Clinical trial NCT03513588
Conditions: Non-alcoholic Steatohepatitis Non-alcoholic Fatty Liver Disease
Sponsor: Pfizer
Start date: 2018-06-21; Completion date: 2019-04-04
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
2-week study in people with nonalcoholic fatty liver disease. Study drug at 1 of 2 doses, or placebo, will be given for 14 days. Blood samples, heart monitoring, vital signs, and imaging procedures will be performed.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Placebo intervention 2: PF-06865571 intervention 3: PF-06865571
Intervention descriptions: intervention 1: tablet, 0 mg, 14 days, every 12 hours intervention 2: tablet, 50 mg, 14 days, every 12 hours intervention 3: tablet, 300 mg, 14 days, every 12 hours

Protocol documents:
Prot_000.pdf: 
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Final Protocol, 27 February 2018
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A PHASE 1B, RANDOMIZED, DOUBLE-BLIND (SPONSOR-OPEN), 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE 
SAFETY, TOLERABILITY, PHARMACODYNAMICS AND 
PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-06865571 FOR 
2 WEEKS IN ADULTS WITH NONALCOHOLIC FATTY LIVER DISEASE
Investigational Product Number:
PF-06865571 
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational 
New Drug (IND) Number:
European Clinical Trials 
Database (EudraCT) Number:
N/A
Protocol Number:
C2541005
Phase:
1b
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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
27 February 2018
N/A


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................8
1. INTRODUCTION ...............................................................................................................11
1.1. Mechanism of Action/Indication.............................................................................11
1.2. Background .............................................................................................................11
1.2.1. Nonclinical Primary Pharmacology............................................................12
1.2.1.1. In Vitro Assays..........................................................................12
1.2.1.2. In Vivo Studies..........................................................................12
1.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................12
1.2.3. Summary of Toxicology Studies ................................................................13
1.2.4. Preliminary Summary of Clinical Experience............................................14
1.3. Study Rationale .......................................................................................................16
1.3.1. Study Design Rationale ..............................................................................16
1.3.1.1. Study Population .......................................................................18
1.3.2. Dose Rationale............................................................................................19
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................20
3. STUDY DESIGN.................................................................................................................21
3.1. Study Overview.......................................................................................................21
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................22
4.1. Inclusion Criteria.....................................................................................................22
4.2. Exclusion Criteria....................................................................................................23
4.3. Randomization Criteria ...........................................................................................27
4.4. Lifestyle Requirements ...........................................................................................27
4.4.1. Meals and Dietary Restrictions...................................................................27
4.4.2. Alcohol, Caffeine, and Tobacco .................................................................28
4.4.3. Activity .......................................................................................................29
4.4.4. Contraception..............................................................................................29
4.5. Sponsor’s Qualified Medical Personnel..................................................................30
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5. STUDY TREATMENTS.....................................................................................................30
5.1. Allocation to Treatment ..........................................................................................30
5.2. Breaking the Blind ..................................................................................................31
5.3. Subject Compliance.................................................................................................32
5.4. Investigational Product Supplies.............................................................................32
5.4.1. Dosage Form and Packaging ......................................................................32
5.4.2. Preparation and Dispensing........................................................................32
5.5. Administration.........................................................................................................32
5.6. Investigational Product Storage ..............................................................................33
5.7. Investigational Product Accountability...................................................................33
5.7.1. Destruction of Investigational Product Supplies ........................................34
5.8. Concomitant Treatments .........................................................................................34
5.8.1. Anti-Hypertensive Medications..................................................................34
5.8.2. Lipid-Modifying Medications ....................................................................34
5.8.3. Other Acceptable Concomitant Medications..............................................35
5.8.4. Prohibited Concomitant Medications .........................................................35
5.9. Rescue Medication ..................................................................................................37
6. STUDY PROCEDURES .....................................................................................................37
6.1. Proposed Chronology of Procedures.......................................................................37
6.2. Screening.................................................................................................................38
6.3. Study Period ............................................................................................................38
6.4. Follow-up ................................................................................................................39
6.5. Subject Withdrawal.................................................................................................39
7. ASSESSMENTS..................................................................................................................41
7.1. Safety.......................................................................................................................41
7.1.1. Laboratory Tests .........................................................................................41
7.1.2. Serum for Cystatin C ..................................................................................43
7.1.3. Physical Examinations................................................................................43
7.1.4. Body Weight...............................................................................................43
7.1.4.1. Adjustment of Caloric Intake to Maintain Stable Body 
Weight ...............................................................................................44
7.1.5. Blood Pressure and Pulse Rate ...................................................................44


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7.1.6. Electrocardiogram.......................................................................................44
7.2. Pharmacokinetics ....................................................................................................45
7.2.1. Plasma for Analysis of PF-06865571.........................................................45
7.5. Imaging Assessments ..............................................................................................49
7.5.2. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis......49
7.5.3. Analysis of MRI-PDFF Images Including Determination of 
Eligibility .........................................................................................................50
7.5.4. Management of Incidental Findings...........................................................50
7.5.5. Post-hoc Analyses.......................................................................................51
7.6. Potential Cases of Acute Kidney Injury..................................................................51
7.7. Blood Volume .........................................................................................................52
8. ADVERSE EVENT REPORTING......................................................................................52
8.1. Requirements...........................................................................................................52
8.1.1. Additional Details on Recording Adverse Events on the CRF...................53
8.1.2. Eliciting Adverse Event Information..........................................................53
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................53
8.1.4. Time Period for Collecting AE/SAE Information......................................54
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................54
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................54
8.1.5. Causality Assessment .................................................................................54
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................55
8.2. Definitions...............................................................................................................55
8.2.1. Adverse Events...........................................................................................55
8.2.2. Abnormal Test Findings .............................................................................56
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8.2.3. Serious Adverse Events ..............................................................................56
8.2.4. Hospitalization............................................................................................57
8.3. Severity Assessment................................................................................................58
8.4. Special Situations ....................................................................................................58
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................58
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................60
8.4.2.1. Exposure During Pregnancy......................................................60
8.4.2.2. Exposure During Breastfeeding ................................................61
8.4.2.3. Occupational Exposure .............................................................61
8.4.3. Medication Errors .......................................................................................62
8.4.3.1. Medication Errors......................................................................62
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................63
9.1. Sample Size Determination.....................................................................................63
9.2. Efficacy Analysis ....................................................................................................63
9.2.1. Analysis of the Primary Endpoint...............................................................63
9.3. Pharmacokinetic Analysis.......................................................................................64
9.3.1. Derivation of Pharmacokinetic Parameters ................................................64
9.6. Safety Analysis........................................................................................................65
9.6.1. Electrocardiogram Analysis........................................................................65
9.7. Interim Analysis ......................................................................................................66
9.8. Data Monitoring Committee ...................................................................................66
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................66
11. DATA HANDLING AND RECORD KEEPING .............................................................67
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................67
11.2. Record Retention...................................................................................................67
12. ETHICS..............................................................................................................................68
12.1. Institutional Review Board/Ethics Committee......................................................68
12.2. Ethical Conduct of the Study ................................................................................68
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12.3. Subject Information and Consent..........................................................................68
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................69
13. DEFINITION OF END OF TRIAL...................................................................................69
13.1. End of Trial in the United States...........................................................................69
14. SPONSOR DISCONTINUATION CRITERIA ................................................................69
15. PUBLICATION OF STUDY RESULTS..........................................................................69
15.1. Communication of Results by Pfizer ....................................................................69
15.2. Publications by Investigators ................................................................................70
16. REFERENCES ..................................................................................................................72
LIST OF TABLES
Table 1.
Overall Visit Schedule and List of Procedures.......................................................8
Table 2.
Schedule of Activities – Study Days -1, 1, 7 & 14...............................................10
Table 3.
Summary of Plasma PF-06865571 PK Parameters Following Single Oral 
Doses in C2541001...............................................................................................15
Table 4.
Summary of Preliminary Steady State (Day 14) Plasma PF-06865571 PK 
Parameters Following Multiple Oral Doses in C2541002....................................16
Table 5.
Predicted Steady-State PF-06865571 Exposures with Administration of 
Multiple Doses of PF-06865571 Under Fed Conditions......................................20
Table 6.
Clinical Laboratory Tests .....................................................................................42
Table 7.
Definition of Steady State (Day 14) Plasma PK Parameters for 
PF-06865571.........................................................................................................64
LIST OF FIGURES
Figure 1.
Design of Study C2541005...................................................................................21
APPENDICES
Appendix 1. Abbreviations......................................................................................................74
Appendix 2. Strong CYP3A Inhibitors and Inducers* ............................................................78


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to Section 6 and Section 7 of the 
protocol for additional information on each procedure and assessment required for compliance with the protocol. The investigator 
may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct evaluations or 
assessments required to protect the well-being of the subject.
Table 1.
Overall Visit Schedule and List of Procedures
Protocol Activity
Screening
Day -2 Study Day (all activities at 0H [prior to dosing] unless otherwise specified)a
Follow-upb
Days Relative to Dosing on Day 1
Screen 1 Screen 2 Screen 3
-1
1
2
3
4
5
6
7
8
9
10
11
12
13 14 15
16
Visit
Contact
Visit
1
2
3
4
5
-
Informed consent & demography
x
Outpatient visit (after ≥8H fast)
x
x
Adverse event monitoring
x
x
→→→
→
→
→
→→
→
→
→
→
→
→→→
x
x
x
Inpatient stay at CRU
xc
→→→
→
→
→
→→
→
→
→
→
→
→→→
x
Medical & medication history
x
x
Refer to Tabl
Refer to Tabl
Refer to Tabl
Refer to Tabl
x
x
Review drug, alcohol/tobacco use
x
x
x
Review prior or concomitant treatments 
x
x
x
Review contraception use
x
x
x
x
Physical examination (height at Screen 1 only)d
x
x
x
Body weight
x
x
x
x
x
x
Triplicate, supine 12-lead ECGe
x
x
x
x
x
Single, supine vital signs assessmente
x
x
x
x
x
Liver fat and stiffness (via FibroScan®)ff
x
x
Liver fat via MRI-PDFF acquisitionf,g
x
x
x
Standardized meals/snacksh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Administration of blinded IPi
x
x
x
x
x
x
x
x
x
x
x
Blood sampling for:
- Clinical laboratory tests and serum cystatin Cj
x
x
x
x
x
- Serum FSH (females only), HIV, HepBsAg, 
HepBcAb, HCVAb testing
x
- Ceruloplasmin, A1AT, HbA1c
x
- PF-06865571 PKk
x
x
x
- Serum TG
x
- Plasma insulinj
x
x
x
x
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Protocol Activity
Screening
Day -2 Study Day (all activities at 0H [prior to dosing] unless otherwise specified)a
Follow-upb
Days Relative to Dosing on Day 1
Screen 1 Screen 2 Screen 3
-1
1
2
3
4
5
6
7
8
9
10
11
12
13 14 15
16
Visit
Contact
Visit
1
2
3
4
5
-
Urine sampling for:
- Urine drug test
x
- Urinalysis (and microscopy, as appropriate)
x
x
x
x
x
a.
Day relative to start of dosing of blinded investigational product (Day 1).
b.
Follow-up visit at 7-10 days following the last dose will be an outpatient visit to the site, while follow-up contact at 28-35 days following the last dose may occur via a follow-
up phone call.  Phone call may be a visit if deemed necessary by the investigator.
c.
Admission to CRU should occur prior to lunch on Day -2. 
d.
Full physical exam at Screen 1 and at Day 15; otherwise, limited exam if findings during previous exam or new/open AEs, if appropriate, at investigator discretion.
e.
Prior to AM dose.
f.
After ≥8H fast at outpatient visits; scans on Days -2 & 15 to occur post overnight fast of ≥8H at approximately same clock time (ie, within a practical window (±2 hours) 
relative to clock time of the Screening visits).  
g.
At Screen 3 visit after confirmation of all other eligibility.
h.
Meals to be provided at approximately 0H, 4H, and 10H post AM dose and snack to be provided at approximately 12H post AM dose, as specified in Section 4.4.1.  Day 16 
meal(s) are optional, according to clinical research unit (CRU) practice.
i.
Dosing to occur with breakfast and snack, as specified in Section 4.4.1.
k.
PK samples to be collected prior to dose.
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Table 2.
Schedule of Activities – Study Days -1, 1, 7 & 14
[Procedures at 0H to be completed prior to dosing or similar clock time, in the case of Day -1]
Hours Relative to Dosing at 0Ha
0
0.5
1
2
3
4
6
8
10
12
14
16
18
24
Continued inpatient stay at CRU
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Adverse event monitoring
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Body weight 
x
Triplicate, supine 12-lead ECG 
x
Single, supine vital sign assessment
x
Blinded IP administration (Days 1, 7 and 14 only)
xb
xc
Randomization (Day 1 only)
x
Blood sampling for:
- Clinical laboratory tests and serum cystatin Cd (Days 1, 7, and 14 only)
x
- PF-06865571 PK (Day 14 only)
x
x
x
x
x
x
x
x
- Serum triglycerides (Days -1, 1 and 14 only)d
xf
x
x
x
x
x
x
x
x
x
- Plasma insulind,g
x
Urine sampling for:
- Urinalysis and microscopy, as appropriate (Days 1, 7, and 14 only)
x
Mealsh
- Standardized meal
x
x
x
- Snack
x
a.
On Day -1, nominal time to approximately match clock time of collection planned on Day 1 to permit time-matched comparison. 
b.
Dosing expected to occur with breakfast.
c.
Dosing expected to occur with snack as specified in Section 4.4.1.
g.
Insulin samples collected in triplicate on Day -1 and Day 14.  On Day 1 and Day 7, only 1 sample will be collected.
h.
Meals/snacks to occur on all days while inpatient; identical meals/snacks on Days -2, -1, 1, 14, and 15.
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1. INTRODUCTION
Diacylglycerol acyltransferases (DGATs) catalyze the terminal step in triglyceride (TG) 
synthesis; specifically, the esterification of a fatty acid (FA) with diacylglycerol (DAG) 
resulting in the formation of TG.1  In mammals, 2 structurally unrelated DGAT enzymes 
(DGAT1 and DGAT2) have been characterized.  DGAT1 is highly expressed in the intestine 
and plays a central role in fat absorption.2  DGAT2 is highly expressed in liver and adipose.3  
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.4,5 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.5,6  
PF-06865571 is an oral, small molecule DGAT2 inhibitor that is postulated to decrease 
hepatic TG synthesis and hepatic lipid burden in non-alcoholic fatty liver disease (NAFLD) 
and non-alcoholic steatohepatitis (NASH).
The current study is the first designed to evaluate the safety, tolerability, pharmacokinetics 
(PK), and pharmacodynamics (PD) following administration of repeated (up to 14 days) oral 
doses of PF-06865571 in the fed state to adult subjects with NAFLD. 
1.1. Mechanism of Action/Indication
PF-06865571 is an oral, small molecule DGAT2 inhibitor that is currently being developed 
for the treatment of NASH.
1.2. Background 
NAFLD is estimated to affect at least 25% of the general population in Western countries, 
while the prevalence of NASH is estimated at 3 to 5%.7  NAFLD is strongly associated with 
obesity, insulin resistance, hypertension, and dyslipidemia and is now regarded as the hepatic 
manifestation of metabolic syndrome.8  NAFLD describes a spectrum of liver conditions 
whose dominant feature is hepatic TG accumulation.9  NASH is diagnosed clinically by liver 
biopsy demonstrating steatosis, inflammation, and ballooning of liver hepatocytes, often with 
varying degrees of fibrosis.  NASH progresses with increasing degrees of fibrosis, with 
cirrhosis and/or hepatocellular carcinoma developing in a subset of patients.10  Although the 
factors that promote TG deposition in the liver and transition from steatosis to NASH and 
cirrhosis in humans have not been clearly defined, hepatic steatosis arises from an imbalance 
between TG acquisition and removal.11  Although there is a growing body of evidence that 
demonstrates the urgent need for therapies for NASH, there are no currently approved 
therapies for the treatment of NASH.10
Hepatic TGs are derived from 3 principal sources: de-novo lipogenesis (DNL), 
re-esterification from FA supplied by the adipose, and dietary intake.11  While the largest 
contribution to the hepatic TG pool appears to be derived from lipolytic products originating 
in adipocytes, the lipogenic pathway plays an important role in the development of NAFLD 
and progression to NASH.12  The contribution of DNL to disease progression in NAFLD is 
supported by analyzing the FA composition of TGs in subjects with and without NAFLD.  
Data demonstrate an increased level of saturated FAs in those with NAFLD, implicating the 


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DNL pathway as an important contributor to hepatic steatosis as saturated FAs represent the 
primary product of DNL.12  These findings are consistent with the increased inclusion of 
DNL-derived TGs in VLDL particles in NAFLD where 15% of TG produced originated from 
DNL compared to only 2 to 5% in normal subjects consuming a typical Western diet.12  
Additionally, elevated rates of hepatic DNL have been reported to be a distinctive 
characteristic of NAFLD.13  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.  Consequently, when comparing the absolute sources of 
FAs incorporated into VLDL-TG, elevated hepatic DNL was the only source significantly 
elevated in subjects with high liver fat.13
Based on observations in nonclinical studies conducted with PF-06865571, it is hypothesized 
that DGAT2 inhibition will impact both physiological drivers contributing to NASH via 
direct inhibition of liver TG synthesis, as well as adaptive responses leading to reduction in 
hepatic DNL. 
1.2.1. Nonclinical Primary Pharmacology
1.2.1.1. In Vitro Assays
PF-06865571 is a potent and selective inhibitor of human DGAT2 (hDGAT2). 
 
 The selectivity of PF-06865571 for DGAT2 was supported 
by in vitro studies demonstrating >2000-fold selectivity by biochemical assessment versus 
related acyltransferases including recombinant human DGAT1 (hDGAT1), 
monoacylglycerol acyltransferase (MGAT)2 and MGAT3, as well as mouse MGAT1.  
 
 
 
1.2.1.2. In Vivo Studies
Following single dose administration, PF-06865571 demonstrates robust, dose-dependent 
reduction of plasma triacylglycerol in rats fed a high sucrose-diet.  In longer term studies in 
Western diet fed rats, PF-06865571 reduces both plasma triacylglycerol and hepatic lipid 
accumulation.  In line with the proposed mechanism of action, administration of
PF-06865571 in both sucrose and Western diet fed rats results in suppression of key genes 
involved in hepatic lipid metabolism, including the messenger ribonucleic acid (mRNA) 
expression of proprotein convertase subtilisin/kexin type 9 (PCSK9).  In these nonclinical 
models dosed with PF-06865571, PCSK9 mRNA was decreased relative to vehicle treated 
animals by 55% and 84% in the Western and sucrose-diet models, respectively.
1.2.2. Nonclinical Pharmacokinetics and Metabolism
Nonclinical data indicate that PF-06865571 has high passive permeability and is a substrate 
for multi-drug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp) and 
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mouse breast cancer resistant protein (mBCRP) efflux transporters.  PF-06865571 was 
rapidly absorbed in rat and moderately absorbed in the monkey with a mean oral 
bioavailability of 31% and 48%, respectively. 
Urinary excretion (rat and monkey) of unchanged drug was 1%, while biliary excretion of 
unchanged drug was <1% when assessed in bile duct cannulated rats.
PF-06865571 was moderately bound to plasma proteins in rat, monkey, and human with 
average fraction unbound (fu) ranging from 0.213 to 0.419, and preferentially distributes into 
plasma relative to blood with blood to plasma concentration ratio ranging between 0.659 and 
0.901.  The major clearance mechanism of PF-06865571 is predicted to be predominantly by 
CYP3A mediated metabolism with minor contributions by CYP2B6 and CYP2C19.  
There is no evidence of human-unique metabolites, and all metabolites detected in human 
cryopreserved hepatocytes were also observed in the nonclinical toxicology species (rat and 
monkey).  Reaction phenotyping studies indicate the total cytochrome P450 (CYP450) 
contribution to PF-06865571 metabolism was >96% and CYP3A is the predominant isoform 
responsible for the metabolism of PF-06865571.  Modeling suggests a moderate risk of 
clinical drug-drug interactions (DDIs) with PF-06865571 as a victim upon co-administration 
with CYP3A4 inhibitors or inducers.
Assessment of the DDI potential for PF-06865571 on selected CYP and UDP 
glucuronosyltransferase (UGT) enzymes and drug transporters is based on the predicted 
mean steady-state unbound Cmax of 555 ng/mL (~1.36 M) corresponding to the highest dose 
of PF-06865571administered in the current study (300 mg Q12H)).  PF-06865571 mediated 
DDIs resulting from inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP3A4/5
are not expected; however, PF-06865571 does have the potential to inhibit CYP2C9 and 
CYP2C19 at clinically relevant concentrations.  It is unlikely PF-06865571 will inhibit UDP 
UGT, 1A4, 1A6, 2B7, and 2B15 enzymes at clinically relevant concentrations; however, 
PF-06865571 does have the potential to inhibit UGT1A1 and UGT1A9.  PF-06865571 
demonstrated induction of CYP3A4 and CYP2B6 activity (mRNA and enzymatic) in human 
hepatocytes.  At the anticipated highest dose of PF-06865571 in currently planned clinical 
trials (300 mg twice daily [BID]), modeling suggests a moderate change in the exposure of 
CYP3A4 substrates primarily due to intestinal CYP induction.  In vitro evaluations indicate 
that PF-06865571 has a low potential to inhibit organic anion transporter (OAT)1, OAT3, 
multidrug and toxin extrusion protein (MATE)2K, organic cation transporter (OCT)1, 
organic anion transporting polypeptide (OATP)1B1, and OATP1B3 at clinically relevant 
concentrations.  However, PF-06865571 does have the potential to inhibit P-gp, breast cancer 
resistance protein (BCRP), MATE1, and OCT2 at clinically relevant concentrations. 
1.2.3. Summary of Toxicology Studies
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 
neuropulmonary and cardiovascular studies in rats and monkeys, respectively.  No adverse 


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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 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 BALB/c 3T3 mouse
fibroblasts. 
The no observed adverse effect levels (NOAELs) in the 6-week studies were the highest dose 
levels tested, 1000 (500 BID) mg/kg/day with associated unbound maximum observed 
concentration (Cmax) and area under the curve (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·hr/mL (ie, NOAEL exposures observed in rats). 
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the investigator’s brochure (IB) for PF-06865571. 
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1.3. Study Rationale 
The current study is the first to evaluate the effect of PF-06865571 (compared to placebo) on 
liver fat, as assessed via magnetic resonance imaging proton density fat fraction 
(MRI-PDFF), 
  The 
investigational product (IP) will be administered orally for 2 weeks.  
1.3.1. Study Design Rationale 
Along with an assessment of the effect of PF-06865571 on liver fat, this study is designed to 
assess the safety and tolerability of 2 different oral dosing regimens of PF-06865571
compared to placebo.  To address the potential effect of PF-06865571 on liver fat, the 
eligible population for study enrollment is subjects with NAFLD, with liver fat ≥6%, as 
assessed by MRI-PDFF at Screen 3.  Subjects who meet all eligibility criteria for the study 
during Screen 1 (including liver fat approximation by FibroScan®) will then undergo an 
additional liver fat approximation by FibroScan®at Screen 2.  These assessments will provide
an initial estimate of liver fat prior to MRI-PDFF.  FibroScan® is an ultrasound based 
technique that estimates liver fat through calculation of the controlled attenuation parameter 
(CAP™), measured in decibels per meter (dB/m).  
 
 
 
 
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Subjects who meet all eligibility criteria for the study during Screen 1 and Screen 
2 (including liver fat approximation by FibroScan®) will then undergo liver fat assessment by 
MRI-PDFF at Screen 3.  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,14 and has been utilized in previous trials of potential NASH therapeutics.15,16
Prior to the assessment of liver fat (
MRI-PDFF), subjects will be 
required to fast (water permitted) for ≥4 hours given the ability of food to impact the imaging 
results (≥8 hours prior to Days -2 and 15 due to lipid sample collection).  Baseline (Day -2) 
assessments for MRI-PDFF
should be at approximately the same clock time 
(ie, within a practical window (±2 hours) relative to the clock time of the Screening visit).  
All post-dose assessments
MRI-PDFF should occur within a 
practical window (±2 hours) relative to clock time of each baseline assessment.
Total duration of dosing PF-06865571/placebo in this study is proposed as 2 weeks, as 
supported by completed nonclinical toxicity studies in rats and monkeys.  This duration is 
also expected to permit sufficient assessment of the primary pharmacology of PF-06865571
and its effect on liver fat. Given the current study is the first to administer repeated doses of 
PF-06865571 to subjects with NAFLD, a baseline day (Day -1) will permit assessment of 
safety (including triplicate ECGs) and tolerability, ie, change from baseline (CFB, within 
subject) and placebo-adjusted comparison of dose-response (between subject), as 
appropriate. 
This study is also designed to assess the effect of PF-06865571 on other PD markers that are 
intended to provide insight into associated metabolic pathways. 
 
 
 
 
The serial collection of blood samples to permit assessment of PD effect in this study will 
assist in understanding the optimal dosing regimen to potentially characterize the dose (or 
exposure) response, as well as to build PK/PD understanding. 
PF-06865571 is not anticipated to have a significant effect on body weight, however, to 
contain the influence of inpatient stay on liver fat, subjects will have their body weight 
assessed on serial days and their daily caloric intake adjusted to minimize change (both 
increase and decrease) in body weight while inpatient – refer to Section 7.1.4.
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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.17  In accordance 
with reported literature on OCT2/MATE inhibition, minor increases in serum creatinine have 
been observed in C2541002 with very limited/no 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).18
1.3.1.1. Study Population
This study will enroll overweight and obese male and female subjects who may be treated for 
co-existing conditions, such as diet-controlled type 2 diabetes mellitus (T2DM), 
hyperlipidemia or hypertension, but who are otherwise clinically stable.  Female subjects will 
be confirmed to be categorized as non-childbearing potential since at the present time 
embryo-fetal developmental toxicology studies with PF-06865571 have not been conducted.  
In male subjects, appropriate measures to minimize potential transfer of PF-06865571 via 
semen to a partner are expected to be followed - refer to Section 4.4.4.
Subjects with a higher body mass index (BMI) of ≥28 kg/m2 will be enrolled to target a 
similar BMI range as patients with NAFLD and NASH.  Subjects with T2DM will be 
permitted in this study, as long as their glycosylated hemoglobin (HbA1c) is ≤7% and their 
T2DM is diet-controlled (ie, they do not require oral or injectable medication treatment for 
T2DM), as there is a potential for PF-06865571 to (1) mildly increase plasma glucose and 
insulin levels, and (2) raise levels of metformin, a common medication in T2DM, due to 
OCT2/MATE inhibition.  Subjects who use tobacco/nicotine-containing products may also 
be eligible (see Section 4.4).  
The eligible population is defined as having liver fat ≥6% as measured by MRI-PDFF at 
Screen 3.  Although NAFLD is a condition marked by excessive (≥5%) fat accumulation in 
the liver, this study will enroll subjects with liver fat values ≥6% at screening to allow for 
potential measurement variability and help ensure baseline liver fat values are likely ≥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 (Day 1) based on 
MRI-PDFF (Screen 3) liver fat ranges of ≥6% to <10%; and ≥10% as a means of providing 
approximate equal balance of liver fat content between the dosing cohorts.  A second-tier 
stratification will also be applied at randomization (Day 1) based on the presence or absence 
of T2DM (refer to Section 4.3) for additional details.
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1.3.2. Dose Rationale
 
 
  The dose and dosing regimen required to maximize the PD effects of 
PF-06865571 are not yet established.  
 
 In order to fully explore the 
effect of DGAT2 inhibition on liver fat, PF-06865571 doses of 50 mg and 300 mg will be 
administered BID in this study.  
 
  These total 
daily doses have been well tolerated with an acceptable safety profile in the ongoing multiple 
ascending dose study (C2541002).
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Table 5.
Predicted Steady-State PF-06865571 Exposures with 
Administration of Multiple Doses of PF-06865571 Under Fed 
Conditions  
Total Daily Dosea
(mg)
Regimen
Predicted
Cmax
(ng/mL)
Predicted
AUC24
(ng•h/mL)
100 mg
50 mg Q12H
430
2198
600 mg
300 mg Q12H
2174
13238
Abbreviations: Q12H = every 12 hours.
a. Predicted Cmax and AUC24 were derived using a preliminary model based on available PK data from 
Studies C2541001 and C2541002.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective: 
Primary Endpoint: 
•
To evaluate the effect of multiple oral doses of PF-
06865571 on whole liver fat, following 14 days of 
administration to subjects with NAFLD.
•
Relative change from baseline in whole liver fat at 
Day 15, as assessed by MRI-PDFF.
Secondary Objectives: 
Secondary Endpoints: 
•
To evaluate the safety and tolerability of multiple oral 
doses of PF-06865571, administered for 14 days to
subjects with NAFLD.
•
Assessment of AEs, clinical laboratory tests, vital 
signs and 12-lead ECGs.
•
To characterize the plasma exposure of multiple oral 
doses of PF-06865571, administered for 14 days to
subjects with NAFLD.
•
PF-06865571 Cmax, AUCtau, Tmax, Cmin, CL/F, and 
PTR on Day 14, as permitted by the data.
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3. STUDY DESIGN
3.1. Study Overview
This will be a randomized, double-blind (sponsor-open), stratified, placebo-controlled, 3-arm 
(placebo, plus 2 active doses of PF-06865571), parallel-group study (refer to Figure 1).
Figure 1.
Design of Study C2541005
Day -2^
Admission to CRU
Day -1
MRI-PDFF
Inpatient stay at Phase 1 Unit Day 
-2 to Day 16 
With supervised transportation to MRI Imaging Center on 
Day 15
Screen 1
Screen 2
MRI -PDFF
Follow-up via telephone contact
28-35 days post Day 14
Day 1
Follow-up Visit
7-10 days post Day 14
Day 15^
MRI-PDFF
Day 14
^All MRI -PDFF
images to be read by sponsor
- identified central 
imaging vendor 
Days 2 - 13
Dosing with double -blind IP x 14 days
PF-06865571 or matching placebo 
Day 16
D/C from CRU
42 days
Screen 3^
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A total of approximately 45 subjects (15 per arm) will be randomized at approximately 4 to 
6 sites to ensure a minimum of 42 subjects complete the study (assuming an approximate 
5% premature withdrawal rate).  Subjects may be replaced at the discretion of the principal 
investigator (PI) and Sponsor.  Subjects will be randomized to receive PF-06865571 
(2 dosing regimens) or matching placebo (1 dosing regimen) in a 1:1:1 ratio.
For a given subject, the total study duration from Screen 1 to the follow-up phone call will be 
up to approximately 13 weeks.  Screen 1 will occur within 42 days prior to the first dose of 
blinded IP (PF-06865571 or matching placebo).  Eligible subjects who meet the entry criteria 
will progress to admission on the morning of Day -2, prior to lunch, for an 18-day (17-night) 
inpatient stay.  While inpatient, subjects will receive blinded IP for 14 consecutive days and 
remain inpatient for approximately an additional 48 hours post AM dose on Day 14.  
Following discharge on Day 16, subjects will return for an on-site follow-up visit 7 to 
10 days following the last dose of blinded IP, and a follow-up phone call (or visit, if 
necessary per the PI) 28 to 35 days following the last dose of blinded IP.
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 in the 
study:
1. Male subjects or female subjects of non-childbearing potential between the ages of 
18 and 65 years, inclusive, at Screen 1.
Female subjects of nonchildbearing 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 
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2. At Screen 1, total body weight of >50 kg (110 lbs) and a BMI 28 kg/m2;
3. At both Screen 1 and Screen 2, a CAPTM 260 dB/m via FibroScanassessment.  Note: 
if the CAPTM value is in the range of 240-259 dB/m, 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;
4. At Screen 3, liver fat 6% 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 (refer to Section 7.5.1);
5. Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study;
6. Subjects who are willing and able to comply with all scheduled visits, clinical research 
unit (CRU) confinement, treatment plan, laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects currently experiencing any clinically significant or unstable medical condition 
that might limit their ability to complete the study, to comply with the requirements of the 
protocol, or interfere with the interpretation of study results which, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study, including: 
dermatologic disease, hematological disease, pulmonary disease, hepatic disease, 
gastrointestinal disease, genitourinary disease, endocrine disease, neurological disease 
and psychiatric disease;
2. Subjects with any of the following clinical laboratory abnormalities at Screen 1, as 
assessed by sponsor-identified central laboratory and confirmed by a single repeat, if 
deemed necessary:

Fasting TG >400 mg/dL;

Fasting direct LDL-C >190 mg/dL;

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma 
glutamyl transferase (GGT) >2.0 x upper limit of normal (ULN);

HbA1c >7.0%;

Total bilirubin >1.5x ULN with a direct bilirubin ULN;


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
NOTE: Subjects with a history of Gilbert syndrome would be eligible for this 
study provided direct bilirubin level is ULN plus ALT met criteria for 
applicable 1st tier stratification plus alkaline phosphatase, hemoglobin, and
reticulocyte count are ULN.

Albumin < lower limit of normal (LLN);

International normalized ratio (INR) 1.3.
3. A positive urine drug test for illicit drugs at Screen 1.  

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;
5. At Screen 1, supine 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, triplicate supine 12-lead ECG (average) demonstrating a 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, 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 deemed 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 at Screen 1 permitted to assess 
eligibility, if needed:

Hepatitis B virus (HBV), defined by presence of hepatitis B surface antigen 
(HepBsAg) and hepatitis B core antibody (HepBcAb);

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb), and
HCV RNA (when reflexed based on a positive result for HCVAb);


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
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;

α-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; 

Diagnosis of T2DM requiring pharmaceutical treatment(s);

NOTE: Subjects with diet-controlled T2DM who have an HbA1c ≤7.0 are 
permitted in this study.

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 
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
Active placement of medical devices in/on thoracic or abdominal cavities such as 
pacemakers, defibrillators.
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 obtained at Screen 3, by the Sponsor-identified central imaging vendor, 
or subjects meeting criteria for contraindication for MRI, including the following:

History of severe claustrophobia impacting ability to perform MRI 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.
11. Subjects taking any prohibited concomitant medication(s) or those unwilling/unable to 
switch to permitted concomitant medication(s) [refer to Section 5.8];
12. Weight loss of 5% within 1 month prior to Screen 1;
13. 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 IP;
14. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or more
within 56 days prior to Screen 1 or during the study until the on-site follow-up visit;  
15. History of sensitivity to heparin or heparin-induced thrombocytopenia only if heparin is 
used to flush intravenous catheters;  
16. 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);  
17. Subjects with known prior participation in a trial involving PF-06865571 (ie, received at 
least 1 dose of IP);
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19. 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;
20. At Screen 1, other acute or chronic medical or psychiatric condition including recent 
(within the past year) or active suicidal ideation or behavior or laboratory abnormality 
that may increase the risk associated with study participation or IPadministration 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.
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 1:1:1 ratio (1 of 2 active dosing regimens of 
PF-06865571 or placebo) prior to the first dose of IP, provided subjects satisfy all of the 
eligibility criteria outlined in Section 4.1 and Section 4.4.2.

An attempt will be made to equally balance the number of subjects assigned to
receive PF-06865571 versus placebo within each stratum by utilizing a 2-tiered 
stratification scheme as follows.  Subjects will be stratified at randomization (Day1) 
first by the MRI-PDFF liver fat measurement determined by the Sponsor-identified 
central imaging vendor of images obtained during Screen 3:

Screening liver fat 6% and <10%;

Screening liver fat 10%.

Subjects will then be stratified by the presence or absence of T2DM.
4.4. Lifestyle Requirements
After confirmation of eligibility at Screen 3, subjects will be instructed to maintain the 
guidelines described below for the duration of participation in the study.  The following 
guidelines are provided.
4.4.1. Meals and Dietary Restrictions

4-hour fast (except water) prior to:

Liver fat assessment at Screen 3 using MRI-PDFF acquisition.

8-hour overnight fast (except water) prior to:

Any blood collection for lipids;


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
Liver fat assessment on Day -2 and Day 15 via FibroScanor MRI-PDFF.

As dosing occurs with meal/snack, restriction regarding water intake prior to or after 
dosing is not expected.

Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices - see 
below) may be consumed with meals and the evening snack.

Breakfast will be provided approximately 30 minutes prior to AM dosing at 0H and is 
expected to be completed approximately 10 minutes prior to AM dosing.

Lunch will be provided approximately 4 hours after dosing at 0H.

Dinner will be provided approximately 10 hours after dosing at 0H.

A snack consisting of at least 400 kcals will be provided at approximately 12 hours 
after the morning dose. 

The snack will be provided approximately 20 minutes prior to dosing.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the first dose of IP until 
collection of the final PK blood sample.

While confined, the total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat, and 15% protein.  

The daily caloric intake per subject should not exceed approximately 3,200 kcal.

The nutritional macronutrient composition consumed by each subject should be 
maintained, as much as practically possible, during the inpatient stay – though 
adjustment may be necessary based on serial assessment of body weight – refer to 
Schedule of Activities – Table 1 and Table 2 as well as Section 7.1.4.

In a given subject, meals and snacks provided on Days -2, -1, 1, 14, and 15 must be 
identical and subjects encouraged to complete consumption of each meal/snack, 
whenever possible;

Meals and snacks offered on other days may vary – both for types of foods as well as 
macronutrient content.
4.4.2. Alcohol, Caffeine, and Tobacco

Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample.  Subjects 
may undergo an alcohol breath test or blood alcohol test at the discretion of the 
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
Subjects will abstain from caffeine-containing products for 2 hours prior to ECG and 
vital sign measurements.  

Subjects will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.  
4.4.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.
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 IP.  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 subject’s 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 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 postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).


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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 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of IP and continuing for at least 28 days after the last dose of IP.
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 IP 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. For sites other than a Pfizer CRU, 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, IP 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 IPs are PF-06865571 and matching placebo and will be administered as 
oral tablets.
5.1. Allocation to Treatment
The IRT system will be used to sequentially assign a unique 8-digit subject identification 
number to each subject who has signed the informed consent document (ICD).  This 
identifying number will be retained throughout the duration of study participation.  


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Allocation of subjects to treatment groups will proceed through the use of an 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.  The IRT system will provide a confirmation report containing the 
subject number and randomization number. 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. 
A computer generated randomization schedule will be used to assign approximately 
45 subjects in a randomization ratio of 1:1:1 of the 3 treatment groups described in Table 5.  
The randomization number will be recorded in the CRF. In accordance with the 
randomization number, the subject will receive the study regimen assigned to the 
corresponding randomization number.
Table 5.
Study Treatment Regimens and Dispensing Schedule
Treatment 
Group
Treatment 
Regimen
Morning
Evening
A
Placebo Q12H
3 x 
Placebo tablets
3 x 
Placebo tablets
B
50 mg 
PF-06865571  
Q12H
1 x 50 mg tablet
PLUS
2 x Placebo tablets
1 x 50 mg tablet
PLUS
2 x Placebo tablets
C
300 mg
PF-06865571  
Q12H
3 x
100 mg tablets
3 x
100 mg tablets

In order to maintain the double-blind design 50 mg, 100 mg, and matching placebo 
tablets will be supplied in the same size and shape;

All dosing regimens (A-C) will consist of 3 tablets (representing PF-06865571 or 
matching placebo) administered Q12H.
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 CRF.


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This is an investigator- and subject-blind (Sponsor open) placebo-controlled study.  Blood 
specimens will be obtained from all subjects for pharmacokinetic analysis to maintain the 
study blind at the investigator site.  The investigator site(s) staff [with the exception of the 
site pharmacist(s) and pharmacy assistant(s)], and blinded study monitor(s), will be blinded 
to investigational product (PF-06865571 or placebo).  Other specified Pfizer personnel, 
including the separate unblinded monitor(s) assigned, will be unblinded to subject 
treatments.  The blinded study monitor will remain blinded to treatment until all 
monitoring for the study has been completed.  
Specimens from subjects randomized to placebo will not be routinely analyzed.  To minimize 
the potential for bias, treatment randomization information will be kept confidential by Pfizer 
unblinded personnel and will not be released to the blinded investigator or blinded 
investigator site personnel until the study database has been locked or the investigator 
requests unblinding for safety reasons.
5.3. Subject Compliance
IP will be administered under the supervision of investigator site personnel.  The oral cavity 
of each subject will be examined following dosing to ensure the IP was taken.
5.4. Investigational Product Supplies
5.4.1. Dosage Form and Packaging
IP will be supplied by the Sponsor as PF-06865571 50 mg and 100 mg, and matching 
placebo tablets for oral administration.  The tablets will be supplied as white to off-white 
tablets packaged in bottles and labeled according to local regulatory requirements. 
5.4.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the IP ready for administration or dispensing to the subject/caregiver by qualified staff.  
Dispensing is defined as the provision of IP, concomitant treatments, and accompanying 
information by qualified staff member(s) to a healthcare provider, subject, or caregiver in 
accordance with this protocol.  Local health authority regulations or investigator site 
guidelines may use alternative terms for these activities.
Tablets will be supplied at the CRU in the individual dosing containers by 2 operators, 1 of 
whom is an appropriately qualified and experienced member of the study staff (eg, physician, 
nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist).
The tablets will be provided in dose containers and labeled in accordance with Pfizer
regulations and the clinical site’s labeling requirements. 
5.5. Administration
Administration of blinded IP will occur under the conditions described in Section 4.4.1.  
Subjects will receive the first dose of IP at approximately 08:00 hours local time (plus or 
minus 2 hours).  The second dose will be administered approximately 12 hours later.  
Investigator site personnel will administer IP with ambient temperature water to a total 


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volume of approximately 240 mL.  Subjects will swallow the IP whole, and will not 
manipulate or chew the IP prior to swallowing. 
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all IPs are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
IPs should be stored in their original containers and in accordance with the labels. 
Any storage conditions stated in the SRSD (ie, IB for PF-06865571) 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 IP receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the IP must be quarantined and not used until Pfizer provides 
permission to use the IP.  It will not be considered a protocol deviation if Pfizer approves the 
use of the investigational product after the temperature excursion. Use of the IP 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.
5.7. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the IP supplies.  All IPs will be accounted for using a drug accountability 
form/record. 


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5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused IP (eg, at the 
site).  If destruction is authorized to take place at the investigator site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer, and all 
destruction must be adequately documented.
5.8. Concomitant Treatments
Subjects in this study will be allowed to take certain concomitant medications to treat 
coexisting conditions such as 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 not to 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 on Day 1 will be documented as a 
prior treatment.  Treatments taken after the first dose of IP will be documented as 
concomitant treatments.
5.8.1. 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.  
5.8.2. 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 and fluvastatin are not permitted as detailed below;

Ezetimibe;

Bile acid sequestrants such as cholestyramine, colestipol, colesevalam;

Gemfibrozil and fenofibrate;

Nicotinic acid/niacin.


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The use of the following medications or classes of agents is not permitted within the 
timelines specified:  
•
Rosuvastatin or fluvastatin within 4 weeks prior to Screen 1 and until on-site 
Follow-up visit;
•
Monoclonal antibodies inhibiting 
such as alirocumab and evolocumab, 
within 12 weeks prior to Screen 1 or within 5 half-lives of dose administered 
(whichever is longer), and until on-site Follow-up visit.
5.8.3. 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.
5.8.4. Prohibited Concomitant Medications
Subjects must abstain from using all anti-diabetic medications for ≥12 weeks prior to Screen 
1 and until on-site Follow-up visit, including the following:
•
Biguanides, such as metformin; 
•
Sulfonylureas such as glyburide, acetohexamide, chlorpropamide, tolazamide, 
tolbutamine, glimepiride, glipizide;
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
Dipeptidyl peptidase-4 (DPP-4i) inhibitors such as sitagliptin, saxagliptin, 
vildagliptin;

-glucosidase inhibitors such as acarbose and miglitol;

TZDs such as pioglitazone and rosiglitazone; 

Subcutaneously administered agents for glycemic control (eg, insulin, exenatide, 
liraglutide, pramlintide);

Sodium-glucose co-transporter 2 inhibitors such as canagliflozin, dapagliflozin, 
empagliflozin.
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 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);


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•
BCRP and P-gp substrates (eg, rosuvastatin and digoxin);
•
Sensitive CYP2C9 substrates (eg, fluvastatin, diclofenac, celecoxib, 
torsemide).
5.9. Rescue Medication
There is no rescue therapy to reverse AEs observed with administration of IP; standard 
medical supportive care should be provided to manage the AEs.
6. STUDY PROCEDURES
A signed and dated ICD will be obtained from each subject at 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 Screen 1.
6.1. Proposed Chronology of Procedures
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.
•
12-lead ECG: obtain prior to vital signs assessment, blood samples, and prior to 
dosing (refer to Section 7.1.6).
•
Vital Signs (BP and pulse rate): obtain after 12-lead ECG collection but prior to 
obtaining blood samples and prior to dosing (refer to Section 7.1.5).
•
Fasting blood samples: after assessment of 12-lead ECG and vital signs but prior to 
dosing (refer to Section 7.1.1).
•
Serial blood samples for plasma PK, insulin, 
as close 
as practically possible to the scheduled time (refer to Schedule of Activities).
•
If the post-dose blood collection nominal time coincides with the nominal time of 
a meal, these blood samples should be collected just prior to meal/snack.
•
Other pre-dose procedures: should be obtained/performed as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection.
•
Dosing: must occur at the scheduled nominal time (refer to Section 5.5) and following 
pre-dose blood sample collection.
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•
If an intravenous catheter is placed for serial blood sample collections, ECGs and 
vital signs (pulse rate, BP) assessments should be either collected prior to the 
insertion of the catheter or sufficient rest period after catheter insertion introduced to 
minimize impact of catheter placement on these assessments.
6.2. Screening
Refer to the Schedule of Activities Table 1 for the study procedures to be completed at the 
Screening visits.  The 3 screening visits are to be performed sequentially.  
•
At Screen 1, subjects will be consented and all screening procedures (except assessment 
of liver fat by MRI-PDFF) undertaken to determine eligibility – refer to Sections 4.1
and 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 all eligibility 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 #4, Section 4.1.  
Subjects will be screened within 42 days prior to the first dose of the blinded IP to confirm 
that they meet the subject selection criteria for the study.  The investigator (or an appropriate 
delegate at the investigator site) will obtain informed consent from each subject in 
accordance with the procedures described in Section 12.3.  
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 42 days is 
exceeded.  In such cases, all screening procedures must be repeated and the subject assigned 
a new 8-digit SSID number.  Subjects must be deemed to meet all the eligibility criteria 
including assessment of liver fat via MRI-PDFF at Screen 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).
6.3. Study Period
Refer to the Schedule of Activities for the study procedures to be completed. 
 
 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
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If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.
6.4. Follow-up 
In this study, there are 2 follow-ups, as listed below:

1st follow-up is an on-site visit where the subjects will return to the CRU between 
7 to 10 days following the last dose of IP.

2nd follow-up is a telephone contact that will occur 28 to 35 days following the last
dose of IP.  If the PI deems it necessary, this contact may be a visit.

Refer to the Schedule of Activities for the study procedures to be completed at each
of the 2 follow-ups.
6.5. Subject Withdrawal
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 
Section 8.1.3) or behavioral reasons, or the inability of the subject to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site.  The 
early termination visit applies only to subjects who are randomized and then are prematurely 
withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  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 for a final visit, if applicable, and follow up with the subject 
regarding any unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the 
early-withdrawal visit, every effort must be made to complete the following assessments:

Conduct an inquiry about any spontaneously reported AEs by asking the subject to 
respond to a non-leading question such as “how do you feel?”

Full physical examination, if there is a new or open AE or clinically significant 
abnormal physical finding from the last visit (refer to Section 7.1.3);


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•
Supine, single standard 12-lead ECG measurement (refer to Section 7.1.6);
•
Single, supine BP and pulse rate measurements (refer to Section 7.1.5);
•
Blood and urine specimens for clinical laboratory tests (refer to Section 7.1.1);
•
Blood sample for PK analysis for PF-06865571 (refer to Section 7.2);
•
Blood for cystatin C (refer to Section 7.1.2);
•
Blood for insulin (refer to Section 7.3.4).
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations as long as the subject’s safety was preserved.
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.
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.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
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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.
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
Refer to Section 6.1 for the recommended order of collection when multiple procedures are 
scheduled at the same timepoint.
7.1. Safety
7.1.1. 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 
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Table 6.
Clinical Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN/urea 
Creatinine
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 bilirubind
Indirect bilirubind
Serum cystatin C
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
•
FSHb
•
Urine drug testc
•
Serology: HIV, 
HepBsAg, 
HepBcAb, HCVAb
(and if positive, 
reflex HCV RNA)c
•
A1ATc
•
HbA1cc
•
Ceruloplasminc
•
PT/INRc
Additional Tests (Needed for Hy’s Law)
•
AST, ALT (repeat)
•
Total bilirubin (repeat)
•
Albumin (repeat)
•
Alkaline phosphatase (repeat)
•
Direct bilirubin
•
Indirect bilirubin
•
Creatine kinase
•
GGT
•
PT/INR
•
Total bile acids
•
Acetaminophen drug and/or protein adduct levels
a. Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b. At Screening only, in all females. 
c. At Screening only.
d. Direct and indirect bilirubin measured only when total bilirubin is >ULN.
For a list of abbreviations, refer to Appendix 1.
•
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.
•
Subjects may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for subjects to receive IP. 
•
Estimated glomerular filtration rate (eGFR) will be calculated using the modification 
of diet in renal disease (MDRD) equation.
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.  
 
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  These data will not be included in the clinical study report (CSR).  Samples 
to be used for this purpose will be shipped to either a Pfizer-approved BBS facility or other 
designated laboratory and retained for up to 1 year following the completion of the study.
7.1.2. 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 CKD-Epi-Cystatin C equation18 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]
7.1.3. 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.  The limited or abbreviated 
physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
7.1.4. Body Weight
In this study, assessment of body weight will occur at the nominal time points specified in 
the Schedule of Activities per the following specifications –
•
Weight will be recorded using a calibrated scale placed on a stable, flat surface;
•
During the inpatient stay, the same scale will be used with the scale reporting weight in 
kilograms, and accuracy to the nearest 0.1 kg [ie, the device must be able to distinguish a 
difference between 68.4 kg and 68.3 kg];
•
Measurement must be undertaken –
•
At approximately the same time of the day, in the morning in the fasting state, at each 
nominal time point while inpatient;
•
After the subject has been asked to void (ie, forced void);
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
Under standard conditions (eg, subjects must wear light clothing with content of their 
pockets emptied or hospital gown and not be wearing shoes or bulky layers of 
clothing/jackets);

With subjects remaining still while on the weighing scale.
7.1.4.1. Adjustment of Caloric Intake to Maintain Stable Body Weight

Daily caloric intake, while inpatient, should be adjusted based on each serial assessment 
of body weight after Day 1 – refer to Section 4.4.1;

The initial caloric intake/menu assigned to each subject will be based on the Harris 
Benedict formula (sedentary lifestyle; to be provided to the site prior to study start) using 
the subject’s body weight measured at screening;

Caloric intake should be adjusted, on the days when body weight is assessed, to ensure 
that the subjects do not gain or lose body weight – defined as no more than 1.0 kg 
change in body weight on any day post Day 1 compared to the body weight at Screen 
1;

NOTE: on selected days when meals and snacks offered are to be identical (ie, Days -2, 
-1, 1, 14, and 15), while body weight measurements may occur on some of these days, 
adjustment to caloric content on these selected days must not occur.
7.1.5. Blood Pressure and Pulse Rate
BP 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.
Supine 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 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.  
7.1.6. Electrocardiogram 
In this study, 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 a supine position;


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
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average 
of the triplicate ECG measurements collected prior to the first dose on Day 1 will serve as 
each subject’s baseline value.

If the average of QTcF values from the triplicate measurements remains above the 
threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.

If QTcF values remain 500 msec (or 45 msec from the baseline) for greater than 
4 hours (or sooner, at the discretion of the investigator), or QTcF intervals get 
progressively longer, the subject should undergo continuous ECG monitoring.  A 
cardiologist should be consulted if QTcF intervals do not return to less than 500 msec (or 
to <45 msec above the baseline) after 8 hours of monitoring (or sooner, at the discretion 
of the investigator).

Further ECG monitoring will occur if a) a post-dose QTcF interval is increased by 
30 msec from the baseline and is >450 msec; or b) an absolute QTcF value is 
500 msec for any scheduled ECG. If either of these conditions occurs, then 2 additional 
ECGs will be collected approximately 2 to 4 minutes apart to confirm the original 
measurement. If the QTcF values from these repeated ECGs remains above the threshold 
value, then a single 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 abnormal 12-lead ECGs to rule out improper 
lead placement as contributing to the ECG abnormality.  It is important that leads are placed 
in the same positions each time in order to achieve precise ECG recordings.  If a 
machine-read QTcF value is prolonged, as defined above, repeat measurements may not be 
necessary if a qualified physician’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG data will be submitted to a central laboratory for overread measurement of ECG 
intervals and overall interpretation.  The central ECG laboratory will be blinded to treatment 
allocation.  The final ECG report from the central laboratory should be maintained in the 
subject’s source documentation and be the final interpretation of the ECG recording.  Any 
clinically significant changes from the Baseline/Day 1 ECG may potentially be adverse 
events (AEs) (Section 8.2) and evaluated further, as clinically warranted.
7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of PF-06865571
Blood samples (approximately 4 mL) to provide a sufficient amount of plasma for PK
analysis will be collected into appropriately labeled tubes containing dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) at times specified in the Schedule of Activities
section of the protocol. 


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PK sampling time points in this study may be adjusted to adequately assess the plasma PK 
profile based on emerging data.  The actual times may change, but the number of samples 
will remain the same.  All efforts will be made to obtain the PK samples at the exact nominal 
time relative to dosing.  However, samples obtained within 2 hours of the nominal time from 
dosing will not be captured as a protocol deviation, as long as the exact time of the sample 
collection is noted on the source document and data collection tool (eg, CRF). 
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the IP, samples may be used for metabolite identification 
and/or evaluation of the bioanalytical method, 
 
  These data will not be included in the CSR. 
 
 
 
 
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7.5. Imaging Assessments 
7.5.1. Assessment of Liver Fat and Stiffness Using FibroScan®
In this study, estimation of liver fat and stiffness using FibroScan® will occur at scheduled
visits outlined in the Schedule of Activities.  Each acquisition will take approximately 
10 minutes and requires the subject to be in a supine position with the right arm placed flat 
above the head.  Acquisition results do not need independent over-read, but steps to ensure 
the acquisition was complete and accurate are required, as per training to be provided by 
EchoSens (vendor supporting the device) at the start of the study.  As much as practically 
possible, attempts will be made to ensure each individual subjects’ assessment is performed 
by the same operator.  All FibroScan® operators will be trained and certified by EchoSens, 
and must be a sonographer or comparable.
Complete details regarding acquisitions using FibroScan® to assess liver fat by CAPTM and 
LSM will be provided by EchoSens before initiation of this study. All images acquired must 
be saved by the study site until the conclusion of the study; the summary of numerical results 
(including quality-related outputs) must be printed and saved by the study site (or Imaging 
facility, as applicable) as part of each subject’s source documents. 
The FibroScan® is performed on the right lobe of the liver through intercostal spaces via a
transducer probe that delivers a painless, mechanical impulse to the liver and measures the 
resulting shear wave. The LSM is directly proportional to the velocity of the shear wave.  
Simultaneously, the CAPTM measures the ultrasonic attenuation coefficient in the forward 
and return path of the radio-frequency pulse through the liver.  The device calculates the 
median LSM and liver fat values by CAPTM after a total of 10 valid, serial measurements are 
acquired per assessment.  
7.5.2. Assessment of Liver Fat Using MRI-PDFF Acquisition and Analysis
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 real time 
review of image quality and readability of the acquired images, 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 the 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 
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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 from baseline 
(Day -2) to end of treatment 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. 
The baseline (Day -2) assessment for MRI-PDFF should be at approximately the same clock 
time (ie, within a practical window (2 hours) relative to clock time of the screening visit).  
All post-dose assessments for MRI-PDFF should occur within a practical window (2 hours) 
relative to clock time of the baseline assessment.
7.5.3. 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 individual 
subject’s liver fat will not be communicated to the study site, only the stratum to which the 
subject is assigned.  In the case of the MRI at Screen 3, study sites will only be informed 
whether a subject meets eligibility criteria or if the screening MRI should be repeated once, 
as determined by the Sponsor-identified central imaging vendor.  For all subsequently 
scheduled MRI-PDFF assessments, study sites will only be informed whether the images are 
deemed evaluable (or not).  Of note, subjects with non-evaluable baseline images (as 
determined by the Sponsor-identified central imaging vendor) may be withdrawn prior to or 
after randomization, at the discretion of the Sponsor. 
7.5.4. 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 MRI images will be reviewed by a Sponsor-identified central imaging vendor.  The 
purpose of this review is to evaluate images for the amount of fat in the liver. Central image 
review is not a complete medical review of the subject.  If, during the central review process, 
an unexpected observation is identified and this finding could, in the opinion of the central 
reviewer, have a significant health or reproductive consequence, this finding may be shared 
with the study sponsor for disclosure to the principal investigator.  All follow-up testing and 
final diagnosis will be left to the discretion of the medical professionals at the site or those 
with an existing physician-patient relationship.  The principal investigator will be responsible 
for reporting any AEs identified from incidental findings as described in the ADVERSE 
EVENT REPORTING section.  Identification of such incidental findings during the central 
review process should not be expected, and the site maintains responsibility for performing a 
general safety review of all images as per study site protocols. 


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7.5.5. Post-hoc Analyses
 
 
 
 
  Any such 
analyses will not be included in the CSR; but a separate supplemental report will be written 
to capture this work, if undertaken.
7.6. Potential Cases of Acute Kidney Injury
Abnormal values in serum creatinine (SCr) concurrent with presence or absence of increase 
in blood urea nitrogen (BUN ) that meet the criteria below, in the absence of other causes of 
kidney injury, are considered potential cases of acute kidney injury and should be considered 
important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 μmol/L) in SCr level relative to the subject’s own 
baseline measurement should trigger another assessment of SCr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second (repeat) result is still increased by ≥0.3 mg/dL (or ≥26.5 μmol/L) relative to the 
subject’s own baseline, assessment of eGFR using serum cystatin C should be performed.  
Based on these measurements, eGFR using SCr and serum cystatin C will be determined and 
reviewed, preferably within 72 hours, and not later than 96 hours from the confirmed (repeat) 
elevated SCr result.
If an individual subject demonstrates CONCOMITANT SCr-based AND serum cystatin 
C-based eGFR decline of ≥30% compared to the subject’s baseline eGFR, then the subject 
should not be further dosed and adequate, immediate, supportive measures and treatment as 
clinically indicated.  Referral to a nephrologist (preferably within 24 hours) is also 
recommended.  If the subject cannot be seen by a nephrologist within 24 hours (as described 
above), then the subject may be sent to a local emergency room for evaluation and treatment 
as clinically indicated. Results should be repeated weekly or as indicated until the renal 
parameters are deemed to be stable by the nephrologist and/or PI.
Subjects should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the second assessment confirming abnormal eGFR result.  
This evaluation should include laboratory tests, detailed history, and physical assessment.  In 
addition to repeating SCr, laboratory tests should include serum BUN, serum creatine kinase, 
and serum electrolytes (including at a minimum potassium, sodium, phosphate/phosphorus, 
and calcium), in addition to urinary dipstick, urine microscopic examination, and urinary 
indices.  All cases confirmed on repeat testing as meeting the laboratory criteria for acute 
kidney injury, with no other cause(s) of laboratory abnormalities identified, should be 
considered potential cases of drug-induced kidney injury irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal SCr.  
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7.7. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
390 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
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 
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.


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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 section)
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 
Requirements section above.


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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 
related” to investigational product, this should be clearly documented on study records. 


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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;

Medication error;


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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 
important medical event should be reported as serious.


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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);

Hospitalization for observation without a medical AE;


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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:
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. 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” 
or are “susceptible.”
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 


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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 
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 


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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 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.
8.4.2. 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.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. 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 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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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 15 subjects per arm are planned in this study for a total of approximately 
45 subjects.  Assuming an approximate 5% premature withdrawal rate, this will ensure a 
minimum of 42 subjects complete the study.  With this sample size the power to detect a 25% 
mean reduction in MRI-PDFF relative to placebo is at least 79% using a 1-sided Type I error 
rate of 0.1.  This calculation assumes the pooled SD of the log-relative change of 0.36 (based 
on an internal study).
9.2. Efficacy Analysis
The primary analysis population for all efficacy analyses will include all randomized subjects 
who received at least 1 dose of study medication (Full Analysis set). 
9.2.1. Analysis of the Primary Endpoint 
The primary endpoint will be the relative change from baseline at Day 15 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 with treatment 
and baseline diabetic status as factors, log-transformed baseline whole liver PDFF value as a 
covariate. Estimates of the mean relative changes between each active dose and placebo at 
Day 15, and the corresponding 80% confidence interval (CI) will be obtained from the 
model.  Each comparison of PF-06865571 dose with the placebo will be performed at a Type I
error rate of 10% (1-sided).
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.
Descriptive summaries of the observed values and percent change from baseline in whole 
liver PDFF for each treatment group will also be produced.
 
 
 
 
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9.3. Pharmacokinetic Analysis
The PK concentration population will be defined as all randomized subjects who received at 
least 1 dose of PF-06865571 and in whom at least 1 plasma PK concentration value is 
reported.  The PK parameter analysis population will be defined as all randomized subjects 
who received at least 1 dose of PF-06865571 and who have at least 1 of the PK parameters of 
interest calculated.  PK samples from placebo samples will not be routinely analyzed.
9.3.1. Derivation of Pharmacokinetic Parameters
The PK parameters for PF-06865571 will be derived from the concentration-time profiles as 
data permit.  The various PK parameters to be assessed in this study, their definition and 
method of determination are outlined in Table 7.  Actual PK sampling times will be used in 
the derivation of PK parameters.
Table 7.
Definition of Steady State (Day 14) Plasma PK 
Parameters for PF-06865571
Parameter
Definition
Method of Determination
AUCtau
Area under the plasma 
concentration-time profile from 
time zero to time tau (τ), the 
dosing interval
Linear/Log trapezoidal 
method
Cmax
Maximum plasma 
concentration during the dosing 
interval
Observed directly from data
Tmax
Time for Cmax 
Observed directly from data 
as time of first occurrence
CL/F
Apparent clearance
Dose/AUCtau
Cmin
Minimum plasma concentration 
during the dosing interval
Observed directly from data
PTR
Peak-to-trough ratio
Cmax/Cmin
The above listed PK parameters will be summarized descriptively by dose. Relationships 
between PF-06865571 PK and safety and/or efficacy endpoints may also be explored, but 
may not be included in the final CSR.
 
 
 
 
 
 
 
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9.6. 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.
Medical history and 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 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.
9.6.1. 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.
The number (%) of subjects with maximum postdose QTcF values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
≥450 - <480
≥480
Absolute change
30-<60
≥60
In addition, the number of subjects with corrected and uncorrected QT values ≥500 msec will 
be listed.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach.  If a PK/PD 
relationship is found, the impact of subject factors (covariates) on the relationship will be 
examined.  The analysis, if conducted, may not be reported.
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9.7. Interim Analysis 
Interim analyses may be performed to assess efficacy and/or safety after at least 50% of the 
planned subjects, ie, approximately 21 subjects, complete the study. Interim analysis results 
may be used for internal business decisions regarding future study planning, stopping for 
futility, conducting a sample size reestimation, or adapting the study after the interim 
analysis. Before any interim analysis is instigated, the details of the objectives, decision 
criteria, dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs 
will be documented and approved in an internal review committee (IRC) charter.  In addition, 
the analysis details will be documented and approved in an interim analysis SAP or final 
SAP.
9.8. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC). This study will potentially use 
an IRC comprised of Pfizer employees (or designees) who are not directly involved in the 
day-to-day conduct of the study.  If an IRC is used then an IRC charter will be developed to 
govern the details of the interim analysis and IRC operations.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, 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.
For studies conducted at non-Pfizer investigator sites, 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. 


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/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 CRFis required and should be completed for each included subject.  The completed 
original CRFsare the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFsand 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 
CRFsmust be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFsare true.  Any corrections to entries made in the CRFsor 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's chart.  In these cases, 
data collected on the CRFsmust match 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 CRFand for which the CRFwill 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, CRFsand hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to 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.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.


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The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
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 the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject 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 
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 study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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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 (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


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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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Fon Tacer K, Rozman D. Nonalcoholic fatty liver disease: focus on lipoprotein and lipid 
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Noureddin M, Lam J, Peterson MR, et al.  Utility of magnetic resonance imaging versus 
histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials.  
Hepatology 2013;58:1930-40.
15.
Le TA, Chen J, Chanqchien C, et al.  Effect of colesevelam on liver fat quantified by 
magnetic resonance in nonalcoholic steatohepatitis: a randomized controlled trial. 
Hepatology 2012;56:922-32.   
16.
Loomba R, Sirlin CB, Ang B, et al.  Ezetimibe for the treatment of nonalcoholic 
steatohepatitis: assessment by novel magnetic resonance imaging and magnetic 
resonance elastography in a randomized trial (MOZART Trial). Hepatology 
2015;61:1239-50.
17.
Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) 
in human kidney. AAPS J 2013; 15(2):581-8.
18.
Inker LA, Schmid CH, Tighiouart H, et al. Estimating Glomerular Filtration Rate from 
Serum Creatinine and Cystatin C. N Engl J Med 2012; 367:20-9.
19.
Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and 
apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005; 
112(22): 3375-83.
20.
Rhainds D, Arsenault BJ, Tardif JC.  PCSK9 inhibition and LDL cholesterol lowering: 
the biology of an attractive therapeutic target and critical review of the latest clinical 
trials.  Clin Lipidol 2012:7(6):621-40.


PF-06865571 
C2541005
Final Protocol, 27 February 2018
Page 74
Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
A1AT
α-1-antitrypsin
Abs
absolute
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the curve
BA
bioavailability
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
CFB
change from baseline
CI
confidence interval
CK
creatine kinase
CLr
renal clearance
Cmax
maximum observed concentration
Cmin
minimum concentration
CO2
carbon dioxide (bicarbonate)
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
CYP450
cytochrome P450
DAG
diacylglycerol
DDI
drug-drug interaction
DGAT
diacylglycerol acyltransferase
DILI
drug-induced liver injury
DMC
data monitoring committee
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C2541005
Final Protocol, 27 February 2018
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Abbreviation
Term
DNL
de novo lipogenesis
DPP-4
dipeptidyl peptidase-4
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)
eGFR
estimated glomerular filtration rate
EU
European Union
EudraCT
European Clinical Trials Database
FA
fatty acids
FFA
free fatty acids
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
H
hour(s)
HbA1c
hemoglobin A1c
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
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 
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
IWR
interactive Web-based response
CCI
CCI
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C2541005
Final Protocol, 27 February 2018
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Abbreviation
Term
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 
MATE
multi-drug and toxin extrusion protein
mBCRP
mouse breast cancer resistant 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
MGAT
monoacylglycerol acyltransferase
MMRM
mixed model for repeated measures 
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
N/A
not applicable
NAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
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
PBPK
physiologically based pharmacokinetic
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
PI
principal investigator
PIB
powder in bottle
PK
pharmacokinetic(s)
PT
prothrombin time
PTR
peak to trough ratio
Q8H
every 8 hours
Q12H
every 12 hours
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C2541005
Final Protocol, 27 February 2018
Page 77
Abbreviation
Term
QTc
corrected QT interval
qual
qualitative
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SD
standard deviation
SOP
standard operating procedure
SRSD
single reference safety document
t1/2
Half-life
TBili
total bilirubin
T2DM
type 2 diabetes mellitus
TG
triglycerides
THC
tetrahydrocannabinol
Tmax
time to reach maximum concentration
UDP
uridine diphosphate
UGT
uridine diphosphate glucuronosyltransferase
ULN
upper limit of normal
US
United States
VLDL
very low density lipoprotein
WBC
white blood cell
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PF-06865571 
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Final Protocol, 27 February 2018
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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 wort3
Tiprinavir/ritonavir
Troglitazone
Antibiotics
Nafcillin
Clarithromycin
Avasimibe4
Troleandomycin
Enzalutamide
Telithromycin
Mitotane
Anti-infectives
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Miscellaneous
Nefazodone
Grapefruit juice1
Conivaptan
Mibefradil2
Idelalisib
1.
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength).
2.
Withdrawn from the United States market.
3.
The effect of St. John’s wort varies widely and is preparation-dependent.
4.
Not a marketed drug.
* 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/DrugInter
actionsLabeling/ucm093664.htm

SAP_001.pdf: 
Protocol C2541005 (PF-06865571) Statistical Analysis Plan
Page 1
PROTOCOL C2541005
A PHASE 1B, RANDOMIZED, DOUBLE-BLIND (SPONSOR-OPEN), 
PLACEBO-CONTROLLED, PARALLEL GROUP STUDY TO ASSESS 
THE SAFETY, TOLERABILITY, PHARMACODYNAMICS AND 
PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-06865571 
FOR 2 WEEKS IN ADULTS WITH NONALCOHOLIC FATTY LIVER 
DISEASE
Version:
1
Date:
17MAY2018


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives .......................................................................................................4
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Primary Endpoint(s) ..................................................................................................6
3.2. Secondary Endpoint(s) ..............................................................................................7
3.3. Other Endpoints.........................................................................................................7
3.4. Baseline Variables.....................................................................................................9
3.5. Safety Endpoints .......................................................................................................9
3.5.1. Adverse Events.............................................................................................9
3.5.2. Laboratory Data..........................................................................................10
3.5.3. Vitals...........................................................................................................10
3.5.4. ECGs...........................................................................................................10
3.5.5. Non-Standard Safety Assessments .............................................................11
4. ANALYSIS SETS ...............................................................................................................11
4.1. Full Analysis Set .....................................................................................................11
4.2. Per Protocol Analysis Set........................................................................................11
4.3. Safety Analysis Set..................................................................................................12
4.4. Other Analysis Sets .................................................................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................13
5.3. Methods to Manage Missing Data ..........................................................................14
6. ANALYSES AND SUMMARIES ......................................................................................15
6.1. Primary Endpoint: Whole Liver PDFF ...................................................................15
6.1.1. Primary Analysis ........................................................................................15
6.1.2. Sensitivity/Robustness Analyses ................................................................16


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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6.2. Secondary Endpoint(s) ............................................................................................16
6.3. Other Endpoint(s)....................................................................................................16
6.4. Subset Analyses.......................................................................................................19
6.5. Baseline and Other Summaries and Analyses.........................................................19
6.6. Safety Summaries and Analyses .............................................................................20
6.6.1. Adverse Events...........................................................................................20
6.6.2. Laboratory Data..........................................................................................20
6.6.3. Vital Signs ..................................................................................................20
6.6.4. Electrocardiogram.......................................................................................21
6.6.5. Non-standard Safety Analysis ....................................................................22
7. INTERIM ANALYSES.......................................................................................................22
8. REFERENCES ....................................................................................................................23
9. APPENDICES .....................................................................................................................24
Categorical Classes for ECG and Vital Signs................................................................24
Calculation of %CBL.....................................................................................................24
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................4
Table 2.
Definition of Steady State (Day 14) Plasma PK Parameters for PF 
06865571 ................................................................................................................7
LIST OF FIGURES
Figure 1.
Design of Study C2541005.....................................................................................6
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Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C2541005 is based on the protocol dated 
27FEB2018.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C2541005.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Primary Objective: 
Primary Endpoint: 
•
To evaluate the effect of multiple oral doses of 
PF-06865571 on whole liver fat, following 14 days 
of administration to subjects with NAFLD.
•
Relative change from baseline in whole liver fat at Day 
15, as assessed by MRI-PDFF.
Secondary Objectives: 
Secondary Endpoints: 
•
To evaluate the safety and tolerability of multiple oral 
doses of PF-06865571, administered for 14 days to 
subjects with NAFLD.
•
Assessment of AEs, clinical laboratory tests, vital signs 
and 12-lead ECGs.
•
To characterize the plasma exposure of multiple oral 
doses of PF-06865571, administered for 14 days to 
subjects with NAFLD.
•
PF-06865571 Cmax, AUCtau, Tmax, Cmin, CL/F, and PTR 
on Day 14, as permitted by the data.
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2.2. Study Design
This will be a randomized, double-blind (sponsor-open), stratified, placebo-controlled, 3-arm 
(placebo, plus 2 active doses of PF-06865571), parallel-group study. A total of 
approximately 45 subjects (15 per arm) will be randomized at approximately 4 to 6 sites to 
ensure a minimum of 42 subjects complete the study (assuming an approximate 
5% premature withdrawal rate).  Subjects may be replaced at the discretion of the principal 
investigator (PI) and Sponsor.  Subjects will be randomized to receive PF-06865571 
(2 dosing regimens) or matching placebo (1 dosing regimen) in a 1:1:1 ratio.
For a given subject, the total study duration from Screen 1 to the follow-up phone call will be 
up to approximately 13 weeks.  Screen 1 will occur within 42 days prior to the first dose of 
blinded investigational product (IP, PF-06865571 or matching placebo).  Eligible subjects 
who meet the entry criteria will progress to admission on the morning of Day -2, prior to 
lunch, for an 18-day (17-night) inpatient stay.  While inpatient, subjects will receive blinded 
IP for 14 consecutive days and remain inpatient for approximately an additional 48 hours 
post AM dose on Day 14.  Following discharge on Day 16, subjects will return for an on-site 
follow-up visit 7 to 10 days following the last dose of blinded IP, and a follow-up phone call 
(or visit, if necessary per the PI) 28 to 35 days following the last dose of blinded IP. The 
schematic of the study design is provided in Figure 1.
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Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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Figure 1.
Design of Study C2541005
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Relative change from baseline in whole liver fat at Day 15, as assessed by MRI-PDFF. The 
relative change will be expressed in % unit, [100*(relative change – 1)]. 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.
Day -2^
Admission to CRU
Day -1
MRI-PDFF
Inpatient stay at Phase 1 Unit Day 
-2 to Day 16 
With supervised transportation to MRI Imaging Center on 
Day 15
Screen 1
Screen 2
MRI -PDFF
Follow-up via telephone contact
28-35 days post Day 14
Day 1
Follow-up Visit
7-10 days post Day 14
Day 15^
MRI-PDFF
Day 14
^All MRI -PDFF
images to be read by sponsor
- identified central 
imaging vendor 
Days 2 - 13
Dosing with double -blind IP x 14 days
PF-06865571 or matching placebo 
Day 16
D/C from CRU
42 days
Screen 3^


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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While deriving the relative change from baseline, 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 15, only 7 segments have
non-missing results, whole liver PDFF will be calculated using the matching individual 
segmental PDFFs at both baseline and Day 15. 
3.2. Secondary Endpoint(s)
•
The secondary endpoints include the standard safety endpoints, namely, adverse 
events (AEs), clinical laboratory tests, vital signs (including blood pressure and pulse 
rate), and 12-lead electrocardiograms (ECG).  These will be further described in 
Section 3.5.
•
PF-06865571 Cmax, AUCtau, Tmax, Cmin, CL/F, and PTR on Day 14, as permitted by 
the data,
The PK parameters for PF-06865571 will be derived from the concentration-time 
profiles as data permit.  The various PK parameters to be assessed in this study, their 
definition and method of determination are outlined in Table 2.  Actual PK sampling 
times will be used in the derivation of PK parameters.
Table 2.
Definition of Steady State (Day 14) Plasma PK 
Parameters for PF 06865571
Parameter
Definition
Method of Determination
AUCtau
Area under the plasma 
concentration-time profile from 
time zero to time tau (τ), the 
dosing interval
Linear/Log trapezoidal 
method
Cmax
Maximum plasma 
concentration during the dosing 
interval
Observed directly from data
Tmax
Time for Cmax 
Observed directly from data 
as time of first occurrence
CL/F
Apparent clearance
Dose/AUCtau
Cmin
Minimum plasma concentration 
during the dosing interval
Observed directly from data
PTR
Peak-to-trough ratio
Cmax/Cmin
 
 
 
 
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Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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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, and body mass index will be summarized by sex at 
birth and treatment in accordance with the sponsor reporting standards. Ethnicity will not be 
summarized. The number and proportion of subjects enrolled in each study site will also be 
presented.
In this study subjects will be stratified at randomization based on the presence or absence of 
Type 2 Diabetes Mellitus (T2DM) and by the MRI-PDFF liver fat categories obtained during 
Visit 3 (Screen 3) listed below:

Screening liver fat 6% and <10%;

Screening liver fat 10%.
Both of these stratification variables will be used as covariates in the efficacy analysis.  For 
baseline diabetic status, data will be obtained from the case report forms (CRFs). Even 
though baseline liver fat was used as a binary variable for stratification purposes, it will be 
used as a continuous covariate in the efficacy analysis in order to maximize the utility of 
information. If there is substantial imbalance in the number of subjects enrolled in each site 
then study site will be considered to be included as a potential covariate.  If included as a 
covariate sites enrolling less than 6 subjects will be pooled. 
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.
3.5.1. Adverse Events
For serious adverse events (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.  


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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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.
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
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. 
3.5.3. Vitals 
Supine 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.
3.5.4. ECGs
Triplicate 12-lead ECGs will be obtained on all subjects at times detailed in the Schedule of 
Activities given in the protocol.  Average of the triplicate will be utilized in all analysis. 
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:


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
Page 11
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 by study day 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.
3.5.5. 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 provided below.
MDRD Formula:
GFR (mL/min/1.73 m²) = 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 provided 
below:

For serum cystatin C (Scys) ≤0.8 mg/L:
eGFR (mL/min/1.73 m²) = 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 m²) = 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. 
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 1
dose of randomized treatment; subjects are assigned to the randomized treatment regardless 
of what treatment was received.  This would be the primary analysis population for all 
efficacy analyses.
4.2. Per Protocol Analysis Set 
This will not be used in the current study.


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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4.3. Safety Analysis Set
All subjects who receive at least 1 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. 
For AE reporting all subjects providing informed consent regardless of their randomization 
status will be included.  
4.4. Other Analysis Sets
The PK concentration population will be defined as all randomized subjects who received at 
least 1 dose of PF-06865571 and in whom at least 1 plasma PK concentration value is 
reported.  The PK parameter analysis population will be defined as all randomized subjects 
who received at least 1 dose of PF-06865571 and who have at least 1 of the PK parameters of 
interest calculated. 
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 each endpoint:
1. 300 mg PF-06865571 Q12H is equal in effect to placebo.
2. 50 mg PF-06865571 Q12H is equal in effect to placebo.
The alternative hypotheses corresponding to the above null hypotheses will be the following 
2-sided hypotheses:
1. The effect of 300 mg PF-06865571 Q12H is different from the effect of placebo.
2. The effect of 50 mg PF-06865571 Q12H is different from the effect of placebo.
The Type I error rate (-level) used with the decision rule for the primary objective is 
10% (1-sided).  No adjustment for multiple comparisons will be made.
Interim analyses may be performed to assess efficacy and/or safety after at least 50% of the 
planned subjects, ie, approximately 21 subjects, complete the study. Interim analysis 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. 


Protocol C2541005 (PF-06865571) Statistical Analysis Plan
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5.2. General Methods 
Descriptive Statistics
Descriptive statistics, including the sample size, mean, standard deviation, median, 
minimum, and maximum values, will be provided for continuous endpoints.  Some measures 
will be summarized using graphical representations by treatment and study day of visit, 
where appropriate.
Analysis of Covariance (ANCOVA)
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 and baseline diabetes status as
covariates.  If there is substantial imbalance in the number of subjects enrolled in each site 
then study site and interaction of study site with treatment will be considered to be included 
as potential covariates for the analysis of primary endpoint only.  If included as a covariate, 
sites enrolling less than 6 subjects will be pooled.  The number of covariates may be reduced 
to improve model fit. Estimates of treatment effects will be assessed using LSMs and CIs.  
Estimates of the mean differences between each active dose and placebo, and the 
corresponding 80% CI will be obtained from the model.  Comparison of each 
PF-06865571 dose with the placebo will be performed at a Type I error rate of 10% (1-sided).
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.
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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 3.5 x standard deviations ± 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 80% CIs will be presented.  In addition the 80% CIs 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 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 lower limit of quantification.) 
In summary tables and plots of the median values at each time point, statistics will be 
calculated having set concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
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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
6.1.1. Primary Analysis

Analysis endpoint: Whole liver PDFF.

Analysis time points: Day 15.

Analysis population: Full Analysis set

Analysis methodology: Natural log-transformed individual relative change (RC)
from baseline to Day 15 in whole liver PDFF will be analyzed using the ANCOVA.  
Log-transformed baseline will be the covariate. The model will include natural 
log-transformed baseline whole liver PDFF and diabetes status. If there is substantial 
imbalance in the number of subjects enrolled in each site then study site and 
interaction of study site with treatment will be considered to be included as potential 
covariates.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and Day 15 visit will be presented for each treatment arm.

%CBL: The sample size, mean, standard deviation, median, minimum and maximum 
will be presented for each treatment arm at Day 15. The LSMs and their 80% CI will 
be exponentiated  to provide estimates of the RC which will be converted to percent 
change as follows:
Percent change = 100* (RC - 1).
The LSMs of the percent change from baseline with the 80% CIs for each treatment 
group and the LSMs of the percent change from placebo with the 80%CIs for each of 
the PF-06865571 groups and the 2-sided p-values will be presented.
Figures

Whole liver PDFF - Bar chart of the model-derived least square means for all 
treatment groups including the placebo group with 80%CI will be provided for 
Day 15 with treatment group on the X-axis.

Whole liver PDFF - Bar chart of the placebo-adjusted least square means with 80%CI 
for the two PF-06865571 treatment groups will be provided for Day 15 with dose on 
the X-axis.


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•
Whole liver PDFF - Box and whisker plots for individual percent change from
baseline versus treatment will be presented and overlaid with arithmetic means.
6.1.2. Sensitivity/Robustness Analyses 
•
Analysis endpoint: Whole liver PDFF.
•
Analysis time points: Day 15.
•
Analysis population: Full Analysis set.
•
Analysis methodology: %CBL to Day 15 in whole liver PDFF will be analyzed 
using the ANCOVA.  The model will include baseline whole liver PDFF and diabetes 
status. If there is substantial imbalance in the number of subjects enrolled in each site 
then study site and interaction of study site with treatment will be considered to be 
included as potential covariates.
Reporting results:
The LSMs, 80% CI for the LSMs, difference between the LSM of each treatment group 
and the placebo group, and the corresponding 80% CI 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.
Presentations for PF-06865571 concentrations will include:
•
A listing of all concentrations sorted by dose, subject ID, day and nominal time post 
dose.  The listing of concentrations will include the actual sample collection times, 
and the time of dosing.  Deviations from the nominal time will be given in a separate 
listing.
•
A summary of concentrations by dose, day, and nominal time post dose, where the set 
of statistics will include n, mean, median, standard deviation, coefficient of variation 
(CV), minimum, maximum and the number of concentrations above the LLQ.
•
  A median plot of steady state (Day 14) plasma concentrations by dose will be 
provided.
•
The PK parameters listed in Section 3.2 will be summarized descriptively by dose.
 
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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 ≥6% and <10%;
•
Screening liver fat ≥10%.
 
 
6.5. Baseline and Other Summaries and Analyses
A breakdown of demographic data will be provided for age, race, weight, and body mass 
index. Each will be summarized by sex at birth and treatment in accordance with the sponsor 
reporting standards.  Baseline summary of parameters of interest, namely, fasting glucose, 
 waist circumference, AST, ALT, alkaline phosphatase, GGT and 
whole liver PDFF will be presented for each treatment group and overall.  Baseline summary 
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of stratification factors, namely, diabetes status (presence or absence) and MRI-PDFF 
categories (≥6% and <10% or 10%) will be provided. The number and proportion of 
subjects enrolled in each study site will also be presented.
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacodynamic (FAS) and pharmacokinetics (PK), 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 administering PF-06865571. 
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.
6.6.1. 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 TEAEs and AEs occurring prior to randomization will only be 
listed.
The 3-Tier approach will not be used to summarize the AEs due to the small sample size.
6.6.2. Laboratory Data
All planned, quantitative, standard safety laboratory data presented in Table 6 of the protocol 
and non-standard safety laboratory data that are not reported independently will be listed and 
summarized at each collection time point by treatment in accordance with the sponsor 
reporting standards as applicable. Baseline is as defined in Section 3.5.2.
6.6.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and study day, according to sponsor 
reporting standards.  Tables will be paged by parameter.  Baseline is as defined in 
Section 3.5.3.


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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 1 line for each treatment, all treatments 
on the same plot including the placebo.  
For baseline subtracted supine 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.  
Maximum absolute values and maximum changes from baseline for vital signs, over all 
measurements taken post dose 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 supine systolic and diastolic blood 
pressures, and maximum increase from baseline for supine pulse rate will be summarized by 
treatment, according to sponsor reporting standards.
6.6.4. Electrocardiogram
Average of the triplicate measurements will be used in all analyses. Absolute values and 
changes from baseline in QT, heart rate, QTcF, PR, RR 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 1 line for each treatment, 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) for each dose and day including follow-up.
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) 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 
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6.6.5. Non-standard Safety Analysis
Serum Creatinine, Serum Cystatin C and Associated eGFRs
Absolute values and changes from baseline in serum creatinine, serum cystatin C, eGFRs 
obtained from serum creatinine 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 1 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.
Liver Function Tests
Raw values, change and %CBL in ALT, AST, Total Bilirubin, GGT, and alkaline 
phosphatase will be summarized by treatment at all relevant collection time points including 
follow-up.  For %CBL group medians and differences in group medians from placebo with 
80% CIs will be presented.  Line plot of medians with 80% CIs for all treatment groups 
including the placebo group with study day on X-axis will be provided.  Three lines 
corresponding to the 3 treatment groups will be overlaid on the same plot.
Body Weight
Raw values, change and %CBL in body weight will be summarized by treatment at all 
relevant collection time points including follow-up.  For %CBL group medians and 
differences in group medians from placebo with 80% CIs will be presented.  Line plot of 
medians with 80% CIs for all treatment groups including the placebo group with study day
on X-axis will be provided.  Three lines corresponding to the 3 treatment groups will be 
overlaid on the same plot.
7. INTERIM ANALYSES
Interim analyses may be performed to assess efficacy and/or safety after at least 50% of the 
planned subjects, ie, approximately 21 subjects, complete the study. Interim analysis results 
may be used for internal business decisions regarding future study planning or stopping for 
futility. Before any interim analysis is instigated, the details of the objectives, decision 
criteria, dissemination plan, and method of maintaining the study blind as per Pfizer’s SOPs 
will be documented and approved in an internal review committee (IRC) charter.  In addition, 
the analysis details will be documented and approved in an interim analysis SAP.


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8. REFERENCES 
1.
McGill, R., John W. Tukey and W. A. Larsen. 1978. "Variations of Box Plots." 
American Statistician 32:12-16


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9. APPENDICES 
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 - ≤60
>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 ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine 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.