methotrexate, tetracyclines, tamoxifen, estrogens at doses greater 
than those used for hormone replacement, anabolic steroids, valproic acid, other 
known hepatotoxins.

Strong inducers and inhibitors of CYP3A enzyme (see Appendix 2);

Note: short term use of potent CYP3A inhibitors (eg, ketoconazole, itraconazole) 
for management of fungal infections 4-weeks prior to Visit 1 (Screen 1) is 
acceptable but use must be avoided post randomization.

Sensitive breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp)
substrates (eg, rosuvastatin and digoxin);

CYP2C9 substrates (eg, fluvastatin, diclofenac, celecoxib, torsemide);

Use of chronic agents which are potent inducers of CYP3A (eg, rifampin);


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
Use of CYP3A4/5 substrates with narrow therapeutic index – eg, alfentanil, 
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, and terfenadine;

Use of chronic agents which are clinically significant organic anion transporter 
polypeptide (OATP) inhibitors (eg, cyclosporine, gemfibrozil, rifampin).
5.9. Rescue Medication
There is no rescue therapy to reverse AEs observed with administration of IP(s); standard 
medical supportive care should be provided to manage the AEs. 
6. STUDY PROCEDURES 
A signed and dated Informed Consent Document (ICD) will be obtained from each subject at 
Visit 1 (Screen 1) before performing any protocol-specific procedures.  All requirements and 
procedures of the trial will be thoroughly reviewed with all subjects.  The results of the 
clinical laboratory assessments and all screening procedures will be evaluated with respect to 
inclusion and exclusion criteria to determine the subject’s eligibility.  If a subject does not 
qualify for the trial, he or she will be considered a screen failure.  Adverse Event (AE) 
reporting, including Serious Adverse Event (SAE) reporting will begin from the time 
the ICD is signed at Visit 1 (Screen 1). 
For the procedures described below, where multiple procedures are scheduled at the same 
time points relative to dosing, the following chronology of events should be adhered to as 
much as possible: 

12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing;

Vital Signs (BP, pulse rate): obtain after 12-lead ECG collection but prior to 
obtaining blood samples and prior to dosing;

Fasting blood samples, including pre-dose PK: after assessment of 12-lead ECG and 
vital signs but prior to dosing;

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 of blinded IP(s): must occur after any pre-dose blood sample collections.
6.1. Screening
Refer to the Schedule of Activities for the study procedures to be completed at the Screening 
visits.  The 3 screening visits are to be performed sequentially. 


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
At Screen 1, subjects will be consented and all screening procedures (except liver fat 
assessment by 2nd FibroScan and by MRI-PDFF) 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 
Screen 2 for another FibroScanassessment as performed at Screen 1;

Following confirmation of liver fat content at Screen 2, subjects should proceed to 
the Imaging center for the Screen 3 visit to undergo liver fat assessment via 
MRI-PDFF acquisition to assess whether they meet inclusion criterion 8, Section 4.1.
For Visit 1, subjects will be instructed to arrive at the study site after at least an 8-hour, but 
preferably 10-hour fast (except water).  For Visits 2 and 3, fasting (water allowed) for 
4 hours is required. 
Subjects will be screened within56 days (including 14 days of single-blind Run-In period) 
prior to the first dose of the blinded IP to confirm that they meet the subject selection criteria 
for the study.  The duration between Screen 1 (Visit 1) and start of Run-In period (Visit 4) 
should be at least 28 days, but should not exceed 42 days. In rare cases, subjects may be 
re-screened; however, this is permitted only when, due to logistical constraints, the 
maximum period between the Screen 1 and Day 1 of 72 days is exceeded.  In such cases, all 
screening procedures must be repeated and the subject assigned a new 8-digit single subject 
identifier (SSID) number.  Subjects must be deemed to meet all the eligibility criteria 
including assessment of liver fat via MRI-PDFF at Screen 3, under the new 8-digit SSID.
To prepare for study participation, subjects will be instructed on the use of Lifestyle 
Requirements (Section 4.4) and Concomitant Treatments (Section 5.8).
6.2. Run-in Period (Visit 4)
After the investigator has determined all eligibility criteria have been satisfied 
(approximately within 1 week following Visit 3), subjects will return to the site after a 
minimum 8-hour, but preferably 10-hour fast (except water).  The single-blind Run-in period 
will serve to familiarize the subject with the study treatment regimen and exclude subjects 
who are not compliant with dosing.  This visit will occur 142 days prior to the planned date 
of randomization (Visit 6, Day 1). 
For all subjects, refer to the Schedule of Activities for the study procedures to be completed 
at the Run-in visit (Visit 4). 
Following completion of the above procedures, single-blind IP will be self-administered 
(with meal) while witnessed by adequately trained site staff.  Subjects will then be 
discharged from the site with enough IP to last until Day 1 (Visit 6). 


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6.3. Baseline MRI-PDFF (Visit 5)
Between 2 to 6 days, inclusive, prior to Visit 6 (Day 1), subjects will be instructed to report 
to the Imaging facility following a 4-hour fast, and within 2 hours of the Visit 3 time to 
undergo liver fat assessment via MRI-PDFF.  Subjects should self-administer single-blind IP 
(with meal) post-MRI-PDFF.

Note: If the subjects are found to have a non-evaluable MRI-PDFF, they may have to 
come back to Imaging center for a single repeat assessment, preferably still within 
2-4 days of the Day 1 visit (Visit 6).

Note: Subjects will be informed via a phone call if they are found not to meet 
eligibility criteria of 8% liver fat.  In that case, the subjects will be discontinued.
6.4. Study Period
6.4.1. Day 1 (Visit 6) 
Approximately 14 days after Visit 4, subjects will return to the site after a minimum of an 
8-hour, but preferably 10-hour fast. 
Subjects will be asked to return IP dispensed at Visit 4 for an assessment of the pill count.  
Subjects must be at least 85% compliant with the placebo run-in IP in order to be 
randomized. 
Refer to the Schedule of Activities for the study procedures to be completed prior to 
administration of IP on Day 1.  Be sure to collect a genomic banked biospecimen for 
OATP genotyping.  If missed, collect at the next available time point when biospecimen are 
being collected in conjunction with a subject visit. 
Subjects who meet safety eligibility ie, ECG, vitals and weight, liver fat eligibility as 
determined by FibroScan (CAP280 dB/m) and MRI-PDFF (8%), compliance criteria 
(>85% compliant) and are negative for urine drug test will be randomized to double-blind 
study treatment on Day 1.  Sites will contact the IRT system for assignment of double-blind 
treatment.  Double-blind IP(s) will be dispensed to subjects via IRT and self-administered.  
Following witnessed dosing of IP (with meal), an approximate 2-week supply of 
double-blind IP will be dispensed, and subjects will be discharged from the site. 
6.4.2. Day 5 (Visit 7) 
At 51 days from Visit 6, subjects will return to the study site after a minimum of an 8-hour, 
but preferably 10-hour fast.  Subjects will bring un-used supply of IP for compliance check.

Note: If subjects do not meet at least 80% compliance, subjects will be re-educated 
on the importance of dosing compliance.
Refer to the Schedule of Activities for the study procedures to be completed prior to 
administration of IP on Day 5. 


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Following witnessed dosing of IP (with meal), subjects will be discharged from the site with 
their un-used IP, to be taken for remainder of the days until their next visit (Visit 8).
6.4.3. Day 14 (Visit 8) and Day 28 (Visit 9)
At 14±2 and 28±2 days from Visit 6, subjects will return to the study site after a minimum of 
an 8-hour, but preferably 10-hour fast.
Refer to the Schedule of Activities for the study procedures to be completed prior to 
administration of IP(s) on Day 14 and on Day 28 respectively. 
•
Note: If, during compliance check it is found that a subject is <80% compliant and if 
this is the first time they were <80% compliant in dosing, the subject will be 
re-educated about importance of compliance at these visits.  If this is subject’s second 
time not meeting a minimum of 80% compliance requirement, the subject may be 
discontinued, after consultation with the Sponsor. 
Following completion of the above procedures, double-blind IP(s) will be dispensed to 
subjects via IRT and self-administered (with meal). 
 
 
6.4.4. Day 42 (Visit 10)
Within approximately 24 hours prior to the Day 42 visit, or on the day of the Day 42 visit, 
subjects will be instructed to report to the Imaging facility following a ≥4-hour fast (if the 
visit to the Imaging facility is 24 hours prior) or a minimum of 8-hour, but preferably 
10-hour fast (if the visit to Imaging facility is on same day as site visit ie Day 42 visit) and 
within ±2 hours of the Visit 5 time to undergo liver fat assessment via MRI-PDFF. 
Refer to the Schedule of Activities for the study procedures to be completed prior to 
administration of IP on Day 42.
Subjects should self-administer double-blind IP(s) (with meal) post-MRI-PDFF.  If subjects 
perform MRI-PDFF in the morning of same day as Visit 10 site visit, they should wait for 
blood collections before administration of morning dose at the site. Subjects will not take 
evening dose on Day 42. 
6.4.5. Follow-up
At ≥7 days and ≤14 days following the last dose of double-blind IP(s), subjects will return to 
the study site for a follow-up visit after a minimum 8-hour, but preferably 10-hour fast. 
Refer to the Schedule of Activities for the study procedures to be completed at this visit.
CCI


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6.4.6. Follow-up Contact
A Follow-up contact via telephone of all subjects will be completed at least 28 calendar days, 
and up to 35 calendar days after the last administration of double-blind IP(s). 
Refer to the Schedule of Activities for the study procedures to be completed during this 
contact.

Note: this contact can be considered as on-site in order to permit follow-up of open 
AEs and/or abnormal laboratory tests from prior visit(s), as needed.
6.5. Subject Withdrawal/Early Termination
In this study, any subject who discontinues participation in the trial any time prior to 
administration of double-blind IP(s) 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 double-blind IP(s), 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 double-blind IP(s).  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.  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.
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 


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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.
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 (see also the 
Withdrawal From the Study Due to Adverse Events section) 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.
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 who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor. 
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.


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7.1. Imaging Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis
The MRI-PDFF technique is an established method that enables quantification of fat content 
in the liver.  Imaging data are acquired with this method in a manner that accounts for 
confounding factors that can otherwise result in inaccurate measures of liver fat, while also 
providing whole-liver coverage such that fat content can be assessed across each of the 
9 Couinaud liver segments.  This noninvasive methodology has been found to be more 
sensitive to change in liver fat content than histologically-determined steatosis grade, and has 
found utility in previous trials of prospective NASH therapeutics. 
C
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At scheduled visits (refer to the Schedule of Activities), liver fat will be assessed via MRI, 
using the PDFF acquisition protocol. 
Across the study 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 facility who are trained by the Sponsor-identified central imaging vendor are 
permitted to acquire images in subjects who consent for this study, however in 
rare/limited situations, exceptions may be granted with written approval of the Sponsor.  
Complete details on the MRI-PDFF acquisition protocol, determination of quality of images, 
and transmission of data to Sponsor-identified central imaging vendor will be provided in an 
Imaging Manual offered to the study sites prior to the start of the study.
As much as practically possible, analysis of the MRI-PDFF images acquired at or prior to 
baseline (Visit 5) and Visit 10 (Day 42) will be undertaken by a single colleague at the 
Sponsor-identified central imaging vendor who will be blinded to individual subject’s 
clinical data, as well as randomization and stratification assignment. 
7.1.3. Analysis of MRI-PDFF Images Including Determination of Eligibility 
A subject’s eligibility for this study based on liver fat as assessed via MRI-PDFF at Screen 3
will be made by the Sponsor-identified central imaging vendor, only.  The study sites will be 
informed whether a subject meets eligibility criteria or if the screening MRI-PDFF should be 
repeated once, as determined by the Sponsor-identified central imaging vendor.  If the 
MRI-PDFF is non-evaluable for the 2nd time, the subject will be screen failed.  For all 
subsequently scheduled MRI-PDFF assessments, study sites will only be informed whether 
the images are deemed evaluable (or not).  If the MRI-PDFF images at baseline (Visit 4) 
and/or Visit 10 (Day 42 or before) are found non-evaluable, the assessment may be repeated 
once after consultation with the Sponsor.  If the MRI-PDFF images are non-evaluable on 
single repeat also, the central imaging vendor will seek Sponsor’s guidance on further steps.  
Sponsor may decide to have the subject re-visit the Imaging center for repeat MRI-PDFF or 
discontinued.  If the single repeat of MRI-PDFF is to be performed for Visit 10, it has to be 
completed prior to Day 42 visit. 
7.1.3.1. 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 MRIs images will be reviewed by the Sponsor-identified central review facility. The 
purpose of this review is to evaluate images for the amount of fat in the liver.  Central image 
review is not a complete medical review of the 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 


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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
7.2.1. Physical Examinations
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, 
and gastrointestinal, musculoskeletal, and neurological systems.  At screening only, physical 
exam will also include arm and waist circumference and height measurements.  The limited 
or abbreviated physical examination will be focused on general appearance, the respiratory 
and cardiovascular systems, and subject-reported symptoms.
7.2.2. Body Weight and Hula-hoop Test
For measuring weight, a scale with appropriate range, resolution and calibration will be used 
and must be placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of 
clothing, and jackets so that only light clothing remains.  They must also remove the contents 
of their pockets and remain still during measurement of weight.
For hula-hoop test, subjects 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,
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 
and confirmed to fit inside the site-specific MRI machine and its respective bore size.
•
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.
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
Note: as much as practically possible, the same position of the arms must be used for 
all MRI-PDFF assessments as used for hula-hoop test.

Note: 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. 
7.2.3. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be measured at times specified in the Schedule of 
Activities section of this protocol.  Additional collection times, or changes to collection 
times, of BP and pulse rate will be permitted, as necessary, to ensure appropriate collection 
of safety data.
Single, seated BP will be measured with the subject’s arm supported at the level of the heart, 
and recorded to the nearest mmHg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study.  Subjects should be 
instructed not to speak during measurements.  The assessment at Visit 6 (Day 1) will serve as 
each subject’s baseline;
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.
7.2.4. Electrocardiogram
In this study, assessment of cardiac conduction via 12-lead ECGs will be collected at the 
nominal time points specified in the Schedule of Activities per the following specifications:

All scheduled 12-lead ECGs should be performed after the subject has rested quietly 
for 10 minutes in supine position.

Single, supine 12-lead ECGs will be obtained and measurement collected prior to 
the first dose on Day 1 (Visit 6) will serve as each subject’s baseline value.

If the QTcF value is (a) above the threshold value (ie, is 60 msec from the baseline, 
or is 500 msec), or (b) if post-randomization QTcF interval is increased by 
30 msec from the baseline and is >450 msec, then ECG must be repeated at least 
hourly until QTcF values from 2 successive ECGs fall below the threshold value that 
triggered the repeat measurement.
In some cases, it may be appropriate to repeat an abnormal 12-lead ECG 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 
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necessary if a qualified physician’s interpretation determines that the QTcF values are in the 
acceptable range.
7.3. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at times defined in the Schedule of 
Activities.  Additional laboratory results may be reported on these samples as a result of the 
method of analysis or the type of analyzer used by the clinical laboratory; or as derived from 
calculated values.  These additional tests would not require additional collection of blood.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety concerns.
Table 7.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Fasting Lipid Panel
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea 
Creatinine [and eGFR 
using MDRD]a
Plasma glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
GGT
Total bile acids
Uric acid
Albumin
Total protein
Direct bilirubinb
Indirect bilirubinb
Serum cystatin C
Creatinine Kinasec
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyd
Total cholesterol, 
VLDL, 
HDL-C, 
Triglycerides
and 
direct LDL-C
Other
FSHe,g
Urine drug testf
Serology (HepBsAg, 
HepBcAb, HCVAb, HCV 
RNA, HIV)g
Ceruloplasming
Coagulationg (Plasma 
aPTT, PT, PT/INR)
1-antitrypsin (A1AT)g
Additional Tests (Needed for Hy’s Law)

AST, ALT (repeat)

Total bilirubin (repeat)

Albumin (repeat)

Alkaline phosphatase (repeat)

Direct bilirubin

Indirect bilirubin

Creatinine kinase

GGT

PT/INR

Total bile acids

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a.
Estimated glomerular filtration rate (eGFR) will be calculated using the modification of diet in renal disease 
(MDRD) equation.
b.
Direct and indirect bilirubin measured at Screen 1 and Visit 6; after initiation of investigational product, direct 
+ indirect bilirubin are measured only when total bilirubin is > ULN.
c.
Test to be assessed at Screen 1 and Visit 6 only; after initiation of investigational product, this test measured only 
when ALT or AST is > ULN.
d.
Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
e.
In females, only.
f.
Subjects may undergo random urine drug testing at the discretion of the investigator.  Drug testing will be 
performed using dipstick and must be negative for subjects to receive IP. 
g.
At Screening visit only.
Abbreviations: Abs = Absolute; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; aPTT = activated 
Partial Thromboplastin Time; BUN = Blood Urea Nitrogen; eGFR = Estimated glomerular filteration rate; 
HbA1c = glycosylated hemoglobin (NGSP certified method); MCH = Mean Corpuscular Hemoglobin; 
MCHC = Mean Corpuscular Hemoglobin Concentration; MCV = Mean Corpuscular Volume; MDRD = Modification of 
diet in renal disease; PT = Prothrombin Time; PT/INR = Prothrombin Time/International Normalized Ratio.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. 
 
 
 
7.3.1. Serum for Cystatin C
Blood samples (approximately 2.5 mL) to provide a sufficient quantity of serum for analysis 
of cystatin C will be collected into appropriately labeled tubes at pre-specified nominal time 
points outlined in the Schedule of Activities.  GFR will be estimated from the cystatin C 
using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi)-Cystatin C 
equation provided below.
•
For serum cystatin C (Scys) ≤0.8 mg/L:
eGFR = 133×(Scys/0.8)-0.499×0.996Age[×0.932 if female].
•
For serum cystatin C (Scys) >0.8 mg/L:
eGFR = 133×(Scys/0.8)-1.328×0.996Age[×0.932 if female].
Review of Cystatin C results are not required for dosing or discharge.
 
 
 
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7.5. Pharmacodynamics Parameters
Blood samples for pharmacodynamics biomarker analysis - including NASH-related 
biomarkers, potential mechanism-related parameters, metabolic parameters, and exploratory 
markers of liver function - will be collected at the nominal time points specified in the 
Schedule of Activities. 
•
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:
•
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.
•
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.
Refer to list of endpoints outlined in Section 2 that encompass these pharmacodynamics 
biomarkers.  As part of understanding the effects of co-administration of the IP(s), samples 
may be used for evaluation of the bioanalytical method, as well as for other internal 
exploratory purposes. 
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7.5.1. Serum for Lipid Panel
At each time point specified in the Schedule of Activities, a sufficient volume of blood 
(approximately 3.5 mL) will be collected into appropriately labeled tubes for analysis of total 
cholesterol, HDL-C, triglycerides and direct LDL-C, with the exception of lipid panel 
performed at Screening, which will be completed as part of Section 7.3. 
Total cholesterol/HDL-C ratio and non-HDL cholesterol will be derived from the lipid panel.
 
 
 
 
 
 
 
 
7.5.3. Apolipoprotein A1, B100 and Apolipoprotein C3
At each time point specified in Schedule of Activities, approximately 4 mL of blood will be 
collected to ensure sufficient serum for analysis of apolipoproteins A1, B100 and C3.  These 
samples will be processed and shipped for analysis to the Sponsor-identified laboratory.
 
 
 
 
 
 
 
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7.5.8. Plasma PCSK9
Blood samples (approximately 2 mL) to provide a sufficient quantity of plasma for PCSK9 
analysis will be collected into appropriately labeled tubes containing K2EDTA at times 
specified in the Schedule of Activities section of the protocol.  These samples will be 
processed and shipped for analysis to the Sponsor-identified laboratory.
7.6. Pharmacogenomics
7.6.1. Genotyping Analysis 
Blood samples for genotyping may be examined to assess the impact of allelic variants of 
drug-metabolizing enzymes and transporters.  Additionally, these samples may also be used 
for retrospective evaluation of additional genetic variants associated with variation in 
pharmacokinetics (PKs) or to explore AEs should these be observed.  Samples will be 
retained for a period of up to 3 years after regulatory approval.
A 4 mL blood sample will be collected from each subject into a plastic dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) tube at times specified in the Schedule of 
Activities section of the protocol. 
As part of further understanding the biological response to IP, samples will be used, at a 
minimum, for OATP genotyping.  In addition, the sample may be used for evaluation of 
other related genotyping as well as development and validation of bioanalytical methods.  
Any data outside of the OATP genotyping will be used for internal exploratory purposes and 
will not be included in the clinical study report (CSR).
The pharmacogenomic (PGx) samples must be processed and shipped as indicated in the 
instructions provided to the investigator site to maintain sample integrity.  Any deviations 
from the PGx processing steps, including any actions taken, must be documented and 
reported to the sponsor.  On a case-by-case basis, the sponsor may make a determination as 
to whether sample integrity has been compromised.  Any sample deemed outside of 
established stability, or of questionable integrity, will be considered a protocol deviation.
7.7. Banked Biospecimens
Banked biospecimens will be collected from subjects for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.  They will be handled in a 
manner that protects each subject’s privacy and confidentiality.  Banked biospecimens will 
be assigned the subject’s study identification code (ID) at the site.  The data generated from 
these banked biospecimens will also be indexed by this ID.  Biospecimen will be kept until 
destruction in facilities with access limited to authorized personnel, and biospecimen-derived 
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data will be stored on password-protected computer systems.  The key between the subject’s 
ID and the subject’s direct personally identifying information (eg, name, address) will be 
held at the study site.  Biospecimens will be used only for the purposes described in the 
protocol and informed consent document; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored for many years (no time limit) to allow for research in the future, 
including research conducted during the lengthy drug-development process and also 
post-marketing research.  Subjects may withdraw their consent for the use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any remaining 
biospecimens will be destroyed, but data already generated from the biospecimen will 
continue to be available to protect the integrity of existing analyses. 
Unless prohibited by local regulations or ethics committee decision, a 2 mL blood genomic 
banked biospecimen Prep D1.5 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected prior to 
dosing at Visit 6 to be retained for potential pharmacogenomic/genomic/biomarker analyses 
related to drug response and disease/condition under study.  For example, putative safety 
biomarkers, drug-metabolizing enzyme genes, drug-transport protein genes, or genes thought 
to be related to the mechanism of drug action may be examined.  The primary purpose is to 
examine DNA; however, the biospecimen may also be used to study other molecules 
(eg, RNA, proteins, and metabolites).
Additional banked biospecimens to be retained for such exploratory analyses in this study 
include the following: 

Prep B1.5 (K2EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): A 2 mL blood biospecimen will be 
collected at times specified in the Schedule of Activities section of the protocol. 

Prep B2.5 (serum collection optimized for biomarker/proteomic/metabolomic 
analysis): a 2 mL blood biospecimen will be collected at times specified in the 
Schedule of Activities section of the protocol. 
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or IRB/EC decision.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document that they will not be compensated 
in this event.
7.7.1. Additional Research
Unless prohibited by local regulations or Institutional Review Board (IRB)/Ethics Committee 
(EC) decision, subjects will be asked to indicate on the consent form whether they will allow 
banked biospecimens to also be used to design and conduct research in order to gain a further 
understanding of other diseases and to advance science, including development of other 
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Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
 
 
 
 
 
8. ADVERSE EVENT REPORTING
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 
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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 the Serious Adverse Events section 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.
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 the Subject 
Withdrawal 6.5)
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 the 
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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 are screen failures, the active collection period ends when screen failure 
status is determined.
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 
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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.
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;

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
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

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 
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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 
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);

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
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.
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:
Severity Assessment
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-Specified 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 (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same 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.
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 >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN 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 >3 × ULN; or >8 × ULN (whichever is 
smaller);

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
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.  
Consideration should also be given to drawing a separate tube of clotted blood and an 


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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. 
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 


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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 
information related to termination of pregnancy).
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 


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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.
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 
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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 SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
Approximately 98 subjects will be randomized in a ratio of 1:2:2:2 to four treatment 
groups A:B:C:D, where A is the placebo group.  Assuming an approximate 14% dropout rate 
this will ensure a minimum of 84 subjects complete the study.  This sample size (12 for the 
placebo group and 24 for the each of monotherapy groups and the combination group) is 
estimated to provide >90% power to detect a difference of 30% mean reduction in whole 
liver fat from MRI-PDFF relative to placebo for the PF-05221304 + PF-06865571 
combination using a 1-sided Type I error rate of 0.05.  This randomization schema will 
enable detection of a smaller effect of the combo vs monotherapy than of the monotherapies 
vs placebo.  Detecting a smaller effect requires a larger sample size and hence the sample 
size is increased for the active arms.  With the sample size of 24 completers for each of the 
active arms the power to detect approximately 16% mean reduction in whole liver fat for the 
PF-05221304 + PF-06865571 combination relative to each monotherapy is approximately 
90% using a 1-sided Type I error rate of 0.25.  These calculations assume a pooled standard 
deviation of the log-relative change of 0.32 (based on an internal study). 
9.2. Analysis of the Primary Endpoint
The analysis population for primary endpoint analyses will include all randomized subjects 
who received at least 1 dose of IP (Full Analysis set). 
The primary endpoint will be the relative change from baseline to Day 42 in whole liver 
PDFF.  Baseline will be the closest measurement prior to first dose on Day 1.  An analysis of 
covariance (ANCOVA) will be performed on log-transformed relative change from baseline 
with treatment and baseline diabetes as factors, and log-transformed baseline whole liver 
PDFF value as a covariate.  Estimates of the mean relative changes between placebo and 
each active drug arm (PF-05221304 monotherapy, PF-06865571 monotherapy and 
PF-05221304 plus PF-06865571 combination) at Day 42, and the corresponding 
90% confidence interval (CI) will be obtained from the model.  Similarly, PF-05221304 plus 
PF-06865571 combination will be compared to each monotherapy through estimates of the 
mean relative change and corresponding 50% and 90% confidence intervals. No adjustment 
for multiple comparisons will be made.  If the model does not fit the data group medians and 
their differences from the placebo median will be presented.  The details will be provided in 
the SAP.


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Descriptive summaries of the observed values and percent change from baseline in whole 
liver PDFF for each treatment group will also be produced.
9.3. Analysis of Secondary Endpoints
Secondary endpoints relate to safety and tolerability whose analyses are described in 
Section 9.7.
9.4. Analysis of Tertiary/Exploratory Endpoints
Percent changes from baseline in LFTs will be summarized; group medians and pairwise 
differences from the comparators will be presented.  Log-transformed relative changes from 
baseline in lipid panel parameters will be analyzed separately using mixed model for 
repeated measures (MMRM) with treatment, study day and interaction of treatment with 
study day as factors, log-transformed baseline values of the dependent variable, baseline 
diabetes status and log-transformed baseline whole liver PDFF as covariates.  
 
 
  If the model does not fit the data model 
reduction techniques might be employed; otherwise, group medians and their differences 
from the placebo median will be presented.  Details will be provided in the SAP.
For all other pharmacodynamic endpoints/biomarkers to be included in the CSR observed 
values, changes from baseline and/or percent changes from baseline will be summarized 
descriptively at all collection time points.  Details and any additional analyses will be 
described in the SAP.
 
 
 
 
9.6. Analysis of Other Endpoints
Pharmacogenomic and biomarker data will be collected and retained for future analyses, but 
will not be analyzed for the purposes of CSR.
9.7. Safety Analysis
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of subjects.  Any clinical laboratory, 
ECG, BP, and pulse rate abnormalities of potential clinical concern will be described.  Safety 
data will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate. 
Physical examination information collected during the course of the study will be considered 
source data and will not be required to be reported, unless otherwise noted.  However, any 
CCI
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untoward findings identified on physical examinations conducted during the active collection 
period will be captured as AEs, if those findings meet the definition of an AE. 
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported. 
Vital Signs Analysis
Changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate will 
be summarized by treatment and time.  The number (%) of subjects with maximum increases 
from baseline will be tabulated by treatment as defined in the SAP.  Numbers and 
percentages of subjects meeting the categorical criteria will be provided and individual 
values listed in the study report.  No formal inferential statistics will be applied to the vital 
signs data.
Electrocardiogram Analysis 
Changes from baseline for the ECG parameters QT interval, heart rate, QTcF interval, PR 
interval, and QRS interval will be summarized by treatment and time.  QTcF will be derived 
using Fridericia’s heart rate correction formula.  The number (%) of subjects with maximum 
increases from baseline will be tabulated by treatment as defined in the SAP.  Numbers and 
percentages of subjects meeting the categorical criteria will be provided and individual 
values listed in the study report.  No formal inferential statistics will be applied to the ECG 
data.
9.8. Interim Analysis
If, after randomization of approximately 50% subjects of planned number of subjects, a 
monthly safety review reveals that the study meets one or more criteria listed in Section 3.3, 
an interim analysis will be performed in an un-blinded manner by a pre-specified IRC, 
independent from study team.
 
 
Before any interim analysis is initiated, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs will be 
documented and approved in an IRC charter.  The analysis details will be documented and 
approved in an interim analysis SAP or final SAP.
9.9. Data Monitoring Committee 
This study will not use a data monitoring committee.
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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.
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 shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
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 


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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 
will be recorded on the CRF, and for which the CRF will stand as the source document.
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. The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
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 
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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 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable law.
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
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 the Clinical Study Agreement and 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, the sharing of data relating to the study and possible risks associated 


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with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 
The 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.
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 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last subject last visit (LSLV) – the date 
the investigator reviews the last subject’s final safety data and determines that no further 
evaluation is required for the subjects to complete the trial.
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 one or 
both IPs (PF-05221304 and PF-06865571) 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 7 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 
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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 
populations.
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 
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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.
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.
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 Invest2006; 116(3):817-24.
2.
Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic 
steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench 
investigation. Cell Metab 2017; 26(3):576. 
3.
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.
4.
Yen CL, Stone SJ, Koliwad S, et al.  Thematic review series: glycerolipids. DGAT 
enzymes and triacylglycerol biosynthesis.  J Lipid Res 2008;49(11):2283-301.
5.
Buhman KK, Smith SJ, Stone SJ, et al.  DGAT1 is not essential for intestinal 
triacylglycerol absorption or chylomicron synthesis.  J Biol Chem 2002;277(28):25474-
9.
6.
Cases S, Stone SJ, Zhou P, et al.  Cloning of DGAT2, a second mammalian 
diacylglycerol acyltransferase, and related family members.  J Biol Chem 
2001;276(42):38870-6.
7.
Choi CS, Savage DB. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but 
not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and 
insulin resistance. J Biol Chem 2007;282(31):22678-88.
8.
Yu XX, Murray SF, Pandey SK, et al.  Antisense oligonucleotide reduction of DGAT2 
expression improves hepatic steatosis and hyperlipidemia in obese mice.  Hepatology 
2005;42(2):362-71.
9.
Liu Y, Millar JS, Cromley DA, et al.  Knockdown of acyl-CoA:diacylglycerol 
acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB secretion 
in mice.  Biochim Biophys Acta 2008;1781(3):97-104.
10.
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.
11.
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.
12.
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.


PF-05221304 and PF-06865571
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Final Protocol Amendment 1, 02 October 2018
Page 89
13.
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.
14.
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.
15.
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.
16.
Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) 
in human kidney. AAPS J 2013; 15(2):581-8.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
A1AT
α-1-antitrypsin
Abs
absolute
ACC1/2
acetyl-CoA (coenzyme A) carboxylase 1 and 2
ACCi
acetyl-CoA (coenzyme A) carboxylase inhibitor
ADR
adverse drug reaction
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BBS
biospecimen banking system
BCRP
breast cancer resistance protein
BE
bioequivalence
BID
twice daily
BMI
body mass index
BP
blood pressure
Bpm
beats per minute
BUN
blood urea nitrogen
CAP
controlled attenuation parameter
CDK-Epi
Chronic Kidney Disease Epidemiology Collaboration
Ceff
efficacious concentration 
CFB
change from baseline
CI
confidence interval
CK
creatine kinase
CLr
renal clearance
Cmax
maximum observed concentration
Cmin
minimum concentration
CNS
central nervous system
CO2
carbon dioxide (bicarbonate)
CoA
coenzyme A
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTCAE
common terminology criteria for adverse events
CV
coefficient of variation


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Abbreviation
Term
CYP450
cytochrome P450
DAG
diacylglycerol
dB/m
decibels per meter
DDI
drug-drug interaction
DGAT
diacylglycerol acyltransferase
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DNL
de novo lipogenesis
DPP-4
dipeptidyl peptidase-4
DPP-IVi
dipeptidyl peptidase-IV inhibitors
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EFD
embryo-fetal development
eGFR
estimated glomerular filtration rate
EU
European Union
EudraCT
European Clinical Trials Database
FA
fatty acids
FFA
free fatty acids
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone
GCP
good clinical practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLDH
glutamate dehydrogenase
GLP
good laboratory practice
GLP-1r
glucagon-like peptide-1 receptor
hr.
hour(s)
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein cholesterol


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Abbreviation
Term
HIV
human immunodeficiency virus
IA
interim analysis
IB
investigator’s brochure
ICD
informed consent document
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug
INR
international normalized ratio
IP 
investigational product 
IR
immediate release
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kPa
kilopascal
LDL-C
low density lipoprotein cholesterol
LFT
liver function test
LLN
lower limit of normal
LSLV
last subject last visit 
LSM
liver stiffness measure
MATE
multi-drug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR1
multi-drug resistance protein 1
MDRD
modification of diet in renal disease equation
MELD
model of end-stage liver disease
MIST
metabolites in safety testing
MK
megakaryocytes
MMRM
mixed model for repeated measures 
MR
modified release
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MTD
maximum tolerated dose
N/A
not applicable
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NMN
N-methylnicotinamide
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Abbreviation
Term
NOAEL
no observed adverse effect level
NSAIDs
non-steroidal anti-inflammatory medications
NYHA
New York Heart Association
OAT
organic anion transporter
OATP
organic anion transporter polypeptide
OCT
organic cation transporter
PCD
primary completion date
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
pharmacodynamic(s)
PDFF
proton density fat fraction
P-gp
P-glycoprotein
pH
potential of hydrogen
PGx
pharmacogenomic
PI
principal investigator
PK
pharmacokinetic(s)
PT
prothrombin time
PTR
peak to trough ratio
Q8hr.
every 8 hours
Q12hr
every 12 hours
QD
quodque die (once daily)
QTc
corrected QT interval
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
Scys
serum cystatin
SD
standard deviation
SGLT2
sodium-glucose co-transporter 2
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
t1/2
half-life
SSID
single subject identifier
TBili
total bilirubin
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
TG
triglycerides
Th17
T-helper 17 lineage
Tmax
time to reach maximum concentration
Treg
regulatory T


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Abbreviation
Term
TZD
thiazolidinediones
ULN
upper limit of normal
US
United States
VCTE
vibration controlled transient elastography
VLDL
very low density lipoprotein
WBC
white blood cell


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Appendix 2. Strong CYP3A Inhibitors and Inducers*
CYP 3A Inhibitors
CYP 3A Inducers
HIV antivirals
HIV antivirals
Indinavir
Nevirapine
Nelfinavir
Miscellaneous
Ritonavir
Barbiturates
Saquinavir
Carbamazepine
Boceprevir
Glucocorticoids (systemic)
Lopinavir/ritonavir
Oxcarbazepine
Amprenavir
Phenobarbital
Atazanavir
Phenytoin
Telaprevir
Rifabutin
Darunavir/ritonavir
Rifampin
Fosamprenavir
St. John's wort2
Tiprinavir/ritonavir
Troglitazone
Antibiotics
Nafcillin
Clarithromycin
Avasimibe3
Troleandomycin
Enzalutamide
Telithromycin
Mitotane
Anti-infectives
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Miscellaneous
Nefazodone
Grapefruit juice1
Conivaptan
Idelalisib
1.
Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits (eg, Seville oranges, 
pomelos).
2.
The effect of St. John’s wort varies widely and is preparation-dependent.
3.
Not a marketed drug.
* This list is not considered as exhaustive.  Any questions regarding use of CYP3A inhibitors and inducers should be 
directed to the Sponsor study team.
Reference: U.S. Food and Drug Administration.  Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers, available at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09366
4.htm


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Appendix 3. Guidance to Investigators –Management of Individual Subjects With 
Decrease in Platelet Count


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Appendix 4. Guidance to Investigators –Management of Individual Subjects With 
Elevation in Fasting Serum Triglycerides

SAP_001.pdf: 
Protocol C3711001 (PF-05221304 and PF-06865571) Statistical Analysis Plan
Page 1
Protocol C3711001
A PHASE 2A, RANDOMIZED, DOUBLE BLIND (SPONSOR-OPEN), 
PLACEBO CONTROLLED, PARALLEL GROUP STUDY TO ASSESS 
THE PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-
05221304 AND PF-06865571 CO-ADMINISTERED FOR 6 WEEKS IN 
ADULTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Version:
Amendment 1
Date:
16-AUG-2019
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Table of Contents
1. VERSION HISTORY..................................................................................................................4
2. INTRODUCTION .......................................................................................................................4
2.1. Study Objectives .............................................................................................................5
2.2. Study Design ...................................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ...................................................................................................................8
3.1. Primary Endpoint(s) ........................................................................................................8
3.2. Secondary Endpoints.......................................................................................................8
3.3. Tertiary/Exploratory Endpoints.......................................................................................9
3.4. Baseline Variables.........................................................................................................10
3.5. Safety Endpoints ...........................................................................................................10
Adverse Events .................................................................................................11
Laboratory Data................................................................................................11
Vital signs .........................................................................................................11
ECGs.................................................................................................................12
Non-Standard Safety Assessments ...................................................................12
4. ANALYSIS SETS .....................................................................................................................13
4.1. Full Analysis Set ...........................................................................................................13
4.2. Per Protocol Analysis Set..............................................................................................13
4.3. Safety Analysis Set........................................................................................................13
4.4. Other Analysis Sets .......................................................................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS..........................................................13
5.1. Hypotheses and Decision Rules ....................................................................................13
5.2. General Methods ...........................................................................................................14
5.3. Methods to Manage Missing Data ................................................................................15
6. ANALYSES AND SUMMARIES ............................................................................................16
6.1. Primary Endpoint: Whole Liver PDFF .........................................................................16
Primary Analysis ..............................................................................................16
6.2. Secondary Endpoint(s) ..................................................................................................17
6.3. Other Endpoints.............................................................................................................17
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6.4. Subset Analyses.............................................................................................................20
6.5. Baseline and Other Summaries and Analyses...............................................................21
6.6. Safety Summaries and Analyses ...................................................................................21
Adverse Events .................................................................................................21
Laboratory Data................................................................................................22
Vital Signs ........................................................................................................22
Electrocardiogram.............................................................................................22
Non-standard Safety Analysis ..........................................................................23
7. INTERIM ANALYSES.............................................................................................................23
8. REFERENCES ..........................................................................................................................24
9. APPENDICES ...........................................................................................................................26
9.1. Categorical Classes for ECG and Vital Signs ...............................................................26
Calculation of %CBL...........................................................................................................26
9.2. Predictive Probability....................................................................................................27
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C3711001 is based on the Final Protocol 
Amendment 1, dated 02 October 2018.  
Table 1 Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
• A few corrections were made:
1) Section 3.5 Vitals: Changed “supine” to 
“seated”
 
 
 
 
 
•Added liver enzymes to Table 3 and Table 
4
• Added detail of Interim Analysis in 
Sections 7, 8 and 9.2.
• Minor edits, clarifications, and 
format/style changes throughout.
• To fix some typos
•To add analysis summary 
for liver enzymes 
• To update the SAP to 
include detail of Interim 
Analysis
• To provide further 
clarity
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3711001.  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.
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2.1. Study Objectives
The study objectives are shown below along with their corresponding endpoints.
Primary Objective(s): 
Primary Endpoint(s): 
To determine the effect of co-administration of 
PF-05221304 and PF-06865571 on whole liver 
fat compared to placebo, PF-05221304 
administered alone, and PF-06865571 
administered alone in subjects with non-
alcohlic fatty liver disease (NAFLD).
Relative change from Baseline in whole liver fat 
at Day 42, as assessed by magnetic resonance 
imaging proton density fat fraction 
(MRI-PDFF).
Secondary Objective(s): 
Secondary Endpoint(s): 
To evaluate safety and tolerability of PF-
05221304 and PF-06865571 co-administration 
compared to placebo, PF-05221304 
administered alone, and PF-06865571 
administered alone in subjects with NAFLD.
Assessment of treatment-emergent adverse 
events (and serious adverse events), clinical 
laboratory tests including lipids, vital signs, and 
12-lead electrocardiograms (ECGs).
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Tertiary/Exploratory Objective(s): 
Tertiary/Exploratory Endpoint(s): 
To evaluate the effect of co-administration of 
PF-05221304 and PF-06865571, on liver 
function tests (LFTs) compared to placebo, PF-
05221304 administered alone, and PF-
06865571 administered alone in subjects with 
NAFLD.
Percent change from Baseline at all time points 
for:
•
Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST).
•
Alkaline Phosphatase.
•
Gamma-glutamyl transferase (GGT).
To evaluate effects of co-administration of PF-
05221304 and PF-06865571 on lipids 
compared to placebo, PF-05221304 
administered alone, and PF-06865571 
administered alone in subjects with NAFLD.
Percent change from Baseline at all time points 
for:
•
Triglycerides.
•
Total cholesterol, HDL-C, direct LDL-C, 
Total cholesterol/HDL-C ratio, and non-
HDL-C. 
 
 
 
 
 
 
 
 
 
 
®  
™
 
To evaluate the PD effects of co-administration 
of PF-05221304 and PF-06865571 compared 
to placebo, PF-05221304 administered alone, 
and PF-06865571 administered alone, in adults 
with NAFLD.
Analyses for PD parameters:
•
% Change from Baseline to Day 42 in 
Apolipoproteins (A1, B100 and C3).
 
 
.
% Change from Baseline to Day 42 in plasma 
proprotein convertase subtilisin/kexin type 9
(PCSK9)
 
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TMF Doc ID: 98.03
 
To collect banked biospecimen for exploratory 
research, unless prohibited by local regulation 
or ethics committee decision.
Collection of banked bio-specimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information on 
collection and potential use is provided in 
Section 7.7 of the Protocol
2.2. Study Design
This is a randomized, double blind (sponsor open), placebo-controlled, 2x2 factorial, 4 arm 
(placebo, monotherapy of PF-05221304 , monotherapy of PF-06865571 and combination of 
PF-05221304 and PF-06865571 ), parallel group study (Figure 1).
Figure 1.
C3711001 Study Design
Determination of eligibility for this study will occur via a sequential, 3 step process, starting 
at the first screening visit (Screen 1).  Subjects identified to be eligible based on Screen 1 
AND Screen 2 procedures will proceed to Screen 3 to measure liver fat by MRI-PDFF.  For 
a given subject, this three-step eligibility assessment may take up to 6 weeks.
Once confirmed to be eligible based on results of Screen 3, subjects will progress to a Run in 
period (Visit 4), at which time subjects will receive single blind placebo for approximately 14 
days to ensure compliance with the administration of investigational product (IP).  
Approximately 4 days prior to randomization, subjects will report to the imaging center 
(Visit 5) to have a Baseline MRI PDFF scan performed.  At Visit 6 (Day 1), subjects will be 
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TMF Doc ID: 98.03
randomized to receive 1 of 4 blinded IP regimens (placebo, PF-05221304 monotherapy, PF-
06865571 monotherapy, or PF-05221304 plus PF-06865571 combination) for a duration 
of up to 6 weeks (ie, 42 days).  This study includes a total of 11 scheduled outpatient visits to 
the study site, including 4 visits to the imaging center, and a safety Follow up telephone 
contact.  The total participation, from Visit 1 (Screen 1) to Follow up telephone phone call 
will be up to approximately 19 weeks.
Approximately 98 subjects (14 for the placebo group, 28 for each of the monotherapy groups 
and 28 for the combination group) will be randomized at approximately 30 sites (refer to 
Section 9.1 of the Protocol).
Subjects who are noted to have non evaluable Baseline MRI-PDFF, as determined by the 
sponsor identified central imaging vendor, should have their MRI-PDFF repeated once; if 
the images are still non evaluable on single repeat, the subject will be considered as screen 
failed; otherwise, there are no plans to replace subjects who are prematurely withdrawn.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Relative change from Baseline (CBL) (ie, observed value / Baseline value) in whole liver fat 
at Day 42, as assessed by MRI-PDFF. Baseline is defined as the planned measurement 
collected closest prior to dosing on Day 1.
The liver fat or the whole liver PDFF is calculated from the pre-defined individual segmental 
PDFFs labeled Segment I, II, III, IVa, IVb, V, VI, VII and VIII as follows:
Whole Liver PDFF = PDFFs for (Segment I + Segment II + Segment III + Segment IVa + 
Segment IVb + Segment V + Segment VI + Segment VII + Segment VIII) / (number of 
segments assessed).
A minimum of 5 non-missing common segments is needed in order to calculate whole liver 
PDFF. All segments are equally weighted.
While deriving the relative CBL, the same segments are to be used at both Baseline and post-
Baseline time points in the calculation of whole liver PDFF. For example, if at Baseline
PDFFs from all segments are available but, on Day 42, only 7 segments have non-missing 
results,  whole liver PDFF will be calculated using the matching individual segmental PDFFs 
at both Baseline and Day 42.
3.2. Secondary Endpoints

The secondary endpoints include the standard safety endpoints, namely, adverse 
events (AEs), serious adverse events (SAEs), clinical laboratory tests including lipids, 


Protocol C3711001 (PF-05221304 and PF-06865571) Statistical Analysis Plan
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vital signs (including blood pressure and pulse rate), and 12-lead ECGs.  These will 
be further described in Section 3.5.
3.3. Tertiary/Exploratory Endpoints
•
% CBL at all time points for ALT, AST, Alkaline Phosphatase, Gamma glutamyl 
transferase (GGT).
•
% CBL at all time points for triglycerides, total cholesterol, HDL-C, direct LDL-C, 
total cholesterol/HDL-C ratio, and non-HDL-C
Baseline is defined as the result closest prior to dosing on Day 1. The parameter of 
non-HDL-C will be calculated as follows:
Non-HDL-C = Total cholesterol – HDL-C
 
 
 
 
  
 
 
 
•
PD Parameters:
-
% CBL to Day 42 in Apolipoproteins (A1, B100 and C3).
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-
% CBL to Day 42 in plasma PCSK9.
 
3.4. Baseline Variables
Baseline variables are those collected on Day 1, prior to dosing, or before Day 1.  The 
demographic data of age, race, weight, height, and body mass index will be summarized by 
sex at birth and treatment in accordance with the sponsor reporting standards.  In addition, 
the demographic data will be summarized by treatment only in accordance with the sponsor 
reporting standards.  The number and proportion of subjects enrolled in each study site will 
also be presented.
Subjects will be stratified at randomization (Day 1) by the MRI-PDFF liver fat measurement 
determined by the Sponsor-identified central imaging vendor of images obtained during 
Screen 3:
•
Screening liver fat ≥8% and <15%;
•
Screening liver fat ≥15%;
•
Subjects will then be stratified by the presence or absence of type 2 diabetes 
mellitus (T2DM).
For Baseline diabetic status, data will be obtained from the case report forms (CRFs).  
Screening liver fat was used as a binary variable for stratification purposes but Baseline liver 
fat will be used as a continuous covariate in the efficacy analysis to maximize the utility of 
information. Baseline diabetic status will only be included as a covariate in the primary 
analysis (analysis of covariance [ANCOVA]) if at least 1/3 of the subjects have T2DM.
3.5. Safety Endpoints
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
AEs,
•
laboratory data,
•
vital signs data,
•
ECG results.
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Adverse Events
For SAEs, the reporting period to Pfizer or its designated representative begins from the time 
that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving IP, through and including 28 calendar days after the last administration of the IP.  
Similarly, the time period for collecting AEs (“active collection period”) for each subject 
begins from the time the subject provides informed consent. The AEs occurring following 
start of the double-blind randomized treatment will be counted as treatment-emergent. The 
AEs occurring prior to the double-blind randomized treatment intake will be listed.
The 3-Tier approach will not be used to summarize the AEs due to the small sample size.
Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum), and urinalysis safety tests will be assessed 
against the criteria specified in the sponsor reporting standards.  The assessment will take 
into account whether each subject’s Baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline is defined as the result closest prior to dosing on Day 1. 
Vital signs
Seated blood pressure and pulse rate measurements will be taken at time points detailed in 
the Schedule of Activities given in the protocol.
Baseline is defined as the result closest prior to dosing on Day 1. The following vital signs 
endpoints will be determined for each subject:
•
The maximum decrease and increase from Baseline over all measurements taken post-
dose for systolic and diastolic blood pressures.
•
The maximum increase and decrease from Baseline over all measurements taken post-
dose for pulse rate.
The maximum increase from Baseline will be calculated by first subtracting the Baseline
value from each post-dose measurement to give the change from Baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken.  Similarly, the maximum decrease from Baseline will be determined by selecting the 
largest negative value of the changes from Baseline.  In cases where a subject does not show 
a decrease, the minimum increase should be taken.
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ECGs
Single 12-lead ECGs will be obtained on all subjects at times detailed in the Schedule of 
Activities given in the protocol.  Baseline is defined as the result closest prior to dosing on 
Day 1.
The QT, QTcF, heart rate, QRS and PR will be recorded at each assessment time.  If not 
supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3, where RR = 60/HR (if RR is not provided)
The maximum absolute value (post-dose) and the maximum increase from Baseline for QTcF, 
heart rate, PR and QRS, will be determined among overall post-Baseline measurements for 
each subject.
The maximum increase from Baseline will be calculated by firstly subtracting the Baseline
value from each post-dose measurement to give the change from Baseline.  The maximum of 
these values over the respective period will then be selected, except in the case where a 
subject does not show an increase.  In such an instance, the minimum decrease should be 
taken preserving the sign of change.
Non-Standard Safety Assessments
Serum creatinine (Scr) and serum cystatin C will be collected as part of the safety panel. 
From Scr estimated glomerular filtration rate (eGFR) will be calculated, if not supplied, 
using the modification of diet in renal disease (MDRD) equation.
MDRD Formula:
GFR (mL/min/1.73 mt) = 175  (Scr)-1.154  (Age)-0.203  (0.742 if female)  (1.212 if 
black)
GFR will be estimated from the cystatin C using the CKD-Epi-Cystatin C equation:
•
For serum cystatin C (Scys) ≤0.8 mg/L:
eGFR (mL/min/1.73 mt) = 133×(Scys/0.8)-0.499×0.996Age[×0.932 if female]
•
For serum cystatin C (Scys) >0.8 mg/L:
eGFR (mL/min/1.73 mt) = 133×(Scys/0.8)-1.328×0.996Age[×0.932 if female]
Baseline is defined as the result closest prior to dosing on Day 1.
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4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
The Full Analysis Set (FAS) is defined as all randomized subjects who received at least one
dose of IP; subjects are assigned to the randomized treatment regardless of what treatment 
was received.  This is the primary analysis population for all efficacy analyses.
4.2. Per Protocol Analysis Set
This will not be used in the current study.
4.3. Safety Analysis Set
All subjects who receive at least one dose of IP post-randomization will be included in the 
safety analyses and listings.  All safety endpoints will be analyzed by the treatment that the 
subjects actually receive (for the majority of the study duration) regardless of which 
treatment group they are randomized.  A randomized but not treated subject will be excluded 
from the safety analyses.  A treated but not randomized subject will be reported under the 
treatment actually received.
4.4. Other Analysis Sets
 
Pharmacogenomic and biomarker data will be collected and retained for future analyses, but 
will not be analyzed for the purposes of CSR.  
5. GENERAL METHODOLOGY AND CONVENTIONS
The analysis will be performed after database release, following last subject last visit.
5.1. Hypotheses and Decision Rules
The following null hypotheses will be tested for the primary endpoint:
1. The PF-05221304 + PF-06865571 combination  is equal in effect to placebo.
2. The PF-05221304 monotherapy is equal in effect to placebo.
3. The PF-06865571 monotherapy is equal in effect to placebo.
4. The PF-05221304 + PF-06865571 combination  is equal in effect to the PF-05221304 
monotherapy.
5. The PF-05221304 + PF-06865571 combination  is equal in effect to the PF-06865571 
monotherapy.
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The alternative hypotheses corresponding to the above null hypotheses will be the following 
2-sided hypotheses:
1. The PF-05221304 + PF-06865571 combination  is different from the effect of 
placebo.
2. The PF-05221304 monotherapy is different from the effect of placebo.
3. The PF-06865571 monotherapy is different from the effect of placebo.
4. The PF-05221304 + PF-06865571 combination  is different from the effect of the PF-
05221304 monotherapy.
5. The PF-05221304 + PF-06865571 combination  is different from the effect of the PF-
06865571 monotherapy.
The following confidence intervals (CIs) associated with the above hypotheses will be 
constructed:
1. 2-sided 90% CI
2. 2-sided 90% CI
3. 2-sided 90% CI
4. 2-sided 90% CI and 2-sided 50% CI
5. 2-sided 90% CI and 2-sided 50% CI
No adjustment for multiple comparisons will be made.
Interim analyses (IAs) may be performed for safety or efficacy (see Section 7 for further 
detail). IA results may be used for internal business decisions regarding future study 
planning or stopping for futility. As such no adjustment in the Type I error rate is proposed.
5.2. General Methods
Descriptive Statistics
Descriptive statistics, including the sample size, mean, standard deviation (STD), median, 
minimum (min), and maximum (max) values, will be provided for continuous endpoints.  
Some measures will be summarized using graphical representations by treatment and study 
day of visit, where appropriate.
Mixed Model for Repeated Measurements (MMRM)
This model will be used for the analysis of endpoints with more than one post-Baseline
collection time point.  All observed data collected during the post-Baseline treatment period 
will be utilized.  The MMRM analysis will be performed with treatment, study day and 
treatment-by-study day interaction as fixed effects, Baseline value of the analysis endpoint, 
and Baseline whole liver PDFF.  If the endpoint being analyzed is log-tranformed, the 
Baseline value of the analysis endpoint and the Baseline whole liver PDFF will also be log-
transformed.  Repeated measures model with unstructured correlation matrix will be utilized.  
If this does not converge then compound symmetry structure will be considered. 
Additionally, the number of covariates may be reduced to improve model fit.  Estimates of 
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treatment effects will be assessed using least square means (LSMs) and CIs at each time 
point.  LSM difference for each comparison along with the CIs and 2-sided p-values will be 
provided.  If there are major deviations from the statistical assumptions underlying this 
model then alternative transformations (eg, log) or non-parametric analyses may be 
presented. Justification for any alternative to the planned analysis will be given in the study 
report.
Analysis of Covariance 
The ANCOVA model will be used with continuous endpoints for landmark (single time 
point) analyses.  The model will include treatment group as fixed effect, Baseline value of 
the endpoint being analyzed, Baseline whole liver PDFF as covariates.  Diabetes status will 
be included as a covariate for the primary endpoint only if at least 1/3 of the subjects have
T2DM. If the endpoint being analyzed is log-tranformed, the Baseline value of the analysis 
endpoint and the Baseline whole liver PDFF will also be log-transformed. Estimates of 
treatment effects will be assessed using LSMs and CIs.  Estimates of the mean differences for 
each comparison and the corresponding CI will be obtained from the model.  If there are 
major deviations from the statistical assumptions underlying this model then alternative 
transformations (eg, log) or non-parametric analyses may be presented.  Justification for any 
alternative to the planned analysis will be given in the study report.  
Non-parametric Analysis
If the data have many outliers even after the log-transformation the following non-parametric 
analysis will be performed instead of the linear model.  An outlier will be defined as any 
datapoint falling outside of 3.5x STD ± the median.  Additional evaluative statistics will be 
conducted to explore the nature of the outliers in order to determine the appropriateness of a 
parametric analysis.
For group medians, 90% CIs will be presented.  In addition the CIs (see Section 5.1) will also 
be presented for differences in group medians from placebo group median.  The method of 
McGill, Tukey, and Larson1 will be employed to calculate the CI for the difference in 
treatment group medians.
5.3. Methods to Manage Missing Data
In case of continuous endpoints, all available data will be utilized in the MMRM.  The 
MMRM will provide unbiased estimates in case of missing at random (MAR).  For the 
analysis of safety endpoints, the sponsor data standard rules for imputation will be applied. In 
case of biomarkers if the concentrations are above the upper limits of quantification such 
values will be truncated at the upper limit of quantification in all summary tables. If the 
concentrations are below the lower limits of quantification (LLQ) such values will be 
imputed by 0.5*LLQ. However, in listings they will appear as reported.
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In all pharmacokinetic data presentations (except listings), concentrations below the limit of 
quantification (BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, 
where “LLQ” will be replaced with the value for the LLQ.)
In summary tables and plots of the median values at each time point, statistics will be 
calculated having set concentrations to missing if one of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged 
anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint: Whole Liver PDFF
Primary Analysis
o
Analysis endpoint:  Whole liver PDFF
o
Analysis time points:  Day 42
o
Analysis population:  Full Analysis set
o
Analysis methodology:  Natural log-transformed individual relative change (RC) 
from Baseline to Day 42 in whole liver PDFF will be analyzed using the 
ANCOVA.  The model will include natural log-transformed Baseline whole liver 
PDFF. Baseline diabetes status will be included as a covariate only if  at least 1/3 
of the subjects have T2DM.
Reporting results:

Raw data:  The sample size, mean, STD, median, min and max at Baseline and Day 
42 visit will be presented for each treatment arm.

%CBL:  The sample size, mean, STD, median, min and max will be presented for 
each treatment arm at Day 42. The LSMs and their CI will be exponentiated to 
provide estimates of the RC which will be converted to percent change as follows:
Percent change = 100* (RC - 1).
Estimates of the mean relative changes between placebo and each active drug arm 
(PF-05221304 monotherapy, PF-06865571 monotherapy and PF-05221304 plus 
PF-06865571 combination) at Day 42, and the corresponding 90% CI will be 
obtained from the model.  The 2-sided p-values will also be presented.
PF-05221304 plus PF-06865571 combination will be compared to each monotherapy 
through estimates of the mean relative change and corresponding 50% and 90% CIs.
The 2-sided p-values will also be presented.
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Figures
•
Mean + CI plot of the model-derived LSMs in %CFB for all treatment groups 
including the placebo group with 90% CI will be provided for Day 42 with treatment 
group on the X-axis.
•
Mean + CI plot of the placebo-adjusted LSMs with 90% CI for the each active drug 
arm (PF-05221304 monotherapy, PF-06865571 monotherapy and PF-05221304 plus 
PF-06865571 combination) will be provided for Day 42 with treatment on the X-axis.
•
Mean + CI plot of the LSM differences with 50% and 90% CIs for the comparison 
between the PF-05221304 plus PF-06865571 combination and each monotherapy will 
be provided for Day 42 with treatment on the X-axis.
•
Box and whisker plots for individual percent change from Baseline versus treatment 
will be presented and overlaid with arithmetic means.
Reporting results:
The LSMs, 90% CI for the LSMs, difference between the LSM for each of the 5 
treatment comparisons (same as those indicated for the primary analysis) , and the 
corresponding 90% CI (as well as 50% CI for the 2 comparions: the PF-05221304 plus 
PF-06865571 combination vs, each monotherapy) and the 2-sided p-values will be 
presented for whole liver PDFF.
6.2. Secondary Endpoint(s)
The analyses of safety endpoints will be described in Section 6.6.
6.3. Other Endpoints
The below table lists the exploratory endpoints with the corresponding descriptive statistics 
to be presented.  Full analysis set will be utilized.
Table 2. Exploratory Endpoints - Descriptive Summary
Exploratory Endpoints
Descriptive Statistics
Raw values and % CBL in ALT, AST, 
Alkaline Phosphatase and GGT, at all relevant 
collection time point(s) including follow-up
N, Mean, Median, STD, Min and Max at 
all planned day(s) of collection
Raw values and % CBL in Triglycerides, Total 
cholesterol, HDL-C, direct LDL-C, Total 
cholesterol/HDL-C ratio, and non HDL-C, at 
all relevant collection time point(s)  including 
follow-up
N, Mean, Median, STD, Min and Max at 
all planned day(s) of collection
 
 
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Raw values and % CBL in Apolipoproteins 
(A1, B100 and C3). at all relevant collection 
time point(s) 
N, Mean, Median, STD, Min and Max at 
all planned day(s) of collection
 
 
 
 
 
 
 
 
 
 
Raw values and % CBL in plasma PCSK9, at 
all relevant collection time point(s) including 
follow-up 
N, Mean, Median, STD, Min and Max at 
all planned day(s) of collection
 
 
The LSMs, 90% CI for the LSMs, difference between the LSM for each of the 5 
treatment comparisons (same as those indicated for the primary analysis) , and the 
corresponding 90% CI and the 2-sided p-values will be calculated using the 
MMRM/ANCOVA methods described in Section 5.2 as appropriate.  The details of the 
model terms are provided in the below table.
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Table 3. Exploratory Endpoints Modeling Details
Exploratory Endpoints
Description of the Model Terms
% CBL in ALT, AST, Alkaline 
Phosphatase and GGT, at all post-
Baseline time points
Model: MMRM
Response: natural log-transformed RC
Covariates: Treatment, Study Day, 
Treatment*Study Day, log (Baseline value), log 
(Baseline whole liver PDFF) 
% CBL in Triglycerides, Total 
cholesterol, HDL-C, direct LDL-C, 
Total cholesterol/HDL-C ratio, and non 
HDL-C at all post-Baseline time points
Model: MMRM
Response: natural log-transformed RC
Covariates: Treatment, Study Day, 
Treatment*Study Day, log (Baseline value), log 
(Baseline whole liver PDFF) 
 
 
 
 
% CBL in fasting plasma PCSK9 at Day 
42
Model: ANCOVA
Response: natural log-transformed RC
Covariates: Treatment, log (Baseline value), log 
(Baseline whole liver PDFF) 
In addition, figures will be generated for the following endpoints.
Table 4. Figures for Exploratory Endpoints
Exploratory Endpoints
Figure Descriptions
 
 
 
 
% CBL in fasting plasma PCSK9 at Day 
Box and whisker plot of individual % CBL 
versus treatment will be presented and overlaid 
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42
with arithmetic means.
% CBL in Triglycerides, Total 
cholesterol, HDL-C, direct LDL-C, Total 
cholesterol/HDL-C ratio, and non HDL-
C at Baseline and all post-Baseline time 
points
Line plot of LSMs with 90% CIs for all 
treatment groups including the placebo group 
with time on X-axis.  Four (4) lines 
corresponding to the 4 treatment groups will be 
overlaid on the same plot.
% CBL in AST, ALT, ALP, GGT at 
Baseline and all post-Baseline time 
points
Line plot of LSMs with 90% CIs for all 
treatment groups including the placebo group 
with time on X-axis.  Four (4) lines 
corresponding to the 4 treatment groups will be 
overlaid on the same plot.
 
 
 
 
 
 
 
 
 
 
• Pharmacogenomic and biomarker data:
Pharmacogenomic and biomarker data will be collected and retained for future 
analyses, but will not be analyzed for the purposes of CSR.
6.4. Subset Analyses
For the primary endpoint subset analysis by the whole liver PDFF stratification categories 
provided below may be considered.
•
Screening liver fat ≥8% and <15%;
•
Screening liver fat ≥15%.
C
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  If any site enrolls 50% or more of the total number of 
subjects in the study site-specific analysis may be conducted.
6.5. Baseline and Other Summaries and Analyses
A breakdown of demographic data will be provided for age, race, weight, height and body 
mass index.  Each of these will be summarized by sex at birth and treatment in accordance 
with the sponsor reporting standards.  In addition, the demographic data will be summarized 
by treatment only in accordance with the sponsor reporting standards.  Baseline summary of 
fasting glucose, triglycerides, HDL-C, waist circumference, AST, ALT, alkaline 
phosphatase, GGT and whole liver PDFF will be presented for each treatment group and 
overall.  Baseline summary of stratification factors, namely, diabetes status (presence or 
absence) and MRI-PDFF categories (≥8% and <15% or ≥15%) will be provided.  The 
number and proportion of subjects enrolled in each study site will also be presented.
Summary tables will show end of study subject disposition and will show which subjects 
were analyzed for pharmacodynamic (FAS) 
 as well as for safety 
(AEs and laboratory data).  Frequency counts will be supplied for subject discontinuation(s) 
by treatment.  Data will be reported in accordance with the sponsor reporting standards.
6.6. Safety Summaries and Analyses
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of the study treatments.
The standard safety endpoints detailed in Section 3.5 will be listed and summarized in 
accordance with sponsor reporting standards, where the resulting data presentations will 
consist of subjects from the safety analysis sets. The analyses of non-standard safety data will 
also utilize safety analysis set and the methods are described below.
Any untoward findings identified on physical examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.
Adverse Events
Adverse events will be summarized by treatment and in accordance with current Pfizer data 
standards. The AEs will be sorted alphabetically within a system organ class. Summary 
tables will be provided for treatment-emergent adverse events (TEAEs) and AEs occurring 
prior to randomization will only be listed.
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Laboratory Data
All planned, quantitative, standard safety laboratory data presented in Table 7 of the protocol 
and non-standard safety laboratory data that are not reported independently will be listed and 
summarized in accordance with the sponsor reporting standards as applicable. Baseline is as 
defined in Section 3.5.2.
Vital Signs
Absolute values and changes from Baseline in seated systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and study day, according to sponsor 
reporting standards.  Tables will be paged by parameter.  Baseline is as defined in Section 
3.5.3.
Mean changes from Baseline for systolic and diastolic blood pressure and pulse rate will be 
plotted against study day.  On each plot there will be one line for each treatment, with all 
treatments on the same plot, including the placebo.  
For Baseline subtracted seated systolic and diastolic blood pressure and pulse rate, the 
differences between each dose and placebo (dose – placebo) will be summarized (N, mean, 
90% CI) and plotted (mean, 90% CI) for each dose and day including follow-up.  
Maximum absolute values and maximum changes from Baseline for vital signs, over all 
measurements taken post-dose after randomization will also be tabulated by treatment using 
categories as defined in the Appendix.  Numbers and percentages of subjects meeting the 
categorical criteria will be provided.  All planned and unplanned post-dose time points will 
be counted in these categorical summaries.  All values meeting the criteria of potential 
clinical concern will be listed.
Maximum decrease and increase from Baseline for seated systolic and diastolic blood 
pressures, and maximum increase from Baseline for seated pulse rate will be summarized by 
treatment, according to sponsor reporting standards.
Electrocardiogram
Absolute values and changes from Baseline in QT, heart rate, QTcF, QTc, PR, and QRS will 
be summarized by treatment and day using sponsor reporting standards.  Tables will be 
paged by parameter.  Baseline is as defined in Section 3.5.4.
Mean changes from Baseline in QT, heart rate and QTcF will be plotted against study day.  
On each plot there will be one line for each treatment, with all treatments on the same plot 
including the placebo.  
In addition for Baseline subtracted QT, heart rate and QTcF, the differences between each 
dose and placebo (dose – placebo) will be summarized (N, mean, 90% CI) and plotted (mean, 
90% CI) for each dose and day including follow-up.
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ECG endpoints and changes from Baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in the Appendix (for QTc these 
correspond to ICH E14).  Numbers and percentages of subjects meeting the categorical 
criteria will be provided.  All planned and unplanned postdose timepoints will be counted in 
these categorical summaries.  All values meeting the criteria of potential clinical concern will 
be listed.
Maximum absolute value (post-dose after randomization) and the maximum increase from 
Baseline for QTcF, PR and QRS will be summarized by treatment according to sponsor 
reporting standards.
Listings of subjects with any single post-dose value >500 msec will also be produced for 
QTcF.
Non-standard Safety Analysis
Serum Creatinine, Serum Cystatin C and Associated eGFRs
Absolute values and changes from Baseline in Scr, serum cystatin C, eGFRs obtained from 
Scr and cystatin C will be summarized by treatment and day. Mean absolute values of all 
four parameters will be plotted separately against study day. On each plot there will be one
line for each treatment, all treatments on the same plot including the placebo. Mean changes 
from Baseline in eGFRs will also be plotted against study day.
7. INTERIM ANALYSES
If, after randomization of approximately 50% subjects of planned number of subjects, a 
monthly safety review reveals that the study meets one or more criteria listed in Protocol
Section 3.3, an interim analysis will be performed in an un-blinded manner by a pre-
specified IRC, independent from study team.  
 
 
 
 
 
  
Before any interim analysis is initiated, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs will be 
documented and approved in an IRC charter.  The analysis details will be documented and 
approved in an interim analysis SAP or final SAP.
An IA will be conducted after approximately 50% of randomized subjects reach their Week 6 
visit (ie, Visit 10 in Schedule of Activities) or drop out of the study before that visit. 
The analysis sets for the IA are:
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1. Safety Analysis Set: All randomized and treated subjects
2. Efficacy/PD Analysis Set: All randomized and treated subjects who completed their 
Week 6 visit (ie, Visit 10 in Schedule of ActivityActivityActivities) or discontinued 
the study.
For whole liver PDFF, triglycerides (and total cholesterol, HDL-C, direct LDL-C, Total 
cholesterol/HDL-C ratio, and non HDL-C, AST, ALT, ALP, GGT), the descriptive 
summarization and inferential statistical analysis (ANCOVA or MMRM) as indicated in 
Section 6 will be performed using the Efficacy/PD Analysis Set.  Standard safety data as 
described in the IRC Charter2 will be summarized using the Safety Analysis Set.  The figures 
related to these descriptive and inferential analyses will be using the “Efficacy/PD Analysis 
Set”.  
For whole liver PDFF and triglycerides, additional analysis related to predictive probability 
will be conducted. The Bayesian predictive probability3 that the following decision critera 
will be met at the end of the study given the interim data will be calculated using Pfizer 
internal validated software4.  The IRC Statistician will utilize the IA outputs (from ANCOVA 
analysis for whole liver PDFF and MMRM analysis for triglycerides) to compute the 
predictive probabilities, and will then provide the probability values to the unblinded 
programmer to be included in the IA table outputs.
Safety:
S-C1: At least 95% confident that change from Baseline to Day 42 in triglycerides level with 
the combination treatment ACC+DGAT is less than the ACC monotherapy treatment
Predictive probability of meeting S-C1 at the end of study, based on interim data, will be 
computed.
Efficacy:
E-C1: At least 95% confident that the relative reduction from Baseline to Day 42 in whole 
liver PDFF with the combination treatment ACC+DGAT is larger than the DGAT 
monotherapy treatment
Predictive probability of meeting E-C1 at the end of study, based on interim data, will be 
computed.
8. REFERENCES
1. McGill, R., John W. Tukey and W. A. Larsen. 1978. "Variations of Box Plots." 
American Statistician 32:12-16
2. C3711001 Internal Review Committee (IRC) Charter Amendment 1.
3. Grieve AP (1991) Predictive probability in clinical trials: Biometrics, 47(1) 323-9
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4. Pfizer Internal Predictive Probability Calculation Tool: http://shiny-
stats.pfizer.com/Statistics/predictive_probabilities/calculator_v1.0/
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9. APPENDICES
9.1. Categorical Classes for ECG and Vital Signs
Categories for QTcF
Categories for Maximum Post-dose QTc (msec)
All subjects
≤450
450 - ≤480
480 - ≤500
>500
Categories for Maximum Increase from Baseline in QTc (msec)
All Subjects
≤30
30 - İ60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from Baseline
Baseline >200 and 
max. ≥25% increase
Baseline ≤200 and 
max. ≥50% increase
QRS (ms)
max. ≥140
QRS (ms) increase 
from Baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from Baseline
max. decrease ı30
max. increase ı30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from Baseline
max. decrease ı20
max. increase ı20
Seated pulse rate (bpm)
min. <40
max. >120
•
Measurements that fulfill these criteria are to be listed in the report.
Calculation of %CBL
%CBL = 100*(Post-Baseline value – Baseline value) / Baseline value
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9.2. Predictive Probability
#R Code to calculate predictive probability from 'Interim Predictive Probability Calculator'
#Version: 1.01
#Created: 07-Aug-2019
#Inputs:
i_e_dir <- 2    # direction of effect of interest
                        # 1 = Group 1 is greater than Group 2; 2 = Group 1 is less than Group 2
i_e_tv <- 0     # tv = target value
i_e_sig <- 0.95    # confidence level
i_e_nAtot <- 28   # sample size for Group 1 at study end
i_e_nPtot <- 28    # sample size for Group 2 at study end
# The following inputs will be taken from the ANCOVA (liver fat) or MMRM (trigylcerides) 
interim analysis
i_r_nAint <-    # sample size for Group 1 at interim
i_r_nPint <-     # sample size for Group 2 at interim
i_r_meanA <-    # model-adjusted mean for Group 1 at interim from MMRM or ANCOVA
i_r_meanP <-     # model-adjusted mean for Group 2 at interim from MMRM or ANCOVA
i_r_sigma <-      # ssigma estimated at interim from MMRM or ANCOVA
  # Adapted from equations 1-4 from 'Bayesian Interim Predictive Analysis Guidance' 
document (v1.0 19 September 2018)
    
  # Derived:
  i_nAU <- i_e_nAtot-i_r_nAint
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Protocol C3711001 (PF-05221304 and PF-06865571) Statistical Analysis Plan
Page 28
  i_nPU <- i_e_nPtot-i_r_nPint
  if(i_e_dir==1){ #Greater than
    z <- qnorm(i_e_sig)  
  } else if(i_e_dir==2){ #Less than
    z <- qnorm(1-i_e_sig)  
  }
  
  #Calculate numerator of equation:
  postSD <- i_r_sigma*sqrt((i_e_nAtot+i_e_nPtot)/(i_e_nAtot*i_e_nPtot))
  num_eq <- i_e_tv + z*postSD - (i_r_meanA - i_r_meanP)
  
  #Calculate denominator of equation:
  den_eq <-
i_r_sigma*sqrt(((i_nAU/i_e_nAtot)^2)*(1/i_r_nAint+1/i_nAU)+((i_nPU/i_e_nPtot)^2)*(1/i_
r_nPint+1/i_nPU))
  
  #Determine predictive probability:
  eq_result <- num_eq/den_eq
  if(i_e_dir==1){ #Greater than
    predProb <- 1-pnorm(eq_result)
  } else if(i_e_dir==2){ #Less than
    predProb <- pnorm(eq_result)
  }
#Predictive probability:
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Protocol C3711001 (PF-05221304 and PF-06865571) Statistical Analysis Plan
Page 29
print(paste0(100*predProb,"%"))
Example Output: Summary of Predictive Probability for IA
Safety:
Treatment
LSM (S.E.)
Difference vs.
PF-05221304 
(S.E)
Predictive 
Probability of 
Passing S-C1*
PF-06865571 + PF-05221304
(ie, DGAT + ACC)
xx.xx (xx.xx)
xx.xx (xx.xx)
0.xx
PF-05221304 (ie, ACC)
xx.xx (xx.xx)
*S-C1 is the safety criterion defined in Section 7  
S.E = Standard Error
Efficacy:
Treatment
LSMeanLSMeanLSM
(S.E.)
Difference 
vs. PF-
06865571 
(S.E)
Predictive 
Probability of 
Passing S-C1*
PF-06865571 + PF-
05221304
(ie, DGAT + ACC)
xx.xx (xx.xx)
xx.xx (xx.xx)
0.xx
PF-06865571 (ie, DGAT)
xx.xx (xx.xx)
*E-C1 is the efficacy criterion defined in Section 7  
S.E = Standard Error
CCI