Clinical trial NCT03796182
Conditions: Healthy
Keywords: Phase 1 Metformin Atopic dermatitis
Sponsor: Pfizer
Start date: 2019-01-10; Completion date: 2019-03-12
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods.

Detailed description:
This is a Phase 1, randomized, 2 way crossover, open label study of the effect of PF-04965842 on metformin (a probe for MATE1/2K activity) PK in healthy adult participants. The effect of PF-04965842 on N1-methylnicotinamide (NMN; an endogenous biomarker for MATE1/2K) PK and its correlation to the effect on metformin PK will also be assessed. Participants will be randomized to 1 of 2 treatment sequences as described below. A total of 12 healthy male and/or female participants will be enrolled in the study so that 6 participants will be enrolled in each treatment sequence. Each treatment sequence will consist of 2 periods. Participants who discontinue from the study may be replaced at the sponsor's discretion. The replacement participant will receive the same treatment sequence as the participant who discontinued.

Participants will be screened within 28 days of the first dose of investigational product. Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1) dosing in Period 1 for both treatment sequences. In both sequences, participants will remain in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2). There will be a minimum 4 day washout period between metformin dosing events. NMN and metformin PK will be assessed in plasma and urine over 24 and 48 hours, respectively.

Arms: arm 1: Patients in sequence 1 will received treatment A (metformin) in Period 1 then complete at least 4 days of washout and continue to period 2 where treatment B (PF-04965842 + metformin) will be administered. arm 2: Patients in Sequence 2 will start treatment B (PF-04965842 + metformin) then go through a washout period of at least 4 days and continue to Period 2 where treatment A (metformin) will be administered.
Interventions: intervention 1: Metformin intervention 2: PF-04965842
Intervention descriptions: intervention 1: Commercially available metformin (GLUCOPHAGE®) as 500 mg tablets. intervention 2: PF 04965842 100 mg tablets

Protocol documents:
Prot_001.pdf: 
PF-04965842 
Protocol B7451034
Final Protocol, 01 November 2018
Page 1
A PHASE 1, RANDOMIZED, 2-WAY CROSSOVER, OPEN LABEL STUDY TO 
ESTIMATE THE EFFECT OF PF-04965842 ON MATE1/2K ACTIVITY, USING 
METFORMIN AS A PROBE, IN HEALTHY PARTICIPANTS
Investigational Product Number:
PF-04965842
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-003683-31
Protocol Number:
B7451034
Phase:
1
Short Title: A Phase 1 Study of PF-04965842 Effect on MATE1/2K Activity in Healthy 
Participants
CCI
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
1 November 2018
Not Applicable (N/A)
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................16
2.1. Study Rationale .......................................................................................................16
2.2. Background .............................................................................................................16
2.2.1. Mechanism of Action/Indication................................................................16
2.2.2. Overview of Disease State..........................................................................17
2.2.3. Rationale for Development of PF-04965842..............................................18
2.2.4. Previous Human Experience with PF-04965842........................................18
2.2.4.1. Summary of Safety Data from Completed Studies ...................18
2.2.4.2. Summary of PF-04965842 Pharmacokinetics, Metabolism 
and In Vitro Enzymology..................................................................19
2.3. Benefit/Risk Assessment.........................................................................................22
3. OBJECTIVES AND ENDPOINTS.....................................................................................22
4. STUDY DESIGN.................................................................................................................23
4.1. Overall Design.........................................................................................................23
4.2. Scientific Rationale for Study Design.....................................................................24
4.3. Justification for Dose ..............................................................................................25
4.4. End of Study Definition ..........................................................................................26
5. STUDY POPULATION......................................................................................................26
5.1. Inclusion Criteria.....................................................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.3. Lifestyle Considerations..........................................................................................30
5.3.1. Meals and Dietary Restrictions...................................................................30
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................31
5.3.3. Activity .......................................................................................................31
5.3.4. Contraception..............................................................................................31
5.4. Screen Failures ........................................................................................................32
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6. STUDY INTERVENTION..................................................................................................32
6.1. Study Intervention(s) Administered........................................................................32
6.1.1. Administration............................................................................................32
6.2. Preparation/Handling/Storage/Accountability ........................................................33
6.2.1. Preparation and Dispensing........................................................................34
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................34
6.3.1. Allocation to Investigational Product .........................................................34
6.4. Study Intervention Compliance...............................................................................35
6.5. Concomitant Therapy..............................................................................................35
6.5.1. Rescue Medicine.........................................................................................35
6.6. Dose Modification...................................................................................................35
6.7. Intervention After the End of the Study..................................................................35
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................36
7.1. Discontinuation of Study Intervention ....................................................................36
7.2. Participant Discontinuation/Withdrawal From the Study.......................................36
7.3. Lost to Follow up ....................................................................................................37
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................37
8.1. Efficacy Assessments..............................................................................................38
8.2. Safety Assessments .................................................................................................39
8.2.1. Physical Examinations................................................................................39
8.2.2. Vital Signs ..................................................................................................39
8.2.2.1. Temperature ..............................................................................39
8.2.3. Electrocardiograms.....................................................................................39
8.2.4. Clinical Safety Laboratory Assessments ....................................................41
8.2.5. Pregnancy Testing ......................................................................................41
8.3. Adverse Events and Serious Adverse Events..........................................................42
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......42
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................42
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................43
8.3.2. Method of Detecting AEs and SAEs ..........................................................43
8.3.3. Follow-up of AEs and SAEs.......................................................................43
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8.3.4. Regulatory Reporting Requirements for SAEs...........................................43
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................44
8.3.5.1. Exposure During Pregnancy......................................................44
8.3.5.2. Exposure During Breastfeeding ................................................44
8.3.5.3. Occupational Exposure .............................................................44
8.3.6. Medication Errors .......................................................................................44
8.4. Treatment of Overdose............................................................................................45
8.5. Pharmacokinetics ....................................................................................................46
8.5.1. Plasma for Metformin Analysis..................................................................46
8.5.2. Urine for Metformin Analysis ....................................................................46
8.6. Pharmacodynamics..................................................................................................47
8.7. Genetics...................................................................................................................47
8.7.1. Specified Genetics ......................................................................................47
8.7.2. Banked Biospecimens for Genetics............................................................47
8.8. Biomarkers ..............................................................................................................48
8.8.1. Plasma for NMN Analysis..........................................................................48
8.8.2. Urine for NMN Analysis ............................................................................48
8.8.3. Other Biomarkers........................................................................................49
8.9. Health Economics ...................................................................................................49
9. STATISTICAL CONSIDERATIONS ................................................................................49
9.1. Statistical Hypotheses .............................................................................................49
9.2. Sample Size Determination.....................................................................................49
9.3. Populations for Analysis .........................................................................................50
9.4. Statistical Analyses .................................................................................................50
9.4.1. Efficacy Analyses .......................................................................................50
9.4.2. Safety Analyses ..........................................................................................50
9.4.2.1. Electrocardiogram Analyses......................................................51
9.4.3. Other Analyses............................................................................................51
9.4.4. Pharmacokinetic Analyses..........................................................................51
9.4.4.1. Analysis of Population ..............................................................51
9.4.4.2. Derivation of Pharmacokinetic Parameters Prior to 
Analysis .............................................................................................52
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9.5. Interim Analyses .....................................................................................................54
9.5.1. Data Monitoring Committee.......................................................................54
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................55
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............55
10.1.1. Regulatory and Ethical Considerations ....................................................55
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................55
10.1.2. Financial Disclosure .................................................................................56
10.1.3. Informed Consent Process ........................................................................56
10.1.4. Data Protection .........................................................................................57
10.1.5. Dissemination of Clinical Study Data ......................................................57
10.1.6. Data Quality Assurance ............................................................................59
10.1.7. Source Documents....................................................................................60
10.1.8. Study and Site Closure..............................................................................60
10.1.9. Publication Policy.....................................................................................61
10.1.10. Sponsor’s Qualified Medical Personnel .................................................61
10.2. Appendix 2: Clinical Laboratory Tests .................................................................63
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................66
10.3.1. Definition of AE .......................................................................................66
10.3.2. Definition of SAE.....................................................................................67
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................68
10.3.4. Reporting of SAEs....................................................................................71
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................72
10.4.1. Male Participant Reproductive Inclusion Criteria....................................72
10.4.2. Female Participant Reproductive Inclusion Criteria.................................72
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................72
10.4.4. Contraception Methods.............................................................................73
10.5. Appendix 5: Genetics............................................................................................76
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........77
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................79
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Appendix 8: Abbreviations ............................................................................................81
11. REFERENCES ..................................................................................................................85
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................13
Table 2.
Pharmacokinetic Sampling Schema .....................................................................15
Table 3.
Treatment Sequences............................................................................................24
Table 4.
Sample Size Determination ..................................................................................49
Table 5.
Safety QTc Assessment ........................................................................................51
Table 6.
Derivation of PK Parameters................................................................................53
Table 7.
Safety Laboratory Tests........................................................................................64
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Rationale
Atopic dermatitis (AD), also known as atopic eczema, is a common, chronic, inflammatory 
skin disorder characterized by flaky skin lesions, intense pruritus, and a general deterioration 
in the quality of life.  Over the past 50 years, AD has become more prevalent, especially in 
industrialized, temperate countries such as the United States (US).1,2  Earlier reports indicated 
that, in up to 70% of cases, the disease greatly improves or resolves until late childhood, 
however more recent findings suggest that disease activity remains manifest for a prolonged 
period of time.  Based on a total of 7157 patients enrolled in the Pediatric Eczema Elective
Registry (PEER) study, comprising a total of 22,550 person-years,3 it was concluded that 
symptoms associated with AD seem to persist well into the second decade of a child’s life
and likely longer. At every age, more than 80% of PEER study participants had symptoms of 
AD and/or were using medication to treat their AD.
There are a limited number of treatments available for AD.  Current treatments for AD 
include emollients, topical corticosteroids (eg, betamethasone, clobetasol, fluocinonide), 
topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar preparations. 
Crisaborole was approved as a topical treatment in December 2016 by the Food and Drug 
Administration (FDA) for use in patients with mild to moderate AD. Additional treatments 
generally reserved for severe AD include phototherapy (eg, ultraviolet A light [UVA] with 
or without psoralen, ultraviolet B light [UVB] narrowband or broadband) and systemic 
agents (eg, corticosteroids, cyclosporine, recombinant interferon [IFN] interferon-gamma 
[IFN-], mycophenolate mofetil, methotrexate [MTX], azathioprine, intravenous [IV] 
immunoglobulin).4  Of the currently available therapies, none offers a cure; therefore, the
main aims of existing treatments are to reduce the occurrence of acute flares, to increase the 
time between relapses, and to reduce pruritus and the resulting sleep disturbance.5,6
Other systemic agents to treat AD are under clinical development or recently approved.  
Dupilumab, an injectable human monoclonal antibody targeting interleukin (IL) -4 and -13,
was approved by the FDA in March 2017 and received marketing authorization in Europe in
September 2017, and offers a novel mechanism of action for the treatment of moderate to
severe AD. However, the approved dosing for Dupilumab as an initial dose of 2 × 300 mg
subcutaneous injections followed by 300 mg every other week injections may limit the
desirability of this route of treatment.
Key cytokines implicated in the pathophysiology of AD including IL-4, IL-5, IL-13, IL-22, 
IL-31, and IFN-require Janus kinase 1 (JAK1) for signal transduction; this suggests that 
selective JAK1 inhibitors that modulate the activity of these cytokines represent a compelling 
approach to the treatment of inflammatory skin diseases such as AD.7
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PF-04965842 is an orally bioavailable small molecule that selectively inhibits JAK1 by 
blocking the adenosine triphosphate (ATP) binding site.  PF-04965842 has a high degree of 
selectivity against other kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 
43-fold over tyrosine kinase 2 (TYK2), as well as a good selectivity profile over the broader 
range of human kinases. The selective inhibition of JAK1 will lead to modulation of 
multiple cytokine pathways involved in the pathophysiology of AD, including IL-4, IL-5, 
IL-13, IL-31 and IFN-.  Data from a Phase 2b proof of concept (POC) study (B7451006) 
that evaluated participants with moderate to severe AD have shown positive efficacy, as well 
as an acceptable safety profile, sufficient to support further clinical development in a larger 
Phase 3 program.
Preclinical in vitro inhibition studies showed that the unbound maximum observed 
concentration (Cmax)/ 50% inhibitory concentration (IC50) ratio is 0.24 and 0.13 for multidrug 
and toxic compound extrusion transporter (MATE)1 and MATE2K, respectively, suggesting 
that PF-04965842 has a potential to inhibit these drug transporters in vivo as ratios exceed 
the in vitro regulatory threshold unbound Cmax/IC50 ratio of 0.02.8  Therefore, a clinical 
interaction study with a sensitive MATE1 and MATE2K substrate is needed to assess the 
effect of PF-04965842 on the activity of these transporters.  The primary purpose of this 
study is to assess the effect of PF-04965842 on the in vivo pharmacokinetics (PK) of 
metformin, a sensitive substrate for MATE1 and MATE2K.8  Metformin is also a substrate 
for organic cation transporter (OCT)1 and OCT2. However, PF-04965842 is not an inhibitor 
of OCT2 (Cmax/IC50 ratio is >300) and despite the unbound PF-04965842 Cmax/IC50 ratio for
OCT1 being just above 0.02 (0.03), inhibition of OCT1, a hepatic uptake transporter, is not 
expected to increase plasma metformin exposures as OCT1 does not modulate metformin 
clearance as it is primarily excreted unchanged in urine.  Both MATE1 and MATE2K are 
renal transporters that are expressed in the apical membrane of the renal proximal tubules
thus play an important role in tubular secretion and reabsorption of drug molecules in the 
kidney.  Therefore, significant MATE1/2K inhibition would primarily impact the renal 
clearance of substrates for these transporters with having minimal effects, if any, on plasma 
exposures. 
N1-methylnicotinamide (NMN), a metabolite of niacin, has been reported to be an 
endogenous biomarker for assessing MATE/OCT2 inhibition.  Renal clearance of NMN was 
shown to be reduced by ~70% by pyrimethamine, a potent MATE/OCT2 inhibitor.9  As such, 
NMN is being assessed in this study to further investigate the utility of this endogenous 
substance as a biomarker for MATE activity in comparison to metformin, the gold standard 
for assessing MATE activity in drug-drug interaction (DDI) studies.8
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Objectives and Endpoints
Objectives:
Endpoints:
Primary:
Primary:

To estimate the effect of PF-04965842 on 
MATE1/2K activity via the pharmacokinetic
assessment of a single, oral dose of metformin in 
healthy participants.

Metformin CLr.
Secondary: 
Secondary: 

To evaluate the PK, safety and tolerability of a 
single oral dose of metformin when 
co-administered with PF-04965842.

Metformin AUCinf, Cmax, Tmax, AUClast, CL/F, 
Vz/F, t½, Ae, and Ae%.

Vital signs, laboratory tests and adverse events.
Tertiary/Exploratory: 
Tertiary/Exploratory:

To evaluate the effects of PF-04965842 on 
N1-methylnicotinamide.

To correlate the effects of PF-04965842 on 
N1-methylnicotinamide versus metformin.

To enableexploratory research through the 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.

N1-methylnicotinamide AUC24, Cmax, Ae and 
CLr.

Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
Overall Design
This is a Phase 1, randomized, 2-way crossover, open label study of the effect of 
PF-04965842 on metformin PK in healthy adult participants.  The effect of PF-04965842 on 
NMN PK and its correlation to the effect on metformin PK will also be assessed.  
Participants will be randomized to 1 of 2 treatment sequences as described below.  A total of 
12 healthy male and/or female participants will be enrolled in the study so that 6 participants 
will be enrolled in each treatment sequence.  Each treatment sequence will consist of 
2 periods. Participants who discontinue from the study may be replaced at the sponsor’s 
discretion. The replacement participant will receive the same treatment sequence as the 
participant who discontinued.
Participants will be screened within 28 days of the first dose of investigational product.  
Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1)
dosing in Period 1 for both treatment sequences.  In both sequences, participants will remain 
in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2). To 
adequately remove any drug effects of metformin (plasma half-life ~ 6 hours/whole blood 
half-life ~ 18 hours), there will be a minimum 4-day washout period between 
metformin dosing events from Period 1 to Period 2.  The minimum 3-day washout for 
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PF-04965842 in Sequence 2 is sufficient as the half-life of PF-04965842 is ~3-5 hours.  The 
metformin PK will be assessed over 48 hours.
Number of Participants
A total of approximately 12 healthy male and/or female participants will be enrolled in the 
study so that approximately 6 participants will be enrolled in each treatment sequence. 
Intervention Groups and Duration
Treatment Sequences
Sequence
Period 1
Washout
Period 2
Sequence 1 (N = 6)
Treatment A
At least 4 days from 
metformin administration
Treatment B
Sequence 2 (N = 6)
Treatment B
At least 4 days from 
metformin + PF-04965842
administrationa
Treatment A
Abbreviations: N = number of enrolled participants; QD = once daily.
Treatment A (Reference): Single oral administration of metformin 500 mg on Day 1.
Treatment B (Test): Concomitant single oral administration of metformin 500 mg on Day 1 and oral 
administration of PF-04965842 200 mg QD for 2 days on Days 1-2.
a.
At least a 3-day washout is required from the last dose of PF-04965842.

All treatments administered on Day 1 will be administered following a moderate-fat meal. 
PF-04965842 can be dosed with or without food on Day 2 in Treatment B.
Data Monitoring Committee: No
Statistical Methods
Natural log transformed area under the curve from zero to infinity (AUCinf), area under the 
plasma concentration-time curve from 0 to the time of last measurement (AUClast), maximum 
observed concentration (Cmax) and renal clearance (CLr) of metformin will be analyzed using 
a mixed effect model with sequence, period and treatment as fixed effects and participant 
within sequence as a random effect.  Additionally, area under the plasma concentration-time 
curve from 0 to 24 hours (AUC24), Cmax and CLr of NMN will also be analyzed using a 
mixed effect model with sequence, period and treatment as fixed effects and participant 
within sequence as a random effect.  Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% confidence intervals will be obtained from the 
model.  The adjusted mean differences and 90% confidence intervals for the differences will 
be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% confidence intervals for the ratios.  Metformin alone will be the 
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Reference treatment (Treatment A), while the metformin co-administered with PF-04965842 
will be the Test treatment (Treatment B).
A sample size of 12 participants will provide 90% confidence intervals for the difference 
between treatments of 0.134, 0.161 and 0.148 on the natural log scale for metformin 
AUCinf, Cmax and CLr, respectively, with 80% coverage probability.  The following table 
presents the width of 90% confidence interval for different estimated effects (Table 4):
Sample Size Determination
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
CLr
60%
51.73, 69.60
17.88
70%
60.35, 81.20
20.85
80%
68.97, 92.80
23.83
90%
77.59, 104.40
26.81
100%
86.21, 115.99
29.79
AUCinf
100%
87.47, 114.32
26.84
120%
104.97, 137.18
32.22
160%
139.96, 182.91
42.95
200%
174.94, 228.63
53.69
Cmax
100%
85.10, 117.50
32.39
120%
102.13, 141.00
38.88
160%
136.17, 188.00
51.83
200%
170.21, 235.00
64.79
Abbreviation: CI = confidence interval
These calculations are based on estimates of within participant standard deviations of 0.156, 
0.188 and 0.173 for loge AUCinf, loge Cmax and loge CLr of metformin, respectively, as 
obtained from internal and/or external data in previous clinical studies with metformin.10, 11
1.2. Schema
Not Applicable.
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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section (Section 8) 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.
Table 1.
Schedule of Activities
Visit Identifier
Screening
Period 1
Period 2a
ET
Phone call
Days Relative to Day 1
-28 to -2
-1
1
2
3
4
1
2
3
28-35 days after 
last dose of 
metforminb
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical, Drug, Tobacco and Alcohol History 
X
Complete Physical Examinationc
X
Demography, Height and Weigh
X
Serum FSH (Postmenopausal Females Only)
X
Serum Pregnancy Test (HCG) for WOCBP only
X
X
X
X
Blood sampling for Pfizer Prep D1 banked sample(s)d
X
Urine Drug Screen
X
X
Single 12-Lead ECG
X
Xe
Xe
X
X
Clinical Safety Labs (Blood and Urine) 
X
X
Xf
X
X
Contraception check
X
X
X
X
X
Serology: HIV, HepBsAg, HepBcAb, HepBsAb, 
HCVAb testing
X
QuantiFERON® - TB Gold Test
X
Vital Signs and Oral Temperature
X
Xg
Xg
X
X
Moderate Fat Meal consumed prior to dosing
X
X
Metformin Dosingh
X
X
PF-04965842 Dosing (Sequence 1)
X
X
PF-04965842 Dosing (Sequence 2)
X
X
Metformin PK Blood Sampling 
Xi

Xi
Xi

Xi
Metformin PK Urine Sampling
Xi

Xi
Xi

Xi
NMN PK Blood Sampling 
Xi
Xi
Xi
Xi
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Table 1.
Schedule of Activities
Visit Identifier
Screening
Period 1
Period 2a
ET
Phone call
Days Relative to Day 1
-28 to -2
-1
1
2
3
4
1
2
3
28-35 days after 
last dose of 
metforminb
NMN PK Urine Sampling
Xi
Xi
Xi
Xi
CRU Confinement
X






X
Serious and non-serious Adverse Event Monitoring
X









X
Prior/Concomitant Treatment Assessment
X









X
Abbreviations: = ongoing/continuous event; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; HepBcAb = 
hepatitis B core antibody; HepBsAb = hepatitis B surface antibody; HepBsAg = hepatitis B surface antigen; HCVAb = hepatitis C antibody; HCG = Human Chorionic 
Gonadotropin; HIV = human immunodeficiency virus; hr = hour; NMN = N1-methylnicotinamide; PK = pharmacokinetic; TB = tuberculosis; WOCBP = women of childbearing 
potential.
a.
Day 1 of Period 2 will be at least 4 days after Day 1 of Period 1.
b.
Phone contact to capture any potential AEs and concomitant treatment(s) and to confirm appropriate contraception usage.
c.
After the complete physical examination on Day -1, further examinations will be performed at the discretion of the investigator.
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.
Perform single 12 lead ECG at pre-dose (before meal) and 2 hours post-dose. 
f.
Clinical safety labs will be collected before Period 2 Day 1.
g.
Supine blood pressure, pulse rate and oral temperature pre dose and 2 hr post dose.
h.
Participants will be dosed with metformin following a moderate-fat breakfast at approximately 08:00 AM (±2 hrs).  On the day of co administration of metformin and 
PF-04965842, metformin will be administered with PF-04965842 concomitantly in no specific order, over no more than 5 minutes apart.
i.
See pharmacokinetic sampling schema.  (Table 2).
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Table 2.
Pharmacokinetic Sampling Schema
Visit Identifier
Periods 1 and 2
Day 1
Day 2
Day 
3
Hours After Dose on Day 1
0a
0.5
1
2
4
6
8
12
16
24
36
48
Blood samples for
PK blood sampling for metformin 
Xa
X
X
X
X
X
X
X
X
X
X
X
PK blood sampling for NMN
Xa
X
X
X
X
X
X
X
X
X
Urine samples for
Predose PK spot urine blank
Xa
Start/Stop PK Urine collection for 
metformin concentrationsb,c
X←------- ------- ------- ------- ------- ------ X←------- X←X←
X
Start/Stop PK Urine collection for 
NMNb,d
X←------- ------- ------- ------- ------- ------ X←-------
X
Abbreviations: NMN = N1-methylnicotinamide; PK = pharmacokinetic.
a.
Predose (metformin administration) sample collection.
b.
Each subject will empty his or her bladder just prior to dosing.  Then, all urine voids must be collected in appropriate 
urine collection containers.  Each collection interval should have its own collection container(s).  At the end of the 
urine collection interval, the total volume will be measured and recorded.  The urine will then be mixed thoroughly.  A 
5 mL aliquot will be transferred to an appropriately labeled, screw capped polypropylene tube for NMN analysis.  A 
second 5 mL aliquot will also be collected and analyzed for metformin PK concentrations.
c.
PK urine collection interval for metformin concentration assessment: 0-12, 12-24, 24-36, and 36-48 hours postdose.
d.
PK urine collection interval for NMN concentration assessment: 0-12 and 12-24 hours postdose.
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2. INTRODUCTION
PF-04965842 is a Janus kinase (JAK) 1 inhibitor that is currently being developed for the 
treatment of moderate to severe atopic dermatitis (AD).
2.1. Study Rationale
With in vitro data indicating PF-04965842 may have the potential to inhibit multidrug and 
toxic compound extrusion transporter (MATE)1 and MATE2K, a clinical interaction study is 
needed to assess the effect of PF-04965842 on the activity of these transporters.
The primary purpose of this study is to assess the effect of PF-04965842 on the in vivo 
pharmacokinetics (PK) of metformin, a sensitive substrate for MATE1 and MATE2K. 
2.2. Background 
2.2.1. Mechanism of Action/Indication
The JAK family, including JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), is a group of 
cytoplasmic tyrosine kinases that mediates signal transduction via interactions with Type 1 
and Type 2 cytokine receptors critical for leukocyte activation, proliferation, survival and 
function. Cytokine receptors demonstrate restricted association with JAKs such that different 
receptors or receptor classes preferentially utilize a given JAK dimer or trimer combination 
to transduce their signal.  JAK1 pairs with JAK3 to mediate γ-common cytokine signaling 
and also with JAK2 or TYK2 to transmit the signals of additional cytokines important in 
inflammation and immune responses including interleukin (IL) -4, -5, -6, -13, -21, -31, 
interferon gamma (IFN-γ), and interferon alpha (IFN-α). JAK2 homodimers are critical for 
the signaling of hematopoietic cytokines and hormones including erythropoietin (EPO), IL-3, 
granulocyte-macrophage colony-stimulating factor (GM-CSF) and prolactin. IL-12 and 
IL-23 are dependent on TYK2 and JAK2 for transmitting their signals.
Following cytokine activation, receptor-associated JAKs are phosphorylated, and in turn 
phosphorylate specific sites on the receptor intracellular domain. Phosphorylation of specific 
sites on the intracellular domain of the receptor allows for the recruitment of signal 
transducers and activators of transcription (STATs) that can subsequently be phosphorylated 
by JAKs.7 Phosphorylated STAT molecules are released from the receptor, translocate to the 
nucleus where they bind to specific sites on the deoxyribonucleic acid (DNA) and regulate 
gene transcription.12
Key cytokines implicated in the pathophysiology of AD including IL-4, IL-5, IL-13, IL-22,
IL-31, and IFN-, require JAK1 for signal transduction, suggesting that selective JAK1 
inhibitors, that modulate the activity of these cytokines, represent a compelling approach to 
the treatment of inflammatory skin diseases such as AD.13
PF-04965842 is an orally bioavailable small molecule that selectively inhibits JAK1 by 
blocking the adenosine triphosphate (ATP) binding site.  PF-04965842 has a high degree of 
selectivity against other kinases: 28-fold selectivity over JAK2, >340-fold over JAK3 and 
43-fold over TYK2, as well as a good selectivity profile over the broader range of human 
kinases.  The selective inhibition of JAK1 will lead to modulation of multiple cytokine 
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pathways involved in the pathophysiology of AD, including IL-4, IL-5, IL-13, IL-31 and 
IFN-.  Data from a Phase 2b proof-of-concept (POC) study (B7451006) that evaluated 
participants with moderate to severe AD have shown positive efficacy, as well as an 
acceptable safety profile, sufficient to support further clinical development in a larger 
Phase 3 program.
2.2.2. Overview of Disease State
AD also known as atopic eczema, is a common, chronic, inflammatory skin disorder 
characterized by flaky skin lesions, intense pruritus, and a general deterioration in the quality
of life.  Over the past 50 years, AD has become more prevalent, especially in industrialized, 
temperate countries such as the United States (US).1,2  Earlier reports indicated that, in up to 
70% of cases, the disease greatly improves or resolves until late childhood, however more 
recent findings suggest that disease activity remains manifest for a prolonged period of time.  
Based on a total of 7157 patients enrolled in the Pediatric Eczema Elective Registry (PEER)
study, comprising a total of 22,550 person-years,3 it was concluded that symptoms associated 
with AD seem to persist well into the second decade of a child’s life and likely longer. At 
every age, more than 80% of PEER study participants had symptoms of AD and/or were 
using medication to treat their AD.
There are a limited number of treatments available for AD. Current treatments for AD 
include emollients, topical corticosteroids (eg, betamethasone, clobetasol, fluocinonide), 
topical calcineurin inhibitors (eg, pimecrolimus, tacrolimus), and coal tar preparations.
Crisaborole was approved as a topical treatment in December 2016 by the Food and Drug 
Administration (FDA) for use in patients with mild to moderate AD. In addition, dupilumab, 
an injectable monoclonal antibody targeting IL-4 and IL-13 was recently approved for the 
treatment of AD. Additional treatments generally reserved for severe AD include 
phototherapy (eg, ultraviolet A light [UVA] with or without psoralen, ultraviolet B light 
[UVB] narrowband or broadband) and systemic agents (eg, corticosteroids, cyclosporine, 
recombinant IFN-, mycophenolate mofetil, methotrexate [MTX], azathioprine, intravenous
[IV] immunoglobulin).4  Of the currently available therapies, none offers a cure; therefore, 
the main aims of existing treatments are to reduce the occurrence of acute flares, to increase 
the time between relapses, and to reduce pruritus and the resulting sleep disturbance.5,6
Other systemic agents to treat AD are under clinical development or recently approved.  
Dupilumab, an injectable human monoclonal antibody targeting interleukin (IL) -4 and -13,
was approved by the FDA in March 2017 and received marketing authorization in Europe in
September 2017, and offers a novel mechanism of action for the treatment of moderate to
severe AD. However, the approved dosing for Dupilumab as an initial dose of 2 × 300 mg
subcutaneous injections followed by 300 mg every other week injections may limit the
desirability of this route of treatment.
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2.2.3. Rationale for Development of PF-04965842
PF-04965842 is being developed as an oral treatment for patients with moderate to severe 
AD based on its mechanism of action, and the clinical results obtained in Phase 1 and 
Phase 2 studies.  The clinical development program for PF-04965842 includes healthy 
participants, participants with psoriasis and participants with AD. 
2.2.4. Previous Human Experience with PF-04965842
PF-04965842 has been assessed in 5 completed clinical studies: 3 Phase 1 studies in healthy 
participants (B7451001, B7451004, and B7451008), 1 Phase 2 study in participants with 
psoriasis (B7451005) and 1 Phase 2 study in participants with AD (B7451006). A total of 
423 participants received PF-04965842 or placebo in the 5 completed clinical studies with 
335 participants having received at least 1 dose of PF-04965842 (n=61 in Study B7451001; 
n=12 in study B7451004; n=6 in study B7451008, n=45 in study B7451005; n=211 in Study 
B7451006).
2.2.4.1. Summary of Safety Data from Completed Studies
Based on the clinical experience with PF-04965842 and its mechanism of action, the 
potential risks of treatment with JAK inhibitors include: (1) viral reactivation; (2) serious 
infection and opportunistic infections; (3) malignancy and lymphoproliferative disorders; 
(4) decreased lymphocyte counts; (5) decreased neutrophil counts; (6) decreased platelets;
and (7) alterations in the lipid profile.
In the completed Phase 1 and 2 studies in healthy participants, participants with psoriasis and 
participants with AD, PF-04965842 was generally safe and well tolerated.
In the completed Phase 1 studies in healthy participants receiving single doses of 
PF-04965842 up to 800 mg and multiple doses up to 200 mg twice daily (BID) or 400 mg 
once daily (QD), the most commonly reported adverse events (AEs) were diarrhea, nausea, 
vomiting, headache, acne, and dizziness.  Following single or multiple dose of PF-04965842, 
most reported treatment emergent AEs (TEAEs) were mild or moderate in severity. In study 
B7451001, during the single-ascending dose phase, 1 participant in the placebo group had 
maximum QT interval calculated using Fridericia’s correction factor (QTcF) interval of 
450-<480 msec, and 1 participant in the PF-04965842 800 mg treatment group had 
maximum QTcF interval increase from baseline of 30 to <60 msec.  In the
multiple-ascending dose phase, 3 participants (1 each in the placebo, PF-04965842 30 mg 
QD, and 100 mg QD treatment groups) had maximum QTcF interval of 450-<480 msec, and 
2 participants in the PF-04965842 200 mg BID treatment group had maximum QTcF interval 
increase from baseline of 30 to <60 msec.
In the completed Phase 2 study in participants with moderate to severe psoriasis (B7451005), 
the most frequently reported AEs across the PF-04965842 treatment groups (200 mg BID, 
200 mg QD, and 400 mg QD) were nausea, followed by headache.  Other commonly 
reported AEs include neutropenia and neutrophil counts decreased, thrombocytopenia and 
platelet count decreased.  One of the participants in the 200 mg QD group with an AE 
categorized as infections and infestations was reported as having VIIth nerve paralysis 
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(Bell’s palsy) and later developed herpes zoster (shingles). The incidence of normal and 
abnormal electrocardiogram (ECG) recordings were similar across all treatment groups at 
each time point. None of the abnormal ECG recordings were determined to be clinically 
significant by the investigator.
In the completed 12-week Phase 2b study (B7451006) in participants with AD, AEs and 
serious AEs (SAEs) were numerically higher in participants receiving PF-04965842 (10, 30, 
100, and 200 mg QD) compared to placebo, but did not appear to increase with dose.  The 
most common AEs were in the infections and infestations, skin and subcutaneous tissue 
disorders and gastrointestinal disorders system organ class (SOC), and the majority of the 
AEs were mild. The most commonly reported TEAE across all the treatment groups were 
dermatitis atopic (38 events), and viral upper respiratory tract infection (33 events).  The 
most frequently reported treatment-related TEAE was nausea. There were 2 cases of 
non-serious herpes zoster, one in the 10 mg group (not treatment-related), and one in the 
30 mg group (treatment-related).  There were 2 participants (doses of 100 mg QD) with 
treatment related SAEs reported, the SAEs were Eczema herpeticum and Pneumonia.  One
participant randomized to the PF-04965842 10 mg group reported an SAE of malignant 
melanoma. Dose-dependent mean platelet count decreases from baseline were observed with 
a nadir at Week 4.  At Week 4 the mean platelet count and the 90% confidence interval (CI)
were within the normal reference range for both the 100 mg dose and 200 mg dose. In these 
treatment groups, the mean platelet count increased towards baseline after Week 4.  There 
were no clinically significant findings in vital signs or physical examinations. Most of the 
ECG results were normal.  The incidence of normal and abnormal ECG recordings was 
similar between PF-04965842 and placebo groups at each time point. 
2.2.4.2. Summary of PF-04965842 Pharmacokinetics, Metabolism and In Vitro 
Enzymology
2.2.4.2.1. Single and Multiple Dose Pharmacokinetics
PF-04965842 was absorbed rapidly following single oral solution/suspension doses of 3 mg 
to 200 mg with median time to maximum concentration (Tmax) observed less than 1 hour
(ranging from 0.55 to 0.77 hours), and more slowly at the higher doses with median Tmax of 
1.5 and 4.0 hours for the 400 mg and 800 mg doses, respectively (Study B7451001).  
Following attainment of maximum observed concentration (Cmax), the disposition of 
PF-04965842 generally showed a monophasic decline at the lower doses of 3 to 30 mg (mean 
apparent terminal half life [t½] of 1.9 to 2.5 hours) while a biphasic decline was observed at 
doses of 100 to 800 mg with a mean t½ of 3.6 to 4.9 hours. Plasma PF-04965842 Cmax
appeared to increase proportionally across the entire dose range from 3 mg to 800 mg, while 
increases in the plasma concentration-time area under the curve (AUC) from time 
0 extrapolated to infinity (AUCinf) were greater than proportional at doses of 400 and 800 mg.
For the 2-fold doses increases between 200 to 400 mg and between 400 to 800 mg, the mean 
AUCinf values in Western participants in this study appeared to increase approximately 
3.5- and 2.7-fold, respectively.
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On Day 10 of multiple-dose administration, PF-04965842 was absorbed rapidly with median 
Tmax of about 1 hour or less (ranging from 0.50-1.05 hours) across the entire range of doses, 
from a total daily dose of 30 mg (30 mg QD) up to 400 mg (200 mg BID or 400 mg QD).  
Following attainment of Cmax, the disposition of PF-04965842 was consistent with that 
observed following single-dose administration, showing a biphasic decline following all but 
the lowest dose and a mean terminal t½ of about 2.8 to 5.0 hours.  Plasma Cmax and AUC 
from time 0 to time tau, the dosing interval (AUCtau) both appeared to show a trend towards 
greater than proportional increases at doses higher than 200 mg given once-daily.  Geometric 
mean values for the observed accumulation ratio (Rac), that compares AUCtau for 
multiple-dose administration to AUCtau for single-dose administration, ranged from 1.3 to 
1.5 for QD dosing and 1.3 to 2.3 for BID dosing.  Similar ratios for Cmax comparison (Rac,
Cmax) ranged from 1.1 to 1.3 for QD dosing and from 1.3 to 2.8 for BID dosing.  These
results showed that drug concentration accumulation after repeated oral QD or BID 
administration is less than about 1.5- and 2.3-fold, respectively; at doses up to 200 mg QD, 
the accumulation was minimal and generally consistent with the prediction from t½. 
At a single 800-mg dose, the geometric mean Cmax was similar in Western and Japanese 
participants. However, geometric mean AUCinf was 26% higher in Western participants than 
that observed in Japanese participants.  Geometric mean Cmax and AUCtau following 
multiple-dose administration of 200 mg BID were 17% and 56% higher, respectively, in the 
Western participants than in Japanese participants. 
The urinary recovery of PF-04965842 was low, with <4% of the dose recovered unchanged 
in urine across all doses and regimens in all cohorts in study B7451001.
The bioavailability (BA) of a solid dose formulation of PF-04965842 relative to a suspension 
formulation was evaluated in an open label, single-dose, 3-way crossover study in 12 healthy 
participants under fasting and fed conditions (Study B7451004). Following single oral 
400 mg doses under fasted conditions, Cmax was reached rapidly for the oral suspension 
(median Tmax 0.52 hours) and more slowly for the tablet formulation (4 × 100 mg, median 
Tmax 2.0 hours).  When the tablet was administered under fed conditions, Tmax was further 
delayed with a median value of 4.0 hours.  Mean terminal t½ was 4.9 hours for the oral 
suspension fasted, 5.3 hours for the tablet fasted, and 3.2 hours for the tablet under fed 
conditions.  Relative BA of 4 × 100 mg PF-04965842 tablets compared to 400 mg oral 
suspension under fasted condition was 96.54% and the 90% CI for the ratio 
(tablet/suspension) of adjusted geometric mean AUCinf values was (90.31%, 103.21%), 
within the 80% to 125% interval demonstrating equivalence of total exposure. The ratio 
(90% CI) for Cmax was 79.48% (62.88%, 100.46%).  Administration of 4 × 100 mg 
PF-04965842 tablets with food did not change AUCinf, and appeared to result in slightly 
lower Cmax with reduced variability compared to fasted conditions. The ratio (90% CI) of 
adjusted geometric means for fed/fasted administration was 100.70% (94.42%, 107.40%) for 
AUCinf and 95.56% (76.22%, 119.82%) for Cmax.  The magnitude of decrease in Cmax (<5%) 
was not considered to be clinically important.  Therefore, PF-04965842 can be administered 
with or without food.  There were no clinically significant changes in ECG findings during 
the study.
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2.2.4.2.2. Metabolism and In Vitro Enzymology
In vitro and in vivo metabolite profiling in rat, monkey, and human indicated that the primary 
clearance mechanism for PF-04965842 was cytochrome P450 (CYP450)-mediated oxidative 
metabolism.  No unique human metabolites were observed clinically compared to metabolite 
profiling in rat and monkey.  There was no evidence of chiral inversion in human plasma 
samples.  Plasma profiling from the [14C]PF-04965842 human mass balance study indicated 
parent as the most prevalent circulating species (26%), with 3 major and more polar 
mono-hydroxylated metabolites identified: 340-1 (3-hydroxypropyl, 11%), 
340-2a (2-hydroxypropyl, 12%), and 340-4 (pyrrolidinone pyrimidine, 14%).
In vitro human CYP450 phenotyping studies indicated that CYP2C19 (fraction metabolized 
[fm] ~0.5), CYP2C9 (fm ~0.3), CYP3A4 (fm ~0.1), and CYP2B6 (~0.1) were involved in 
the metabolism of PF-04965842.  Early assessment of clinical genotypes from first-in-human 
(FIH) participants indicated PK variability of all available non-wild-type genotypes 
(CYP2C19*1/*2, *2/*3, *2/*2, *1/*17, and *17/*17; CYP2C9*1/*2, *1/*3) were within the 
variability seen in wild-type CYP2C9*1/*1 and CYP2C19*1/*1 participants. 
PF-04965842 did not inhibit the major CYP enzymes (50% inhibitory concentration [IC50]
values >100 M) by competitive inhibition and did not cause time-dependent inhibition 
without the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH).  In the 
presence of NADPH, PF-04965842 caused relatively weak time-dependent inhibition of 
CYP2C19 (IC50, 42 M), CYP2D6 (IC50, 92 M), and CYP3A4/5 (IC50, 40 to 81 M).
PF-04965842 concentration dependently induced CYP3A4 messenger ribonucleic acid 
(mRNA) in 2/3 hepatocyte lots at 10 M and CYP2B6 mRNA in 3/3 hepatocyte lots at 
10 M.  Enzyme activity of CYP2B6 increased >2-fold at 30 M in 1 of 3 lots of 
hepatocytes.  Conversely, PF-04965842 caused a concentration-dependent decrease in 
CYP3A4 and CYP1A2 enzyme activities in 3/3 hepatocyte lots. Clinically, PF-04965842 PK
showed apparent dose proportionality of single and multiple daily doses up to 200 mg, with 
no significant changes (~ <20%) in the CYP3A plasma biomarker 
4β-hydroxycholesterol/cholesterol ratio following 10 days of dosing (Study B7451001).  
Preliminary SimCYPmodelling of PF-04965842 dosed 200 mg QD for 10 days indicated a 
low risk of precipitating a significant drug interaction with midazolam (CYP3A), buproprion 
(CYP2B6), or mephenytoin (CYP2C19). 
PF-04965842 did not inhibit the major uridine diphospho-glucuronosyltransferase (UGT)
enzymes; all IC50 values >100 M.  PF-04965842 was not a substrate for organic anion 
transporting polypeptide (OATP) 1B1 or OATP1B3, nor inhibited these transporters (IC50
values >300 M).  PF-04965842 did not inhibit organic anion transporter (OAT) 1 
(IC50 >300 M) or organic cation transporter (OCT) 2 (IC50 >300 M), but weekly inhibited 
OAT3 (IC50 = 26 M), multi-drug resistance 1 (MDR1) (IC50 = 100 M), OCT1 
(IC50 = 44 M), and showed some inhibitory activity of breast cancer resistance protein 
(BCRP) (IC50 = 9.8 M), MATE1 (IC50 = 5.5 M), and MATE2K (IC50 = 10.7 M).  
Clinically, PF-04965842 did not significantly affect 24 hour (hr) urinary creatinine (OCT2 
and MATE1/2K substrate) up to doses of 800 mg (Study B7451001).  Preliminary SimCYP
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modelling of PF-04965842 dosed at 200 mg QD indicated a low risk of precipitating a 
significant drug interaction with metformin (OCT2/MATE substrate) or digoxin (MDR1 
substrate).
2.2.4.2.3. Population Pharmacokinetics
Population PK analysis was conducted by pooling data from 2 Phase 1 studies (B7451001, 
and B7451004) in healthy participants and the POC study (B7451006) in AD patients.  A
total of 2465 PK observations from 354 participants were included in the analysis and the 
data were described using a 2 compartment model with first-order absorption.  The estimates 
of apparent clearance (CL/F), apparent central volume of distribution (Vc/F) and apparent 
peripheral volume of distribution (Vp/F) were 44.8 L/hr, 147 L and 20.8 L, respectively.  The 
apparent clearance of PF-04965842 in AD patients was estimated to be ~38% lower than that 
in healthy participants.  Baseline body weight, race, age and sex were tested as covariates on 
clearance and did not appear to impact the PK of PF-04965842.
2.3. Benefit/Risk Assessment
PF-04965842 and metformin are 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.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of PF-04965842 may be found in the investigator’s brochure 
(IB), which is the single reference safety document (SRSD) for this study.  The SRSD for 
metformin is the GLUCOPHAGEBelgian summary of product characteristics (SmPC).14
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 

To estimate the effect of PF-04965842 on 
MATE1/2K activity via the pharmacokinetic
assessment of a single, oral dose of metformin in 
healthy participants.

Metformin CLr.
Secondary: 
Secondary: 

To evaluate the PK, safety and tolerability of a 
single oral dose of metformin when 
co-administered with PF-04965842.

Metformin AUCinf, Cmax, Tmax, AUClast, CL/F, 
Vz/F, t½, Ae, and Ae%.

Vital signs, laboratory tests and adverse events.
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Tertiary/Exploratory: 
Tertiary/Exploratory:

To evaluate the effects of PF-04965842 on 
N1-methylnicotinamide.

To correlate the effects of PF-04965842 on 
N1-methylnicotinamide versus metformin.

To enable exploratory research through the 
collection of banked biospecimens, unless 
prohibited by local regulations or ethics 
committee decision.

N1-methylnicotinamide AUC24, Cmax, Ae and 
CLr.

Potential results from exploratory analysis of 
banked biospecimens (these results may or may 
not be generated in the context of the present 
study).
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, randomized, 2-way crossover, open label study of the effect of 
PF-04965842 on metformin PK in healthy adult participants.  The effect of PF-04965842 on 
N1-methylnicotinamide (NMN) PK and its correlation to the effect on metformin PK will 
also be assessed.
A total of approximately 12 healthy male and/or female participants will be enrolled in the 
study so that approximately 6 participants will be enrolled in each treatment sequence.  Each 
treatment sequence will consist of 2 periods. Participants who discontinue from the study 
may be replaced at the sponsor’s discretion. The replacement participant will receive the 
same treatment sequence as the participant who discontinued.
Participants will be screened within 28 days of the first dose of investigational product.  
Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie Day -1)
dosing in Period 1 for both treatment sequences.  In both sequences, participants will remain 
in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2). To 
adequately remove any drug effects of metformin (plasma half-life ~ 6 hours/whole blood 
half-life ~ 18 hours) from Period 1 to Period 2, there will be a minimum 4-day washout 
period between 2 dosing events.  The minimum 3-day washout for PF-04965842 in Sequence 
2 is sufficient as the half-life of PF-04965842 is ~3-5 hours.  The metformin PK will be 
assessed over 48 hours.  Participants will be assigned to one of the following 2 treatment
sequences (Table 3):
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Table 3.
Treatment Sequences
Sequence
Period 1
Washout
Period 2
Sequence 1 (N = 6)
Treatment A
At least 4 days from 
metformin administration
Treatment B
Sequence 2 (N = 6)
Treatment B
At least 4 days from 
metformin + PF-04965842
administrationa
Treatment A
Abbreiviation: N = number of enrolled participants; QD = once daily.
Treatment A (Reference): Single oral administration of metformin 500 mg on Day 1.
Treatment B (Test): Concomitantly single oral administration of metformin 500 mg on Day 1 and oral 
administration of PF-04965842 200 mg QD for 2 days on Days 1-2.
a.
At least a 3 day washout is required from the last dose of PF-04965842.

All treatments administered on Day 1 will be administered following a moderate-fat meal. 
PF-04965842 can be dosed with or without food on Day 2 in Treatment B.
4.2. Scientific Rationale for Study Design
In preclinical in vitro inhibition studies, the potential for PF-04965842 to inhibit MATE1 and 
MATE2K was assessed.  A steady-state total Cmax of PF-04965842 was 3.7 M (1199 
ng/mL) at a maximum clinical dose of 200 mg daily and unbound Cmax/IC50 ratio is 0.24 and 
0.13 for MATE1 and MATE2K, respectively, suggesting that PF-04965842 has a potential to 
inhibit these drug transporters in vivo as ratios exceed the in vitro regulatory threshold 
unbound Cmax/IC50 ratio of 0.02.8
Therefore, a clinical interaction study with a sensitive MATE1 and MATE2K substrate is 
needed to assess the effect of PF-04965842 on the activity of these transporters.  The primary 
purpose of this study is to assess the effect of PF-04965842 on the in vivo pharmacokinetics 
(PK) of metformin, a sensitive substrate for MATE1 and MATE2K.8  Metformin is also a 
substrate for organic cation transporter (OCT)1 and OCT2 however PF-04965842 is not an 
inhibitor of OCT2 (Cmax/IC50 ratio is >300) and despite the unbound PF-04965842 Cmax/IC50
ratio for OCT1 is just above 0.02 (0.03), inhibition of OCT1, a hepatic uptake transporter, is 
not expected to increase plasma metformin exposures as OCT1 does not modulate metformin 
clearance as it is primarily excreted unchanged in urine.  Both MATE1 and MATE2K are 
renal transporters that are expressed in the apical membrane of the renal proximal tubules
thus play an important role in tubular secretion and reabsorption of drug molecules in the 
kidney.  Therefore, significant MATE1/2K inhibition would primarily impact the renal 
clearance of substrates for these transporters with having minimal effects, if any, on plasma 
exposures.
NMN, a metabolite of niacin, has been reported to be an endogenous biomarker for assessing 
MATE/OCT2 inhibition.  Renal clearance of NMN was shown to be reduced by ~70% by 
pyrimethamine, a potent MATE/OCT2 inhibitor.9  As such, NMN is being assessed in this 
study to further investigate the utility of this endogenous substance as a biomarker for MATE
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activity in comparison to metformin, the gold standard for assessing MATE activity in DDI 
studies.8
Preliminary SimCYPmodelling of PF-04965842 dosed at 200 mg QD indicated a low risk 
of precipitating a significant drug interaction with metformin, a MATE1 and MATE2K
substrate.  Additionally, PF-04965842 did not significantly affect 24 hour urinary creatinine 
(a MATE1/2K and OCT2 substrate) up to doses of 800 mg in clinical studies.
Banked biospecimens will be collected for exploratory 
pharmacogenomic/genomic/biomarker analyses and retained in the Biospecimen Banking 
System (BBS), which makes it possible to better understand the investigational product’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.
4.3. Justification for Dose
An oral dose of 200 mg QD PF-04965842 and a single oral dose of metformin 500 mg will 
be used in this study.
An oral dose of 200 mg QD PF-04965842 for 2 days will be used as it is the highest dose and 
administration frequency being evaluated in the Phase 3 AD program. Drug concentration 
accumulation of PF-04965842 is minimal after repeated oral administration at doses lower 
than 200 mg BID, consistent with the prediction from the short half-life. PF-04965842 also 
displays linear PK at the 200 mg dose with no evidence of mechanism-based inhibition. Oral 
doses of PF-04965842 as high as 800 mg (single dose), 400 mg QD and 200 mg BID (up to 
10 days) have been found to be safe and well tolerated. Based on the safety data of 
PF-04965842 and prior clinical experience as described above, administration of 
PF-04965842 200 mg QD for 2 days is expected to pose little risk to healthy adult 
participants. 
Metformin is approved to improve glycemic control in adults and pediatric patients 10 years 
of age and older with type 2 diabetes mellitus.  An oral dose of 500 mg of metformin will be 
used in this study as this is the lowest approved single dose used in clinical practice and will 
provide metformin exposures at the lower end of clinically-relevant metformin doses in the 
even that metformin exposures are increased in the presence of PF-04965842.  The most 
common adverse reactions (>5.0%) in clinical studies following multiple dose administration 
of metformin were diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal 
discomfort, and headache with the risk of adverse events likely to be lower with a single dose 
administration.  Thus, a single 500 mg dose of metformin is anticipated to be safe and 
generally well-tolerated in healthy participants.
The absolute bioavailability of a metformin 500 mg tablet given under fasting conditions is 
approximately 50% to 60%.  After oral administration of a single 500 mg dose of metformin
in healthy participants, Cmax occurs at approximately 3 hour post administration in the fasted 
state. Studies using single oral doses of metformin 500 to 1500 mg and 850 to 2550 mg, 
indicate that there is a lack of dose proportionality with increasing doses, which is due to 
decreased absorption rather than an alteration in elimination.  Intravenous single-dose studies 
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in normal subjects demonstrate that metformin is excreted unchanged in the urine and does 
not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary 
excretion.  Renal clearance is approximately 3.5 times greater than creatinine clearance, 
which indicates that tubular secretion is the major route of metformin elimination.  Following 
oral administration, approximately 90% of the absorbed drug is eliminated via the renal route 
within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours.  In 
blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte 
mass may be a compartment of distribution.14, 15
Metformin will be administered following consumption of a moderate fat meal as metformin 
is administered with food, in standard clinical practice, to improve its tolerability.  Food 
decreases the extent of absorption of metformin and slightly delays its absorption, as shown 
by an approximate 40% lower mean Cmax, 25% lower AUC, and a 35-minute prolongation of 
Tmax following administration of a single 850 mg tablet of metformin with food, compared to 
the same tablet strength administered fasting.14, 15  Administration of 4 × 100 mg 
PF-04965842 tablets (400 mg) with food did not change AUCinf, and appeared to result in 
slightly lower Cmax with reduced variability compared to fasted conditions. As such, 
PF-04965842 will also be administered with a moderate fat meal during co-administration 
with metformin and can be administered with or without food when dosed on Day 2.
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 contact phone call.
The end of the study is defined as the date of the last scheduled procedure shown in the 
schedule of activities of the last participant in the study.
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 informed consent document (ICD).
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
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including a detailed medical history, complete physical examination, 
laboratory tests, and cardiovascular tests.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4. Female participants who are of child-bearing potential must not be intending to 
become pregnant, currently pregnant, or lactating.  The following conditions apply: 
a.
Female participants of childbearing potential must have a confirmed negative 
pregnancy test prior to treatment with investigational product;
b. Female participants of childbearing potential must agree to use a highly effective 
method of contraception (as per Appendix 4 Section 10.4.4) for the duration of 
the active treatment period and for at least 28 days after the last dose of 
investigational product. 
5. Female participants of non-childbearing potential (as defined per Section 10.4.3). 
Weight:
6. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg 
(110 lb).
Informed Consent:
7. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic (including alcoholic liver disease, 
nonalcoholic steatohepatitis (NASH), autoimmune hepatitis, and hereditary liver 
diseases), psychiatric, neurological, or allergic disease (including drug allergies, but 
excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
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2. Any condition possibly affecting drug absorption (eg, gastrectomy).
3. History of human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C
virus infection; positive testing for HIV, hepatitis B surface antigen (HepBsAg), 
hepatitis B core antibody (HepBcAb), or hepatitis C virus antibody (HCVAb).
As an exception, a positive hepatitis B surface antibody (HepBsAb) as a result of 
participant vaccination is permissible.
4. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
5. Evidence or history of clinically significant dermatological condition (eg, atopic
dermatitis or psoriasis) or visible rash present during physical examination.
6. Clinically relevant history of lactic acidosis.
Prior/Concomitant Therapy:
7. 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 
investigational product.  (Refer to Section 6.5 for additional details).
Prior/Concurrent Clinical Study Experience:
8. 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 investigational 
product used in this study (whichever is longer). 
Diagnostic Assessments:
9. A positive urine drug test.
10. Screening supine systolic blood pressure (BP) <90 mm Hg or 140 mm Hg following 
at least 5 minutes of supine rest OR
Screening supine diastolic BP <50 mm Hg or 90 mm Hg following at least 
5 minutes of supine rest.
If a participant meets any of these criteria, 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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11. Screening supine 12-lead ECG demonstrating:

QTcF >450 msec OR

QRS interval >120 msec.
12. If QTcF exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 
2 more times and the average of the 3 QTcF or QRS values should be used to 
determine the participant’s eligibility.  Computer-interpreted ECGs should be 
overread by a physician experienced in reading ECGs before excluding participants.
13. 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: 

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT) level 1.5 × upper limit of normal (ULN).

Total bilirubin level >1.0 × 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 1.0 × ULN.

Prothrombin Time (PT)/International Normalized Ratio (INR) or partial 
thromboplastin time (PTT)/activated partial thromboplastin time (aPTT)
>1.0 × ULN.

Estimated creatinine clearance <90 mL/min (see Appendix 2 for Cockcroft-Gault 
formula).
Other Exclusions:
14. History of regular alcohol consumption exceeding 14 drinks/week for female 
participants or 21 drinks/week for male participants (1 drink = 5 ounces [150 mL] of 
wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 
months before screening.
15. Known relevant history of elevated liver function tests (LFTs).
16. History of tuberculosis (TB) (active or latent) or inadequately treated TB infection.  
Positive QuantiFERON– TB Gold test. 
17. Any history of chronic infections, any history of recurrent infections, any history of
latent infections, or any acute infection within 2 weeks of baseline. 
18. History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent 
localized dermatomal herpes zoster. 
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19. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
20. Use of tobacco- or nicotine- containing products in excess of the equivalent of
5 cigarettes per day.
21. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to first dose of investigational product.
22. History of hypersensitivity to metformin.
23. Unwilling or unable to comply with the criteria in the Section 5.3 of this protocol.
24. Have any malignancies or have a history of malignancies with the exception of 
adequately treated or excised non-metastatic basal cell or squamous cell cancer of the 
skin, or cervical carcinoma in situ. 
25. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
5.3. Lifestyle Considerations
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 safety laboratory evaluations.

Water is permitted until 1 hour prior to investigational product administration (with 
exception of water served during breakfast).  Water may be consumed without 
restriction beginning 1 hour after metformin or PF-04965842 dosing on Day 1.  
Noncaffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices—see 
below) may be consumed with meals and the evening snack.

A moderate fat meal (breakfast) will be provided 30 minutes before dosing and will 
be consumed up to at least 10 minutes prior to administration of metformin and/or 
PF-04965842 on Day 1.  The caloric intake of a moderate fat breakfast should be 
approximately 840 kcal of which approximately 50% of its composition (400-
440 kcal) should come from fat.

On Day 2 (Treatment B), PF-04965842 can be dosed with or without food. 

Food may be consumed without restriction beginning 4 hours after dosing on Day 1 
of each Period.  No restriction to breakfast on the other days provided other 
restrictions are followed.
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
Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of investigational product until collection of the final PK blood sample. 

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.
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 clinical 
research unit (CRU) and continue abstaining from alcohol until collection of the final 
PK sample of each 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.
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, pulse rate, and 
ECG measurements), eating, and 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 her/his partner from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4 will confirm that the participant has been instructed in its 
consistent and correct use.  At time points indicated in the schedule of activities (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 
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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 investigational product/entered in the study.
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, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
For this study, the investigational products are PF-04965842 (provided as 100 mg tablets)
and metformin (provided as 500 mg tablets).
PF-04965842 100 mg tablets will be supplied to the CRU in bulk along with individual 
dosing containers for unit dosing.
Commercially available metformin (GLUCOPHAGE®) will be acquired from an 
external/local supplier as 500 mg tablets. The CRU will ensure that all containers of 
metformin tablets to be used in the study are from the same lot.
6.1.1. Administration
Administration of investigational product will be carried out according to the conditions 
described in the Section 1.3 and Section 5.3.1 of this protocol.
For Treatment A, following consumption of a moderate fat meal (provided 30 minutes prior 
to administration), participants will receive metformin at approximately 08:00 AM
(±2 hours), followed by intake of approximately 240 mL of ambient temperature water. 
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For Treatment B, following consumption of a moderate fat meal (provided 30 minutes prior 
to administration), the PF-04965842 200 mg dose and metformin 500 mg dose will be 
concomitantly administered, in no specific order, over no more than 5 minutes at 08:00 AM
± 2 hours with ambient temperature water to a total volume of approximately 240 mL.  The 
second dose of PF-04965842 200 mg administered approximately 24 hours after the 
administration of the first dose will be administered with or without food. 
Participants will swallow the investigational product whole, and will not manipulate or chew 
the investigational product prior to swallowing. 
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention.  All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). All study 
interventions (PF-04965842 oral tablets and metformin oral tablets) will be accounted 
for using an investigational product accountability form/record.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
5. Study interventions should be stored in their original containers and in accordance 
with the labels. PF-04965842 investigational product and metformin 500 mg tablets
should be stored in its original container and in accordance with the label. See the 
Belgian SmPC for GLUCOPHAGE® for storage conditions of metformin.
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6. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention
must be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use 
of the study intervention after the temperature excursion. Use of the study 
intervention prior to Pfizer approval will be considered a protocol deviation. Specific 
details regarding the definition of an excursion and information the site should report 
for each excursion will be provided to the site by the sponsor or designee.
7. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the participant by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, or to a participant in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.
PF-04965842 tablets will be prepared at the CRU in the individual dosing containers by 
2 operators, one of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist).  The tablets will be provided in unit dose containers and 
labeled in accordance with Pfizer regulations and the clinical site’s labeling requirements.
Metformin tablets will be packaged at the CRU in the individual dosing containers by 
2 operators, one of whom is an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
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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.
6.4. Study Intervention Compliance
Investigational product will be administered under the supervision of qualified investigator 
site personnel.  The oral cavity of each participant will be examined following dosing to 
ensure the investigational product was taken.
6.5. Concomitant Therapy
Participants will abstain from all concomitant treatments, except for the treatment of 
AEs. Limited use of non-prescription medications that are not believed to affect participant’s
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.
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.
Treatments taken within 28 days before the first dose of investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of investigational 
product will be documented as concomitant treatments, while hormonal contraception will 
not be allowed.
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.  (see Appendix 4).
6.5.1. Rescue Medicine
There is no rescue therapy to reverse the adverse events (AEs) observed with PF-04965842
and/or metformin; standard medical supportive care must be provided to manage the AEs. 
6.6. Dose Modification
Dose modification is not allowed in this study. 
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
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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 
investigational product.  If investigational product is permanently discontinued, the 
participant will not remain in the study.  See the Table 1 for data to be collected at the time of 
discontinuation of investigational product.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are randomized and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  The participant will be permanently discontinued both from the study 
intervention and from the study at that time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) for 
disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the case report form (CRF) and reported on the Clinical Trial (CT) SAE Report.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
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Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the 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. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
Participants will be screened within 28 days prior to administration of the investigational 
product to confirm that they meet the study population criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) must obtain a signed and dated ICD
before performing any study-specific procedures.  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.
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A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study.  In 
addition, other clinical assessments or specimen collections, eg, banked biospecimens, may 
be used without repeat collection, as appropriate. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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.
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 participant in this study is approximately 
185 mL for both Sequence 1 and Sequence 2.  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 
Section 5.3 and Section 6.5 of the protocol.
8.1. Efficacy Assessments
Not applicable.
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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
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 and pulse rate will be measured at times specified in the Table 1 of this protocol.  
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the 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 pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
8.2.2.1. Temperature
Temperature will be measured orally.  No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.2.3. Electrocardiograms
Single 12-Lead ECGs should be collected at times specified in the Table 1 of this protocol.
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All scheduled ECGs should be performed after the participant has rested quietly for at least 
10 minutes in a supine position.  Supine body position with fully lowered headrest should be 
consistently maintained for each ECG performed.  Environmental distractions in the clinic 
(TV, radio, conversation) and other study procedures (eg, BP measurement, PK sampling) 
during both the pre-ECG rest and the ECG recording period must be minimized.  In 
particular, changes in heart rate should be avoided.  Whenever the nominal time points for 
different procedures coincide, the ECGs should always be collected prior to any other 
procedures (including vital signs and blood collection).  ECGs should not be collected 
approximately within 2 hours of a meal in order to avoid the effect of food intake on the 
ECG.  The time of meals must be standardized (15 minutes) between study days and study 
periods (see also the Section 5.3).
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements from the current period. Additional ECG monitoring 
will occur if a) a postdose corrected QT interval (QTc) interval is increased by 30 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.
If a postdose QTc interval remains 30 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 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). 
Special attention should be given to ensure identical ECG lead placement during every 
measurement.  In some cases, it may be appropriate to repeat abnormal ECGs to rule out 
improper lead placement as contributing to an observed ECG abnormality.  The lead to be 
used for interval measurements should be pre-specified; baseline and on-treatment 
measurements should be using the same lead.
In this study, a semi-automated approach to ECG acquisition will be used.  This technique 
uses a computer algorithm for the initial placement of reference marks on the waveforms to 
note where on the tracing the computer is making its measurements.  A standard 
semi-automated algorithm will be used so that a limited number of CRU staff will review 
program-determined interval onsets and offsets and modify using digital calipers on the rare 
occasion when this is necessary.  This review must be performed by an appropriately 
qualified member of CRU staff.  Use of this semi-automated algorithm is designed to further 
improve the validity of the automated ECG readout by reducing the variability associated 
with interpretation of the ECG waveform.  This approach can have the advantage of greater 
consistency and reproducibility than fully manual readings, while providing an opportunity to 
correct any mistakes made by the algorithmic methods.  Recent evidence suggests that 
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automated techniques are capable of detecting small changes in the QTc similar to those with 
manual readings and with the same conclusion.
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.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
Participants may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for participants to receive 
investigational product. 
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 women of childbearing potential 
(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 
investigational product.  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 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations.
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8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study intervention (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
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 investigational product), through and including 
a minimum of 28 calendar days after the last administration of the investigational product.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF), not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
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SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study intervention and until 28 days after the last dose.
If a pregnancy is reported, the investigator should inform the sponsor within [24 hours] of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
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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 investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-04965842 greater than 8 × 100 mg tablets within a 24-hour 
time period [12 hours] or administering 4 tablets per day for 4 consecutive days will be 
considered an overdose.
The Sponsor does not recommend specific treatment for an overdose for PF-04965842.  
Observation and if required, supportive care would be expected.
Any dose of metformin greater than 5 × 500 mg capsules within a 24-hour time period 
[12 hours] will be considered an overdose.
Hemodialysis may be considered for removal of accumulated metformin from participants 
and may be used in case of overdose.  Please see the GLUCOPHAGEBelgian SmPC for 
further information.
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-04965842 or metformin can no longer be detected systemically (at least 3 days).
3. Obtain a blood sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
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 
8.5.1. Plasma for Metformin Analysis
Blood samples of approximately 3 mL, to provide approximately 1 mL plasma, will be 
collected into appropriately labeled tubes containing tripotassium ethylenediaminetetraacetic 
acid (K3EDTA) for measurement of plasma concentrations of metformin as specified in the 
Table 1 and Table 2.
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 (eg, within 6 minutes of a 60-minute sample) 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 data collection tool (eg, 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 data collection tool (eg, CRF/DCT).
8.5.2. Urine for Metformin Analysis
Urine samples will be collected at times specified in the Table 1 and Table 2.  Each subject 
will empty his or her bladder just prior to dosing.  All urine voids must be collected in 
appropriate urine collection containers.  Each collection interval should have its own 
collection container(s).  At the end of the urine collection interval, the total volume will be 
measured and recorded.  The urine will then be mixed thoroughly and a 5 mL aliquot will be 
collected for measurement of metformin PK.
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.
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Further detail instructions for the collection,handling, aliquoting, storage, and shipping of PK
plasma and urine samples will be provided in the laboratory manual or by the sponsor.
Samples collected for measurement of plasma and urine concentrations of metformin will be 
analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
The plasma and urine samples may be used for exploratory analysis and/or evaluation of the 
bioanalytical method.  These data will be used for internal exploratory purposes and will not 
be included in the clinical study report (CSR).
8.6. Pharmacodynamics
Pharmacodynamic (PD) 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
Banked biospecimens will be collected for exploratory 
pharmacogenomic/genomic/biomarker analyses and retained in the Biospecimen Banking 
System (BBS), which makes it possible to better understand the investigational product’s 
mechanism of action and to seek explanations for differences in, for example, exposure, 
tolerability, safety, and/or efficacy not anticipated prior to the beginning of the study.
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 drug response. Genes and other 
analytes (eg, proteins, ribonucleic acid (RNA), nondrug metabolites) may be studied using 
the banked samples. 
Unless prohibited by local regulations or IRB/EC decision, participants will be asked to 
indicate on the consent document whether they will allow their banked biospecimens to also 
be used to design and conduct research in order to gain a further understanding of other 
diseases and to advance science, including development of other medicines for patients.  This 
component of the sampling banking is optional for participants; they may still participate in 
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the study even if they do not agree to the additional research on their banked biospecimens.  
The optional additional research does not require the collection of any further samples.
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in the laboratory manual.
8.8. Biomarkers
8.8.1. Plasma for NMN Analysis
Blood samples of approximately 3 mL, to provide approximately 1 mL plasma, will be 
collected into appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic 
acid (K2EDTA) for measurement of plasma concentrations of NMN as specified in the Table 
1 and Table 2. 
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 (eg, within 6 minutes of a 60-minute sample) 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 data collection tool (eg, 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 data collection tool (eg, CRF/DCT).
8.8.2. Urine for NMN Analysis
Urine samples will be collected at times specified in the Table 1 and Table 2.  Each subject 
will empty his or her bladder just prior to dosing.  All urine voids must be collected in 
appropriate urine collection containers.  Each collection interval should have its own 
collection container(s).  At the end of the urine collection interval, the total volume will be 
measured and recorded.  The urine will then be mixed thoroughly and a 5 mL aliquot will be 
collected for measurement of NMN PK.
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.
Further detail instructions for the collection, handling, aliquoting, storage, and shipping of 
PK plasma and urine samples will be provided in the laboratory manual or by the sponsor.
Samples collected for measurement of plasma and urine concentrations of NMN will be 
analyzed using a validated analytical method in compliance with applicable standard 
operating procedures (SOPs).
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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.
The plasma and urine samples may be used for exploratory analysis and/or evaluation of the 
bioanalytical method.  These data will be used for internal exploratory purposes and will not 
be included in the clinical study report (CSR).  The plasma and urine samples may be stored 
at a facility selected by the sponsor for a maximum of 3 years (or according to local 
regulations) following the last participant’s last visit for the study.
8.8.3. Other Biomarkers
Leftover plasma and urine samples could be used to assess concentrations of endogenous 
biomarkers for OCT1, OCT2, MATE1, and/or MATE2K.
8.9. 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 statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Statistical Hypotheses
No formal inferential statistics will be applied to the safety or PK data.
9.2. Sample Size Determination
A sample size of 12 participants will provide 90% confidence intervals for the difference 
between treatments of 0.134, 0.161 and 0.148 on the natural log scale for metformin 
AUCinf, Cmax and CLr, respectively, with 80% coverage probability.  The following table 
presents the width of 90% confidence interval for different estimated effects (Table 4):
Table 4.
Sample Size Determination
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
CLr
60%
51.73, 69.60
17.88
70%
60.35, 81.20
20.85
80%
68.97, 92.80
23.83
90%
77.59, 104.40
26.81
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100%
86.21, 115.99
29.79
AUCinf
100%
87.47, 114.32
26.84
120%
104.97, 137.18
32.22
160%
139.96, 182.91
42.95
200%
174.94, 228.63
53.69
Cmax
100%
85.10, 117.50
32.39
120%
102.13, 141.00
38.88
160%
136.17, 188.00
51.83
200%
170.21, 235.00
64.79
Abbreviation: CI = confidence interval
These calculations are based on estimates of within participant standard deviations of 0.156, 
0.188 and 0.173 for loge AUCinf, loge Cmax and loge CLr of metformin, respectively, as 
obtained from internal and/or external data in previous clinical studies with metformin.10, 11
Participants who discontinued from the study may be replaced at the sponsor’s discretion.
9.3. Populations for Analysis
Population
Description
Enrolled 
All participants who sign the ICD.
Randomly assigned to 
investigational product
Participants will be randomized to 1 of 2 treatment sequences in 
a 2-way crossover design.  A total of 12 healthy participants will 
be enrolled in the study so that 6 participants will be enrolled in 
each treatment sequence.
PK Population
The pharmacokinetic (PK) concentration population is defined 
as all enrolled subjects who received at least 1 dose of 
metformin and in whom at least 1 plasma concentration value is 
reported.
Safety Population
All participants randomly assigned to investigational product
and who take at least 1 dose of investigational product.  
Participants will be analyzed according to the product they 
actually received.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in 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 secondary endpoints.
9.4.1. Efficacy Analyses
An efficacy analysis is not applicable to this study. 
9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.
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AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants.  Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described.  Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination 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.
9.4.2.1. 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.
The number (%) of participants with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment (Table 5): 
Table 5.
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
Abbreviation: msec = millisecond
In addition, the number of participants with uncorrected QT values >500 msec will be 
summarized.
9.4.3. Other Analyses 
Pharmacogenomic (PGx) and endogenous biomarker PK data, other than NMN, will be 
collected and retained for potential future analyses, but will not be analyzed, specifically, for 
this study.
9.4.4. Pharmacokinetic Analyses
9.4.4.1. Analysis of Population
The PK concentration population is defined as all participants randomized and treated who 
have at least 1 concentration in at least 1 treatment period.
The PK parameter analysis population is defined as all participants randomized and treated 
who have at least 1 of the PK parameters of primary interest in at least 1 treatment period.
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9.4.4.2. Derivation of Pharmacokinetic Parameters Prior to Analysis
PK parameters for metformin and NMN will be derived from the plasma concentration-time 
profiles and urine concentrations as shown below in Table 6.
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Table 6.
Derivation of PK Parameters
Parameter
Definition
Method of Determination
Analyte
AUC24
Area under the plasma 
concentration-time profile from 
time zero to 24 hours
Linear/Log trapezoidal method.
N
AUClast
Area under the plasma 
concentration-time profile from 
time zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method.
N, M
AUCinf
a
Area under the plasma 
concentration-time profile from 
time zero extrapolated to infinity 
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable time 
point estimated from the log-linear 
regression analysis.
M
Cmax
Maximum plasma concentration
Observed directly from data.
N, M
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence.
N, M
t½
a
Terminal elimination 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.  Only 
those data points judged to describe the 
terminal log-linear decline will be used in 
the regression.
M
CL/F
Apparent clearance for 
extravascular dosing 
Dose/AUCinf.
M
V/F
Apparent volume of distribution 
for extravascular dosing
Apparent volume of distribution, estimated 
from terminal phase, for extravascular 
dosing.
M
Ae
Cumulative amount of drug 
recovered unchanged in urine
Sum of amount excreted for each collection 
period (Urine Concentration * Volume of 
Urine).
N, M
Ae%
Cumulative amount of drug 
recovered unchanged in urine, 
expressed as percent of dose
100 × (Ae/Dose).
M
CLr
Renal clearance
Ae/AUC.
N, M
Abbreviations: N = N1-methylnicotinamide; M = metformin; PK = pharmacokinetic.
a.
If data permit.
Actual PK sampling times will be used in the derivation of PK parameters.
PK parameters in Table 6 will be summarized descriptively by analyte and by treatment, as 
applicable, in accordance with Pfizer Data Standards.  Concentrations will be listed and 
summarized descriptively by analyte, nominal PK sampling time and treatment.  Individual 
subject and median profiles of the plasma concentration-time data will be plotted by 
treatment using actual and nominal times, respectively.  Median profiles will be presented on 
both linear-linear and log-linear scales.  Individual changes from baseline for metformin CLr
versus NMN CLr will be plotted and a Pearson correlation coefficient (r) will be presented. 
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Natural log transformed AUCinf, AUClast, Cmax and CLr of metformin will be analyzed using a 
mixed effect model with sequence, period and treatment as fixed effects and participant 
within sequence as a random effect.  Additionally, AUC24, Cmax and CLr of NMN will also be 
analyzed using a mixed effect model with sequence, period and treatment as fixed effects and 
participant within sequence as a random effect.  Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% confidence intervals will be obtained from the 
model.  The adjusted mean differences and 90% confidence intervals for the differences will 
be exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% confidence intervals for the ratios.  Metformin alone will be the 
Reference treatment, while the metformin co-administered with PF-04965842 will be the 
Test treatment.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. However, as this is an 
sponsor-open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating dose-escalation 
decisions, facilitating PK/PD modeling, and/or supporting clinical development.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, IB, and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
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, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data.
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant.
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The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research.  Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period.  A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research.  Participants who decline to participate in this optional research will not provide 
this separate signature.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code. 
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred. All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code. The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data. Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
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Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.  This 
verification may also occur after study completion.  It is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan/contracts.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
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When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in investigator site file.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
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10.1.9. Publication Policy
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after end of the study (or 
study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications 
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 30 
days before submission. This allows the sponsor to protect proprietary information and to 
provide comments and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites.  In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.10. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Investigators Site Master File.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 
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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 safety laboratory tests listed in Table 7 below 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 concerns. Creatinine clearance is 
estimated using the Cockcroft-Gault formula to estimate glomerular filtration rate at 
screening:
Creatinine Clearance (estimated) / Conventional mL/min =
((140 - Age (years)) X Weight (kg) X Factora) / (72 X Serum Creatinine (mg/dL))
a Factor is equal to 0.85 in females and 1.00 in males.
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Table 7.
Safety Laboratory Tests
Hematology
&Coagulation
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)
PT/INR
PTT/aPTT
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
QuantiFERON-TB Gold 
Teste
FSHc,e
Urine drug screeningf
Serum Pregnancy Test (HCG)f
Serologyb panel to include: 

Hepatitis B surface antigen;

Hepatitis B surface Ab;

Hepatitis B core antibody;

Hepatitis C antibody;

Human immunodeficiency 
virus.
Additional Tests 
(Needed for Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
Abbreviations: Abs = absolute, ALT = alanine aminotransferase, aPTT = activated partial thromboplastin time, 
AST = aspartate aminotransferase, BUN = blood urea nitrogen, CO2 = carbon dioxide (bicarbonate), FSH = 
follicle-stimulating hormone, GGT = gamma-glutamyl transferase, HCG = Human Chorionic Gonadotropin, 
MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, MCV = mean 
corpuscular volume, pH = measure of acidity, PT/INR = prothrombin time/international normalized ratio, qual 
= qualitative, RBC = red blood cell, TB = tuberculosis, WBC = white blood cell.
a.
Only if urine dipstick is positive for blood, protein, nitrites, glucose or leukocyte esterase.
b.
Serology at Screening only, additional 5 mL blood sample required.
c.
For confirmation of postmenopausal status only.
d.
Serum HCG for female participants of childbearing potential at screening, admission and discharge.
e.
Screening only.
f.
Screening and admission only.

The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines, and amphetamines.
Investigators must document their review of each laboratory safety report.
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Any remaining serum 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 clinical study report (CSR).  Samples to be used for this purpose 
will be shipped to either a Pfizer-approved Biospecimen Banking System (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 (ie, not related to progression of 
underlying disease).

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 
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.
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
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 
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
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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 Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product 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 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 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure.
None
All (and exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  
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
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.

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.
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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the sponsor.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
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 professionals.

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.
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
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.

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 and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which
corresponds to the time needed to eliminate study intervention(s):

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
OR

Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person.

In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
10.4.2. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not 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 an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 28 days after the last dose of study 
intervention).  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 (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
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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.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female.

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
Females of childbearing potential participating in this study cannot use oral, transdermal, 
intrauterine, injected or implanted hormonal methods of contraception and must use one of 
the below options:  
1. Copper-containing intrauterine device (IUD).
2. Bilateral tubal occlusion.
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3. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days.
4. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Collection of Pregnancy Information.
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
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10.5. 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.

Genetic research may consist of the analysis of 1 or more candidate genes or the 
analysis of genetic markers throughout the genome.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention 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 clinical study report (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 (see Section 8.7.2) will be stored indefinitely or other 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 drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a 
participant presents with clinical signs/symptoms, such LFT results should be managed and 
followed as described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).
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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

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 premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

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).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
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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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Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
AD
Atopic dermatitis
Ae
cumulative amount of drug recovered unchanged in urine
Ae%
cumulative amount of drug recovered unchanged in urine, expressed 
as percent of dose
AE
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
AUC24
area under the curve from zero to 24 hours
AUCinf
area under the curve from zero to infinity
AUClast
area under the plasma concentration-time curve from 0 to the time of 
last measurement
AUCtau
area under the plasma concentration-time curve over the dosing 
interval 
BA
bioavailability 
BBS
Biospecimen Banking System
BCRP
breast cancer resistance protein
BID
twice daily 
BMI
body mass index
BP
blood pressure
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CI
confidence interval 
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL
clearance 
CLr
renal clearance
CL/F
clearance for extravascular dosing
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
CYP450
cytochrome P450
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Abbreviation
Term
DCT
data collection tool
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
EMA
European Medicines Agency
EPO
erythropoietin
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
GM-CSF
granulocyte-macrophage colony-stimulating factor
HepBcAb
hepatitis B core antibody
HepBsAb
hepatitis B surface antibody 
HepBsAg 
hepatitis B surface antigen
HCG
serum pregnancy test
HCVAb
hepatitis C antibody
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
hr
hour
IB
Investigator’s brochure 
ICD
informed consent document
ICH
International Conference on Harmonisation
IC50
50% inhibitory concentration
IFN
interferon 
IFN-
interferon alpha 
IFN-
interferon gamma
IL
interleukin
IND
Investigational New Drug
INR
international normalized ratio
IGA
Investigator’s Global Assessment
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
JAK
Janus kinase 
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Abbreviation
Term
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
loge
logarithm 
MATE
multidrug and toxin extrusion transporter
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
multi-drug resistance
mRNA
messenger ribonucleic acid
msec
millisecond
MTX
methotrexate
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate
NASH
nonalcoholic steatohepatitis
NMN
N1-methylnicotinamide  
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PCD
primary completion date
PD
pharmacodynamic(s)
PEER
Pediatric Eczema Elective Registry
PGx 
pharmacogenomic(s)
PK
pharmacokinetic(s)
POC
proof of concept 
PT
prothrombin time
PTT
partial thromboplastin time
PVCs
premature ventricular complexes
QD
once daily 
QTc
corrected QT interval
QTcF
QT interval calculated using Fridericia’s correction factor
qual
qualitative
Rac
accumulation ratio
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
summary of product characteristics
SOC
system organ class
SOP
standard operating procedure
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Abbreviation
Term
SRSD
single reference safety document
STAT
signal transducers and activators of transcription
SUSARs
suspected unexpected serious adverse reactions
t½
apparent terminal half-life
TB
Tuberculosis 
TBili
total bilirubin
TEAEs
treatment emergent adverse events
THC
tetrahydrocannabinol
Tmax
time to maximum concentration
TYK
Tyrosine kinase 
UGT
uridine diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
UVA
ultraviolet A light
UVB
ultraviolet B light
V/F
apparent volume of distribution
Vc/F
apparent central volume of distribution
Vp/F
apparent peripheral volume of distribution
WBC
white blood cell
WOCBP
women of childbearing potential
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11. REFERENCES
1.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg 2012;31:S3-5.
2.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001;109(6):119-27.
3.
Margolis JS, Abuabara K, Bilker W, et al. Persistence of mild to moderate atopic 
dermatitis. JAMA Dermatol 2014;150(6):593-600.
4.
Slater NA, Morrell DS. Systemic therapy of childhood atopic dermatitis. Clin Dermatol 
2015;33(3):289-99.
5.
Leung DY, Bieber T. Atopic dermatitis. Lancet 2003;361(9352):151-60.
6.
Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of atopic eczema (atopic 
dermatitis) part I. J Eur Acad Dermatol Venereol 2012;26(8):1045-60.
7.
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007;178(5):2623-29. 
8.
U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). In Vitro Metabolism- and Transporter-
Mediated Drug-Drug Interaction Studies, Draft Guidance for Industry.  October 2017.
9.
Ito S, Kusuhara H, Kumagai Y, et al. N-methylnicotinamide is an endogenous probe for 
evaluation of drug-drug interactions involving multidrug and toxin extrusions (MATE1 
and MATE2-K). Clin Pharmacol Ther. 2012; 92(5): 635-41.
10.
Oh J, Chung SI, Park JY, et al. Inhibition of the multidrug and toxin extrusion (MATE) 
transporter by pyrimethamine increases the plasma concentration of metformin but does 
not increase antihyperglycaemic activity in humans. 
11.
Jennifer EH, Arik AZ, Richard AC, et al. The Effect of Famotidine, a MATE1-Selective 
Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin. Clin 
Pharmacokinet. 2016; 55(6): 711-21. Diabetes Obes. Metab. 2016; 18: 104-08.
12.
O’Sullivan LA, Liongue C, Lewis RS, et al. Cytokine receptor signaling through the 
Jak-Stat-Socs pathway in disease. Mol Immunol 2007;44(10):2497-2506.
13.
Auriemma M, Vianale G, Amerio P, et al. Cytokines and T cells in atopic dermatitis. 
Eur Cytokine Netw 2012;24(1):37-44.
14.
GLUCOPHAGE® (metformin hydrochloride) Summary of Product Characteristics, 
Merck-Serono Ltd, January 2017.
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15.
GLUCOPHAGE® (metformin hydrochloride) United States Prescribing Information, 
Bristol-Myers Squibb, May 2018.
16.
PF-04965842 2018 Investigator’s Brochure, April 2018:
http://gdms.pfizer.com/gdms/drl/objectId/090177e18e0b13f1.
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SAP_000.pdf: 
Protocol B7451034 (PF-04965842) Statistical Analysis Plan
Page 1
Protocol B7451034
A PHASE 1, RANDOMIZED, 2-WAY CROSSOVER, OPEN 
LABEL STUDY TO ESTIMATE THE EFFECT OF PF-04965842 
ON MATE1/2K ACTIVITY, USING METFORMIN AS A PROBE, 
IN HEALTHY PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
Date:
14-DEC-2018
PPD
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Table
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Final
December 14, 2018
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.1.1. Concentration Analysis Set...........................................................................7
5.1.2. Parameter Analysis Set.................................................................................7
5.2. Pharmacodynamic Analysis Set................................................................................7
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................7
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoint(s) .................................................................................................8
6.2. Safety Endpoints .......................................................................................................8
6.2.1. Adverse Events.............................................................................................9
6.2.2. Laboratory Safety Tests................................................................................9
6.2.3. Vital Signs Data............................................................................................9
6.2.4. ECG Results..................................................................................................9
6.2.5. Other Safety Data .........................................................................................9
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints..............................................................................................10
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6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................10
7.1. Concentrations Below the Limit of Quantification.................................................10
7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................11
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Subjects.......................................................13
8.3.2. Demographic and Clinical Examination Data............................................13
8.3.3. Discontinuation(s).......................................................................................13
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. Other Safety Data .......................................................................................14
8.3.9. Concomitant Treatments.............................................................................14
8.3.10. Screening and Other Special Purpose Data ..............................................15
8.3.11. Other Analyses..........................................................................................15
9. REFERENCES ....................................................................................................................16
10. APPENDICES ...................................................................................................................17
LIST OF TABLES
Table 1.
Study Schematics....................................................................................................6
Table 2.
Noncompartmental PK Parameters.......................................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Treatment ...........................12
LIST OF FIGURES
None.
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................17
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
PF-04965842 is a Janus kinase (JAK) 1 inhibitor that is currently being developed for the
treatment of moderate to severe atopic dermatitis (AD).
Within vitro data indicating PF-04965842 may have the potential to inhibit multidrug and
toxic compound extrusion transporter (MATE)1 and MATE2K, a clinical interaction study is
needed to assess the effect of PF-04965842 on the activity of these transporters.
The primary purpose of this study is to assess the effect of PF-04965842 on the in vivo
pharmacokinetics (PK) of metformin, a specific substrate for MATE1 and MATE2K.
2.1. Study Design
This is a Phase 1, randomized, 2-way crossover, open label study of the effect of
PF-04965842 on metformin PK in healthy adult participants. The effect of PF-04965842 on
N1-methylnicotinamide (NMN) PK and its correlation to the effect on metformin PK will also 
be assessed.
A total of approximately 12 healthy male and/or female participants will be enrolled in the
study so that approximately 6 participants will be enrolled in each treatment sequence. Each
treatment sequence will consist of 2 periods. Participants who discontinue from the study
may be replaced at the sponsor’s discretion. The replacement participant will receive the
same treatment sequence as the participant who discontinued.
Participants will be screened within 28 days of the first dose of investigational product.
Participants will report to the clinical research unit (CRU) the day prior to Day 1 (ie,
Day -1) dosing in Period 1 for both treatment sequences. In both sequences, participants 
will remain in the CRU for a total of 8 days and 7 nights (including Period 1 and Period 2).
To adequately remove any drug effects of metformin (plasma half-life ~ 6 hours/whole blood
half-life ~ 18 hours) from Period 1 to Period 2, there will be a minimum 4-day washout
period between 2 dosing events. The minimum 3-day washout for PF-04965842 in Sequence
2 is sufficient as the half-life of PF-04965842 is ~3-5 hours. The metformin PK will be
assessed over 48 hours. Participants will be assigned to one of the following 2 treatment
sequences.
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Table 1.
Study Schematics
Sequence
Period 1
Washout Period
Period 2
1
(6 subjects)
Treatment A
At least 4 days from
metformin administration
Treatment B
2
(6 subjects)
Treatment B
At least 4 days from
metformin + PF-04965842
administrationa
Treatment A
Abbreviation: QD = once daily.
a. At least a 3 day washout is required from the last dose of PF-04965842.

Treatment A (Reference): Single oral administration of metformin 500 mg on Day 1.

Treatment B (Test): Concomitantly single oral administration of metformin 500 mg 
on Day 1 and oral administration of PF-04965842 200 mg QD for 2 days on Days 
1-2.
All treatments administered on Day 1 will be administered following a moderate-fat meal.
PF-04965842 can be dosed with or without food on Day 2 in Treatment B.
2.2. Study Objectives
Primary Objective

To estimate the effect of PF-04965842 on MATE1/2K activity via the 
pharmacokinetic assessment of a single, oral dose of metformin in healthy 
participants.
Secondary Objective

To evaluate the PK, safety and tolerability of a single oral dose of metformin when 
co-administered with PF-04965842.
Exploratory/Tertiary Objectives

To evaluate the effects of PF-04965842 on N1-methylnicotinamide.

To correlate the effects of PF-04965842 on N1-methylnicotinamide versus metformin.

To enable exploratory research through the collection of banked biospecimens, 
unless prohibited by local regulations or ethics committee decision.
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3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No formal interim analysis will be conducted for this study. However, as this is an
sponsor-open study, the sponsor may conduct unblinded reviews of the data during the
course of the study for the purpose of safety assessment, facilitating dose-escalation 
decisions, facilitating PK/PD modeling, and/or supporting clinical development.
Final analysis will follow the official database release.  As this will be an open-label study, 
there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses.
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The pharmacokinetic (PK) concentration population is defined as all enrolled subjects who 
received at least 1 dose of metformin and in whom at least 1 plasma concentration value is
reported.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all participants randomized and treated
who have at least 1 of the PK parameters of primary interest in at least 1 treatment period.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants randomly assigned to investigational product and who take at least 1 dose of 
investigational product. Participants will be analyzed according to the product they actually 
received.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.
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If a subject takes a treatment that is not consistent with the treatment they are randomized to, 
for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety, PK and 
pharmacodynamic analyses, where applicable.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg, lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

Adverse events;

Laboratory data;

Vital signs data;

ECG results.
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6.2.1. Adverse Events
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Washout or Follow-up) will be 
counted as treatment emergent and attributed to the previous treatment taken.
6.2.2. Laboratory Safety Tests
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each subject’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline is defined as the last predose measurement taken in each study period.
6.2.3. Vital Signs Data
Supine measurements will be taken at times detailed in the Schedule of Activities given in 
the protocol.
Baseline is the last predose recording in each study period.
6.2.4. ECG Results
QT interval, QTc, PR, RR, QRS and heart rate will be recorded at each assessment time 
indicated in the Schedule of Activities given in the protocol.
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)
Baseline is the last predose recording in each study period.
The average of the triplicate measurements will be calculated prior to analyzing the data.  
Baseline will be defined as the average of the triplicate predose recordings in each study 
period. 
6.2.5. Other Safety Data
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database.
6.3. Other Endpoints
6.3.1. PK Endpoints
PK analysis of metformin and NMN (N1-methylnicotinamide) will be taken according to the 
Schedule of Activities given in the protocol.
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The following PK parameters will be calculated by treatment and by analyte (if applicable) 
from the concentration-time data and urine concentrations using standard noncompartmental 
methods:
Table 2.
Noncompartmental PK Parameters
PK 
Parameter
Analysis 
Scale
Metformin
NMN
(N1-methylnicotinamide)
AUCinf
*
ln
A, D
AUClast
ln
A, D
D
AUC24
ln
D
A, D
Cmax
ln
A, D
A, D
Tmax
R
D
D
t1/2
*
R
D
CL/F*
ln
D
V/F*
ln
D
Ae*
R
D
D
Ae%*
R
D
CLr
*
ln
A, D
A, D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics, ln=natural-log 
transformed, R=raw (untransformed), *=if data permits
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. 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.)
7.2. 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.
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Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. 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 treatment with 3 evaluable measurements.  For statistical 
analyses (ie, analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
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 in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The interactive effect on PK parameters will be determined by constructing 90% confidence 
intervals around the estimated difference between the Test and Reference treatments using a 
mixed effects model based on natural log transformed data.  The mixed effects model will be 
implemented using SAS Proc Mixed, with REML estimation method and Kenward-Roger 
degrees of freedom algorithm.
8.2. Statistical Analyses
Actual PK sampling times will be used in the derivation of PK parameters.
Natural log transformed AUCinf, AUClast, Cmax and CLr of metformin will be analyzed 
using a mixed effect model with sequence, period and treatment as fixed effects and 
participant within sequence as a random effect. 
Additionally, AUC24, Cmax and CLr of NMN will also be analyzed using a mixed effect 
model with sequence, period and treatment as fixed effects and participant within sequence 
as a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% confidence intervals will be obtained from the model. The adjusted 
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 
90% confidence intervals for the ratios. Metformin alone will be the Reference treatment, 
while the metformin co-administered with PF-04965842 will be the Test treatment.
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PK parameters will be summarized descriptively by analyte and by treatment, as applicable, 
in accordance with Pfizer Data Standards. Concentrations will be listed and summarized 
descriptively by analyte, nominal PK sampling time and treatment. Individual subject and 
median profiles of the plasma concentration-time data will be plotted by treatment using 
actual and nominal times, respectively.  Median profiles will be presented on both 
linear-linear and log-linear scales.
Individual changes from baseline for metformin CLr versus NMN CLr will be plotted and a 
Pearson correlation coefficient (r) will be presented.
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analysis will be given in the report of the 
study.
Table 3.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
AUCinf, AUClast,
AUC24, Cmax, 
CL/F, CLr, V/F
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2, AE, Ae%
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.
Supporting data from the estimation of t½ and AUCinf will be listed by treatment and 
analyte: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, 
last, and number of time points used in the estimation of kel.  This data may be included in 
the clinical study report.
Presentations for metformin and NMN concentrations will include:

A listing of all concentrations sorted by analyte, subject ID, period and nominal time 
postdose.  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 (for each analyte) by treatment and nominal time 
postdose, where the set of statistics will include n, mean, median, standard deviation, 
coefficient of variation (cv), minimum, maximum and the number of concentrations 
above the lower limit of quantification.
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
Median concentrations time plots (on both linear and semi-log scales for each 
analyte) against nominal time postdose by treatment (all treatments on the same plot 
per scale, based on the summary of concentrations by treatment and time postdose).

Mean concentrations time plots (on both linear and semi-log scales for each analyte) 
against nominal time postdose by treatment (all treatments on the same plot per scale,
based on the summary of concentrations by treatment and time postdose).

Individual concentration time plots by treatment (on both linear and semi-log scales
for each analyte) against actual time postdose (there will be separate spaghetti plots 
for each treatment per scale).

Individual concentration time plots by subject (on both linear and semi-log scales for 
each analyte) against actual time postdose [there will be separate plots for each 
subject (containing all treatments) per scale].

Individual changes from baseline for metformin CLr versus NMN CLr will be 
evaluated using a regression line and Pearson correlation coefficient (r).
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.
8.3. Safety Analysis
A set of summary tables split by treatment will be produced to evaluate any potential risk 
associated with the safety and toleration of administering study treatments.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break-down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
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8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment.
8.3.5. Laboratory Data
Laboratory data will be listed and summarized by treatment in accordance with the sponsor 
reporting standards.  Baseline is as defined in Section 6.2.2.
8.3.6. Vital Signs Data
Supine blood pressure, pulse rate and oral temperature will be measured as per the Schedule 
of Activities at the time points as mentioned in the protocol.
For each planned time point, baseline values and change from baseline values within each 
treatment will be summarized with descriptive statistics (using sponsor default standards).  
Baseline is as defined in Section 6.2.3.
These data will be listed in accordance with the sponsor reporting standards.
8.3.7. ECG Data
Baseline and changes from baseline in PR, QT, QRS, heart rate and QTcF will be 
summarized by treatment and time postdose.  Baseline is as defined in Section 6.2.4.
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.
The number (%) of participants with maximum postdose QTc values and maximum increases
from baseline in the following categories will be tabulated by treatment:
Safety QTc Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
In addition, the number of participants with uncorrected QT values >500 msec will be
summarized.
These data will be listed in accordance with the sponsor reporting standards.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
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8.3.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, urine drug screen, 
serum or urine B-hCG for all females of childbearing potential, Serology (HIV, HepBsAg, 
HepBcAb, HepBsAb, HCVAb testing), QuantiFERON® - TB Gold Test, Medical, Drug, 
Tobacco and Alcohol History, and urine or blood cotinine concentration will be obtained at 
Screening.
These data will not be brought in-house, and therefore will not be listed.
8.3.11. Other Analyses
Pharmacogenomic (PGx) and endogenous biomarker PK data, other than NMN, will be
collected and retained for potential future analyses, but will not be analyzed, specifically, for
this study.
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9. REFERENCES
1.
ICH E14 - The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs.  CHMP/ICH/2/04.
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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES

Analyze AUCinf, AUClast, Cmax and CLr of metformin.

Analyze AUC24, Cmax and CLr of NMN.
An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
class seq period trt subject;
model l&var=seq period trt/ ddfm=KR;
random subject(seq) /subject=subject(seq);
lsmeans trt;
estimate 'Test vs Reference' trt -1  1  /cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
A = metformin alone (Reference);
B = metformin co-administered with PF-04965842 (Test) */;
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