Clinical trial NCT03969719
Conditions: Non-alcoholic Steatohepatitis
Keywords: Non-alcoholic steatohepatitis; Type 2 Diabetes Mellitus
Sponsor: Pfizer
Start date: 2019-07-18; Completion date: 2021-03-30
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, placebo-controlled study in adults with non-alcoholic steatohepatitis and Type 2 Diabetes Mellitis on stable dose of metformin monotherapy. Participants will be treated for 16 weeks with placebo or 1 of 2 doses of investigational product to determine the effect on liver fat, HbA1c, safety, tolerability and pharmacodynamics.

Detailed description:

Arms: arm 1: Palacebo arm 2: 150 mg arm 3: 300 mg
Interventions: intervention 1: Placebo intervention 2: PF-06835919 intervention 3: PF-06835919
Intervention descriptions: intervention 1: Placebo intervention 2: 150 mg once daily intervention 3: 300 mg once daily

Protocol documents:
Prot_002.pdf: 
PF-06835919
Protocol C1061011
Final Protocol Amendment 2, 11 September 2019
PFIZER CONFIDENTIAL
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
3-ARM, PARALLEL GROUP STUDY TO EVALUATE SAFETY, TOLERABILITY 
AND PHARMACODYNAMICS OF PF-06835919 ADMINISTERED DAILY FOR 
16 WEEKS IN ADULTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE AND 
TYPE 2 DIABETES MELLITUS ON METFORMIN
Investigational Product Number:
PF-06835919
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:
C1061011
Phase:
2a
Short Title: Phase 2a, 3-arm, 16-week, double-blind safety and pharmacodynamic study in 
adults with non-alcoholic fatty liver disease and type 2 diabetes mellitus
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
endpoints now includes modeling details: The 
derived endpoints will be analyzed using 
MMRM with treatment, time and treatment by 
time interaction as fixed effects and baseline 
value as a covariate.  Additional covariates, if 
considered for inclusion in the model, will be 
described in the SAP. 
Section 10.2. Appendix 2 (Clinical Laboratory 
Tests) will remove ALT and glucose as 
blinded parameters, as there is no significant 
risk of unintentional blinding based on these 
parameters. The previously issued PACL 
described this change.
Section 10.4.1. Appendix 4 (Male Participant 
Reproductive Inclusion Criteria) will be 
changed to state that, in addition to male 
condom use, a highly effective method of 
contraception is required (previously 
'considered') for WOCBP partners of male 
participants.
Section 10.4.4. Appendix 4 (Contraception 
Methods) has been changed to remove 
reference to user dependency, and to no longer 
permit the following methods of contraception 
in potentially child-bearing female partners of 
male participants: Progestogen only oral 
hormonal contraception where inhibition of 
ovulation is not the primary mode of action; 
Male or female condom with or without 
spermicide; Cervical cap, diaphragm, or 
sponge with spermicide; A combination of 
male condom with either cervical cap, 
diaphragm, or sponge with spermicide (double 
barrier methods). These methods by 
themselves would not be considered highly 
effective.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
11 September 2019
Incorporation of results of C1061016 
midazolam drug-drug interaction study to 
relevant background sections, and based on the 
results of this study, removal of relevant 
restrictions of CYP3A4 concomitant 
medications, given that clinical results indicate 
PF-06835919 does not induce 3A4 
metabolism. 
Specific changes are as follows:
2.2.1. (Nonclinical Overview) has now been 
revised to no longer indicate the potential for 
CYP3A4 induction with PF-06835919.
2.2.2. (Clinical Overview) now makes 
reference to the C1061016 study, alongside 
other completed clinical studies.
2.2.3. (Preliminary Pharmacokinetic Results of 
PF-06835919-Midazolam Drug-Drug
Interaction Study [C1061016]) has been added 
as a new subheading within the Clinical 
Overview, to provide a summary of the results 
of this study, including a stable on the effect of 
PF-06835919 on midazolam pharmacokinetic 
parameters. 
4.3. (Justification for Dose) now states that 
there is not expected to be any effect of 
PF-06835919 on the PK of CYP3A4 
substrates, and has removed reference to the 
former concomitant medication restrictions, 
accordingly. 
6.5. (Concomitant Therapy) has been updated 
to; remove the previous caution of potential 
altered exposure of lipid-modifying agents that 
are 3A4 substrates; lift the restrictions on 
antihypertensive agents that are significantly 
metabolized by 3A4; remove text in section on 
Other Prohibited Concomitant Medications 
which previously stated potential altered 
exposure of sensitive 3A4 substrates.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES ...................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities (SoA)...................................................................................12
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Overview.................................................................................15
2.2.2. Clinical Overview.......................................................................................16
2.2.3. Preliminary Pharmacokinetic Results of PF-06835919-Midazolam 
Drug-Drug Interaction Study (C1061016).......................................................17
2.3. Benefit/Risk Assessment.........................................................................................18
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................19
4. STUDY DESIGN.................................................................................................................22
4.1. Overall Design.........................................................................................................22
4.2. Scientific Rationale for Study Design.....................................................................22
4.3. Justification for Dose ..............................................................................................26
4.4. End of Study Definition ..........................................................................................26
5. STUDY POPULATION......................................................................................................27
5.1. Inclusion Criteria.....................................................................................................27
5.2. Exclusion Criteria....................................................................................................28
5.3. Lifestyle Considerations..........................................................................................32
5.3.1. Contraception..............................................................................................32
5.3.2. Dietary Restrictions ....................................................................................32
5.3.3. Alcohol, Caffeine, and Tobacco .................................................................33
5.3.4. Activity .......................................................................................................33
5.3.5. Confinement to Site....................................................................................33
5.3.6. Confinement at Imaging Facility................................................................33
5.4. Screen Failures ........................................................................................................34


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6. STUDY INTERVENTION..................................................................................................34
6.1. Study Intervention(s) Administered........................................................................34
6.1.1. Administration............................................................................................35
6.2. Preparation/Handling/Storage/Accountability ........................................................35
6.2.1. Preparation and Dispensing........................................................................36
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................37
6.3.1. Allocation to Investigational Product .........................................................37
6.3.2. Breaking the Blind......................................................................................37
6.4. Study Intervention Compliance...............................................................................37
6.5. Concomitant Therapy..............................................................................................38
6.5.1. Rescue Medicine.........................................................................................41
6.6. Dose Modification...................................................................................................41
6.7. Intervention After the End of the Study..................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................41
7.1. Discontinuation of Study Intervention ....................................................................41
7.2. Participant Discontinuation/Withdrawal From the Study.......................................42
7.3. Lost to Follow-up....................................................................................................43
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................43
8.1. Efficacy Assessments..............................................................................................44
8.1.1. Imaging Assessments..................................................................................44
8.1.1.1. Assessment of Liver Fat and Stiffness Using FibroScan........44
8.1.1.2. Assessment of Liver Fat Using MRI-PDFF Acquisition 
and Analysis ......................................................................................44
8.1.1.3. Analysis of MRI-PDFF Images Including Determination 
of Eligibility.......................................................................................45
8.2. Safety Assessments .................................................................................................46
8.2.1. Physical Examinations................................................................................46
8.2.1.1. Measurement of Waist Circumference......................................46
8.2.2. Body Weight...............................................................................................47
8.2.3. Vital Signs ..................................................................................................47
8.2.4. Electrocardiograms.....................................................................................48
8.2.5. Clinical Laboratory Assessments ...............................................................48


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8.2.5.1. Management of Glycemic Control............................................49
8.3. Adverse Events and Serious Adverse Events..........................................................52
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......52
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................52
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................53
8.3.2. Method of Detecting AEs and SAEs ..........................................................53
8.3.3. Follow-up of AEs and SAEs.......................................................................53
8.3.4. Regulatory Reporting Requirements for SAEs...........................................53
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................54
8.3.5.1. Exposure During Pregnancy......................................................54
8.3.5.2. Exposure During Breastfeeding ................................................54
8.3.5.3. Occupational Exposure .............................................................54
8.3.6. Medication Errors .......................................................................................54
8.4. Treatment of Overdose............................................................................................55
8.5. Pharmacokinetics ....................................................................................................56
8.6. Pharmacodynamics..................................................................................................57
8.6.1. Glucose, Insulin, and HbA1c......................................................................57
8.6.2. Lipid Panel..................................................................................................57
8.6.3. Urine for Albumin-to-Creatinine Ratio ......................................................57
8.6.4. hs-CRP........................................................................................................57
8.8. Biomarkers ..............................................................................................................58
8.8.1. Specified Gene Expression (RNA) Research .............................................58
8.8.2. Specified Protein Research.........................................................................58
8.8.3. Specified Metabolomic Research ...............................................................59
8.8.4. Banked Biospecimens for Biomarkers .......................................................59
8.9. Health Economics ...................................................................................................59
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9. STATISTICAL CONSIDERATIONS ................................................................................59
9.1. Estimands and Statistical Hypotheses.....................................................................59
9.1.1. Estimands....................................................................................................59
9.2. Sample Size Determination.....................................................................................61
9.3. Populations for Analysis .........................................................................................61
9.4. Statistical Analyses .................................................................................................62
9.4.1. Efficacy Analyses .......................................................................................62
9.4.2. Safety Analyses ..........................................................................................63
9.4.2.1. Electrocardiogram Analyses......................................................64
9.5. Interim Analyses .....................................................................................................64
9.5.1. Data Monitoring Committee.......................................................................64
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................66
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............66
10.1.1. Regulatory and Ethical Considerations ....................................................66
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................66
10.1.2. Financial Disclosure .................................................................................67
10.1.3. Informed Consent Process ........................................................................67
10.1.4. Data Protection .........................................................................................68
10.1.5. Dissemination of Clinical Study Data ......................................................68
10.1.6. Data Quality Assurance ............................................................................70
10.1.7. Source Documents....................................................................................71
10.1.8. Study and Site Closure..............................................................................71
10.1.9. Publication Policy.....................................................................................72
10.1.10. Sponsor’s Qualified Medical Personnel .................................................72
10.2. Appendix 2: Clinical Laboratory Tests .................................................................74
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................76
10.3.1. Definition of AE .......................................................................................76
10.3.2. Definition of SAE.....................................................................................77
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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................78
10.3.4. Reporting of SAEs....................................................................................81
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................83
10.4.1. Male Participant Reproductive Inclusion Criteria....................................83
10.4.2. Female Participant Reproductive Inclusion Criteria.................................83
10.4.3. Woman of Childbearing Potential ............................................................83
10.4.4. Contraception Methods.............................................................................84
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........88
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................90
10.8. Appendix 8: Abbreviations ...................................................................................92
11. REFERENCES ..................................................................................................................97
LIST OF TABLES
Table 1.
Statistical Summary of Effect of PF-06835919 on Plasma 
Midazolam PK Parameters (AUCinf, AUClast and Cmax), Protocol 
C1061016..................................................................................................18
LIST OF FIGURES
Figure 1.
Study C1061011 Design...........................................................................11
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Since all sites conducting the study will be located in North America, this is considered not 
applicable (N/A).
1.2. Schema
The overall study design is captured below in Figure 1.








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2. INTRODUCTION
PF-06835919 is a ketohexokinase (KHK) inhibitor that is currently being investigated in 
participants with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis 
(NASH).
KHK is an enzyme catalyzing the conversion of fructose and adenosine triphosphate (ATP) 
to fructose-1-phosphate (F1P) and adenosine diphosphate (ADP), the first committed step in 
fructose metabolism.  In humans, Loss-of-function in KHK manifests as Essential 
Fructosuria, a rare, asymptomatic genetic condition1 that is only recognized by the 
appearance of fructose in the urine after fructose consumption.2,3 PF-06835919 is a potent, 
reversible inhibitor of human KHK.  In nonclinical experiments, treatment with 
PF-06835919 reduces the incidence of fructose-induced hepatic steatosis and genetic deletion 
of KHK protects mice from fructose-induced hypertriglyceridemia, hyperinsulinemia, and 
hepatic steatosis (see investigators’ brochure [IB] Section 5). Based on initial experience in 
short duration clinical trials, inhibition of KHK appears generally safe and well tolerated. In 
addition, PF-06835919 treatment has shown the potential to reduce liver fat and biomarkers 
of inflammation (see Section 2.2.2).  It is anticipated that inhibition of KHK will decrease 
hepatic de novo lipogenesis and steatosis, thereby ameliorating the pathogenesis of NAFLD
and its progression to NASH.
2.1. Study Rationale 
The purpose of this study is to assess the safety and tolerability of PF-06835919 over a 
16-week treatment period, as well as the effect of PF-06835919 treatment on liver fat, 
hemoglobin A1c (HbA1c), and additional pharmacodynamic (PD)/
 parameters in 
participants with NAFLD and type 2 diabetes mellitus (T2DM).
2.2. Background 
Fructose metabolism, unlike glucose metabolism, is not subject to regulatory feedback 
inhibition in normal human biology.  As a consequence of unrestrained metabolism, fructose 
rapidly generates a number of reactive and signaling metabolites that contribute to metabolic 
disease progression.  Along with the lack of feedback inhibition, hepatic fructose metabolism 
has been shown to reduce liver ATP concentrations after a single intravenous (IV) bolus of 
fructose.4 Depletion of ATP leads to the activation of adenosine monophosphate (AMP) 
deaminase5 and subsequent increases in uric acid levels that have been shown to directly 
regulate hepatic lipogenesis through generation of mitochondrial oxidative stress.6
Additionally, preclinical studies have demonstrated that fructose rapidly enriches glycolytic 
metabolite pools, leading to activation of the Carbohydrate Response Element Binding 
Protein (ChREBP), a highly lipogenic transcription factor, that can promote both steatosis 
and insulin resistance with carbohydrate over-feeding.7 Post-prandial hypertriglyceridemia is 
observed in both rodents and humans following fructose feeding, as fructose both decreases 
very low-density lipoprotein (VLDL) clearance and promotes de novo lipogenesis.8
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Excessive fructose consumption has been shown to cause features of metabolic syndrome 
and NAFLD.8 In humans, supplementation of a normal diet with 25% of the calories as 
fructose, but not as glucose, caused hyperlipidemia within 2 weeks.9 Additionally, these 
participants developed insulin resistance as evidenced by increased insulin excursion during 
an oral glucose tolerance test.9 Increased sugar intake, in the form of carbonated beverages, 
has been associated with NAFLD in patients who lack other features of metabolic syndrome, 
suggesting that fructose intake independent of metabolic disease can increase liver fat.10,11 In 
a separate study with participants consuming weight-neutral diets containing 25% of dietary 
calories as fructose, increased hepatic lipid and decreased hepatic insulin sensitivity were 
observed after 9 days of high-fructose consumption.12 Conversely, restricting dietary sugar 
intake from 28% to 10% for 9 days improved insulin sensitivity and reduced hepatic lipid in 
obese adolescents.13 In a separate study, fructose at 5%, 8.75%, or 12.5% of the daily caloric 
intake showed a dose-responsive slight elevation in plasma triglycerides (TG) and elevation 
in uric acid.14 In studies with matched calories provided as free glucose, fructose was unique 
in its ability to promote insulin resistance, visceral obesity and hyperlipidemia.9
Collectively, these data suggest that the fructose, not glucose, component of dietary sugar is 
unique in its ability to promote features of metabolic syndrome, including steatosis, insulin 
resistance, and obesity. 
NASH is a clinical and histological subset of NAFLD that is associated with increased
all-cause mortality, cirrhosis and end-stage liver disease, increased cardiovascular mortality, 
and increased incidence of both liver-related, and non-liver-related cancers.15 Prevalence of 
NAFLD is estimated at 30-40% of the US population, while prevalence of NASH is 
estimated at 3-5% of the United States (US) population.15 Risk factors for NASH include 
obesity, insulin resistance, T2DM, hypertension, and dyslipidemia, as manifested by low 
levels of high density lipoprotein cholesterol (HDL-C) and elevated TGs. 
There are no therapies currently approved for the treatment of NASH, although a growing 
body of evidence demonstrates the urgent need for such therapies.15 NASH is diagnosed 
clinically by liver biopsy demonstrating steatosis, inflammation, and cytological ballooning 
of hepatocytes, often with varying degrees of fibrosis.  The clinical progression of NASH 
involves increasing degrees of fibrosis, with cirrhosis and/or hepatocellular carcinoma 
developing in a subset of patients.15  Patients with NASH may be asymptomatic or have 
non-specific symptoms such as fatigue, despite having significant disease shown by liver 
biopsy.  More severe NASH is associated with elevated risk for progression to cirrhosis and 
liver-related mortality.
2.2.1. Nonclinical Overview
In exploratory and/or pivotal toxicity studies conducted in rats and dogs, testes and ovary 
(rat), and the cardiovascular (rat, dog) and neuromuscular (dog) systems were identified as 
primary targets. Adverse findings identified in the pivotal toxicity studies in rats were 
degeneration of spermatids in seminiferous tubules of testes at ≥100 mg/kg/day 
(no-observed-adverse-effect level [NOAEL] = 30 mg/kg/day in the 6-month study, 2.8x the 
predicted human unbound area under the curve over 24 hours (AUC24) at the highest planned 
clinical dose of 300 mg once daily [QD]), and an increased incidence (relative to controls) of 
decreased/absent corpora lutea in the ovary at ≥30 mg/kg/day (NOAEL = 10 mg/kg/day in 


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the 6-month study, 0.9x the predicted human unbound AUC24 at the highest planned clinical 
dose of 300 mg QD). The ovary finding was not observed in shorter term toxicity studies in 
rats at doses up to 175 mg/kg/day for up to 6 weeks (up to 8.2x the predicted human unbound 
AUC24 at the highest planned clinical dose of 300 mg QD). Increases in heart rate and blood 
pressure were noted at ≥20 mg/kg in safety pharmacology and general toxicology studies in 
dogs with a no-observed-effect level (NOEL) of 10 mg/kg and a margin of 1.5x the predicted 
human unbound maximum concentration (Cmax) at the highest planned clinical dose of 
300 mg QD. No PF-06835919-related arrhythmia or structural injuries to the heart or blood 
vessels were observed in any of the studies. Tremors were noted in earlier exploratory 
toxicity studies and in a single dog during the 6-week pivotal study in dogs, ranging from 
being mild and self-terminating at 50-60 mg/kg to being lasting and severe, with 
accompanying clinical signs (eg, ataxia, panting, rapid breathing), at doses up to and 
including a non-tolerated dose of 300 mg/kg. Tremors were seen at exposures representing 
4.3-9.1x the predicted human unbound Cmax, but convulsions were not seen at equivalent 
exposures in any study. PF-06835919 had an ultraviolet (UV) light absorbance but was 
negative in the in vitro phototoxicity assay, which indicates that it is not phototoxic and no 
further photosafety testing is recommended.
Although in vitro data indicated that PF-06835919 had the potential to induce CYP3A and 
CYP2B6 in humans at the highest planned clinical dose (300 mg QD), based on clinical 
drug-drug interaction (DDI) data (see Section 2.2.3), PF-06835919 does not appear to induce 
CYP3A4 at the highest dose administered in this study (300 mg QD). In addition, 
PF-06835919 has the potential to inhibit UGT1A1 and UGT1A4. Further, in vitro 
evaluations suggest that PF-06835919 has a low potential to inhibit intestinal P-glycoprotein 
(P-gp), breast cancer resistance protein (BCRP), OAT3, OATP1B1, and OATP1B3.  
The nonclinical safety profile of PF-06835919 has been adequately characterized to support 
clinical trials of up to 16 weeks.
2.2.2. Clinical Overview
As of February 2019, there are 3 completed sponsor-initiated clinical trials that administered
PF-06835919 (C1061001, C1061002, and C1061003). Safety and tolerability findings from 
these studies are summarized below. In addition, a PF-06835919 midazolam DDI study 
(C1061016) is complete in the clinic and preliminary results are provided below.
The safety and tolerability of PF-06835919 has been assessed in 2 Phase 1 studies in healthy 
adults, C1061001 and C1061002.  Across these 2 studies, 78 healthy adult participants (all 
males) were randomized, 68 (87%) were exposed to at least a single dose of PF-06835919, 
and 52 of these participants were exposed to repeated doses of PF-06835919.  Single oral 
doses (up to 600 mg) and repeated daily doses (up to 330 mg) were found to be generally 
well tolerated with an acceptable safety profile. There were no treatment-emergent adverse 
events (TEAEs) of ‘severe’ intensity in the Phase 1 studies, and all of the TEAEs were ‘mild’ 
in intensity except for 4 ‘moderate’ intensity TEAEs (abdominal pain, rash, and 
2 participants with headaches).  The most frequently reported adverse event (AE) following 
multiple dose administration of PF-06835919 in Study C1061002 was headache (see 
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Median plasma midazolam concentrations were similar following multiple doses of 
PF-06835919 compared to those observed for midazolam administered alone.  Midazolam 
Tmax values were similar between treatment periods (median Tmax of 0.5 hours).  Plasma 
concentrations declined in a monophasic manner with a similar mean terminal half-life (t1/2) 
observed between the treatments: 5.267 hours for midazolam administered alone and 
4.986 hours when administered with multiple doses of PF-06835919.
The statistical comparison of plasma concentrations of midazolam administered alone and
with multiple doses of PF-06835919 are summarized in Table 1. The adjusted geometric 
mean for AUCinf and Cmax were similar, following co-administration with multiple doses of 
PF-06835919 as compared to midazolam administration alone. The ratio of the adjusted 
geometric means of midazolam AUCinf, and Cmax (90% confidence interval [CI]) were 
97.55% (79.91%, 119.08%) and 98.92% (76.44%, 128.01%), respectively, following 
administration of midazolam with multiple doses of PF-06835919, relative to midazolam 
administered alone.  Overall, these results indicate that there is no evidence of a meaningful 
effect of 300 mg PF-06835919 on CYP3A4.
Table 1.
Statistical Summary of Effect of PF-06835919 on Plasma Midazolam PK 
Parameters (AUCinf, AUClast and Cmax), Protocol C1061016
2.3. Benefit/Risk Assessment
In completed clinical studies, PF-06835919 was determined to be well tolerated and to have 
an acceptable safety profile. There are no important identified risks for PF-06835919. The 
important potential risks for PF-06835919 identified in the nonclinical safety studies include 
ovarian changes, cardiovascular effects, tremors, and spermatid degeneration. In the ovary, 
an increased incidence (relative to controls) of decreased/absent corpora lutea was observed 
in female rats during the pivotal 6-month GLP toxicity study at doses similar to the higher 
dose levels anticipated for use in human studies (see Section 2.2.1). This was considered 
adverse due to the potential negative effect on the animal’s fertility. However, these effects 
were not observed in rat studies up to 6 weeks duration, nor seen in any studies of 


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PF-06835919 in dogs up to 16 weeks. Based on available data, the effect of PF-06835919 on 
female ovaries and fertility is uncertain. As a precaution, women of child bearing potential 
(WOCBP) are excluded from this study.
Cardiovascular effects relate to an increase in heart rate seen at doses higher than those 
anticipated for human studies, which were considered non-adverse with no other correlating 
ECG, clinical or anatomic pathology findings, or impact to overall animal health. Tremors 
and spermatid degeneration were all observed at exposures higher than those tested in 
clinical studies. No adverse cardiovascular effects or tremors have been observed in clinical 
studies to date. 
Based on Study C1061003, PF-06835919 administered at the 300 mg dose level was shown 
to reduce liver fat over a 6-week period.  There have been no significant adverse clinical 
trends in laboratory values, vital signs, or changes in ECG parameters.  
The sponsor considers that the available information about PF-06835919 from the 
non-clinical and clinical studies completed to date provides a favorable benefit-risk profile 
and supports the continued investigation of the compound as a potential treatment for NASH 
with liver fibrosis.
More detailed information about the known and expected benefits and risks, and reasonably 
expected AEs of PF-06835919 may be found in the IB, which is the single reference safety 
document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary:

To evaluate the effect of 2 dose
levels of PF-06835919 compared
to placebo on whole liver fat
measured by MRI-PDFF.

To evaluate the effects of 2 dose
levels of PF-06835919 compared 
to placebo on HbA1c.

Estimand 1:

This estimand is intended 
to provide a population 
level estimate of the 
treatment effect of the IP 
alone relative to placebo 
under the scenario of no 
discontinuation of study 
intervention, without the 
potential confounding 
effects of additional 
prohibited medications, 
regardless of the 
participant’s compliance 
with the IP dosing.  
Details in Section 9.1.1.

%CFB in whole liver fat at 
16 weeks using MRI-PDFF.

CFB in HbA1c at 16 weeks.














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4.3. Justification for Dose
This study is planned as a 3-arm, parallel group study with 2 active PF-06835919 treatment 
arms (150 mg QD and 300 mg QD) and placebo to evaluate changes in liver fat and HbA1c
in participants with elevated liver fat and T2DM. 
In Study C1061003 where PF-06835919 or placebo was administered to participants with 
elevated liver fat, 300 mg was found to have been associated with a meaningful decrease in 
liver fat (approximate 20% reduction) while the lower dose of 75 mg was not significantly 
different than placebo.  Both doses in C1061003 were generally well tolerated.  The doses for 
this study were selected in order to further evaluate the effects of 300 mg (in a different 
population and for a longer duration) and to determine if a dose between those studied in 
C1061003 would be associated with meaningful improvement in liver fat and/or other PD 
markers being evaluated in this study.  Notably, based on systems modeling based on data 
from the multiple ascending dose study in healthy participants (C1061002), KHK inhibition 
in the liver at the 300 mg dose is expected to be near maximal.
With the exception of a decreased/absent corpus lutea finding in the 6-month rat study (note: 
women of child-bearing potential [WOCBP] are excluded from this study), anticipated 
unbound exposures of PF-06835919 in this study are expected to provide sufficient margins 
over findings in the 6-month rat and 16-week dog toxicology studies (see Section 2.2.1).  As 
exposures observed in the C1061002 study were approximately dose proportional, the 
anticipated exposure at the low dose (150 mg) is approximately half that of the high dose.
It is anticipated that the 300 mg dose of PF-06835919 administered in this study will have a 
similar effect on OATP substrates, as the 280 mg dose administered in Part B of the 
C1061002 study (see IB) which demonstrated an approximately 1.6-fold increase in 
atorvastatin AUC. Based on preliminary results of C1061016, PF-06835919 administered at 
the highest dose in this study (300 mg QD) has approximately no meaningful effect on 
plasma concentrations of a co-administered sensitive 3A4 substrate (midazolam). Based on 
these results, CYP3A4 substrates are allowed in this study. Specific concomitant medication
exclusions are detailed in Section 6.5.
In summary, the 300 mg QD dose selected for this study is intended to fully assess the 
potential for KHK inhibition to reduce liver fat and HbA1c in adults with NAFLD and 
T2DM.  The 150 mg dose was selected to explore if a dose between those that were 
previously shown to be effective (300 mg) and not effective (75 mg) in lowering liver fat in a 
previous 6-week study (C1061003)  has potential for further clinical development.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the follow-up call (or visit, if required by investigator).
The end of the study is defined as the date of the last visit or follow-up phone call of the last 
participant in the study.


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5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 and 70 years, inclusive, at Visit 1 
(Screen 1).  Females must be of non-childbearing potential.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Participants with T2DM on stable doses (500 mg/day) of metformin monotherapy 
for at least 8 weeks of Visit 1 (Screen 1).
4. At Visit 1 (Screen 1), waist circumference >102 centimeters for males and 
>89 centimeters for females with a maximum that allows for a subject to fit 
comfortably within the MRI machine.
5. At Visit 1 (Screen 1) and Visit 2 (Screen 2), a CAPTM 280 dB/m via FibroScan
assessment.  If either CAPTM value is in the range of 260-279 dB/min, the 
measurement may be repeated, on a different day, following at least a 4-hour fast
(except water).
6. At Visit 3 (Screen 3), liver fat 8% measured by MRI-PDFF acquisition protocol at 
the sponsor-qualified imaging facility, confirmed via a single repeat, if deemed 
necessary by the sponsor-identified central imaging vendor (refer to Section 8.1.1).
7. HbA1c at Screen 1 (Visit 1), as assessed by the sponsor-identified central laboratory 
of 7.0-10.5%, inclusive.  Repeat assessments of HbA1c to determine study eligibility 
are NOT permitted.


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Weight:
8. At Visit 1 (Screen 1), total body weight of >50 kg (kilograms; 110 lbs [pounds]) and 
a BMI of 25.0 – 40.0 kg/m2, inclusive.
Informed Consent:
9. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Recent (ie, within 6 months prior to Screen 1) evidence or medical history of unstable 
concurrent disease such as: clinically significant hematological, endocrine, 
pulmonary, gastrointestinal (including severe gastroparesis), cardiovascular, hepatic, 
psychiatric, neurologic, or clinically significant allergic disease (including drug 
allergies, but excluding treated and untreated seasonal allergies at the time of dosing).
2. History or evidence of diabetic complications with significant end-organ damage, 
such as:

Proliferative retinopathy and/or macular edema; or diabetic neuropathy 
complicated by neuropathic ulcers or judged to be clinically significant as 
signified by need for chronic pharmacological intervention;
3. 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 IP administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study.
4. Participants with any of the following medical conditions: 

Any condition possibly affecting drug absorption (eg, prior bariatric surgery, 
gastrectomy, ileal resection);

Diagnosis of type 1 diabetes mellitus; 

Recent (ie, within the previous 6 months) history of congestive heart failure 
(New York Heart Association [NYHA] class III or IV) or unstable angina;

A history of myocardial infarction, stroke, or transient ischemic attack, within
6 months of Screen 1 (Visit 1);


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
Any malignancy not considered cured (except basal cell carcinoma and squamous 
cell carcinoma of the skin); a subject is considered cured if there has been no 
evidence of cancer recurrence in the previous 5 years;

Active placement of medical devices in/on thoracic or abdominal cavities such as 
pacemakers or defibrillators.
5. Participants 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 (Visit 3), by the 
sponsor-identified central imaging vendor, or participants 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;

Participants with metal implants, devices, paramagnetic objects contained within 
the body, and excessive or metal-containing tattoos;

Participants 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;

Participants with abdominal girth greater than the bore size of the site’s MRI 
system.
Prior/Concomitant Therapy:
6. Refer to Section 6.5 for details regarding prohibited prior/concomitant therapies.
Prior/Concurrent Clinical Study Experience:
7. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of IP used in this 
study (whichever is longer). 
8. Participants with known prior participation in a trial involving PF-06835919 (ie, 
received at least 1 dose of IP).
Diagnostic Assessments:
9. Fasting plasma glucose levels >270 mg/dL (15.0 mmol/L) at the Screen 1 (Visit 1) or
run-in visit (Visit 4), as assessed by the sponsor-identified central laboratory and
confirmed by a single repeat, if deemed necessary.


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10. 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 Visit 1 (Screen 1)
permitted to assess eligibility, if needed:

Hepatitis B virus (HBV), defined by presence of hepatitis B surface antigen 
(HBsAg);

Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb), 
and HCV ribonucleic acid (RNA, when reflexed based on a positive result for 
HCVAb);

Human Immunodeficiency Virus (HIV) infection, defined as presence of 
HIV antibody;

Known diagnosis of primary biliary cirrhosis, primary sclerosing cholangitis, 
autoimmune hepatitis, or overlap syndrome;

History of esophageal varices, ascites, or hepatic encephalopathy;

Alcoholic liver disease;

Wilson's disease, defined as ceruloplasmin level < lower limit of normal (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.
11. At Visit 1 (Screen 1), participants with an estimated glomerular filtration rate (GFR)
<60 mL (milliliter)/min (minute)/1.73m2 as calculated by the modification of diet in 
renal disease equation (MDRD), and confirmed via a single repeat, if deemed 
necessary. 
12. Participants with ANY of the following abnormalities in clinical laboratory tests at 
Screen 1 (Visit 1), as assessed by the sponsor-identified central laboratory and 
confirmed by a single repeat, if deemed necessary: 

C-peptide concentration <0.8 ng/mL (267 pmol/L [picomoles per liter]);


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
Fasting serum triglycerides 500 mg/dL (5.65 mmol/L);

Fasting direct LDL-C >190 mg/dL (4.92 mmol/L);

AST or ALT 2.0x upper limit of normal (ULN);

Total bilirubin 1.5x ULN and direct bilirubin ULN.
13. Seated systolic BP >160 mmHg and/or diastolic BP >100 mmHg after at least a 
5-minute rest at Screen 1 (Visit 1).  BP is determined as the mean of triplicate 
measurements collected with 2-4 minutes of rest between measurements.
14. At Screen 1 (Visit 1), standard 12-lead ECG that demonstrates clinically relevant 
abnormalities that may affect participant safety or interpretation of study results (eg, 
baseline corrected QT [QTcF] interval >450 msec, complete left bundle branch block 
[LBBB], signs of an acute or indeterminate-age myocardial infarction, ST-T interval 
changes suggestive of myocardial ischemia, second- or third-degree atrioventricular 
[AV] block, or serious bradyarrhythmias or tachyarrhythmias).  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 
participant’s eligibility.  Computer-interpreted ECGs should be overread by a 
physician experienced in reading ECGs before excluding participants.
15. A positive urine drug test for potential drugs of abuse at Screen 1 (Visit 1), including 
medical marijuana.  Participants that have been medically prescribed opiates/opioids 
or benzodiazepines and report the use of these drugs to the investigator at Screen 1
(Visit 1) may be allowed to participate if approved by the sponsor.
Other Exclusions:
16. Compliance of <90% (based on pill count) during the 2-week, single-blind run-in 
period, as assessed prior to randomization on Day 1 (ie, participants cannot miss more 
than 1 dose).
17. History (within the last 6 months) of regular alcohol consumption exceeding 
21 drinks per week for men and 14 drinks a week for women (1 drink = 5 ounces of
wine (150 mL) or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor).
18. Male participants with partners who are currently pregnant; or male participants able 
to father children and are unwilling or unable to use a highly effective method of 
contraception for the duration of the study and for at least 5 days after the last dose of 
IP.
19. Participation in a formal weight loss program or use of agents suspected to cause
weight loss within 3 months prior to Visit 1 (Screen 1).
20. Weight loss of 5% within 1 month prior to Visit 1 (Screen 1).


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21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 56 days prior to randomization on Day 1 (Visit 6).
22. 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 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant’s partner.
5.3.2. Dietary Restrictions
•
Participants must abstain from all food and drink (except water) for ≥8 hours prior to 
any blood sample collections for clinical laboratory tests, fasting glucose monitoring, 
•
Water may be consumed as desired (ad libitum);
•
Blinded IP must be administered every day with the morning meal;
•
On scheduled outpatient visits to the site, in the morning, from Visit 4 (Day -14) 
through Visit 12 (Week 16), participants must be instructed to arrive without having 
morning meal/breakfast, self-administration of the blinded IP, and morning dose of 
allowed concomitant medication(s), if applicable, for the given day;
•
At Visit 4 (Day -14) through Visit 12 (Week 16), inclusive, the morning meal will 
be consumed with above-mentioned medications at the site [with the meal either
provided by the site, or the participant provided a voucher (or similar) by the site 
to purchase the meal before arriving at the site for each visit].
•
Each outpatient visit to the imaging facility (for MRI-PDFF) will occur following a 
fast (water permitted) of ≥4 hours; 
•
For assessment via FibroScan®, visits will occur following a fast (water permitted) of 
≥4 hours;
CCI




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
Similar to MRI-PDFF, each assessment via FibroScanto occur at the same time 
of day (2 hours) relative to FibroScanassessment completed at 
Visit 1 (Screen 1).
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to investigational product. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE.
Individuals who were considered screen failures may be rescreened only after a discussion 
with the sponsor. If rescreened, these participants should be assigned a different participant 
number from the initial screening.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term IP may be used synonymously with study 
intervention.
6.1. Study Intervention(s) Administered
Intervention Name
PF-06835919
Placebo for 
PF-06835919
ARM Name
Active
Placebo
Type
Drug
Drug
Dose Formulation
Tablet
Tablet
Unit Dose Strength(s)
Mg
mg
Dosage Level(s)
150 or 300, QD
0, QD
Route of Administration
Oral
Oral
Investigational Medicinal Product (IMP)
and Noninvestigational Medicinal Product 
(NIMP)
IMP
IMP 
Sourcing
Provided centrally by the 
sponsor.
Refer to IP Manual for 
further information.
Provided centrally by the 
sponsor.
Refer to IP Manual for 
further information.
Packaging and Labeling
Study intervention will 
be provided in bottles.  
Each bottle will be 
labeled in blinded 
fashion as required per 
country requirement.
Study intervention will 
be provided in bottles.  
Each bottle will be 
labeled in blinded 
fashion as required per 
country requirement.


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6.1.1. Administration
Participants will swallow the IP whole and will not manipulate or chew the IP prior to 
swallowing.
To maintain the blind, administration of IP will use a strategy so that all participants will 
receive an equal number of tablets, regardless of which dose they are assigned.  Tablets will 
be active drug (50 mg or 100 mg) or placebo.
Participants will take a total of 3 tablets of PF-06835919 and/or placebo at approximately the 
same time each day and recommended to be taken with the morning meal.  Dosing will be 
witnessed by the investigator site staff at Visit 4, and Visits 6, 7, 8, 9,10, and 12.  Participants 
will be instructed to delay self-administration of IP and concomitant medications on 
scheduled visit days until they arrive for their outpatient clinic visit, except participants in the 
sub-study at their Week 14 (Visit 11).  At visits when participants report to the imaging
center, dosing and breakfast should be delayed until completion of the MRI-PDFF procedure.
Participants should be instructed that if they forget to take their morning dose at their usual 
time, they should take the missed dose as soon as possible on the day it was missed, however, 
there must be at least an 8-hour interval between the missed dose and the next dose.  If the 
participant remembers missing a dose the next day or later, they should be instructed NOT to 
take 2 doses in the same day. 
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions will be accounted for using an IP accountability form/record.  All empty 
containers should be returned to the site at each visit when drug accountability will be 
performed.  


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4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual or other specified location.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
Specific details regarding the definition of an excursion and information the site 
should report for each excursion will be provided to the site in the IP manual.
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (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.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.
6.2.1. Preparation and Dispensing
Participants will be assigned a subject identification number using an interactive response 
technology (IRT) drug management system.  The IP will be dispensed using IRT at each visit 
from Visit 4 (single-blind) to Visit 10 (double-blind), excluding Visits 5 and 11 (Note: 
Visit 11 applicable only to participants in the substudy).  A qualified staff member will 
dispense the IP via unique container numbers in the bottles provided, in quantities 
appropriate for the study visit schedule.  The participant should be instructed to maintain the 
product in the bottles provided throughout the course of dosing and return the bottles to the 
site at the next study visit.  Dosing instructions will be provided to the sites and individual 
participants.  Upon receipt of the new bottle, the used bottle will be returned.  Participants
will be instructed to store the study drug at room temperature and out of the reach of small 
children.


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6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
Allocation of participants 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 participant number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when IP is being supplied via the IRT system.  The IRT system will provide a confirmation 
report containing the participant number, randomization number, and DU or container 
number assigned.  The confirmation report must be stored in the site’s files. 
IP will be dispensed at the study visits summarized in the SoA. 
Returned IP must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and case report form (CRF).
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
Compliance of single-blind placebo administration during the run-in period will be assessed 
by pill count on Day 1 (Visit 6) for the purpose of inclusion into the study.  Acceptable 
compliance will be defined as self-administration by the participants of:

90% of the study-supplied blinded placebo taken by the participant during the run-in 
period (ie, Visit 4 to Visit 5) - only 1 dose is permitted to be missed.
Compliance of IP administration will be assessed during the treatment phase of the study by 
the number of tablets returned by the participants at Visits 7, 8, 9, 10, and 12.

>80% compliance with self-administration of the IP is expected from Day 1 (Visit 6) 
to Day 112 (Visit 12); investigators must closely monitor non-compliant participants
in order to enhance their adherence to the study treatment.


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At Visit 4 (run-in), participants will be provided with a dosing diary (or similar) and 
instructed on how to record each dose taken throughout the study through Visit 12 
(Week 16).  Participants will bring the dosing diary to each clinic visit to be reviewed by 
clinic staff.
6.5. Concomitant Therapy
All concomitant medications taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  Attempts must be made to not alter the 
doses and regimens of chronic background medications after randomization and for the 
duration of participation in this study.  Any changes made to background medications must 
be communicated to the sponsor’s medical monitor as soon as practically possible, and if 
agreed, be captured in the CRF.  All participants must be questioned about concomitant 
medication at each outpatient visit to the clinical site. 
Medications taken before Visit 6 (Day 1) will be documented as prior medications.  
Medications taken after dosing of double-blind IP at Visit 6 (Day 1) and until the second 
Follow-up (telephone contact or visit) will be documented as concomitant medications.
Medications for Glycemic Control
Participants must be on a stable dose of metformin (500 mg /day) starting at 8 weeks 
prior to Visit 1 (Screen 1) and until Visit 13 (on-site Follow-up).
The use of the following classes of agents is not permitted within 8 weeks prior to 
Visit 1 (Screen 1) and until Visit 13 (on-site Follow-up):

Thiazolidinediones (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;

Sulfonylureas such as acetohexamide, chlorpropamide, tolazamide, tolbutamine, 
glimepiride, glipizide, glyburide;

Meglitinide analogues such as repaglinide, nateglinide;

Dipeptidyl peptidase-4 inhibitors (DPP-4i) such as sitagliptin, saxagliptin, linagliptin, 
vildagliptin; or

glucosidase inhibitors such as acarbose and miglitol.


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Lipid-modifying Medications
Use of background lipid-modifying agent(s) are permitted unless otherwise specified in this 
protocol. If possible, doses of lipid modifying agents should be stable for 4 weeks prior to 
Visit 1 (Screen 1) and for the duration of the study.  Any changes to dose of lipid modifying 
agents should be noted on the CRF.
Participants are permitted to be on stable doses of the following lipid-modifying agents,
starting at 4 weeks prior to Visit 1 (Screen 1) and until Visit 13 (on-site Follow-up), 
including (but not limited to) the following:

Statins such as atorvastatin, simvastatin, rosuvastatin, fluvastatin, pitavastatin, and 
pravastatin;

Ezetimibe.
The following lipid-modifying agents are not permitted in this study within 4 weeks prior to 
Visit 1 (Screen 1) and for the duration of the study:

Bile acid sequestrants such as cholestyramine, colestipol, colesevalam;

Fenofibrate and gemfobrozil;

Nicotinic acid/niacin; or

Monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 
9 (PCSK9), such as alirocumab and evolocumab.
Antihypertensive Medications
Use of background antihypertensive agent(s) is permitted unless otherwise specified in this 
protocol.  
For participants that enter the study taking allowable antihypertensive agents, doses should 
be stable for 4 weeks prior to Visit 1 (Screen 1) and for the duration of the study.  Any 
changes to dose of blood pressure modifying agents should be avoided if possible; however, 
if any changes occur, they must be noted on the CRF.
Other Acceptable Concomitant Medications
Any participant on the following list of medications must be on stable doses [ie, 8 weeks
prior to Visit 1 (Screen 1) and until Visit 13 (on-site Follow-up), if possible]:

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, 
diclofenac, naproxen, indomethacin, meloxicam, and celecoxib.  Intermittent use of 
these medications is also permitted;


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
Intermittent use of acetaminophen/paracetamol at doses of up to 1 gram per day;

Inhaled and topical corticosteroids;

Thyroid replacement therapy and hormone replacement therapy (in eligible females);

Anti-psychotic medications such as olanzapine and risperidone;

Antidepressant medications such as tricyclic agents, selective serotonin reuptake 
inhibitors, and serotonin/norepinephrine reuptake inhibitors;

Vitamin E, including high doses provided the regimen is stable;

Certain herbal supplements but only following consultation with sponsor;

Limited use of non-prescription 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.
Other Prohibited Concomitant Medications
Participants must abstain from using the following medications for 4 weeks prior to 
Visit 1 (Screen 1) and until Visit 13 (on-site Follow-up):

Use of medications that are known OATP inhibitors including:

Rifampin, gemfibrozil, cyclosporine, erythromycin and clarithromycin;

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 including:

Coumadin-type anticoagulants or other anticoagulants (eg, dabigatran); though
aspirin at doses ≤325 mg/day is permitted;

Anticonvulsants; or


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
Antiarrhythmics, except for beta blockers if used for the management of 
conditions other than arrhythmias (eg, blood pressure control);

Medications historically associated with fatty liver are prohibited if used for 
4 weeks of continuous use in the previous 13 months prior to Screen 1 (Visit 1), 
examples include: 

Amiodarone, methotrexate, tetracyclines, tamoxifen, estrogens at doses greater 
than those used for hormone replacement, anabolic steroids, valproic acid, or 
other known hepatotoxins.
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with PF-06835919; standard medical 
supportive care must be provided to manage the AEs. 
6.6. Dose Modification
No dose modifications are permitted in this study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue IP.  Also, 
it should be stressed that if the study medication is discontinued for any reason, it is fully 
anticipated that subjects continue in the study per protocol (Off Drug In Study or ODIS) per 
treatment policy estimand.  Should the ODIS subject withdraw from the study, an Early 
Termination Visit should be scheduled at the time consent is withdrawn and evaluated for 
early termination procedures as listed in the SoA. 
ECG Changes 
A participant who meets either bulleted criteria based on the average of triplicate 
ECG readings will be withdrawn from the study. 

QTcF >500 msec;

Change from baseline (CFB): QTcF >60 msec.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new, clinically relevant finding should be reported as an AE.


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See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request (and choose 
not to continue as an ODIS subject) or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants 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 participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of IP or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page.  In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.


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7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record;

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.






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section.  Identification of such incidental findings during the central review process should 
not be expected, and the site maintains responsibility for performing a general safety review 
of all images as per site protocols. 
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
A complete physical examination will occur at times specified in the SoA and include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological
systems. Height (at Screen 1 only) and weight will also be measured and recorded.
A limited physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.1.1. Measurement of Waist Circumference
As part of the physical examination at Screen 1 only, waist circumference will be measured 
using a flexible anthropometric tape and ideally, reporting the measurement in centimeters 
with accuracy to the nearest 0.1 centimeter.  Measurement will be undertaken as follows:

While participant is in a standing position with arms resting comfortably at the side;

Under standard conditions including post-void, with the tape touching the skin (not 
clothing);

At the end of a normal expiration (when lungs are at their residual capacity).
The measurement will consider the following anatomical features as benchmarks:

Circumference of the narrowest part of the torso as viewed from the anterior aspect 
or;

If the narrowest part of the torso cannot be identified, the measurement must be made 
of the smallest horizontal circumference in the area between the ribs and the iliac 
crest.


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8.2.2. Body Weight
In this study, assessment of body weight will occur at the nominal time points specified in 
the SoA per the following specifications: 

Weight will be recorded using a scale placed on a stable, flat surface;

Same scale, as much as practically possible, will be used with the scale reporting 
weight in kilograms or pounds, and accuracy to the nearest 0.1 kg (or 0.2 pounds), ie, 
the device used for this study must be able to distinguish a difference between 68.4 kg 
and 68.3 kg;

Measurement must be undertaken:

At approximately the same time of the day at each nominal time point;

After the participant has been asked to void (ie, forced void);

Under standard conditions (eg, participants must wear light clothing with content 
of their pockets emptied or hospital gown and not be wearing shoes or bulky 
layers of clothing/jackets).
8.2.3. Vital Signs
Pulse rate and BP will be assessed in triplicate (2-4 minutes between measurements) at times 
specified in the SoA section of this protocol per the following specifications:

At Screen 1 (Visit 1) only, the participant’s arm circumference should be measured at 
the midpoint of the length of the upper arm using a flexible anthropometric tape to 
select the appropriate cuff to be used throughout the study to measure BP/pulse rate 
via an automated device using an oscillometric method (not auscultation);

Participants with arm circumference greater than the largest cuff size available at 
each study site are not eligible.

Seated BP/pulse rate will be measured with the participant’s arm supported at the 
level of the heart, and recorded to the nearest mmHg, following a rest of 5 minutes;

The same arm (preferably the dominant arm) will be used for BP/pulse rate 
assessment throughout the study;

Participants should be instructed not to speak during BP/pulse rate measurements.
Additional collection times, or changes to collection times of BP/pulse rate will be permitted, 
as necessary, to ensure appropriate collection of safety data.


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8.2.4. Electrocardiograms
Standard 12-lead ECGs should be collected at times specified in the SoA section of this
protocol using an ECG machine that automatically calculates the heart rate and measures 
pulse rate, QT, and QTcF intervals and QRS complex. All scheduled ECGs should be 
performed after the participant has rested quietly for 10 minutes in a supine position. 
If a postdose QTcF interval remains ≥30 msec from the baseline and is >450 msec; or an 
absolute QTcF value is ≥500 msec for any scheduled ECG for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than the criterion listed above after 8 hours of 
monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.5. Clinical Laboratory Assessments
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.


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If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.5.1. Management of Glycemic Control
Hypoglycemic adverse events (HAEs) and fasting plasma glucose will be routinely 
monitored during participation in the study.
Based on this information, as well as review of the results reported by the central laboratory, 
an assessment of any symptomatic and asymptomatic occurrence of hypo- or hyper-glycemia 
must be undertaken.
8.2.5.1.1. Home Glucose Monitoring

To aide in management of their T2DM, all participants will be provided home 
glucose monitoring supplies including a sponsor-provided glucometer, instructions on 
the use of the glucometer and accompanying supplies.

Home glucose monitoring logs will be provided to participants for completion at 
home and brought to each outpatient visit to the site along with the glucometers.
Investigators must review the home glucose monitoring logs completed by the 
participants and the readings stored in the glucometer device at each visit to the site 
after the run-in visit (Visit 4).

Participants must perform home glucose monitoring at least 3 times weekly
following at least an 8- (preferably 10-) hour fast (except water). However, the 
investigator may recommend more frequent home glucose monitoring if needed.

Less frequent glucose monitoring will NOT be considered a protocol deviation unless 
the participant fails to monitor his/her glucose for 3 or more consecutive days.

If the participant experiences symptoms of hypoglycemia, home glucose monitoring 
should be performed, and these symptoms, along with the glucometer measurement, 
should be captured on the home glucose monitoring log.

If the participant uses his/her own glucometer, and not one provided by the sponsor, a 
protocol deviation will NOT be recorded provided the investigator is still able to 
monitor the participant’s daily glucose values according to the criteria stated above.
8.2.5.1.2. Management of Hypoglycemia
Any episode of hypoglycemia must be captured on the Hypoglycemia Adverse Event CRF.
For the definition of a hypoglycemic episode and severity categorization see 
Section 8.2.5.1.2.1 below.


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Participants noted to have a fasting plasma glucose value (during home glucose monitoring) 
meeting the definition of hypoglycemia must be instructed to repeat the measurement the 
next day (following at least an 8- (preferably 10-) hour fast, except water). If the second 
measurement also meets the below definition, participants must be asked to return to the site 
within 1 to 3 days (following at least an 8- (preferably 10-) hour fast, except water) and have 
blood collected and sent to the central laboratory for analysis of fasting plasma glucose.
8.2.5.1.2.1. Definition and Severity of Categorization of Hypoglycemic Adverse Event 
(HAE)
Based on review of the participant completed home glucose monitoring log at each site visit, 
as well as results reported by the central laboratory, the investigator must assess the glucose 
values as well as any symptoms documented.
HAE is defined as 1 of the following: 
1. Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
HAE but a plasma glucose value of <70 mg/dL (3.9 mmol/L) using glucometer (or 
sponsor-identified central laboratory);
2. Documented symptomatic hypoglycemia: An event during which typical symptoms 
of HAE are accompanied with a glucose value of <70 mg/dL (3.9 mmol/L) using 
glucometer (or sponsor-identified central laboratory) and the clinical picture includes 
prompt resolution with food intake, subcutaneous glucagon, or intravenous (IV) 
glucose; 
3. Probable symptomatic hypoglycemia: An event during which symptoms of HAE are 
not accompanied by a plasma glucose determination but was presumably caused by a 
plasma glucose concentration of <70 mg/dL (3.9 mmol/L), and the clinical picture 
includes prompt resolution with food intake, subcutaneous glucagon, or IV glucose.
Each episode of HAE must be categorized with respect to severity. In order to characterize 
the event as severe, all 3 criteria below must be met:
1. The participant was unable to treat him/herself. Neurologic impairment, and not the 
age of the participant, is the explanation for why the participant could not treat 
him/herself and required the assistance of another person.
2. The participant exhibited at least one of the following neurological symptoms:

Memory loss;

Confusion;

Uncontrolled behavior;

Irrational behavior;


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
Unusual difficulty in awakening;

Suspected seizure;

Seizure;

Loss of consciousness.
3. Either:

If blood glucose was measured and was ≤54 mg/dL (2.7 mmol/L) using 
glucometer (or central laboratory); or

If blood glucose was not measured, the clinical manifestations were reversed by 
oral carbohydrates, subcutaneous glucagon, or intravenous glucose.
Events that do not meet all the criteria above for severe HAE are characterized as mild or 
moderate in severity.
Any episode of HAE must be captured on the HAE CRF.
8.2.5.1.3. Management of Hyperglycemia
Hyperglycemia is defined as the following:

Fasting plasma glucose ≥270 mg/dL (15.0 mmol/L) using glucometer (or central 
laboratory). 
After randomization, participants noted to have a fasting plasma glucose value (during home 
glucose monitoring) meeting the above definition of hyperglycemia must be instructed to 
repeat the measurement the next day (following at least an 8- (preferably 10-) hour fast, 
except water). If the second measurement also meets the above definition, participants must 
be asked to return to the site a day later (following at least an 8- (preferably 10-) hour fast, 
except water) and have blood collected for fasting plasma glucose (and shipped to the central 
laboratory for analysis).
The investigator should determine if the participant collected the samples after an adequate 
fasting period; and if the participant is following recommended dietary guidelines. Proper 
dietary and collected procedures should be reinforced with the participant.
If the results from the central laboratory confirm the readings using glucometer, the 
participant should receive glycemic rescue medication at the discretion of the investigator 
(see Section 6.5.1).


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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the
study (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving IP), through and including a minimum of 
28 calendar days, except as indicated below.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF, not the AE section.
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.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.


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SAEs occurring in a participant 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.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.


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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female partners of male participants will be collected after the 
start of study intervention and until 28 days after the last dose.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. 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.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the IP by the wrong 
participant, or at the wrong time, or at the wrong dosage strength.


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Exposures to the IP under study may occur in clinical trial settings, such as medication 
errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the IP;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on 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.
8.4. Treatment of Overdose
For this study, any dose of PF-06835919 greater than 600 mg within a 24-hour time period 
will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
PF-06835919 can no longer be detected systemically (at least 5 days).










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Estimand 1:
Estimand 1 is intended to provide a population level estimate of the treatment effect of the 
IP alone relative to placebo under the scenario of no discontinuation of study intervention, 
without the potential confounding effects of additional prohibited medications, regardless of 
the participant’s compliance with the IP dosing.
Population: 
The target population consists of patients with NAFLD and T2DM on stable doses 
(500 mg/day) of metformin monotherapy.
Intercurrent Events: 
a.
Withdrawal from study intervention – All data collected after a participant stops 
taking study medication will be excluded. 
b. Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the primary endpoints will be omitted from the 
analysis.  Receiving a medication prohibited due to drug-drug interaction (DDI) risk 
will not affect this estimand.  The list of concomitant medications would be reviewed 
prior to database lock to determine which would be classed as “prohibited” for this 
estimand.
c.
Inadequate compliance – Participants with inadequate compliance will have their 
primary endpoint measurements used as recorded in the analysis.  
Population level summary: 
The population level summary will be the mean difference in change from baseline between 
PF-06835919 and placebo arms for the endpoint of interest.
Estimand 2:
Estimand 2 is intended to provide a population level estimate of the treatment effect of the IP 
alone relative to placebo on liver fat measured by MRI-PDFF and HbA1c at Week 16 
without regard to compliance or discontinuation of study drug or administration of prohibited 
medication.  
Population: 

The target population consists of patients with NAFLD and T2DM on stable doses 
(500 mg/day) of metformin monotherapy.


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Intercurrent Events: 
a.
Withdrawal from study intervention – All data collected regardless of a participant’s 
withdrawal from the study medication will be included in the analysis. 
b. Prohibited medications – All data collected for a participant regardless of the use of 
prohibited medications will be used in the analysis.
c.
Inadequate compliance – Participants with inadequate compliance will have their 
primary endpoint measurements used as recorded in the analysis. 
Population level summary: 
The population level summary will be the mean difference in change from baseline between 
PF-06835919 and placebo arms for the endpoint of interest.
9.2. Sample Size Determination
A sufficient number of participants will be screened to achieve approximately 
150 participants randomly assigned to IP and an estimated total of 50 evaluable participants 
per intervention group.  A maximum of approximately 150 participants will be randomly 
assigned to IP such that approximately 132 evaluable participants complete the study.
This assumes an approximate 12% dropout rate resulting in 44 completers per arm.  With this 
sample size, the power to detect a 25% mean reduction in whole liver fat from MRI-PDFF
compared to placebo is 98% using a 2-sample t-test and a 2-sided Type I error rate of 0.1.  
This calculation assumes the pooled standard deviation (SD) of 0.36 in the log-scale (based 
on an internal study).  For the co-primary endpoint of HbA1c, the power to detect a 
0.75% mean reduction compared to placebo is 96% using a 2-sample t-test and a 2-sided 
Type I error rate of 0.1 assuming a pooled SD of 1%.  There will not be any adjustment for 
multiplicity in the assessment of hypotheses for the 2 co-primary endpoints.
The number of participants in the sub-study will be recruited based on feasibility.
9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Pre-randomization
All participants entering the placebo run-in phase.
Randomly assigned to 
Treatment
Defined according to Full Analysis Set.
Safety
All participants randomly assigned to treatment and who 
take at least 1 dose of treatment.  Participants will be 
analyzed according to the dose they actually received.










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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICD.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide 
this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
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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 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally 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 participant 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 participants 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.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.


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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.


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When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the study monitoring plan.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.


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10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer 
intervention-related information necessary for the appropriate scientific presentation or 
understanding of the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study team on demand (SToD) 
system.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 


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advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.




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Laboratory results that could unblind the study will not be reported to investigator sites or 
other blinded personnel until the study has been unblinded are as follows: HbA1c, insulin, 
hs-CRP, uric acid, and GGT.










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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.






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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 5 days after the last dose of study intervention, which
corresponds to the time needed to eliminate study intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception is 
required for WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria

A female participant is eligible to participate if she is not a WOCBP (see definitions 
below in Section 10.4.3).
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.


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For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Highly Effective Methods
The following apply to WOCBP partners of male participants:
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner:
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective method 
of contraception should be used.  The spermatogenesis cycle is approximately 
90 days.


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6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Collection of Pregnancy Information
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 participant’s partner becomes or is found to be pregnant during the participant’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 


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regarding environmental exposure to a Pfizer product in a pregnant woman to Pfizer Safety 
using the EDP supplemental form.  This must be done irrespective of whether an AE has 
occurred and within 24 hours of awareness of the exposure.  The information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure 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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.




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


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








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Abbreviation
Term
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
dB/m
decibels per meter
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
dL
deciliter
DMC
data monitoring committee
DPP-4i
dipeptidyl peptidase-4 inhibitors
DU
dispensable unit
EC50
50% of the maximum effect
EC
ethics committee
ECG
electrocardiogram
e-CRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EFD
embryo-fetal development
Emax
efficacy
EU
European Union
EudraCT
European Clinical Trials Database
F1P
fructose-1-phosphate
F
bioavailability
FIH
first in human
FSH
follicle-stimulating hormone
fu
unbound plasma fraction
F/U
Follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
GLP-1r
glucagon-like peptide 1 receptor
HAE(s)
hypoglycemia adverse event(s)
HbA1c
hemoglobin A1C
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatic cellular carcinoma
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
HDL-C
high-density lipoprotein cholesterol
CCI


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Abbreviation
Term
HEK
human embryonic kidney
HepB
hepatitis B
HepC
hepatitis C
hERG
human Ether-a-go-go related gene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HOMA-IR
homeostatic model assessment of insulin resistance
hs-CRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IC50
50% of the inhibition concentration
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identification
IDL
intermediate-density lipoprotein
IL-6
interleukin 6
IMP
Investigational Medicinal Product
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISAP
interim statistical analysis plan
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IWR
interactive web response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kg
kilogram
KHK
ketohexokinase
Ki
inhibitory constant
kPa
kilopascals
LBBB
left bundle branch block
lbs
pounds
LDL-C
low-density lipoprotein cholesterol
LLN
lower limit of normal
LFT
liver function test
LSLV
last subject last visit 
LSM
liver stiffness measure
m2
meter squared
MAR
missing at random
max
maximum
MCH
mean corpuscular hemoglobin


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Abbreviation
Term
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MELD
model of end-stage liver disease
mg
milligram
min
minute
mL
milliliter
mmHg
millimeters of mercury
mmol/L
millimoles per liter
MMRM
mixed model with repeated measures
MOA
mechanism of action
MRI
magnetic resonance imaging
msec
millisecond
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
ND
not determined
ng
nanograms
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NIMP
non investigational medicinal product
NSAID
non-steroidal anti-inflammatory drugs
NYHA
New York Heart Association
OAT
organic anion-transporter
OATP
organic anion-transporting polypeptide
OMIM
Online Mendelian Inheritance in Man
PACL
protocol administrative change letter
PCD
primary completion date
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
pharmacodynamic(s)
PDE
phosphodiesterase
PDFF
proton density fat fraction
P-gp
P-glycoprotein
PGx
pharmacogenomic(s)
PI
principal investigator
PK
pharmacokinetic
pmol/L
picomoles per liter
PT
prothrombin time
PVCs
premature ventricular complexes
QD
once daily
QRS
pulses in a heart beat
QT
Q wave to end of T wave
QTc
QT corrected


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Abbreviation
Term
QTcF
QTc corrected by Fridericia's formula
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SEM
standard error of the mean
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
SOP
standard operating procedure
SPF
sun protection factor
SRSD
single reference safety document
SSID
study-specific subject identification number
SUSAR
suspected unexpected serious adverse reaction
t½
terminal half-life
T2DM
Type 2 Diabetes Mellitus
T4
thyroxine
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TG
triglycerides
THC
tetrahydrocannabinol
Tmax
time to reach maximum concentration
TRLP
triglyceride-rich lipoprotein particles
TSH
thyroid stimulating hormone
TZD
thiazolidinediones
UGT
uridine diphosphate-glucuronosyltransferase
ULN
upper limit of normal
US
United States
UV
ultraviolet
V
visit
VLDL
very low-density lipoprotein
VCTE
vibration controlled transient elastography
VS
vital signs
Vss
volume of distribution
WBC
white blood cells
WOCBP
women of childbearing potential
CCI


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11. REFERENCES
1.
Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, 
MD. MIM Number: {229800}: {June 2016}: World Wide Web URL: http://omim.org/.
2.
Sachs B, Sternfeld L, Kraus G. Essential fructosuria: Its pathophysiology. Am J Dis 
Child 1942;63:252-69.
3.
Boesiger P, Buchli R, Meier D, et al.  Changes of liver metabolite concentrations in 
adults with disorders of fructose metabolism after intravenous fructose by 31P magnetic 
resonance spectroscopy. Pediatr Res 1994;4:436-40.
4.
Abdelmalek MF, Lazo M, Horska A, et al. Fatty Liver Subgroup of Look, A. R. G., 
Higher dietary fructose is associated with impaired hepatic adenosine triphosphate 
homeostasis in obese individuals with type 2 diabetes. Hepatology 2012;56:952-60.
5.
Maenpaa PH, Raivio KO, Kekomaki MP. Liver adenine nucleotides: fructose-induced 
depletion and its effect on protein synthesis. Science 1968;161:1253-4.
6.
Lanaspa MA, Sanchez-Lozada LG, Choi YJ, et al. Uric acid induces hepatic steatosis by 
generation of mitochondrial oxidative stress: potential role in fructose-dependent and 
-independent fatty liver. J Biol Chem 2012;287:40732-44.
7.
Erion DM, Popov V, Hsiao JJ, et al. The role of the carbohydrate response 
element-binding protein in male fructose-fed rats. Endocrinology 2013;154:36-44.
8.
Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis 
in fatty liver disease. Dig Dis Sci 2016;61:1282-93.
9.
Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not 
glucose-sweetened, beverages increases visceral adiposity and lipids and decreases 
insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119:1322-34.
10.
Abid A, Taha O, Nseir W, et al. Soft drink consumption is associated with fatty liver 
disease independent of metabolic syndrome. J Hepatol 2009;51:918-24.
11.
Assy N, Nasser G, Kamayse I, et al. Soft drink consumption linked with fatty liver in 
the absence of traditional risk factors. Can J Gastroenterol 2008;22:811-6.
12.
Schwarz JM, Noworolski SM, Wen MJ, et al. Effect of a high-fructose weight-
maintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab 
2015;100:2434-42.
13.
Lustig R, Mulligan K, Noworolski SM, et al. Isocaloric fructose restriction and 
metabolic improvement in children with obesity and metabolic syndrome. Obesity 
2016;24:453-60.


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Final Protocol Amendment 2, 11 September 2019
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Page 98
14.
Stanhope KL, Medici V, Bremer AA, et al. A dose-response study of consuming high-
fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for 
cardiovascular disease in young adults. Am J Clin Nutr 2015;101:1144-54.
15.
Sanyal AJ, Friedman SL, McCullough AJ, et al. American Association for the Study of 
Liver Diseases, United States Food and Drug Administration. Challenges and 
opportunities in drug and biomarker development for nonalcoholic steatohepatitis: 
findings and recommendations from an American Association for the Study of Liver 
Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015; 
61:1392-05.
16.
Ishimoto T, Lanaspa MA, Le MT, et al. Opposing effects of fructokinase C and A 
isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci USA 
2012;109:4320-5.
17.
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.  
18.
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.
19.
Stanhope KL, Schwarz JM, Keim NL et al.  Consuming fructose-sweetened, not 
glucose-sweetened, beverages increases visceral adiposity and lipids and decreases 
insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119 (5):1322-34.

SAP_001.pdf: 
Protocol C1061011 (PF-06835919) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C1061011
A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
3-ARM, PARALLEL GROUP STUDY TO EVALUATE SAFETY, TOLERABILITY 
AND PHARMACODYNAMICS OF PF-06835919 ADMINISTERED DAILY FOR 
16 WEEKS IN ADULTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE AND 
TYPE 2 DIABETES MELLITUS ON METFORMIN
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
17July2019


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PFIZER CONFIDENTIAL 
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Table of Contents
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................4
2.1.1. Primary Estimand .........................................................................................6
2.1.2. Secondary Estimand .....................................................................................7
2.2. Study Design .............................................................................................................8
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ............................................................................................10
3.4. Baseline Variables...................................................................................................12
3.5. Safety Endpoints .....................................................................................................13
3.5.1. Adverse Events ...........................................................................................13
3.5.2. Laboratory Data..........................................................................................14
3.5.3. Vitals...........................................................................................................14
3.5.4. ECGs...........................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................16
5.1. Hypotheses and Decision Rules ..............................................................................16
5.2. General Methods .....................................................................................................16
5.3. Methods to Manage Missing Data ..........................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................19
6.1. Primary Endpoint 1: Whole Liver Fat using MRI-PDFF........................................19
6.1.1. Main Analysis.............................................................................................19
6.1.2. Sensitivity/Robustness Analyses ................................................................20
6.1.3. Supplementary Analysis 1 ..........................................................................20
6.2. Primary Endpoint 2: HbA1c....................................................................................21
6.2.1. Main Analysis.............................................................................................21
6.2.2. Supplementary Analysis .............................................................................22
6.3. Secondary Endpoints...............................................................................................22
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6.3.1. Secondary Endpoint 1: Hs-CRP .................................................................22
6.3.2. Secondary Endpoint 2: Fasting Insulin, Glucose, and HOMA-IR .............23
6.3.3. Secondary Endpoint 3: ALT.......................................................................24
6.3.4. Secondary Endpoint 4: HbA1c at all time points prior to Week 16...........25
6.5. Subset Analyses.......................................................................................................27
6.6. Baseline and Other Summaries and Analyses.........................................................28
6.7. Safety Summaries and Analyses .............................................................................28
6.7.1. Adverse Events ...........................................................................................28
6.7.2. Laboratory Data..........................................................................................29
6.7.3. Vital Signs ..................................................................................................29
6.7.4. Electrocardiogram.......................................................................................30
7. INTERIM ANALYSES.......................................................................................................31
8. REFERENCES ....................................................................................................................31
APPENDIX 1: CATEGORICAL CLASSES FOR ECG AND VITAL SIGNS .....................32
APPENDIX 2: TIER 1 ADVERSE EVENTS.........................................................................32
APPENDIX 3: LIST OF ABBREVIATIONS.........................................................................34
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
17 July 2019
Original 
21 Mar 2019
N/A
N/A
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C1061011.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary:

To evaluate the effect of 2 dose 
levels of PF-06835919 compared 
to placebo on whole liver fat
measured by MRI-PDFF.

To evaluate the effects of 2 dose 
levels of PF-06835919 compared 
to placebo on HbA1c.
Estimand 1:

This estimand is intended 
to provide a population 
level estimate of the 
treatment effect of the IP 
alone relative to placebo 
under the scenario of no 
discontinuation of study 
intervention, without the 
potential confounding 
effects of additional 
prohibited medications, 
regardless of the 
participant’s compliance 
with the IP dosing.  

%CFB in whole liver fat at 
16 weeks using MRI-PDFF.

CFB in HbA1c at 16 weeks.
Secondary: 
Secondary:
Secondary:

To evaluate the safety and 
tolerability of 2 dose levels of 
PF-06835919 administered daily 
for 16 weeks.

To evaluate the effects of 2 dose 
levels of PF-06835919 compared 
to placebo on hs-CRP.

No estimand is defined for 
safety and tolerability 
endpoints.  These will be 
analyzed using Pfizer Data 
Standards, as applicable.

hs-CRP, measures of 
glycemic metabolism, 
ALT and HbA1c will be 

Assessment of AEs, including 
hypoglycemia AEs, clinical 
laboratory tests, vital signs and 
12-lead ECGs.

%CFB in hs-CRP over 
16 weeks.






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Page 7

CFB in HbA1c at 16 weeks.
Note: CFB or %CFB in tertiary/exploratory endpoints over 16 weeks will also be analyzed 
using the primary estimand.
Intercurrent Events: 
a.
Withdrawal from study intervention – All data collected after a participant stops 
taking IP will be excluded. 
b. Prohibited medications – All assessments after a participant receives prohibited 
medications that would modulate the primary endpoints will be omitted from the 
analysis.  Receiving a medication prohibited due to drug-drug interaction (DDI) risk 
will not affect this estimand.  The list of concomitant medications would be reviewed 
prior to database lock to determine which would be classed as “prohibited” for this 
estimand.
c.
Inadequate compliance – Participants with inadequate compliance will have their 
primary endpoint measurements used as recorded in the analysis.  
Population level summary: 
The population level summary will be the mean difference in change from baseline between 
PF-06835919 and placebo groups for the endpoint of interest.
2.1.2. Secondary Estimand
Secondary Estimand is a treatment policy estimand intended to provide a population level 
estimate of the treatment effect of the IP alone relative to placebo on liver fat measured by 
MRI-PDFF and HbA1c at Week 16 without regard to compliance or discontinuation of study 
drug or administration of prohibited medication.  
Population: 

The target population consists of patients with NAFLD and T2DM on stable doses 
(500 mg/day) of metformin monotherapy.
Variable(s):
The 2 co-primary endpoints will be analysed using this estimand:

%CFB in whole liver fat at 16 weeks using MRI-PDFF;

CFB in HbA1c at 16 weeks.
Intercurrent Events:
a.
Withdrawal from study intervention – All data collected regardless of a participant’s 
withdrawal from the IP will be included in the analysis. 


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Page 8
b. Prohibited medications – All data collected for a participant regardless of the use of 
prohibited medications will be used in the analysis.
c.
Inadequate compliance – Participants with inadequate compliance will have their 
primary endpoint measurements used as recorded in the analysis. 
Population level summary: 
The population level summary will be the mean difference in change from baseline between 
PF-06835919 and placebo groups for the endpoint of interest.
2.2. Study Design
This is a Phase 2a, placebo-controlled, randomized, double-blind, parallel-group, multicenter 
study to evaluate the safety, tolerability, and pharmacodynamics (PD) of PF-06835919 
administered once daily (QD) for 16 weeks in adults with NAFLD and T2DM on stable 
doses of metformin.
A total of approximately 150 participants (50 per group) will be randomized in a ratio of 
1:1:1 between PF-06835919 at 150 mg and 300 mg, and placebo to ensure a minimum of 
approximately 132 participants (44 per group) complete.  The dropout rate for this study is 
presumed to be not more than approximately 12%.
For individual participants, the total duration of the study from the Screen 1 visit to the 
on-site follow-up visit (Visit 13) will be approximately 24 weeks.  The time between 
Screen 1 (Visit 1) and Screen 3 (Visit 3) should be approximately 3 weeks, and 
approximately 6 weeks (42 days) between Screen 1 (Visit 1) and Day 1 (Visit 6), refer to 
Figure 1 below.
Figure 1: C1061011 Study Design












Protocol C1061011 (PF-06835919) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 14
be considered as hypoglycemia AE (‘No Hypoglycemic Adverse Event’box in the 
hypoglycemia CRF will be checked).
For programming purposes, hypoglycemic AEs should be reported as a separate listing based 
on the first 4 categories defined by the ADA, which are:
a.
Severe Hypoglycemia: Severe is checked in the severity criteria of the CRF. This 
assessment will be made by the PI based on the protocol definition.
b. Documented Symptomatic Hypoglycemia: If (1 – Did the subject have symptoms of 
hypoglycemia?) Yes and (2 – Was the blood glucose measured?) Yes and result<=70 
mg/dL on the CRF, but hypoglycemia is not classified as severe.
c.
Asymptomatic Hypoglycemia: If (1 – Did the subject have symptoms of 
hypoglycemia?) No and (2 – Was the blood glucose measured?) Yes and result<=70 
mg/dL on the CRF, but hypoglycemia is not classified as severe.
d. Probable Symptomatic Hypoglycemia: If (1) Yes and (2) No and (2b – If blood 
glucose was not measured, did symptoms resolve when treated with carbohydrate or 
glucagon?) Yes on the CRF, but hypoglycemia is not classified as severe.
In the above categories Severe Hypoglycemia (a) and Documented Symptomatic 
Hypoglycemia (b) will be treated as Tier 1 events and Asymptomatic Hypoglycemia and 
Probable Symptomatic Hypoglycemia (d) will be treated as Tier 2 events.
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 be made 
regardless of whether each participant’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 at Visit 6 (Day 1). Results from only 
the planned study visits will be considered for baseline assessment.
3.5.3. Vitals 
Seated blood pressure and pulse rate measurements will be taken at time points detailed in 
the Schedule of Activities (SOA) given in the protocol. The average of the triplicate values at 
any time point will be used as the measurement.  
Baseline is defined as the measurement closest prior to dosing at Visit 6 (Day 1). Results 
from only the planned study visits will be considered for baseline assessment. The following 
vital signs endpoints will be determined for each participant:


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
The maximum increase and decrease 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 
participant does not show an increase.  In such an instance, the minimum decrease should be 
taken.  Similarly, the maximum decrease from baseline will be determined by selecting the 
largest negative value of the changes from baseline.  In cases where a participant does not 
show a decrease, the minimum increase should be taken.
3.5.4. ECGs
Single 12-lead ECGs will be obtained on all participants at times detailed in the SOA given 
in the protocol.  Baseline is defined as the measurement closest prior to dosing at Visit 
6 (Day 1). Results from only the planned study visits will be considered for baseline 
assessment.
The QT, QTcF, heart rate, QRS and PR will be recorded at each assessment time.  If not 
supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3
where RR = 60/HR (if RR is not provided)
The maximum absolute value (post dose) and the maximum increase from baseline for QTcF, 
heart rate, PR and QRS, will be determined by study day for each participant.
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 
participant does not show an increase.  In such an instance, the minimum decrease should be 
taken preserving the sign of change.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Population
Description
Pre-randomization
All participants entering the placebo run-in phase.
Randomly assigned to 
Treatment
Defined according to Full Analysis Set
Safety
All participants randomly assigned to treatment and who take at 




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Analysis of Covariance (ANCOVA)
The ANCOVA model will be used with continuous endpoints for landmark (single time
point) analyses.  Early termination data will be used with Estimand 2 and not with Estimand 
1. The model will include treatment group as a fixed effect and baseline value as a covariate.  
If there is substantial imbalance in the number of participants enrolled in each site then study 
site and the interaction of study site with treatment will be considered to be included as 
potential covariates for the analysis of primary endpoints only.  The assessment of imbalance 
will be made following randomization of all participants but prior to database release (DBR). 
If included as a covariate, sites enrolling less than 6 participants will be pooled. Estimates of 
treatment effects will be assessed using least square means (LSMs) and 90% Confidence 
Intervals (CIs).  Estimates of the mean differences between each active dose and placebo at 
Week 16, and the corresponding 90% CI will be obtained from the model.  Both comparisons
of PF-06835919 doses with the placebo will be performed at a Type I error rate of 10%
(2-sided). If there are major deviations from the statistical assumptions underlying this 
model then alternative transformations or non-parametric analyses may be presented. 
Justification for any alternative to the planned analysis will be given in the study report.
Mixed Model for Repeated Measurements (MMRM)
This model will be used for the analysis of endpoints with more than 1 post-baseline 
collection time point.  All observed data collected during the post-baseline treatment period 
will be utilized. Early termination data will be used with Estimand 2 and not with Estimand 
1. Data collected during the follow-up period will be excluded. The MMRM analysis will be 
performed with treatment, study day and treatment-by-study day interaction as fixed effects, 
baseline value as a covariate. When early termination data are utilized, the closest nominal 
study visit following the actual study day of early termination visit will be used in the model. 
Additional covariates such as, baseline whole liver PDFF, baseline HbA1c or baseline eGFR 
may also be considered for inclusion in the model. If there is substantial imbalance in the 
number of participants enrolled in each site then study site and the interaction of study site 
with treatment will be considered to be included as potential covariates for the analysis of 
primary endpoints only.  The assessment of imbalance will be made following randomization 
of all participants but prior to DBR. Repeated measures model with unstructured correlation 
matrix will be utilized.  Time will be fitted as a repeated effect. If this does not converge then 
compound symmetry structure will be considered. Additionally, the number of covariates 
may be reduced to improve model fit. Estimates of treatment effects will be assessed using 
LSMs and 90% CIs at each time point.  LSM difference between each dose of PF-06835919 
and placebo group along with the 90% CIs and 2-sided p-values will be provided.  If there 
are major deviations from the statistical assumptions underlying this model then alternative 
transformations (e.g. log) or non-parametric analyses may be presented. Justification for any 
alternative to the planned analysis will be given in the study report.
Non-parametric Analysis
If the data have many outliers even after the log-transformation the following non-parametric 
analysis will be performed instead of the linear model. An outlier will be defined as any 




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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint 1: Whole Liver Fat using MRI-PDFF 
6.1.1. Main Analysis

Analysis time point:  Week 16

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline and Week 16 
measurements to be included.

Analysis methodology: Natural log-transformed individual response ratios (RR) at Week 
16 to baseline (RR = observed value at Week 16 / baseline value) in whole liver fat using 
MRI-PDFF will be analyzed using the ANCOVA.  Log-transformed baseline will be the 
covariate.

Intercurrent events and missing data:  Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.  
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and Week 16 visit will be presented for each treatment group.

%CFB: The sample size, mean, standard deviation, median, minimum and maximum 
will be presented for each treatment group at Week 16. The LSMs and their 90% CIs
will be exponentiated to provide estimates of the RRs which will be converted to 
percent change as follows:
Percent change = 100* (RR - 1).
The LSMs of the percent change from baseline with the 90% CIs for each treatment 
group and the LSMs of the percent change from placebo with the 90% CIs for each of 
the PF-06835919 groups and the 2-sided p-values will be presented.
Figures

%CFB in Whole liver fat using MRI-PDFF – A bar chart of the model-derived least 
square mean %CFB for all treatment groups including the placebo group with 90% 
CIs will be provided for Week 16 with dose on the X-axis.

%CFB in Whole liver fat using MRI-PDFF - Box and whisker plots for individual 
percent change from baseline versus treatment will be presented and overlaid with 
arithmetic means.


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6.1.2. Sensitivity/Robustness Analyses 

Analysis time point: Week 16

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline and Week 16 
measurements to be included.

Analysis methodology: %CFB to Week 16 in whole liver PDFF will be analyzed using 
the ANCOVA.  The model will include baseline whole liver PDFF.

Intercurrent events and missing data: Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.    
Reporting results:

%CFB: The LSMs, 90% CIs for the LSMs, difference between the LSM of each 
treatment group and the placebo group, and the corresponding 90% CI and the 2-
sided p-values will be presented.
6.1.3. Supplementary Analysis 1

Analysis time point: Week 16; Early Termination visit will be included and treated as 
Week 16

Estimand strategy: Treatment policy

Analysis set: Full Analyis Set; Participants must have a baseline measurement and a 
post-baseline measurement to be included.

Analysis methodology: Natural log-transformed individual RRs at Week 16 to baseline 
in whole liver fat using MRI-PDFF will be analyzed using the ANCOVA.  Log-
transformed baseline will be the covariate. Site may be included as a covariate.

Intercurrent events and missing data: Data collected regardless of a participant’s 
withdrawal from the study medication or the use of prohibited medications will be 
included in the analysis.  
Reporting results:

The LSMs and their 90% CIs will be exponentiated to provide estimates of the RRs
which will be converted to percent change as follows:
Percent change = 100* (RR - 1).


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The LSMs of the percent change from baseline with the 90% CIs for each treatment 
group and the LSMs of the percent change from placebo with the 90% CIs for each of 
the PF-06835919 groups and the 2-sided p-values will be presented.
6.2. Primary Endpoint 2: HbA1c 
6.2.1. Main Analysis

Analysis time point: Week 16 (primary time point); model will include all relevant time 
points

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline measurement and at 
least one post-baseline measurement on treatment to be included.

Analysis methodology: CFB in HbA1c will be analyzed using MMRM with treatment, 
time and treatment by time interaction as fixed effects and baseline HbA1c value as a 
covariate. Time will be fitted as a repeated effect.

Intercurrent events and missing data: Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.  
Reporting results:

Raw data: The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and all post-baseline time points will be presented for each 
treatment group.

CFB: The sample size, mean, standard deviation, median, minimum and maximum 
will be presented for each treatment group at all post-baseline time points. The LSMs, 
90% CIs for the LSMs, difference between the LSM of each treatment group and the 
placebo group, and the corresponding 90% CI and the 2-sided p-values will be 
presented.
Figures

HbA1c CFB – A bar chart of the model-derived least square means for all treatment 
groups including the placebo group with 90% CIs will be provided for Week 16 with 
dose on the X-axis.

HbA1c CFB - A line plot of the model-derived LSMs for all treatment groups 
including the placebo group with 90% CIs will be provided with time on X-axis. 
Separate lines will be plotted for each treatment group with 0 values at Baseline for 
all treatment groups.

HbA1c CFB - A line plot of the model-derived LSM differences from placebo for the 
two PF-06835919 treatment groups with 90% CIs will be provided with time on 
X-axis. Separate lines will be plotted for each treatment group with 0 values at 
Baseline for all treatment groups.


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6.2.2. Supplementary Analysis 

Analysis time point: Week 16; model will include all relevant time points

Estimand strategy: Treatment policy

Analysis set: Full Analyis Set; Participants must have a baseline measurement and a 
post-baseline measurement to be included.

Analysis methodology: CFB in HbA1c will be analyzed using MMRM with treatment, 
time and treatment by time interaction as fixed effects and baseline HbA1c value as a 
covariate. Time will be fitted as a repeated effect. Site may be included as a covariate.

Intercurrent events and missing data: Data collected regardless of a participant’s 
withdrawal from the study medication or the use of prohibited medications will be 
included in the analysis.    
Reporting results:

CFB:  The LSMs, 90% CIs for the LSMs, difference between the LSM of each 
treatment group and the placebo group, and the corresponding 90% CI and the 2-
sided p-values will be presented.
6.3. Secondary Endpoints
The analyses of standard safety endpoints will be described in section 6.7. The description of 
analysis of other secondary endpoints is provided below.
6.3.1. Secondary Endpoint 1: Hs-CRP

Analysis time point:  All planned post-baseline time points

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline measurement and a 
postbaseline measurement to be included.

Analysis methodology: %CFB in hs-CRP will be analyzed using MMRM as described 
in section 5.2. The model will include treatment, study day and treatment-by-study day
interaction as fixed effects, baseline hs-CRP and baseline whole liver PDFF as 
covariates. If there are major deviations from the statistical assumptions underlying the 
MMRM model the non-parametric analysis defined in Section 5.2 will be applied.

Intercurrent events and missing data: Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.    


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Reporting results:

Raw data:  The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and all post-baseline visits will be presented for each treatment 
group.

%CFB: The sample size, mean, standard deviation, median, minimum and maximum 
will be presented for each treatment group at all postbaseline collection time points. 
The LSMs, 90% CIs for the LSMs, difference between the LSM of each treatment 
group and the placebo group, and the corresponding 90% CI and the 2-sided p-values 
will be presented. If the MMRM does not fit then medians, 90% CIs for the medians, 
difference between the median of each treatment group and the placebo group, and 
the corresponding 90% CI will be presented. 
Figures

A line plot of the model-derived LSMs for all treatment groups including the placebo 
group with 90% CIs will be provided with time on X-axis. Separate lines will be 
plotted for each treatment group with 0 values at Baseline for all treatment groups. If 
MMRM does not fit the data then this plot will not be produced. 

A line plot of medians and 90%CIs or medians±standard diviations for all treatment 
groups including the placebo group will be provided with time on X-axis. Separate 
lines will be plotted for each treatment group with 0 values at Baseline for all 
treatment groups. All planned time points including the follow-up time point will be 
presented.
6.3.2. Secondary Endpoint 2: Fasting Insulin, Glucose, and HOMA-IR

Analysis time point:  All planned post-baseline time points

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline measurement and a 
postbaseline measurement to be included.

Analysis methodology: CFB in each endpoint will be analyzed separately using 
MMRM as described in section 5.2. The model will include treatment, study day and 
treatment-by-study day interaction as fixed effects, baseline value and baseline HbA1c 
as covariates. If there are major deviations from the statistical assumptions underlying 
the MMRM model the non-parametric analysis defined in Section 5.2 will be applied. 

Intercurrent events and missing data: Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.    


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Reporting results:

Raw data:  The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and all post-baseline visits will be presented for each treatment 
group.

CFB: The sample size, mean, standard deviation, median, minimum and maximum 
will be presented for each treatment group at all postbaseline collection time points. 
The LSMs, 90% CIs for the LSMs, difference between the LSM of each treatment 
group and the placebo group, and the corresponding 90% CI and the 2-sided p-values 
will be presented. If the MMRM does not fit then medians, 90% CIs for the medians, 
difference between the median of each treatment group and the placebo group, and 
the corresponding 90% CI will be presented. 
Figures

For each endpoint a separate line plot of the model-derived LSMs for all treatment groups 
including the placebo group with 90% CIs will be provided with time on X-axis. Separate 
lines will be plotted for each treatment group with 0 values at Baseline for all treatment 
groups. If MMRM does not fit the data then this plot will not be produced.

For each endpoint a line plot of medians and 90%CIs or medians±standard diviations for 
all treatment groups including the placebo group will be provided with time on X-axis. 
Separate lines will be plotted for each treatment group with 0 values at Baseline for all 
treatment groups. All planned time points including the follow-up time point will be 
presented.
6.3.3. Secondary Endpoint 3: ALT

Analysis time point:  All planned post-baseline time points

Estimand strategy: Hypothetical

Analysis set: Full Analyis Set; Participants must have a baseline measurement and a 
postbaseline measurement to be included.

Analysis methodology: %CFB in ALT will be analyzed using MMRM as described in 
section 5.2. The model will include treatment, study day and treatment-by-study day
interaction as fixed effects, baseline ALT and baseline whole liver PDFF as covariates. 
If there are major deviations from the statistical assumptions underlying the MMRM 
model the non-parametric analysis defined in Section 5.2 will be applied. 

Intercurrent events and missing data: Data collected after a participant stops taking 
study medication or receives prohibited medications that would modulate the primary 
endpoints will be excluded.    








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6.6. Baseline and Other Summaries and Analyses
A breakdown of demographic data will be provided for age, gender, race, weight, height and 
body mass index summarized by treatment and overall in accordance with the sponsor 
reporting standards.  Baseline summary (median, minimum and maximum) of primary and 
secondary endpoints will be presented for each treatment group and overall. Baseline 
summary of stratification factors, namely, number and proportion of participants in main 
study only and in sub-study plus main study will be provided. The number and proportion of 
participants enrolled in each study site by baseline stratification factors and overall will also 
be presented.
Participant evaluation groups will show which participants were analyzed for the 2 
estimands, as well as for safety (adverse events and laboratory data).  Frequency counts will 
be supplied for participant discontinuation(s) by treatment. If the proportion of 
discontinuations is more than 10% then table with participant disposition by visit will be 
produced.  Data will be reported in accordance with the sponsor reporting standards.
6.7. 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-06835919. 
No formal analyses are planned for safety data.  The 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.
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.  
6.7.1. 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 separately for TEAEs and baseline symptoms. For baseline symptoms 
limited number of tables will be provided including all causality summary tables as well as 
incidence and severity tables by System Organ Class and Preferred Terms.
In addition to standard safety displays, a 3-tier approach will be used to summarize AEs. 
Under this approach, AEs are classified into 1 of 3 tiers. All subjects in the Safety Analysis 
Set will have their safety data included in the tiered analysis below.  

Tier-1 events:  Displays of Tier 1 events will include proportions, risk differences, 
95% CIs and p-values.  The risk difference will be computed for PF-06835919 dose 
group versus placebo. The confidence intervals and p-values will not be adjusted for 
multiplicity and therefore must be considered accordingly.


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
Tier-2 events: Displays of Tier 2 events will include proportions, risk differences,  
and 95% CIs. The risk difference will be computed for PF-06835919 dose group 
versus placebo. P-values will not be presented. The confidence intervals are for 
estimation purposes only.

Tier-3 events: These are events that are neither tier-1 nor tier-2 events. Tier 3 events 
will not be explicitely tabulated and listed.  They will be included with the overall AE 
displays described earlier in this subsection.  
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates this exploratory analysis.
Analysis of Hypoglycemia
Hypoglycemia events will also be analyzed following 3-tier approach.
6.7.2. Laboratory Data
All planned, quantitative, standard safety laboratory data presented in Appendix 2 of the 
protocol and non-standard safety laboratory data that are not reported independently will be 
listed and summarized by treatment in accordance with the sponsor reporting standards as 
applicable.  Baseline is as defined in Section 3.5.2.
6.7.3. Vital Signs
The average of the triplicate values at any time point will be used as the measurement.  
Absolute values and changes from baseline in seated systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and time postdose, according to sponsor 
reporting standards.  Tables will be paged by parameter.  Baseline is as defined in Section 
3.5.3.
Mean changes from baseline for the pre-dose systolic and diastolic blood pressure and pulse 
rate will be plotted against study week.  On each plot there will be 1 line for each treatment, 
all treatments on the same plot including the placebo.  Corresponding individual plots of 
changes from baseline may be produced for each treatment if deemed necessary based on the 
data.
For baseline subtracted seated systolic and diastolic blood pressure and pulse rate, the 
differences between each dose and placebo (dose – placebo) will be summarized (N, mean, 
90% CI) and plotted (mean, 90% CI) for each dose and day.  
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 1.  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 


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categorical summaries.  All values meeting the criteria of potential clinical concern will be 
listed.
Maximum decrease and increase from baseline for seated systolic and diastolic blood 
pressures, and maximum increase from baseline for seated pulse rate will be summarized by 
treatment, according to sponsor reporting standards.
Additional Analyses

Analysis Endpoints:  Systolic blood pressure (SBP), Diastolic blood pressure 
(DBP) and Pulse Rate (PR)

Analysis Time Points: 
o
Pre-dose values: Weeks 2, 4, 8, 12 and 16.  Additionally the follow-up 
time point will be used for descriptive statistics only.
o
1-2-hr post-dose: Weeks 2, 8 and 12

Analysis population:  Safety Analysis Set

Analysis methodology:  Change from baseline will be analyzed using the 
MMRM model or non-parametric methods.  The model will include treatment, 
study day and treatment-by-study day interaction as fixed effects, baseline value 
as a covariate.
Reporting results:

Raw data:  The sample size, mean, standard deviation, median, minimum and 
maximum at baseline and all post-baseline visits will be presented for each treatment 
group.

Change from baseline:  The sample size, mean, standard deviation, median, minimum 
and maximum will be presented for each treatment group and at each post-baseline 
visit. Models will be fitted separately for pre-dose and 1-2-hr post dose assessment 
times.  The LSMs, 90% CI for the LSMs, difference between the LSMs of each 
PF-06835919 group and the placebo group with the corresponding 90% CI and the 2-
sided p-values derived from the model will be presented at the time points specified 
above.
Figures

A line plot of the model-derived LSMs for all treatment groups including the placebo 
group with 90% CIs will be provided with time on X-axis. Separate lines will be 
plotted for each treatment group with 0 values at Baseline for all treatment groups. 
6.7.4. Electrocardiogram
Absolute values and changes from baseline in QT, heart rate, QTcF, PR, and QRS will be 
summarized by treatment and day using sponsor reporting standards.  Tables will be paged 
by parameter. Baseline is as defined in Section 3.5.4.
Mean changes from baseline in QT, heart rate and QTcF will be plotted against study week.  
On each plot there will be 1 line for each treatment, all treatments on the same plot including 


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the placebo.  Corresponding individual plots of changes from baseline may be produced for 
each treatment based on the data.
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 week.
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in the Appendix 1 (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 QT 
and QTcF. 
7. INTERIM ANALYSES
Interim analyses may be performed to assess efficacy or/and safety after at least 30% of the 
planned participants (ie, approximately 45 participants), complete their study participation 
through the end of the treatment phase of the study (ie, Week 16).  Interim analysis results 
may be used for internal business decisions including, but not limited to, future study
planning, stopping for futility, stopping for early success, conducting a sample size 
re-estimation, 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 IRC
charter.  In addition, the analysis details will be documented and approved in an interim 
analysis SAP.
8. REFERENCES 
McGill, R., John W. Tukey and W. A. Larsen. 1978. "Variations of Box Plots." American 
Statistician 32:12-16




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Renal impairment
Proteinuria
Neutropenia
Genital infection fungal
Candida infection
Rash
Photosensitivity reaction
Liver function test abnormal
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Transaminases abnormal
Transaminases increased
Hypokalaemia