Clinical trial NCT04427917
Conditions: Healthy
Keywords: NASH, KHK, PF-06835919, Japanese
Sponsor: Pfizer
Start date: 2020-11-24; Completion date: 2021-03-31
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of multiple oral doses of PF-06835919 in healthy adult Japanese participants.

A total of approximately 8 healthy participants will be enrolled in this study. Participants will be randomized to 2 groups to receive PF-06835919 or placebo treatment with a randomization ratio of 3:1.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: PF-06835919 intervention 2: Placebo
Intervention descriptions: intervention 1: PF-06835919 300 mg repeated doses intervention 2: Placebo repeated doses

Protocol documents:
Prot_000.pdf: 
PF-06835919 
Protocol C1061010
Final Protocol, 4 March 2020
PFIZER CONFIDENTIAL
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-06835919 IN 
HEALTHY ADULT JAPANESE PARTICIPANTS
Study Intervention Number:
PF-06835919
Study Intervention Name:
N/A
US IND Number:
131743
EudraCT Number:
2020-000218-13
Protocol Number:
C1061010
Phase:
1
Short Title: A Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of 
multiple oral doses of PF-06835919 in healthy adult Japanese participants
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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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
4 March 2020
N/A


PF-06835919 
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Final Protocol, 4 March 2020
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities .............................................................................................11
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.3. Nonclinical Safety ......................................................................................16
2.2.4. Clinical Overview.......................................................................................17
2.2.4.1. Summary of Clinical safety.......................................................17
2.2.4.2. Summary of Pharmacokinetic of PF-06835919........................18
2.3. Benefit/Risk Assessment.........................................................................................19
3. OBJECTIVES AND ENDPOINTS.....................................................................................20
4. STUDY DESIGN.................................................................................................................20
4.1. Overall Design.........................................................................................................20
4.2. Scientific Rationale for Study Design.....................................................................21
4.3. Justification for Dose ..............................................................................................22
4.4. End of Study Definition ..........................................................................................22
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................23
5.2. Exclusion Criteria....................................................................................................24
5.3. Lifestyle Considerations..........................................................................................26
5.3.1. Meals and Dietary Restrictions...................................................................26
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................26
5.3.3. Activity .......................................................................................................27
5.3.4. Contraception..............................................................................................27
5.4. Screen Failures ........................................................................................................27
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6. STUDY INTERVENTION..................................................................................................27
6.1. Study Intervention(s) Administered........................................................................28
6.1.1. Administration............................................................................................28
6.2. Preparation/Handling/Storage/Accountability ........................................................28
6.2.1. Preparation and Dispensing........................................................................29
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................29
6.3.1. Allocation to Study Intervention ................................................................29
6.3.2. Breaking the Blind......................................................................................30
6.4. Study Intervention Compliance...............................................................................30
6.5. Concomitant Therapy..............................................................................................30
6.5.1. Rescue Medicine.........................................................................................31
6.6. Dose Modification...................................................................................................31
6.7. Intervention After the End of the Study..................................................................31
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................31
7.1. Discontinuation of Study Intervention ....................................................................31
7.2. Participant Discontinuation/Withdrawal From the Study.......................................32
7.2.1. Withdrawal of Consent...............................................................................32
7.3. Lost to Follow up ....................................................................................................33
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................33
8.1. Efficacy Assessments..............................................................................................34
8.2. Safety Assessments .................................................................................................34
8.2.1. Physical Examinations................................................................................34
8.2.2. Vital Signs ..................................................................................................35
8.2.3. Electrocardiograms.....................................................................................35
8.2.4. Clinical Safety Laboratory Assessments ....................................................36
8.2.5. Pregnancy Testing ......................................................................................37
8.3. Adverse Events and Serious Adverse Events..........................................................37
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......37
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................38
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................38


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8.3.2. Method of Detecting AEs and SAEs ..........................................................38
8.3.3. Follow-up of AEs and SAEs.......................................................................38
8.3.4. Regulatory Reporting Requirements for SAEs...........................................39
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................39
8.3.5.1. Exposure During Pregnancy......................................................39
8.3.5.2. Exposure During Breastfeeding ................................................41
8.3.5.3. Occupational Exposure .............................................................41
8.3.6. Medication Errors .......................................................................................42
8.4. Treatment of Overdose............................................................................................42
8.5. Pharmacokinetics ....................................................................................................43
8.6. Pharmacodynamics..................................................................................................44
8.7. Genetics...................................................................................................................44
8.7.1. Specified Genetics ......................................................................................44
8.7.2. Banked Biospecimens for Genetics............................................................44
8.8. Biomarkers ..............................................................................................................44
8.8.1. Banked Biospecimens for Biomarkers .......................................................44
8.9. Immunogenicity Assessments.................................................................................45
8.10. Health Economics .................................................................................................45
9. STATISTICAL CONSIDERATIONS ................................................................................45
9.1. Statistical Hypotheses .............................................................................................45
9.2. Sample Size Determination.....................................................................................45
9.3. Analysis Sets ...........................................................................................................45
9.4. Statistical Analyses .................................................................................................46
9.4.1. Primary Endpoint(s)....................................................................................46
9.4.1.1. Safety Analyses.........................................................................46
9.4.1.2. Pharmacokinetic Analyses of PF-06835919 .............................47
9.4.2. Exploratory Endpoint(s) .............................................................................48
9.5. Interim Analyses .....................................................................................................48
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............48
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................49
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............49
10.1.1. Regulatory and Ethical Considerations ....................................................49
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................49
10.1.2. Informed Consent Process ........................................................................50
10.1.3. Data Protection .........................................................................................51
10.1.4. Dissemination of Clinical Study Data ......................................................51
10.1.5. Data Quality Assurance ............................................................................53
10.1.6. Source Documents....................................................................................54
10.1.7. Study and Site Start and Closure ..............................................................54
10.1.8. Publication Policy.....................................................................................55
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................56
10.2. Appendix 2: Clinical Laboratory Tests .................................................................57
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................58
10.3.1. Definition of AE .......................................................................................58
10.3.2. Definition of SAE.....................................................................................59
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................60
10.3.4. Reporting of SAEs....................................................................................63
10.4. Appendix 4: Contraceptive Guidance ...................................................................65
10.4.1. Male Participant Reproductive Inclusion Criteria....................................65
10.4.2. Female Participant Reproductive Inclusion Criteria.................................65
10.4.3. Woman of Childbearing Potential ............................................................65
10.4.4. Contraception Methods.............................................................................66
10.5. Appendix 5 Genetics .............................................................................................67
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........68
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................70
10.8. Appendix 8: Abbreviation.....................................................................................72
11. REFERENCES ..................................................................................................................76


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LIST OF TABLES
Table 1.
List of Procedures for Study Days 1 and 7...............................................13
Table 2.
Study Design and Treatments...................................................................20
Table 3.
Definition of Plasma PK Parameters for PF-06835919 and 
..................................................................................................47
Table 4.
Protocol-Required Safety Laboratory Assessments .................................57
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics of 
multiple oral doses of PF-06835919 in healthy adult Japanese participants
Rationale
KHK is an enzyme catalyzing the conversion of fructose and ATP to F1P and ADP, the first 
committed step in fructose metabolism.  PF-06835919 is a KHK inhibitor that is currently 
being developed for the treatment of NASH with fibrosis.  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. 
In the ongoing 16-week Phase 2a study of PF-06835919 in participants with NAFLD and 
T2DM (C1061011), 300 mg QD is the highest dose administered.  To support Japanese
participation in future clinical studies, this study (C1061010) will assess the safety,
tolerability and PK of PF-06835919 in healthy adult Japanese participants administered 
multiple oral doses of 300 mg QD.  
 
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the safety and tolerability of 
PF-06835919 following multiple oral doses 
of PF-06835919 administration in healthy
adult Japanese participants.
•
To evaluate the PK of PF-06835919 
following single and multiple oral doses of 
PF-06835919 administration in healthy
adult Japanese participants.
•
Assessment of AEs, clinical laboratory tests, vital 
signs (including BP and PR) and 12-lead ECG.
•
PK parametersa for PF-06835919:
Day 1 and Day 7: Cmax, Tmax, AUCtau
Day 7: t½, as data permit.
Exploratory:
Exploratory:
•
To evaluate the PK parameters of 
PF-06835919
following 
single and multiple oral doses of 
PF-06835919 administration in healthy
adult Japanese participants.
•
PK parametersa for PF-06835919:
Day 1 and Day 7: dose normalized Cmax and AUCtau
Day 7: Cmin, Rac, Rac,Cmax, PTR, CL/F and Vz/F, as 
data permit.
•
a.
For complete definition of all PK parameters refer to Section 9.4.1.2.
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Overall Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to 
evaluate the safety, tolerability and PK of multiple oral doses of PF-06835919 300 mg QD in 
healthy adult Japanese participants.
Number of Participants
A sample size of approximately 8 participants to be assigned to PF-06835919 or placebo in 
3:1 ratio (6 active and 2 placebo) has been empirically selected as a compromise between the 
need to minimize exposure of participants to PF-06835919 and the requirement to provide 
adequate safety and PK information.  No formal statistical inferences will be derived.
Intervention Groups and Duration
Approximately 6 participants are planned to receive 300 mg QD PF-06835919, and 
approximately 2 participants are planned to receive placebo QD, for 7 days.
Participants will be screened within 28 days of the first dose of study intervention.  Eligible 
participants will be admitted to the CRU on Day -1 and will be required to remain in the 
CRU until the morning of Day 10 for a total of 10 overnight days.  After PK sampling at 
72 hours post last dosing, all participants will be discharged from the CRU following 
completion of the discharge evaluation, which includes adverse event monitoring, physical 
examination, vital signs, ECG measurements, and safety laboratory tests. Participants will 
receive a Follow-up telephone contact 28-35 days after the last dose on Day 7.  The total 
duration of participation for each participant, including screening and Follow-up telephone 
contact, will be approximately 7 to 10 weeks.
Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.
Statistical Methods
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, PR, and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants.  Any clinical laboratory, 
ECG, BP, and PR abnormalities of potential clinical concern will be described.  Safety data 
will be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
Plasma concentration of PF-06835919
will be descriptively summarized 
and plotted by nominal PK sampling time and day.  The plasma PK parameters for 
PF-06835919
will be summarized descriptively by study day as applicable.  
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Median trough (predose) plasma concentrations for PF-06835919
will be 
plotted by day in order to assess the attainment of steady state.
1.2. Schema
Not Applicable.
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifier
Abbreviations used in this table may
be found in Appendix 8
Screening
Study Day
Follow-up 
Contact
Early 
Termination/
Discontinuation
Days Relative to Day 1 
Day -28 to 
Day -2
-1
1
2
3
4
5
6
7
8
9
10
28-35 
Daysa
Informed Consent 
x
Refer to Table 1
Refer to Table 1
CRU confinement
x







x
CRU discharge
x
Inclusion/exclusion criteria
x
x
Medical/medication history (update) 
x
x
Demography, body weight and height
x
Physical examb
x
x
x
x
Review alcohol and tobacco use
x
x
Contraception check/reviewc
x
x
x
x
x
Review prior or concomitant treatments
x
x
x
Single, supine 12-lead ECG
x
xd
x
x
Single, supine vital signs (BP and PR)
x
xd
x
x
Serious and non-serious adverse event 
monitoring
x








x
x
x
PF-06835919 administratione
x
x
x
x
x
Meals/snacksf
x






x
Blood Sampling For:
Clinical Laboratory tests (after ≥4-hour fast)
x
x
x
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Visit Identifier
Abbreviations used in this table may
be found in Appendix 8
Screening
Study Day
Follow-up 
Contact
Early 
Termination/
Discontinuation
Days Relative to Day 1 
Day -28 to 
Day -2
-1
1
2
3
4
5
6
7
8
9
10
28-35 
Daysa
HIV, HBsAg, HBcAb, HBsAb, HCVAb
x
FSH (for confirmation of postmenopausal 
status for females only)
x
Serum pregnancy test (WOCBP only)
x
x
x
x
PF-06835919 
 PK (predose)
x
x
x
xg
xh
xh
x
Urine Sampling For:
Urine drug testing
x
x
Urinalysis (and microscopy, if needed) 
x
x
x
x
x
a.
Contact may occur via telephone contact and must occur 28 to 35 days from administration of the final dose of study intervention.
b.
Complete physical examination can be performed either at Screening or at Day -1.  A brief physical examination at any time point as deemed necessary by 
the investigator.
c.
Contraception check for correct and consistent use (WOCBP only).
d.
Predose measurement.
e.
Participants will receive PF-06835919/placebo following an overnight fast of at least 8 hours, on Days 1-7 at approximately 0800 hours (±2 hours), 
approximately 20 minutes prior to the start of breakfast.
f.
Breakfast will be provided approximately 20 minutes after morning doses.
g.
PK samples collected at 24 and 36 hours (Day 8) following the Day 7 morning dose.
h.
PK samples collected at 48 hour (Day 9) and 72 hours (Day 10) following the Day 7 morning dose.
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Table 1.
List of Procedures for Study Days 1 and 7
Hours Relative to PF-06835919/Placebo Dosing at 0H on
Day 1 and Day 7
0
0.5
1
2
3
4
6
8
10
12
16
Inpatient Stay at CRU
→
→
→
→
→
→
→
→
→
→
→
Serious and non-serious adverse event monitoring
→
→
→
→
→
→
→
→
→
→
→
Single, supine 12 lead ECG
x
x
Single, supine vital signs (BP and PR)
x
x
PF-06835919/Placebo administrationa
x
Meals/snacksb
x
x
x
Blood Sampling For:
Pfizer Prep D1 Banked Biospecimen(s)c,d
x
Pfizer Prep B2 Banked Biospecimen(s)c,d
x
PF-06835919 
PK
x
x
x
x
x
x
x
x
x
x
Clinical laboratory tests (after ≥4-hour fast)e
x
Urine Sampling For:
Urinalysis (and microscopy, as appropriate)e
x
a.
Participants will receive PF-06835919/placebo following an overnight fast of at least 8 hours at approximately 
0800 hours (±2 hours), approximately 20 minutes prior to the start of breakfast.
b.
Breakfast will be provided approximately 20 minutes after morning doses.
c.
Pre-dose on Day 1 only. This can be done on Day-1 based on site preference.
d.
If not collected on the designated collection day, collect at the next available time point when biospecimens 
are being collected in conjunction with a participant visit.
e.
Pre-dose on Day 7 only.
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2. INTRODUCTION
PF-06835919 is a potent, reversible inhibitor of human KHK that is currently being 
developed for the treatment of NASH with fibrosis.  KHK is an enzyme catalyzing the 
conversion of fructose and ATP to F1P and ADP, the first committed step in fructose 
metabolism.  Loss of function mutation in KHK, known as Essential Fructosuria, is a rare 
autosomal genetic condition (Online Mendelian Inheritance in Man or OMIM #229800)1
which is asymptomatic and only recognized by the appearance of fructose in the urine after 
fructose consumption.2,3  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.  In addition, it is anticipated that KHK inhibition will improve 
circulating lipid and lipoprotein profiles as well as insulin sensitivity.
2.1. Study Rationale
In the ongoing 16-week Phase 2a study of PF-06835919 in participants with NAFLD and 
T2DM (C1061011), 300 mg QD is the highest dose administered.  To support Japanese
participation in future clinical studies, this study (C1061010) will assess the safety, 
tolerability and PK of PF-06835919 in healthy adult Japanese participants administered 
multiple oral doses of 300 mg QD.  
 
2.2. Background 
Fructose metabolism, unlike glucose metabolism, is normally not subject to regulatory 
feedback inhibition in 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 IV bolus of 
fructose.4  Depletion of ATP leads to the activation of 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, 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 VLDL clearance and promotes de novo 
lipogenesis.8
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 
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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 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% and 18% of the US and Japanese populations, respectively,
while prevalence of NASH is estimated at 3%-5% of both the US and Japanese 
population.15,16  Risk factors for NASH include obesity, insulin resistance, T2DM, 
hypertension, and dyslipidemia, as manifested by low levels of HDL-C and elevated 
triglycerides.
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.
 
 
 
 
 
 
 
 
 
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2.2.3. Nonclinical Safety
PF‑06835919 was evaluated in safety pharmacology and toxicity studies in Wistar Han rats 
and beagle dogs up to 6 months and 39 weeks in duration, respectively.  Additional studies 
included genotoxicity assays and female fertility and/or EFD studies in rats and rabbits.  
 
 
  
 
 
 
 
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PF-06835919 displayed no mutagenic or clastogenic potential in any of the genetic 
toxicology studies conducted.  PF-06835919 had an UV light absorbance but was negative in 
the in vitro phototoxicity assay, indicating it is not phototoxic and no further photosafety 
testing is recommended.
2.2.4. Clinical Overview
2.2.4.1. Summary of Clinical safety
As of February 2020, there are 4 completed sponsor-initiated clinical trials that administered
PF-06835919 (C1061001, C1061002, C1061016, and C1061003). Safety and tolerability 
findings from these studies are summarized below.
The safety and tolerability of PF-06835919 in healthy adults was assessed in the C1061001 
and C1061002 studies, in addition to the C1061016 DDI study. These studies collectively 
comprised participation of 88 healthy adult males, of which 78 were exposed to at least a 
single oral dose of PF-06835919, and 62 subjects exposed to repeated doses of PF-06835919. 
Single oral doses (up to 600 mg) and repeated daily doses (up to 330 mg over 14 days) were 
found to be well tolerated and generally safe. The DDI segment of C1061002 also 
demonstrated PF-06835919 was well tolerated and with an acceptable safety profile when co-
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administered with atorvastatin. There were no TEAEs of ‘severe’ intensity across the 
Phase 1 studies. In C1061001 all TEAEs were ‘mild’ in intensity. In the C1061002 study, 
4 ‘moderate’ intensity TEAEs were reported in active treatment groups: 1 headache with
PF-06835919 50 mg; 1 for each of headache and rash with PF-06835919 130 mg; and 
1 moderate headache in the DDI segment of the study, reported during PF-06835919 280 mg
co-administration with atorvastatin 20 mg.  The most frequently reported AE following 
multiple dose administration of PF-06835919 in Study C1061002 was headache (see 
IB Section 6.2). In C1061016, the impact of repeated doses (10 days) of PF-06835919 
300 mg QD on midazolam PK was evaluated in a 2-way crossover design in 10 healthy 
participants. The results indicate PF-06835919 was well tolerated when given alone or when 
co-administered with midazolam, with no new trends in safety laboratory abnormalities, 
ECG, or vital sign changes of clinical concern. The majority of TEAEs were mild in 
severity, with 3 episodes of moderate headache experienced by 1 participant (who reported 
1 episode following administration of midazolam alone, 1 episode with PF-06835919 alone, 
and 1 episode following co-administration); 1 participant reporting moderate backpain, and 
1 participant reporting hand fracture following co-administration treatment of midazolam and 
PF-06835919 (sustained through trauma 12 days after discharge from the unit, and 
determined by investigator to be unrelated to treatment). 
In the C1061003 Phase 2 study, PF-06835919 was administered at QD doses of 75 mg, 
300 mg, or placebo to a total of 53 participants (of which 26 were female, and 27 male) with 
NAFLD over a 6-week period. Both dose levels were found to be generally well tolerated 
with an acceptable safety profile.  The majority of TEAEs were mild: one participant in the 
300 mg group (5.9%) reported a severe TEAE of lower back pain, which was considered 
unrelated to study drug. One participant in the PF-06835919 300 mg group (5.9%) was 
withdrawn from the study due to a moderate TEAE of rash, and 1 participant in the placebo 
group (5.3%) was withdrawn from the study due to a moderate TEAE of dysuria. 
Cumulatively, 141 adults have participated in sponsor-initiated PF-06835919 clinical trials 
completed worldwide, with 112 exposed to at least a single oral dose of PF-06835919, and 
96 subjects exposed to repeated doses of PF-06835919. In clinical trials to date, there have 
been no SAEs reported. There has been no clear, dose-related increase in the frequency of 
AEs with increasing doses of PF-06835919. Similarly, there have been no apparent adverse 
dose-related trends in analyses of safety laboratory abnormalities, ECGs, or vital signs.
2.2.4.2. Summary of Pharmacokinetic of PF-06835919
Following administration of single oral doses of 10 to 600 mg, PF-06835919 was rapidly 
absorbed with a median Tmax ranging from 1 to 3 hours.  Following attainment of Cmax, 
plasma concentrations declined with a half-life ranging from approximately 11.4 to
15.1 hours.  Both the Cmax and AUC24 increased in an approximate dose-proportional manner 
across the dose range studied.


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Following multiple oral doses of PF-06835919 ranging from 15 to 330 mg QD over 14 days, 
absorption was rapid, with median Tmax occurring at approximately 0.5 to 1 hour post‑dose.  
Steady-state was achieved within 4 days of dosing.  Consistent with study C1061001, 
AUC24 and Cmax increased in an approximately dose proportional manner over the doses 
studied.  Accumulation of PF-06835919 was modest, with an AUC24 accumulation ratio 
(Day 14/Day 1) averaging from approximately 1.4- to 1.5-fold.  No clear dose‑related trend 
in terminal t½ was observed, with arithmetic mean values ranging from 13.3 to 16.8 hours.  
Less than 1% of the oral dose was excreted unchanged in urine.  
There was minimal effect of repeated dosing of PF-06835919 on the exposure of a single, 
oral dose of midazolam in healthy participants (C1061016).  The adjusted geometric mean 
for midazolam AUCinf and Cmax were similar following co-administration with multiple doses 
of PF-06835919 as compared to midazolam administration alone.  The ratio (90% CI) of the 
adjusted geometric means of AUCinf and Cmax for midazolam with multiple doses of 
PF-06835919, relative to midazolam administered alone were 97.55% (79.91%, 119.08%)
and 98.92% (76.44%, 128.01%), respectively.
2.3. Benefit/Risk Assessment
PF-06835919 is not expected to provide any clinical benefit to healthy participants.  This 
study is designed primarily to generate safety, tolerability, and PK data for further clinical 
development.
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. 
 
 
 
 
 
 
 
  
 
 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06835919 may be found in the investigator’s brochure, which 
is the SRSD for this study.
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3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To evaluate the safety and tolerability of 
PF-06835919 following multiple oral doses 
of PF-06835919 administration in healthy
adult Japanese participants.
•
To evaluate the PK of PF-06835919 
following single and multiple oral doses of 
PF-06835919 administration in healthy
adult Japanese participants.
•
Assessment of AEs, clinical laboratory tests, vital 
signs (including BP and PR) and 12-lead ECG.
•
PK parametersa for PF-06835919:
Day 1 and Day 7: Cmax, Tmax, AUCtau
Day 7: t½, as data permit.
Exploratory:
Exploratory:
•
To evaluate the PK parameters of 
PF-06835919 and 
 following 
single and multiple oral doses of 
PF-06835919 administration in healthy 
adult Japanese participants.
•
PK parametersa for PF-06835919:
Day 1 and Day 7: dose normalized Cmax and AUCtau
Day 7: Cmin, Rac, Rac,Cmax, PTR, CL/F and Vz/F, as 
data permit.
•
a.
For complete definition of all PK parameters refer to Section 9.4.1.2.
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to 
evaluate the safety, tolerability and PK of multiple oral doses of PF-06835919 300 mg QD in 
healthy adult Japanese participants.
A total of approximately 8 healthy participants will be enrolled in this study. Participants 
will be randomized to 2 groups to receive PF-06835919 or placebo treatment with a 
randomization ratio of 3:1. The overall study design is summarized below in Table 2.
Table 2.
Study Design and Treatments
Group
Number of Participants
Treatmentsa (7 Days)
1
6
PF-06835919 300 mg QD
2
2
Placebo QD 
a.
Study treatment as 3 x 100 mg PF-06835919 or matching Placebo tablets.
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All participants will provide informed consent and undergo screening evaluation to 
determine their eligibility. Participants will be screened within 28 days of the first dose of 
study intervention.  Eligible participants will be admitted to the CRU on Day -1 and will be 
required to remain in the CRU until morning of Day 10 for a total of 10 overnight days.  
After PK sampling at 72 hours post last dosing, all participants will be discharged from the
CRU following completion of the discharge evaluation, which includes AE monitoring, 
physical examination, vital signs, ECG measurements, and safety laboratory tests.
Participants will receive a Follow-up telephone contact 28-35 days after the last dose on 
Day 7.  The total duration of participation for each participant, including screening and 
Follow-up telephone contact, will be approximately 7 to 10 weeks.
Participants discontinued prior to completion of the study may, at the discretion of the 
investigator and sponsor and for reasons other than safety, be replaced by another participant
who will repeat the treatment of the participant being replaced.
4.2. Scientific Rationale for Study Design
This study is the first clinical study with PF-06835919 in the Japanese population.  The 
safety and PK of PF-06835919 after multiple dose administration will be collected and 
evaluated to support inclusion of Japanese participants in future clinical studies of 
PF-06835919. Placebo treatment is included to maintain the study blind for site and 
participants to avoid any bias for the safety assessment.
 
The half-life of PF-06835919 ranged from 11.4 to 16.8 hours, and the plasma concentration 
seemed to have reached steady state after 4 days of treatment (See Section 2.2.4.2).  
However, since there is no available information about the disposition of 
in 
humans, a 7-day treatment is set in this study to secure sufficient dosing duration to attain 
steady state for both parent (PF-06835919) 
 
 
 
 
 
 
  However, all female participants are required to use highly 
effective methods of contraception during this study (see Appendix 4).
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The potential risk of exposure to PF-06835919 in a sexual partner of a male participant in 
this study via ejaculate is low, and therefore, no contraception (condom) use in male 
participants is warranted.  The calculated safety margin is ≥100-fold between the estimated 
partner exposure due to seminal transfer and the NOAEL for serious manifestations of 
developmental toxicity in nonclinical studies.  The safety margin of 100-fold is based on 
applying a 10-fold safety factor for interspecies extrapolation and a 10-fold safety factor for 
susceptible populations.18
Banked Biospecimens will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention.
4.3. Justification for Dose
The highest dose in the ongoing PF-06835919 Phase 2a study (C1061011) is 300 mg QD, 
  To support Japan’s
participation in future clinical studies, 300 mg QD is selected in this study to evaluate safety, 
tolerability and PK of PF-06835919 in healthy adult Japanese participants following multiple 
oral dose administration.
This dose has been selected based on prior experience in healthy participants and NAFLD 
patients (see Section 2.2.4.1).  PF-06835919 was found to be well-tolerated with an 
acceptable safety profile with single doses up to 600 mg (C1061001) and repeated doses up 
to 330 mg/day (C1061002) in healthy participants.  A maximum tolerated dose was not 
identified.  In addition, both 75 mg and 300 mg QD dose levels were found to be generally 
well tolerated with an acceptable safety profile over 6-week treatment in NAFLD patients
(C1061003).
 
  
 
 
 
 Based on these in 
vitro PK characteristics, no meaningful difference would be expected in PF-06835919 PK
between Japanese and non-Japanese participants.
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 last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA
for the last participant in the trial.
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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 and female participants must be 18 to 55 years of age, inclusive, at the time of 
signing the ICD.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
2. A Japanese participant is defined as having 4 biological Japanese grandparents who 
were born in Japan. 
Type of Participant and Disease Characteristics:
3. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, physical examination, laboratory tests, and 
cardiovascular tests.
4. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
Informed Consent:
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.


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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).  
3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
HBcAb or HCVAb.  Hepatitis B vaccination (positive HBsAb) is allowed.
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
5. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention (Refer to Section 6.5 for additional details).
Prior/Concurrent Clinical Study Experience:
6. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or 5 half-lives preceding the first dose of study intervention
used in this study (whichever is longer). 
Diagnostic Assessments:
7. A positive urine drug test.
8. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest: If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.


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9. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may
affect participant safety or interpretation of study results (eg, baseline QTc interval
>450 msec, complete LBBB, signs of an acute or indeterminate-age myocardial
infarction, ST-T interval changes suggestive of myocardial ischemia, second- or 
third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the 
baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected 
using the Fridericia method (QTcF) and the resulting QTcF should be used for 
decision making and reporting.  If QTc exceeds 450 msec, or QRS exceeds 120 msec, 
the ECG should be repeated 2 more times and the average of the 3 QTc 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.
10. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

AST or ALT level ≥1.25 × ULN;

Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN.
Other Exclusions:
11. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening.  Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours.  As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
12. Use of tobacco- or nicotine-containing products in excess of the equivalent 
>5 cigarettes/day or 2 chews of tobacco per day.
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.  
14. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
15. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.


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5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any clinical laboratory evaluations, and at least 8 hours prior to the collection of the 
predose PK sample.  

Water is permitted until 1 hour prior to study intervention administration and may be 
consumed without restriction beginning 20 minutes after dosing (or beginning of 
breakfast).

Participants will not be allowed to eat or drink grapefruit or grapefruit-related-citrus 
fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first dose of 
study intervention (PF-06835919/placebo) on Day 1 until collection of the final PK 
blood sample.

Participants will be dosed following an overnight fast of at least 8 hours.

Breakfast will be served at approximately 20 minutes post-morning dose. 

Lunch will be served at approximately 4 hours post-morning dose. 

Dinner will be served at approximately 10 hours post-morning dose 

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein.  The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
Participants should be encouraged to consume meals within 25 minutes.
5.3.2. Caffeine, Alcohol, and Tobacco

Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period.

Participants will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol until collection of the final PK sample of study 
period.  Participants may undergo an alcohol breath test or blood alcohol test at the 
discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.


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5.3.3. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests.  Walking at a normal pace will be permitted.

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, PR, and ECG 
measurements), drinking beverages other than water during the first 4 hours after 
dosing.
5.3.4. 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 or her 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 or partner.
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 study intervention. Screen failure data are 
collected and remain as source and are not reported to the clinical database.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.  
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to PF-06835919 and matching 
placebo.


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6.1. Study Intervention(s) Administered
6.1.1. Administration
PF-06835919 will be supplied by Pfizer as 100-mg tablets along with matching placebo 
tablets. Tablets will be supplied to the CRU in bulk along with individual dosing containers 
for unit dosing.
Following an overnight fast of at least 8 hours, on Days 1-7 participants will receive study 
intervention at approximately 0800 hours (plus or minus 2 hours), approximately 20 minutes 
prior to the start of breakfast.  Investigator site personnel will administer study intervention
with ambient temperature water to a total volume of approximately 240 mL.  Participants 
may receive additional ambient temperature water up to 100 mL, if needed. Participants will 
swallow the study intervention whole, and will not manipulate or chew the study intervention
prior to swallowing.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally-controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site
by the sponsor or designee.
4. Any storage conditions stated in the SRSD will be superseded by the storage
conditions stated on the label.
5. Study interventions should be stored in their original containers.


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6. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent.  All study interventions will be accounted for 
using a study intervention accountability form/record.
7. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s site procedures.  All destruction must be 
adequately documented.  If destruction is authorized to take place at the investigator 
site, the investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff.  Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant in accordance with this protocol.  Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
PF-06835919 tablets and matching placebo tablets will be prepared at the CRU by qualified 
unblinded site personnel and will be administered in a blinded fashion to the participant.
Study intervention tablets will be prepared at the CRU in the individual dosing containers by 
2 operators, 1 of whom is an appropriately qualified and experienced pharmacist.  The tablets 
will be provided in unit dose containers and labeled in accordance with Pfizer regulations and 
the clinical site’s labeling requirements.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator will assign participant numbers to the participants as they are screened for 
the study.  Pfizer will provide a randomization schedule to the investigator and, in 
accordance with the randomization numbers, the participant will receive the study treatment 
regimen assigned to the corresponding randomization number.


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6.3.2. Breaking the Blind
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind. The method will be a manual process. 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.
Blinding codes should be broken only in exceptional circumstances when knowledge of the 
actual treatment code is absolutely essential for further management of the participant. 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. Investigators are encouraged to discuss with a 
member of the study team if they believe that unblinding is necessary. If a participant’s 
treatment assignment is unblinded, the sponsor must be notified within 24 hours after 
breaking the blind. When the blinding code is broken, the reason must be fully documented 
and entered on the CRF/DCT.
Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site.  Only the investigator site staff and blinded study monitor, if 
assigned, will be blinded to study treatment.  Other Pfizer personnel will be unblinded to 
participant treatments in order to permit real-time interpretation of the safety and PK data.  
Specimens from participants randomized to placebo will not be routinely analyzed.  To 
minimize the potential for bias, treatment randomization information will be kept 
confidential by Pfizer unblinded personnel and will not be released to the blinded 
investigator or blinded investigator site personnel until the study database has been locked or 
the investigator requests unblinding for safety reasons.
6.4. Study Intervention Compliance
Study intervention will be administered under the supervision of investigator site personnel.  
The date and time of each dose administered in the clinic will be recorded in the source 
documents and recorded in the CRF.  The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff 
other than the person administering the study intervention. Study site personnel will examine 
each participant’s mouth to ensure that the study intervention was ingested.
6.5. Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention.  Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤1 g/day.


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Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment.  Treatments taken after the first dose of study intervention
will be documented as concomitant treatments.
In order to minimize any possible effect on PK assessment, females using hormonal 
contraceptives or taking hormone replacement therapy may be eligible to participate in this 
study if they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study.  Depo-Provera®
must be discontinued at least 6 months prior to the first dose of study treatment.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All participants will be questioned about 
concomitant treatment at each clinic visit.
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
Not Applicable.
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 study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following: intolerance of the study drug, SAE, pregnancy, clinically 
relevant laboratory, vital signs or ECG changes.
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation.  See the SoA for data to be collected at the time of discontinuation of 
study intervention.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.


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7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;
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 enrolled/randomized and 
then are prematurely withdrawn from the study.  Participants should be questioned regarding 
their reason for withdrawal.  
The participant will be permanently discontinued both from the study intervention and from 
the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of study intervention or also from study procedures 


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and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the 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. 
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.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether 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.


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Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(PR and BP) should be collected prior to the insertion of the catheter.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
155 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1. Efficacy Assessments
Analysis of efficacy is not applicable to this study. 
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 issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 


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A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA.  For measuring 
weight, a scale with appropriate range and resolution is used and must be placed on a stable, 
flat surface. Participants must remove shoes, bulky layers of clothing, and jackets so that 
only light clothing remains.  They must also remove the contents of their pockets and remain 
still during measurement of weight. 
8.2.2. Vital Signs
Supine BP will be measured with the participant’s arm supported at the level of the heart and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and PR is acceptable.  When the timing of 
these measurements coincides with a blood collection, BP and PR should be obtained prior to 
the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and PR will be permitted, 
as necessary, to ensure appropriate collection of safety data.
8.2.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) 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 PR, QT, and QTc intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) is not 
recommended given the potential risk of discrepancies with ECGs acquired using standard 
limb lead placement. All scheduled ECGs should be performed after the participant has 
rested quietly for at least 10 minutes in a supine position.
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  Additional ECG monitoring will occur if a) a 
postdose QTc interval is increased by ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG.  If either of these conditions 
occurs, then 2 additional ECGs will be collected approximately 2 to 4 minutes apart to 
confirm the original measurement.  If the QTc values from these repeated ECGs remain 
above the threshold value, then a single ECG must be repeated at least hourly until QTc 
values from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.


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If a) a postdose QTc interval remains ≥60 msec from the baseline and is >450 msec; or b) an 
absolute QTc value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator); or c) QTc intervals get progressively longer, the 
participant should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTc 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 QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 7.
8.2.4. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.  All protocol required laboratory assessments, as defined in
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.


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8.2.5. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations.  
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 the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days after the last administration of the study intervention or until 
study completion or withdrawal, whichever is longer.  
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.


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If a participant definitively discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE after the participant has concluded 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as 
described in Section 8.3.1 are recorded on the CRF.  AEs and SAEs that begin after obtaining 
informed consent but before the start of study intervention will be recorded on the Medical 
History/Current Medical Conditions section of the CRF, not the AE section. AEs and SAEs 
that begin after the start of study intervention are recorded on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 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).


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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, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if:  

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:  


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
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by inhalation or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 28 days after 
the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the completed 
CT SAE Report Form is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the study intervention. 


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Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if: 

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.  
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred.  The 
information must be reported using the CT SAE Report Form.  When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file.
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.


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8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of 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.


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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).
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Safety only when associated with an SAE.
5. Obtain a blood sample for PK analysis at the time specified by the medical monitor if 
requested by the medical monitor (determined on a case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood samples of approximately 3 mL, to provide a minimum of plasma of 1 mL, will be 
collected for measurement of plasma concentrations of PF-06835919
as 
specified in the SoA.  Instructions for the collection and handling of biological samples will 
be provided in the laboratory manual or by the sponsor. The actual date and time (24-hour 
clock time) of each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF/DCT.  Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF/DCT. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows.
Samples will be used to evaluate the PK of PF-06835919 
 Samples 
collected for analyses of PF-06835919
 (plasma) concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study, for metabolite identification and/or evaluation of the bioanalytical method, or for other 
internal exploratory purposes.
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained.
CCI
CCI
CCI


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Samples collected for measurement of plasma concentrations of PF-06835919 
 
will be analyzed using a validated analytical method in compliance with 
applicable SOPs.  Potential metabolites may be analyzed with either validated or exploratory 
methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected as local 
regulations and IRBs/ECs allow. 
Banked Biospecimens may be used for research related to the study intervention(s).  Genes 
and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the banked 
samples. 
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in supporting documentation location.
8.8. Biomarkers
8.8.1. Banked Biospecimens for Biomarkers
Additional Banked Biospecimens in this study are:
•
10-mL whole blood (Prep B2 optimized for serum).
Banked Biospecimens will be collected as local regulations and IRB/ECs allow.  
Banked Biospecimens may be used for research related to the study intervention(s).  Genes 
and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the banked 
samples. 
CCI


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See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the lab manual.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
There are no statistical hypotheses for this study.
9.2. Sample Size Determination
A sample size of approximately 8 participants to be assigned to PF-06835919 or placebo in 
3:1 ratio (6 active and 2 placebo) has been empirically selected as a compromise between the 
need to minimize exposure of participants to PF-06835919 and the requirement to provide 
adequate safety and PK information.  No formal statistical inferences will be derived.
Participants discontinuing prior to completion of the study for reasons other than safety may, 
at the discretion of the investigator and sponsor, be replaced by another participant who will 
repeat all dosings of the participant being replaced.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis 
Set
Description
Evaluable
All participants randomly assigned to and receiving at least 1 
dose of study intervention
PK Concentration
The PK concentration population is defined as all participants
who receive at least 1 dose of PF-06835919 and who have at 
least 1 measurable concentration of PF-06835919 
 
C
CI


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Participant Analysis 
Set
Description
PK Parameter
The PK parameter population is defined as all participants
who receive at least 1 dose of PF-06835919 and who have at 
least 1 of the PK parameters of interest calculated.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data.  
This section is a summary of the planned statistical analyses of the primary and exploratory
endpoints.
9.4.1. Primary Endpoint(s)
9.4.1.1. Safety Analyses
All safety analyses will be performed using the safety population.
AEs, ECGs, BP, PR, and safety laboratory data may be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of participants.  Any clinical laboratory, 
ECG, BP, and PR abnormalities of potential clinical concern will be described.  Safety data 
will be presented in tabular and/or graphical format and summarized descriptively using 
sponsor’s reporting standards, where appropriate.
Medical history and physical examination and neurological examination information, as 
applicable, collected during the course of the study will be considered source data and will 
not be required to be reported, unless otherwise noted.  However, any untoward findings 
identified on physical and/or neurological examinations conducted during the active 
collection period will be captured as AEs, if those findings meet the definition of an AE.  
Data collected at screening that are used for inclusion/exclusion criteria, such as laboratory 
data, ECGs, and vital signs, will be considered source data, and will not be required to be 
reported, unless otherwise noted.  Demographic data collected at screening will be reported.
Electrocardiogram Analyses
Changes from baseline for the ECG parameters, QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.


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The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Categories for Maximum Post-dose QTcF (msec)
All participants
≤450
450 - ≤480
480 - ≤500
>500
Categories for Maximum Increase from Baseline in QTcF (msec)
All participants
≤30
30 - ≤60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.4.1.2. Pharmacokinetic Analyses of PF-06835919
The PK parameters (Cmax, Tmax, AUCtau and t½) for PF-06835919 following single and 
multiple dose administration will be derived from the concentration-time profiles as detailed 
in Table 3.  Actual PK sampling times will be used in the derivation of PK parameters. In 
the case that actual PK sampling times are not available, nominal PK sampling times will be 
used in the derivation of PK parameters.
Table 3.
Definition of Plasma PK Parameters for PF-06835919
Parameter
Day(s)
Definition
Method of Determination
AUCtau
1, 7
Area under the plasma concentration
time profile from time zero to time tau 
(τ), the dosing interval, where τ = 
24 hours for QD dosing.
Linear/Log trapezoidal method
Cmax
1, 7
Maximum plasma concentration during 
the dosing interval
Observed directly from data
Tmax
1, 7
Time for Cmax   
Observed directly from data as time of 
first occurrence
Cmin
7
Minimum plasma concentration during 
the dosing interval
Observed directly from data
Rac
7
Observed accumulation ratio
Day 7 AUCtau/Day 1 AUCtau
Rac,Cmax
7
Observed accumulation ratio for Cmax
Day 7 Cmax/Day 1 Cmax
PTR
7
Peak to trough ratio
Cmax/Cmin
t½a
7
Terminal half life
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a 
linear regression of the log-linear 
concentration-time curve.  
CL/Fa,b
7
Apparent clearance
Dose/AUCtau
Vz/Fa,b
7
Apparent volume of distribution
Dose/(AUCtau * kel)
AUCtau (dn)b
1, 7
Dose normalized AUCtau
AUCtau/Dose
Cmax(dn)b
1, 7
Dose normalized Cmax
Cmax/Dose
 
 
a.
As data permit.
b.
To be calculated for PF-06835919 only.
CCI
CCI
C
C


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The plasma PK parameters for PF-06835919 will be summarized descriptively by study day 
as applicable.
9.4.2. Exploratory Endpoint(s)
The PK parameters for PF-06835919 (additional parameters other than those in Section 
9.4.1.2) and 
following single and multiple dose administration of PF-06835919 
will be derived from the concentration-time profiles as data permit.  The PK parameters to be 
assessed are shown in Table 3. 
Plasma concentration of PF-06835919 and 
will be descriptively summarized 
and plotted by nominal PK sampling time and day.  The plasma PK parameters for 
PF-06835919 and 
 will be summarized descriptively by study day as applicable.  
Median trough (predose) plasma concentrations for PF-06835919 and 
will be 
plotted by day in order to assess the attainment of steady state.
 
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is a sponsor-open
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, and/or supporting clinical development. 
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will not use a DMC.
CCI
CCI
CCI
CCI
CCI


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


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


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Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research.  The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional 
research.  Participants will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period.  A separate 
signature will be required to document a participant's agreement to allow specimens to be 
used for additional research.  Participants who decline to participate in this optional 
additional research will not provide this separate signature.
10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site will be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations.  In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website.  Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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10.1.5. 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 IQMP.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.6. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the investigator site file.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.7. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/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;


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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.8. 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 the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.


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10.1.9. 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 CTMS.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant numbers, contact information for the investigator site, and contact 
details for a contact center in the event that the investigator site staff cannot be reached to 
provide advice on a medical question or problem originating from another healthcare 
professional not involved in the participant’s participation in the study.  The contact number 
can also be used by investigator staff if they are seeking advice on medical questions or 
problems; however, it should be used only in the event that the established communication 
pathways between the investigator site and the study team are not available.  It is therefore 
intended to augment, but not replace, the established communication pathways between the 
investigator site and the study team for advice on medical questions or problems that may 
arise during the study.  For sites other than a Pfizer CRU, the contact number is not intended 
for use by the participant directly, and if a participant calls that number, he or she will be 
directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety issues.
Table 4.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs+%)
Eosinophils (Abs+%)
Monocytes (Abs+%)
Basophils (Abs+%)
Lymphocytes (Abs+%)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya

Urine drug screeningc

Pregnancy test (-hCG)d
At screening only:

FSHb

Hepatitis B surface 
antigen

Hepatitis B core Antibody

Hepatitis B surface 
antibody

Hepatitis C antibody

Human immunodeficiency 
virus
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
FSH = follicle-stimulating hormone; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; qual = qualitative; RBC = red blood cell; 
WBC = white blood cell. 
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol (THC), 
opiates/opioids, benzodiazepines, and amphetamines (others are site and study specific).
d.
Serum -hCG for female participants of childbearing potential.
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigator 
sites or other blinded personnel until the study has been unblinded.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study.  Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings.  These data will not be included in the CSR.  Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator.  Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either 
an increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported 
as an AE/SAE unless it is an intentional overdose taken with possible 


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suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a 


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complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; 
and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must 


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be completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours 
of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and EDP 
supplemental form for 
EDP)  

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.


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


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
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data
become available.


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
After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.


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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, as described below during the 
intervention period and for at least 28 days after the last dose of study intervention,
which corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. 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 no menses for 12 months without an 
alternative medical cause. In addition, a

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 

For women using HRT, FSH should be measured after an appropriate washout 
of HRT (at least 14 days after the last dose of HRT). HRT must be 
discontinued at least 28 days before the first dose of investigational product 
and for at least 28 days after the last dose of PF-06835919.

Females whose menopausal status is in doubt will be required to use one of 
the allowed non-hormonal highly effective contraception methods.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
Highly Effective Methods That Have Low User Dependency
1. Non-hormonal Intrauterine device (IUD).
2. Bilateral tubal occlusion.
3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP 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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10.5. Appendix 5 Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to PF-06835919 or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Samples for banking will be stored indefinitely or for another period as per local 
requirements.

Participants may withdraw their consent for the storage and/or use of their Banked 
Biospecimens at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed.  Data already generated from the samples will 
be retained to protect the integrity of existing analyses.  

Banked Biospecimens will be labeled with a code.  The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held at the 
study site and will not be provided to the sample bank.


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


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


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


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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(heart rate <40 bpm), accelerated idioventricular rhythm (HR >40 bpm to
<100 bpm), and monomorphic/polymorphic ventricular tachycardia (HR 
>100 bpm (such as torsades de pointes)).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.8. Appendix 8: Abbreviation
The following is a list of abbreviations that used in the protocol.
Abbreviation
Term
Abs
absolute
ADP
adenosine diphosphate
AE
adverse event
ALT
alanine aminotransferase
AMP
adenosine monophosphate
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AUCinf
area under the plasma concentration-time curve from zero to infinity
AUC24
area under the plasma concentration-time curve from zero to 24 hours
AUCtau
area under the plasma concentration-time curve over dosing interval
AV
atrioventricular
BCRP
breast cancer resistance protein
-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
apparent clearance
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trial
CTMS
clinical trial management system
CYP
cytochrome P450
DCT
data collection tool
DDI
drug drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
dn
dose normalized
DNA
deoxyribonucleic acid


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Abbreviation
Term
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EFD
embryo fetal development
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
F1P
fructose-1-phosphate
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HbsAb
hepatitis B surface antibody
HbsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDL-C
high density lipoprotein – cholesterol
hERG
human ether-a-go-go related gene
Hg
mercury
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
investigator’s brochure
IC50
50% inhibition of concentration
ICD
informed consent document
ICH
International Council for Harmonisation
IND
investigational new drug application
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IQMP
Integrated Quality Management Plan
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
kel
terminal phase rate constant
KHK
ketohexokinase
LBBB
left bundle branch block
LFT
liver function test
Log
logarithm


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Abbreviation
Term
LV +dP/dt 
max
maximum rate of rise in left ventricular pressure (index of myocardial 
contractility)
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
 
msec
millisecond
MW
molecular weight
N/A
not applicable
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis
Nav
nerve artery vein
NOAEL
no-observed-adverse-effect level
NOEL
no observed effect level
OAT
organic anion transporter
OATP
organic anion-transporting polypeptide
P-gp
P-glycoprotein
PCRU
Pfizer clinical research unit
PDE
phosphodiesterase
PK
pharmacokinetic
PR
pulse rate
PT
prothrombin time
PTR
peak to trough ratio
PVC
premature ventricular contraction/complex
QD
once daily
QT
measure between Q wave and T wave
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
qual
qualitative
Rac
observed accumulation ratio
Rac, Cmax
observed accumulation ratio for Cmax
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities
SOP
standard operating procedures
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment emergent adverse event
CCI


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Abbreviation
Term
THC
tetrahydrocannabinol
Tmax
time for Cmax
t½
terminal half-life
T2DM
type 2 diabetes mellitus
UGT
uridine diphosphate-glucuronosyltransferase
ULN
upper limit of normal
US
United States
UV
ultraviolet
VLDL
very low density lipoprotein
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
women of child-bearing potential


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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/.
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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.
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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.
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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 
weightmaintaining 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 
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Protocol C1061010
Final Protocol, 4 March 2020
PFIZER CONFIDENTIAL
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14.
Stanhope KL, Medici V, Bremer AA, et al. A dose-response study of consuming 
highfructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for 
cardiovascular disease in young adults. Am J Clin Nutr 2015;101:1144-54.
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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.
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Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, 
France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 
of 2016-2030. J Hepatol 2018;69(4):896-904.
 
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Banholzer ML, Wandel C, Barrow P, et al. Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner: update. 
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SAP_001.pdf: 
Protocol C1061010 (PF-06835919) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C1061010
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, PLACEBO-
CONTROLLED STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND 
PHARMACOKINETICS OF MULTIPLE ORAL DOSES OF PF-06835919 IN 
HEALTHY ADULT JAPANESE PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
18MAR2020  


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TABLE OF CONTENTS
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives, Endpoints, and Estimands............................................................4
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................5
3.1. Primary Endpoints.....................................................................................................5
3.2. 
/Exploratory Endpoint(s)..................................................................................6
3.3. Baseline Variables.....................................................................................................7
3.4. Safety Endpoints .......................................................................................................7
3.4.1. Adverse Events.............................................................................................7
3.4.2. Laboratory Data............................................................................................7
3.4.3. Vital Signs ....................................................................................................8
3.4.4. ECG ..............................................................................................................8
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS).....................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.3. Methods to Manage Missing Data ..........................................................................10
5.3.1. Safety Data: ................................................................................................10
5.3.2. Pharmacokinetics Data: ..............................................................................11
6. ANALYSES AND SUMMARIES ......................................................................................11
6.1. Primary Endpoints...................................................................................................11
PK Endpoint (s)..............................................................................................................11
6.2. Exploratory Endpoint(s)..........................................................................................12
6.3. Baseline and Other Summaries and Analyses.........................................................13
6.4. Safety Summaries and Analyses .............................................................................13
6.4.1. Adverse Events...........................................................................................14
6.4.2. Laboratory Data..........................................................................................14
6.4.3. Vital Signs ..................................................................................................14
6.4.4. Electrocardiograms.....................................................................................14
7. INTERIM ANALYSES.......................................................................................................15
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7.1. Introduction .............................................................................................................15
7.2. Interim Analyses and Summaries............................................................................15
8. APPENDIX 1.......................................................................................................................16




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2.2. Study Design
This is a Phase 1, randomized, double-blind, sponsor-open, placebo-controlled study to 
evaluate the safety, tolerability and pharmacokinetics (PK) of multiple oral doses of 
PF-06835919 300 mg QD in healthy adult Japanese participants.
A total of approximately 8 healthy participants will be enrolled in this study.  Participants 
will be randomized to 2 groups to receive PF-06835919 or placebo treatment with a 
randomization ratio of 3:1. The overall study design is summarized below in Table 11.
Table 1.
Study Design and Treatments
Group
Number of Participants
Treatmentsa (7 Days)
1
6
PF-06835919 300 mg QD
2
2
Placebo QD 
a.
Study treatment as 3 x 100 mg PF-06835919 or matching Placebo tablets
All participants will provide informed consent and undergo screening evaluation to 
determine their eligibility. Participants will be screened within 28 days of the first dose of 
study intervention.  Eligible participants will be admitted to the Clinical Research Unit 
(CRU) on Day -1 and will be required to remain in the CRU until morning of Day 10 for a 
total of 10 overnight days.  After PK sampling at 72 hours post last dosing, all participants
will be discharged from the CRU following completion of the discharge evaluation, which 
includes adverse event (AE) monitoring, physical examination, vital signs, electrocardiogram 
(ECG) measurements, and safety laboratory tests.  Participants will receive a Follow-up 
telephone contact 28-35 days after the last dose on Day 7.  The total duration of participation 
for each participant, including screening and Follow-up telephone contact, will be 
approximately 7 to 10 weeks.
Participants discontinuing prior to the completion of the study may, at the discretion of the 
investigator and sponsor and for reasons other than safety, be replaced by another participant
who will repeat the treatment of the participant being replaced.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
The primary endpoints include safety and PK of PF-06835919 whose details are provided 
below.
Safety:






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account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline will be the last predose measurement collected on Day -1 prior to Day 1 
randomization and dosing. Results from only the planned study visits will be considered for 
baseline assessment.
3.4.3. Vital Signs
Single supine blood pressure and pulse measurements will be taken at all time points listed in 
the Schedule of Activities given in the protocol. Baseline will be defined as the measurement 
obtained on Day 1 0H predose.   
The maximum decrease and increase from baseline over all measurements taken postdose for 
supine systolic and diastolic blood pressures will be determined. The maximum increase 
from baseline will be calculated by first subtracting the baseline value from each postdose 
measurement to give the change from baseline.  The maximum of these values over the entire 
study will then be selected, except in the case where a subject does not show an increase.  In 
such an instance, the minimum decrease should be taken.
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a subject does not show a 
decrease, the minimum increase should be taken.
3.4.4. ECG
Single supine 12-lead ECG will be taken at all time points listed in the Schedule of Activities 
given in the protocol. Baseline will be defined as the measurement obtained on Day 1 0H 
predose.
The QT, QTcF, PR, QRS and heart rate 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 not provided)
The maximum absolute value (postdose) and the maximum increase from baseline will be 
determined over all measurements taken postdose for QTcF, PR and QRS.
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each postdose measurement to give the change from baseline.  The maximum of 
these values over the entire study will then be selected, except in the case where a subject 
does not show an increase.  In such an instance, the minimum decrease should be taken.


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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 releasing the database. For purposes of 
analysis, the following analysis sets are defined:


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Participant Analysis 
Set
Description
Evaluable
All participants randomly assigned to and receiving at least 1 
dose of study intervention
PK Concentration
The PK concentration population is defined as all participants
who receive at least 1 dose of PF-06835919 and who have at 
least 1 measurable concentration of PF-06835919 
 
PK Parameter
The PK parameter population is defined as all participants 
who receive at least 1 dose of PF-06835919 and who have at 
least 1 of the PK parameters of interest calculated.
Safety
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.  Participants 
will be analyzed according to the product they actually 
received.
  
5. GENERAL METHODOLOGY AND CONVENTIONS
This is a double-blind and sponsor-open study.  Specific Pfizer personnel (analytical staff, 
medical monitor, clinical leads, clinicians, statistician, programmers, data managers and 
pharmacokineticists and people shadowing these team members) will be unblinded to 
participant treatments in order to permit real-time interpretation of the safety and PK data.  
Treatment randomization information will be kept confidential by Pfizer personnel and will 
not be released to the investigator/site staff until the conclusion of the study.  Final analysis 
will follow the official database release.
5.1. Hypotheses and Decision Rules
There are no statistical hypotheses or decision rules.
5.2. General Methods
Descriptive statistics, including the sample size, mean, standard deviation, median, 
minimum, and maximum values, will be provided for continuous endpoints.  Some measures 
will be summarized using graphical representations by treatment and visit, where 
appropriate.
5.3. Methods to Manage Missing Data
5.3.1. Safety Data:
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied. 
C
CI


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5.3.2. Pharmacokinetics Data:
Methods to handle missing PK data are described below.
Concentrations Below the Limit of Quantification:
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
Deviations, Missing Concentrations and Anomalous Values:
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
Pharmacokinetic Parameters:
Actual PK sampling times will be used in the derivation of PK parameters. If a PK parameter 
cannot be derived from a subject’s concentration data, the parameter will be coded as NC (ie 
not calculated). (Note that NC values will not be generated beyond the day that a subject 
discontinues.) In summary tables, statistics will be calculated by setting NC values to 
missing; and statistics will be presented for a particular dose with ≥3 evaluable 
measurements.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed from 
the gastrointestinal tract), this will be footnoted in summary tables and will not be included in 
the calculation of summary statistics or statistical analyses.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
The analyses of primary endpoints for safety will be described in the Section 6.4. 
PK Endpoint (s)
To assess the pharmacokinetics of PF-06835919, the PK parameters detailed in Section 3.1
will be listed, summarized and plotted by PK sampling days for subjects in the PK parameter
set (as defined in Section 4).  Missing values will be handled as detailed in Section 5.3.2.  
Each plasma parameter will be summarized by day and will include the set of summary 
statistics as specified in the table below:




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
a listing of all concentrations sorted by subject ID, day and nominal time post dose.  The 
concentration listing will also include the actual times.  Deviations from the nominal time 
will be given in a separate listing.

a summary of concentrations by day and nominal time post dose, where the set of 
statistics will include n, mean, median, STD, CV, min, max and the number of 
concentrations above the lower limit of quantification.

median concentrations time plots (on both linear and semi-log scales) against nominal 
time post dose by day (Days 1 and 7 plotted on the same graph) based on the summary of 
concentrations by day and time post dose.

mean concentrations time plots (on both linear and semi-log scales) against nominal time 
post dose by day (Days 1 and 7 plotted on the same graph), based on the summary of 
concentrations by day and time post dose.

individual concentration time plots by subject (on both linear and semi-log scales) against 
actual time post dose (there will be separate plots for each subject, with all days on the 
same graph).
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used, for individual subject plots by time, the actual PK sampling time will be 
used.
6.3. Baseline and Other Summaries and Analyses
Demographic data collected at screening will be reported as part of the standard baseline 
summary tables. A breakdown of demographic data will be provided for age, race, weight, 
body mass index, and height. Each will be summarized by treatment in accordance with the 
sponsor reporting standards.  
Subject evaluation groups will show end of study subject disposition. The table will present 
counts of subjects who were analyzed for PK and for safety (adverse events and laboratory 
data).  Frequency counts will be supplied for subject discontinuation(s) by treatment.
6.4. 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 3.4
will be listed and summarized in accordance with sponsor reporting standards, where the 
resulting data presentations will consist of subjects from the safety analysis set.
Medical history and physical examination information, as applicable, collected during the 
course of the study will be considered source data and will not be required to be reported, 
unless otherwise noted.  However, any untoward findings identified on physical 
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.  


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6.4.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.
6.4.2. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 3.4.2.
6.4.3. Vital Signs
Absolute values and changes from baseline in supine systolic and diastolic blood pressure 
and pulse rate will be summarized by treatment and time postdose, according to sponsor 
reporting standards.  Tables will be paged by parameter.  Baseline is as defined in Section 
3.4.3.
Mean changes from baseline for supine systolic and diastolic blood pressure and pulse rate 
will be plotted separately for 0 hr pre-dose and 1 hr post-dose time points against days of 
collection.  On each plot there will be 1 line for each treatment, both PF-06835919 and 
placebo on the same plot.  Corresponding individual plots of changes from baseline will also 
be produced for each treatment.
For supine systolic and diastolic blood pressure and pulse rate, the differences between 
PF-06835919 and placebo (dose – placebo) will be summarized (N, mean, 90% CI) and 
plotted (mean) for each timepoint (including baseline).
Maximum absolute values and changes from baseline for vital signs will be summarized 
descriptively by treatment using categories as defined in Appendix 1.  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 increase or decrease in vital signs will also be summarized; all planned and 
unplanned postdose timepoints will be included in these summaries.
6.4.4. Electrocardiograms
Absolute values and changes from baseline in QT, heart rate, QTcF, PR and QRS will be 
summarized by treatment and time postdose using sponsor reporting standards.  Tables will 
be paged by parameter. Baseline is as defined in Section 3.4.4.
Mean changes from baseline in pre-dose QT, heart rate and QTcF will be plotted against days 
of collection.  On each plot there will be 1 line for each treatment, Both PF-06835919 and 
placebo on the same plot.  Corresponding individual plots of changes from baseline will also 
be produced for each treatment.
Changes from baseline in QTcF will also be plotted separately against drug concentrations.  
This will be a scatter plot for all observations where QTcF and drug concentration are 
recorded.  Placebo data will also be included (with drug concentration set to zero).  Different 
symbols will be used for each treatment.  


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In addition for QTcF, heart rate and QT, the differences between PF-06835919 and placebo 
(dose – placebo) will be summarized and plotted (N, mean, 90% CI) for each timepoint 
(including baseline). 
ECG endpoints and changes from baseline (QTcF, PR and QRS) will also be summarized 
descriptively by treatment using categories as defined in Appendix 1.  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.
The number of subjects with corrected (QTcF) and uncorrected single post-dose QT values 
500 msec will be listed.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study.  As this is a sponsor-open 
study, the sponsor may conduct unblinded reviews of the data during the course of the study 
for the purpose of safety assessment, and/or supporting clinical development.
7.2. Interim Analyses and Summaries
Available safety and PK data may be reviewed.  


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8. APPENDIX 1
Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Categories for Maximum Post-dose QTcF (msec)
All participants
≤450
450 - ≤480
480 - ≤500
500
Categories for Maximum Increase from Baseline in QTcF (msec)
All participants
≤30
30 - ≤60
60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120
Standing pulse rate (bpm)
min. <40
max. >140
Measurements that fulfill these criteria are to be listed in the clinical study report.