Conditions: Ulcerative Colitis
Keywords: Mayo score
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 319
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether PF-06651600 and PF-06700841 are effective in treatment of moderate to severe ulcerative colitis.

Detailed description:

Arms:
arm 1: Delivered orally for 8 weeks arm 2: Delivered orally for 8 weeks arm 3: Delivered orally for 8 weeks. arm 4: Delivered orally for 8 weeks. arm 5: Delivered orally for 8 weeks arm 6: Delivered orally for 8 weeks. arm 7: Delivered orally for 8 weeks. arm 8: Delivered orally for 8 weeks. arm 9: Delivered orally for 24 weeks. arm 10: Delivered orally for 24 weeks.

Interventions: intervention 1: PF-06651600 or Placebo intervention 2: PF-06700841 or Placebo intervention 3: PF-06700841 intervention 4: PF-06651600
Intervention descriptions: intervention 1: Delivered orally for 8 weeks. intervention 2: Delivered orally for 8 weeks. intervention 3: Delivered orally for 24 weeks. intervention 4: Delivered orally for 24 weeks.

Protocol document:
Prot_000.pdf: 
PF-06651600, PF-06700841
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PFIZER CONFIDENTIAL
Page 1
A PHASE 2B, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PARALLEL GROUP, DOSE RANGING STUDY OF ORAL PF-06651600 AND 
PF-06700841 AS INDUCTION AND CHRONIC THERAPY IN SUBJECTS WITH 
MODERATE TO SEVERE ULCERATIVE COLITIS
Investigational Product Number:
PF-06651600, PF-06700841
Investigational Product Name:
brepocitinib, ritlecitinib
United States (US) Investigational New 
Drug (IND) Number:
(PF-06651600)
(PF-06700841)
European Clinical Trials Database 
(EudraCT) Number:
2016-003708-29
Protocol Number:
B7981005
Phase:
2b
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version 
Date
Summary of Changes and Rationale
Amendment 7
18 Nov 
2020

Protocol Summary: Changes made to Protocol Summary.
Rationale: To align with changes made in the main 
protocol.
 

Sections 1.4.1 and 1.4.2: Summary of Clinical 
Experience with PF-06700841 updated.
Rationale: To align with the updated Investigator 
Brochure.

Sections 2.1- 2.2: Corrected definition of remission based 
on total Mayo score per Section 7.3.3. Corrected the
definition of remission based on modified Mayo Score to 
align with Section 7.3.3.
Rationale: Clarification of endpoints.

Sections 2.2: Added PRO objective to align with the PRO 
endpoints for the Chronic period.
Rationale: To align with the PRO objective in Induction 
period.

Sections 3.1: Updated to clarify placebo treatment in 
chronic dosing in protocol and protocol amendments 
prior to protocol amendment 5. 
Rationale: Clarification of no placebo arm in chronic 
dosing post-amendment 4.

Section 4.2: Exclusion criterion 34 added to exclude 
subjects with history of thrombotic event(s) including 
DVT and known inherited conditions that predispose to 
hypercoagulability.
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Rationale: Per regulatory request.

Section 6.5: Guidelines for Monitoring and 
Discontinuations updated to include discontinuation of 
study drug for thrombotic or thromboembolic events.
Rationale: Per regulatory request.

Section 7.3.3: Added definition of endoscopic response 
and definition of remission based on modified Mayo 
Score. Removed Clinical Remission.
Rationale: Definition for these endpoints was missing in 
the earlier version of the protocol. Definition of Clinical 
Remission is not applicable to the study and hence 
removed.

Section 7.3.4: Definition of Remission based on change 
in partial Mayo score is revised.
Rationale: Definition corrected.

Section 9.1: Updated Type 1 error by removing
adjustment for multiplicity.
Rationale: Due to the reduction of the sample size (study 
enrollment was stopped earlier than expected) the 
multiplicity adjustment was removed to retain power. 
This flexibility was acceptable for early phase studies.

Sections 9.2.1 and 9.2.3: Clarified description of the 
mixed model to be used for the primary analysis. The 
references to the relevant literature (eg, sections of the 
books of Fitzmaurice, Laird and Ware (2011) and 
Malicrodt and Lipkovich (2017)) were added. Also 
clarified that the Bayesian emax model is supporting the 
primary analysis.
Rationale: Corrected typographical errors in the earlier 
version and added relevant references.
Amendment 6
17 Sep
2020

Protocol Summary and Section 1.1: Investigational 
product names (brepocitinib, ritlecitinib) added.
Rationale: Names assigned to Investigational products.

Correction made to Document History for Amendment 5: 


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Section 1.5.3 should be Section 1.5.5. 
Rationale: To correct the error (PACL dated 
23Oct2018).

Schedule of Activities, Section 6.1, Section 7 and Section 
7.3.6: Reference to Appendix 10 regarding Alternative 
Measures during Public Emergencies added.
Rationale: To provide guidance on study conduct during 
public emergencies including COVID-19 (PACL dated
27Apr2020).

Section 3.1: Removed footnote from the study schematic
Rationale: Footnote already explained in the text 
immediately below.

Schedule of Activities Footnote “d” and Section 7.2.11 
updated to clarify that breast and external genitalia 
examination as a part of physical exam is optional, but 
skin examination should include a visual examination of 
the breast and external genitalia to assess rashes.
Rationale: To ensure that rashes are detected early
(PACL dated 23Oct2018).
 

Section 1.4: Summary of Clinical Experience updated to 
include additional studies (i) PF-06651600 in Crohn’s 
disease, Alopecia Areata and Vitilligo (ii) PF-06700841 
in healthy cohorts for ADME, bioavailability, QT study, 
skin irritation study and in plaque psoriasis.
Rationale: To align with Investigator Brochure.

Section 2: Objectives and Endpoints listed separately for 
the Induction and Chronic dosing periods. Safety 
Endpoints for Induction and Chronic dosing periods
updated to include laboratory abnormalites, vital signs 
and 12-lead ECG.
Rationale: To facilitate the reporting of the induction 
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and chronic periods and update safety endpoints.

Section 4.1 Inclusion criteria #6, Section 5.8.2 and 
Appendix 1: Updated to reference Steroid conversion 
table in Appendix 9.
Rationale: to provide guidance on steroid conversions
(PACL dated 13Mar2020).

Section 4.2: Exclusion criterion #14 updated to exclude
re-testing of a positive IGRA test even though protocol 
states that all screening labs with abnormal results may 
be repeated within the screening window to confirm 
abnormal results.
Rationale: to clarify that re-testing of positive IGRA test 
is not allowed (PACL dated 4Jun2019).

Section 4.3.1: Updated to indicate that the protocol 
specified contraception language is in alignment with the 
recommendations from the B7981018 study.
Rationale: To align with the Investigator brochure 
(PACL dated 4Jun2019).

Section 5.4.2: Updated to include reference to 
Appendix 10 on alternative measures during public 
emergencies.
Rationale: To provide guidance on IP preparation and 
dispensing during public emergencies including 
COVID-19 (PACL dated 27Apr2020).

Section 6.5 (Guidelines for Monitoring and 
Discontinuations): Added Lymphocytes <800/mm3; 
<0.8 x 109/L and CK >3x ULN as additional labs to 
monitor.
Rationale: To monitor subjects who experience 
decreased lymphocytes <0.8 x 109 /L or CK >3 x ULN 
to ensure that these lab abnormalities are followed up in 
a timely manner and appropriate actions taken (PACL 
dated 13Mar2020). 

Section 6.5 (Guidelines for Monitoring and 
Discontinuations): Clarified definition of serious 


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infections by referencing Section 7.2.8.
Rationale: To clarify definition of serious infections. 

Section 7.2.6 updated to allow central lab to replace 
QuantiFERON®-TB Gold test (QFT-G), 
QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and 
T-SPOT® TB test with other acceptable QFT tests. 
Rationale: To permit central lab to replace the above 
tests with new ones (PACL dated 4 Jun2019).

Section 7.2.12 updated to indicate that audiogram results 
maybe reviewed by an external audiologist.
Rationale: To summarize audiology results.

Section 7.3.1: updated to indicate that a Colonoscopy 
should not be performed at the Early Termination (ET) 
visit if the previous colonoscopy was less than 8 weeks 
prior to this.
Rationale: To avoid consecutive endoscopies if less than 
8 weeks apart on early termination.
 
 
 

Section 7.3.3: Provided clarification on the window for 
stool diary to be used for MAYO score calculation at 
study visits (PACL dated 4Jun2019). 
Rationale: To provide clarification (PACL dated 
4Jun2019).

Section 7.3.3: Updated to clarify the use of central versus 
local endoscopy scores in PGA assessment at Baseline, 
Week 8 and Week 32/ET visit.
Rationale: to provide guidance on use of central versus 
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local endoscopy scores in PGA assessment.

Section 9.1 Sample Size Determination.
Rationale: To update the sample size since the study 
closed screening early due to business reasons.

Sections 9.2, 9.3 and 9.4: revised to describe the analyses 
for induction and chronic dosing periods.
Rationale: To align with the the objectives and 
endpoints for induction and chronic dosing period in 
Section 2.

Section 9.7: Protocol updated to include adjudication of 
opportunistic infections and cardiovascular events. 
Rationale: Adjudication committee added based on 
known mechanism of acton of JAK inhibitors.

Appendix 9: Steroid conversion table Appendix 9 added.
Rationale: to provide guidance on steroid conversions
(PACL dated 13Mar2020).

Appendix 10 on Alternative Measures During Public 
Emergencies added.
Rationale: To provide guidance on study conduct during 
public emergencies including COVID-19 (PACL dated 
27Apr2020).
Amendment 5
16 August 
2018

Background and rationale in protocol summary updated.
Rationale: To align with Investigator Brochure.

In the Protocol Summary, Schedule of Activities (SoA), 
Section 1 Introduction, Section 2 Study Objectives and 
Endpoints, Section 3 Study Design, Section 6 Study 
Procedures, and Section 9 Data Analysis/Statistical 
Methods, placebo treatment has been removed from the 
chronic dosing period. 
Rationale: To enable all subjects to receive active 
treatment after the 8 weeks double-blind induction period. 

In the Protocol Summary, SoA footnote b, Section 


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5.5 Administration, Section 5.9 Rescue Medication it has 
been clarified that subjects discontinuing early from 
active treatment should undergo the procedures for an 
Early Termination visit and then enter the follow-up 
period. 
Rationale: To provide clarification and align sections. 

SoA footnote d and Section 7.2.11 Medical History, 
Physical Examination, Height and Weight clarifies that 
skin examinations should include visual inspection of the 
breast/and or external genitalia as part of the physical 
examination, even if a subject does not wish to have 
breast and/or external genitalia examined as part of the 
physical examination.
Rationale: To clarify that whilst skin examination of the 
breasts and/or external genitalia is a requirement, the 
physical examination of breast and/or external genitalia is 
optional.

SoA footnote p and Section 7.2.4 Pregnancy testing are 
revised to delete the requirement of doing a second 
pregnancy test within 5 days after the first day of the 
menstrual period (counting the first day of the menstrual 
period as Day 1). 
Rationale: Two highly sensitive negative pregnancy tests 
at screening and at randomization are sufficient to ensure 
that the subject is not pregnant prior to first dose of study 
drug. 

SoA table, Section 6.1 Screening and Section 6.2.1
Baseline amended so fecal calprotectin is measured at 
screening and not baseline, and aligns with stool 
microbiome collection.  SoA footnote q, Section 7.4.5
Fecal calprotectin and Section 7.4.6 Stool Samples for 
Microbiome Analysis wording amended to permit some 
flexibility in the collection of these samples relative to 
bowel preparation for endoscopy.
Rationale: to align fecal calprotectin and stool 
microbiome sample collection at screening and reduce 
stool sample collection frequency.  The updated wording 
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bowel preparation for endoscopy.

SoA footnote u and Section 7.3.1 amended to instruct that
endoscopy at Weeks 8 and 32 be performed at the site 
visit, where possible. 
Rationale: To reduce the burden of visits to the site and
subjects participating in the study, whilst retaining some 
flexibility in the event that endoscopy being performed in 
the week prior to visits 8 and 32 is required. 

SoA footnote x and Section 5.5 Administration added 
clarification regarding procedures to follow in the event 
that a subject administers study drug the morning prior to 
site visit.
Rationale: To provide clarification. 

Section 1 Introduction and reference 3, updated 
Tofacitinib information.
Rationale: To reflect the most recent information publicly 
available.

Section 1.5.1 Study Rationale updated with information 
on dermatological, auditory, and laboratory assessments 
and prohibited medication.
Rationale: To give further information for the 
assessments being conducted in this study.
 
 
 
 

Section 1.1: Background and rationale section updated.
Rationale: To align with Investigator Brochure.
 
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
Section 1.4.1: Summary of clinical experience of 
PF-06651600 section updated.
Rationale: To align with Investigator Brochure.

Section 1.4.2: Pharmacokinetics of PF-06651600 section 
updated.
Rationale: To align with Investigator Brochure.
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Section 3.1 Study Overview schematic has been updated 
to reflect the removal of placebo in the chronic dosing 
period.
Rationale: To show in the schematic that no subject in the 
chronic dosing period will be receiving placebo.

Section 3.3: 15 months has been added to the enrolment 
and total study duration.
Rationale: To reflect current recruitment expectations.

Section 4.1 Inclusion criteria 1 upper age limit increased 
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from 70 to 75 years old. 
Rationale: To allow older subjects to participate in the
trial. 

Section 4.1 Inclusion criteria 2 reworded and disease
duration requirement lowered from 4 months to 
3 months. 
Rationale: Reworded to simplify the language.  Duration 
amended to allow subjects with a shorter diagnosis period 
to participate in the trial. 

Section 4.1 Inclusion criteria 5 guidance information 
moved into Appendix 1. 
Rationale: Guidance information moved into 
Appendix 1 to simplify.

Section 4.2 Exclusion criteria re-ordered and 
consequently renumbered. 
Rationale: For ease of use. 

Section 4.2 Exclusion Criterion 1 reworded.

Rationale: To simplify.

Section 4.2 Exclusion Criterion 25 (formerly Exclusion 
Criterion 28): The eGFR related criterion was lowered 
from <80 mL/min/1.73m2 to <60 mL/min/1.73m2.  
Subsequently the exclusion of subjects with serum 
creatinine levels > ULN has now been removed.  
Reference to subjects with serum creatinine > ULN has 
been removed from Section 7.2.2 Creatinine and Cystatin 
C and Section 8.4.3 Potential Cases of Decreased eGFR.
Rationale: There is no increased risk to include subjects 
with eGFR >60 and <80 based on available nonclinical 
and clinical data to date. 

Section 4.2 Exclusion criteria 17 (now #15) and Section 
7.2.7 Screening for Clostridium Difficile updated to 
permit treatment and re-testing or re-screening of 
subjects.
Rationale: to permit subjects with appropriately resolved 


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infection to enter the study. 

Section 4.3.1 on contraception was updated.
Rationale: to align with the Clinical Trials Facilitation 
Group (CTFG) European guidance of the Heads of 
Medicines Agencies (HMA) and TransCelerate initiative 
across Pharma.

Included instruction to male subjects to refrain from 
sperm donation for a period of 90 days after completion 
of active treatment.

Rationale: to be in alignment with previous 
Regulatory request.

Section 5.8.2 Permitted Medications now allows steroid 
tapering in the chronic dosing period.
Rationale: To allow modification of steroid therapy. 

Section 5.8.3 Prohibited Medications updated to clarify 
timeframe in which the listed medications are not 
permitted for those for which the information is not 
already stated.
Rationale: to provide clarification and to avoid potential 
drug-drug interactions.

Section 11 Data Handling and Record Keeping and 
Section 12.3 Subject Information and Consent have been 
updated to comply with the European Union General 
Data Protection Regulation (GDPR) which became 
effective on 25th May 2018.
Rationale: To comply with GDPR requirements.
 

Several additional minor editorial changes were made to 
protocol language for the purposes of improving clarity 
and readability and for maintaining consistency 
throughout the document.
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Amendment 4
06 March 
2018

Section 4.2: Exclusion Criterion 5: The exclusion 
criterion “Subjects with colonic dysplasia or neoplasia” 
was removed and combined with the exclusion 
criterion 10 “Subjects with evidence of colonic adenomas, 
or dysplasia”.
Rationale: This change was made to remove redundancy 
in the protocol.

Section 4.2: Exclusion Criterion 13: It was clarified that 
subjects who have not responded to or have been 
intolerant of other JAK inhibitors are not permitted into 
the study.
Rationale: Subjects who have previously been intolerant 
to or have been non-responders to other JAK inhibitors 
would not be suitable for participating in a study with 
PF-06651600 (a JAK 3 selective inhibitor) and 
PF-06700841 (dual inhibitor of TYK2 and JAK 1).

Section 4.2: Exclusion Criterion 16: It was clarified that 
subjects with repeat indeterminate IGRA results may be 
enrolled after a documented evaluation by appropriately 
qualified personnel (which may include a pulmonary or 
infectious disease specialist, or locally acceptable expert 
as defined by local guidelines), that in their opinion, the 
probability of reactivation is low (ie, subject would be 
acceptable for immunosuppressant treatment without 
additional action).
Rationale: While the previous protocol version required 
those subjects with repeat indeterminate IGRA to have a 
consultation with a pulmonary or infectious disease 
specialist, it wasn’t made clear that this consultation 
should be documented or that local guidelines should be 
followed.  This has been clarified.

Section 4.2: Exclusion Criterion 16: It was clarified that 
subjects adequately treated (in the opinion of the 
appropriately qualified personnel - which may include a 
pulmonary or infectious disease specialist, or locally 
acceptable expert as defined by local guidelines) for 
latent and/or active tuberculosis infection may be 
enrolled regardless of Mantoux or IGRA results provided 
the treatment is well documented in the subject’s medical 
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in the study.
Rationale: For subjects who have adequately treated for 
latent and/or active tuberculosis infection, there is a 
probability of a false positive Mantoux or IGRA result.  
Therefore if adequate treatment is well documented in the 
medical records, the subject is eligible to participate in 
the study.

Section 4.2: Exclusion Criterion 28 and Schedule of 
Activities: Clarification was provided regarding the 
testing for hepatitis B and C and the following sentence 
was removed “Subjects with false positive anti-HBc may 
be enrolled based upon consultation with hepatologist 
confirming no infection with hepatitis B”.
Rationale: Given that reflex testing criteria can identify 
subjects with false positive testing for hepatitis B or C 
infection, this was incorporated into the protocol.

Section 4.2: Exclusion Criterion 28: The eGFR related 
criterion was lowered from <90 mL/min/1.73m2 to 
<80 mL/min/1.73m2.
Rationale: This was modified to allow elderly subjects 
with creatinine values within normal range, but lower age 
adjusted eGFR to enter the study.

Section 4.2: The criteria to have abnormal screening lab 
results repeated once was removed and it was clarified 
that repeat testing to confirm abnormal results can be 
performed anytime during the screening period.
Rationale: This was modified to give the opportunity to 
retest abnormal lab results that was considered by the 
investigator to be transient and/or inconsistent with the 
subject’s clinical condition and/or past medical history.

Section 4.2: It was stated in this section that “Subjects 
who do not meet eligibility criteria (ie, screen fail) may 
be re-screened once (with a new screening number) at 
the discretion of the investigator”.
Rationale: This was added here to be consistent with 
what was already stated in Section 6.1 of the protocol.

Section 7.2.6 (Interferon Gamma Release Assay 


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Tuberculin Test): It was clarified that subjects with 
repeat indeterminate IGRA results may be enrolled after a 
documented evaluation by appropriately qualified 
personnel (which may include a pulmonary or infectious 
disease specialist, or locally acceptable expert as defined 
by local guidelines), to rule out the possibility of low risk 
of infection.
Rationale: This was added here to be consistent with 
Section 4 of the protocol.

Section 7.2.12 Audiogram Testing: Clarification was 
provided that results of the audiogram test must be 
available by the time of the following clinic visit.
Rationale: The results of the audiogram must be available 
by the baseline visit to establish the baseline hearing for 
the subject.  Following this, the reports from the 
audiologist must be available no later than the next visit 
to allow evaluation of any meaningful decline in hearing 
from baseline.
 
 
 
 

Several additional minor editorial changes were made to 
protocol language for the purposes of improving clarity 
and readability and for maintaining consistency 
throughout the document. 
Amendment 3
5 April 
2017
 
 
 
 

Section 4.1, Inclusion Criterion #1, revised for subjects in 
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Korea only, indicating that they must be ≥19 years to 
≤70 years of age at the time of informed consent.
Rationale: The lower age limit is increased to 19 years 
old for subjects in Korea to comply with country
regulations. 

Section 4.1, Inclusion Criterion #7, Section 8.1.2, 
Eliciting Adverse Event Information, and Section 12.3, 
Subject Information and Consent revised to remove all 
references to legally acceptable representative.
Rationale: References to legally acceptable representative 
have been removed throughout the protocol because 
subjects who lack capacity to consent for themselves are 
not eligible to participate in this study.

Section 4.1, Inclusion Criteria, Section 5.8.2 Permitted 
Medications, Section 5.8.3 Prohibited Medications and 
Section 5.9 Rescue Medication, revised to place all 
washout periods relative to baseline visit and also revised 
to note that medications are prohibited through end of 
study (Week 36).
Rationale: Revisions made to ensure consistency with 
regards to washout and timing for prohibited 
medications.

Section 4.2, Exclusion Criterion #13 and Section 5.8.3, 
Prohibited Medications, revised to exclude subjects 
receiving azathioprine, 6-mercaptopurine, or 
methotrexate within 2 weeks prior to baseline and 
through end of study (Week 36).
Rationale: This revision is to clarify that subjects must 
not have treatment with azathioprine, 6-mercaptopurine, 
or methotrexate for at least 2 weeks prior to baseline. 

Section 4.2, Exclusion Criterion #16 and Section 7.2.6, 
Interferon Gamma Release Assay revised to note that 
IGRA is tested locally where feasible. 
Rationale: This revision is made so that sites that are 
unable to perform IGRA at their local laboratory, will 
have IGRA testing performed by the central laboratory.

Section 4.2, Exclusion Criterion #18 revised to note that 


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HIV is tested locally where feasible.
Rationale: This revision is made so that sites that are 
unable to perform HIV at their local laboratory, will have 
HIV testing performed by the central laboratory.

Section 4.2, Exclusion Criterion #24 and Section 5.8.3, 
Prohibited Medications, revised with note excluding 
simvastatin or simvastatin containing products from 
5 days prior to baseline and through end of study 
(Week 36).
Rationale: Subjects receiving drugs that are substrates of 
CYP3A (simvastatin or simvastatin-containing products) 
are excluded from participation in the study to limit any 
potential interactions with the investigational product.

Section 5.5, Administration, revised to note that for 
study visit days (ie, baseline, Weeks 2, 4, 8, 12, 16, 20, 
and 24), subjects are to be instructed to refrain from 
dosing at home, bring their blister cards or bottles to the 
site, and are to take the dose in the clinic from their 
current blister card or bottle.
Rationale: This revision is made to highlight that on 
visits where dosing is at the clinic, subjects are to take the 
dose at the clinic and from their current blister card or 
bottle.

Section 6.1, Screening, Section 6.2.1, Baseline/(Week 0, 
Day 1), Section 7.3.1, Endoscopy and Schedule of 
Activities footnote w, revised to clarify that the stool 
frequency, rectal bleeding and centrally read endoscopy 
subscores from the screening endoscopy and the PGA 
obtained at baseline are used to determine eligibility.
Rationale: This revision is made to clarify how Mayo 
score is calculated for eligibility.
 
 
 
 
 
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
Administrative changes and sentence revisions made 
throughout the document.
Rationale: Revisions made for clarity and to correct 
grammatical, spelling or other errors.
Amendment 2
14 March 
2017

Section 4.1, Inclusion Criteria #5, revised definition of 
inadequate response to, loss of response to, or intolerance 
to infliximab to at least one 14-week regimen and 
vedolizumab to at least one 10-week regimen.
Rationale: The definition of inadequate response to, loss 
of response to, or intolerance to infliximab and 
vedolizumab is revised to reflect the Summary of Product 
Characteristics.

Section 4.2, Exclusion Criteria #1 and Section 4.3.1, 
Contraception, removed highly when referencing highly 
effective contraception.
Rationale: Highly has been removed when referencing 
highly effective contraception as not all of the methods 
described in the protocol are recognized as highly
effective in all countries.

Section 5.2, Breaking the Blind is revised to state that 
discussion with a member of the study team in advance of 
unblinding is not required. 
Rationale: Clarification to breaking the blind is included 
to ensure that it is clear to investigators that they are not 
required to discuss unblinding plans with the Sponsor in 
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advance of emergency unblinding.

Section 5.8.3, Prohibited Medications revised to prohibit 
any live (attenuated) vaccines from 30 days prior to 
baseline and through the end of study (Week 36).
Rationale: The prohibition of live (attenuated) vaccines is 
extended from through Week 32 to through Week 36 to 
ensure that there is no residual investigational product on 
board prior to vaccinations. 

Section 5.8.4, Vaccinations is added.
Rationale: Vaccinations section is added to further clarify 
prohibition of live (attenuated) vaccines and to provide 
examples of such vaccines.  Additionally, section is 
added to clarify that, current routine household contact 
with individuals who have been vaccinated with live 
vaccine components should be avoided during treatment 
and through the end of the study.

Section 6.5, Guidelines for Monitoring and 
Discontinuations revised to state that an absolute 
neutrophil count <1.0x 109/L (<1000/mm3) or platelet 
count <75x 109/L (<75,000/mm3) or lymphocyte count 
<500/mm3 (<0.5x109/L) must be repeated as soon as
feasible and within 3 days.
Rationale: The requirement to repeat an absolute 
neutrophil count <1.0x 109/L (<1000/mm3) or platelet 
count <75x 109/L (<75,000/mm3) or lymphocyte count 
<500/mm3 (<0.5x109/L) as soon as feasible and within 
3 days is to ensure that these laboratory abnormalities are 
followed up on in a timely manner and appropriate 
actions taken in case of subsequent abnormal values.

Section 6.5, Guidelines for Monitoring and 
Discontinuations, added criteria to state that subjects who 
are inadequately responding to investigational product in 
the opinion of the investigator should be withdrawn from 
the study.
Rationale: In order to provide additional direction to PIs 
and further ensure subject safety, subjects who are 
inadequately responding to investigational product in the 
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study.

Section 7.2.13, Electrocardiogram revised to include a 
statement defining QTc prolongations.
Rationale: In order to provide additional guidance to 
investigators, QTc prolongations are defined as a QTc 
≥480 msec or an absolute change in QTc ≥60 msec.

Section 9.5, Interim Analysis is revised to incorporate 
futility stopping guidelines and remove reference to 
re-estimation of sample size. 
Rationale: Futility stopping guidelines are incorporated 
for transparency.  References to re-estimation of sample 
size is removed for internal business and operational 
aspects.  The adjustment of the randomization ratio is no 
longer an option for the interim analysis.
Amendment 1
27 Octobe
r 2016

In the Schedule of Activities, Section 6 Study 
Procedures, and Section 7.2.12 Audiogram, added 
audiogram assessments at regular intervals.
Rationale: Audiogram assessments are included at regular 
intervals to monitor for potential hearing changes.

In the Schedule of Activities and Section 6 Study 
Procedures, added Serum Cystatin C (and eGFR) at all 
time points.
Rationale: Serum Cystatin C (and eGFR) assessed at all 
time points to facilitate interpretability of any findings in 
individual subjects.

In the Schedule of Activities, Section 6.5 Guidelines for 
Monitoring and Discontinuations,
Section 7.2.2 Creatinine and Cystatin C, and 
Section 8.4.3 Potential Cases of Decreased eGFR, 
removed statement that a creatinine increase above the 
ULN will trigger a reflex test for serum cystatin-C in 
order to facilitate both serum cystatin-C based, and serum 
creatinine based eGFR calculation.
Rationale: Serum Cystatin C (and eGFR) assessed at all 
time points to facilitate interpretability of any findings in 
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
Section 7.2.2 Creatinine and Cystatin C, clarified that 
creatinine elevations above the ULN will be followed 
until resolution or baseline.
Rationale: Creatinine levels above the ULN will be 
followed until resolution or baseline to monitor subject 
safety.

In the Schedule of Activities and Section 6 Study 
Procedures, added that the screening urinalysis will 
include a spot urine albumin/creatinine ratio.
Rationale: Urine albumin/creatinine ratio included at 
screening to further ensure subject safety is fully 
evaluated prior to study entry.

In the Schedule of Activities, Section 5.3, Subject 
Compliance, Section 5.5, Administration, and Section 6, 
Study Procedures, removed reference to subject dosing 
diary.
Rationale: All references to subject dosing diary have 
been removed as dosing compliance will be monitored by 
tablet counts. 
 
 
 
 
 
 
 

Section 4.1, Inclusion Criteria, added definition of 
intolerance to anti-TNF inhibitors.
Rationale: Definition of anti-TNF inhibitors added to 
clarify criteria for inclusion to ensure appropriate study 
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population is enrolled.

Section 4.1, Inclusion Criteria, Section 4.2 Exclusion 
Criteria, Section 5.8.2, Permitted Medications, and 
Section 5.8.3, Prohibited Medications, increased the
dosage of prednisone permitted to <25 mg/day.
Rationale: Prednisone dose increased to 25 mg/day to 
more closely identify with clinical practice as well as help 
with study recruitment. 

Section 4.2, Exclusion Criteria, added the following 
exclusions: subjects with active renal disease, including 
recent kidney stones and subjects with severe hepatic 
impairment (defined as Child-Pugh C).
Rationale: Subjects with active renal disease, including
recent kidney stones and subjects with sever hepatic 
impairment (defined as Child-Pugh C) are excluded from 
participation to ensure subject safety is fully evaluated 
prior to study entry.

Section 4.2, Exclusion Criteria, added exclusion of 
subjects with current or recent history of clinically 
significant severe, progressive hearing loss or auditory 
disease.
Rationale: Subjects with current or recent history of 
clinically significant severe, progressive hearing loss or 
auditory disease are excluded from participation to 
exclude subjects in whom any further reduction in 
hearing ability would have the greatest impact.

Section 4.2, Exclusion Criteria and Section 5.8.3, 
Prohibited Medications, added exclusion of subjects 
receiving strong P-gp inhibitors and subjects receiving 
drugs that are substrates of MDRI (eg, digoxin), OCT2 or 
MATE (dofetilide) which have a narrow therapeutic 
index.
Rationale: Subjects receiving strong P-gp inhibitors and 
drugs that are substrates of MDRI (eg, digoxin), OCT2 or 
MATE (dofetilide) are excluded from participation in the 
study to limit any potential interactions with the 
investigational product.

Section 4.2, Exclusion Criteria, modified the lymphocyte 


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count and hemoglobin criteria for study entry and added 
an exclusion subjects with ≥3+ proteinuria. 
Rationale: The lymphocyte count and hemoglobin criteria 
are modified and exclusion of subjects with 
≥3+ proteinuria is added to ensure that subjects entering 
the study are not put at additional risk of experiencing 
CTCAE Grade 3 adverse events by entering the study 
with these laboratory values on the lower end of the 
normal range. 

Section 5.8.1, Oral Corticosteroids, removed requirement 
for subject to record oral corticosteroids on a daily diary.
Rationale: To eliminate duplication of effort and for ease 
of subject, there is no need for daily diary collection of 
corticosteroids.  This data will be captured on the CRF.

Section 6.5, Guidelines for Monitoring and 
Discontinuations, added that treatment with 
investigational product will be discontinued and the 
subject withdrawn from the study if they have 
symptomatic anemia and a hemoglobin of <7 g/dL or any 
anemia requiring a blood transfusion.
Rationale: Subjects with symptomatic anemia and a 
hemoglobin of <7 g/dL or any anemia requiring a blood 
transfusion will be discontinued from the study to further 
evaluate subject safety and feasibility of continuation 
based on emerging data.

Section 6.5, Guidelines for Monitoring and 
Discontinuations, added that treatment with 
investigational product will be discontinued and subject 
withdrawn from the study if there is an AST or ALT 
elevation ≥3 times the upper limit of normal with an INR 
>1.5.
Rationale: Subjects who develop an AST or ALT 
elevation ≥3 times the upper limit of normal with an INR 
>1.5 will be discontinued from the study to further 
evaluate subject safety and feasibility of continuation 
based on emerging data.

Section 6.5, Guidelines for Monitoring and 
Discontinuations, added that any clinically meaningful, 
treatment related decline in hearing from baseline will 
result in the subject being discontinued from treatment 
with investigational product and withdrawn from the 


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study.
Rationale: Subjects who develop a clinically meaningful, 
treatment related decline in hearing from baseline will be 
discontinued from treatment and withdrawn from the 
study to further evaluate subject safety.

Section 7.2.11 Medical History, Physical Examination, 
Height and Weight, clarified that both complete and 
targeted physical examinations include full body skin 
examinations.  Additionally, clarified that skin 
examinations should include visual inspection of the 
breasts and external genitalia.
Rationale: Full body skin examinations, including the 
breast and external genitalia are required to ensure subject 
safety and monitor for any dermatological adverse events.

Section 9.6 Data Monitoring Committee, added a 
statement that the E-DMC will review accumulating renal 
safety data and propose changes to the protocol as needed 
to ensure subject safety.
Rationale: The E-DMC will review accumulating renal 
safety data and propose changes to the protocol as needed 
to ensure subject safety on an ongoing basis and amend 
the protocol as requiring based on emerging safety data.

Minor administrative changes and sentence revisions 
made throughout the document.
Rationale: Revisions made for clarity and to correct 
minor grammatical or spelling errors.
Original 
Protocol 
29 August
2016
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................30
APPENDICES .........................................................................................................................31
PROTOCOL SUMMARY.......................................................................................................32
SCHEDULE OF ACTIVITIES................................................................................................38
1. INTRODUCTION ...............................................................................................................43
1.1. Background and Rationale ......................................................................................44
1.2. Non-Clinical Pharmacokinetics and Metabolism....................................................44
1.3. Non-Clinical Safety Studies....................................................................................46
1.4. Summary of Clinical Experience ............................................................................47
1.4.1. Summary of Clinical Experience of PF-06651600.....................................47
1.4.1.1. Summary of Clinical Safety of PF-06651600...........................47
1.4.2. Summary of Clinical Experience with PF-06700841.................................62
1.4.2.1. Summary of Clinical safety of PF-06700841............................62
1.4.2.2. Pharmacokinetics of PF-06700841 ...........................................75
1.5. Rationale..................................................................................................................77
1.5.1. Study Rationale...........................................................................................77
1.5.2. Dose Rationale............................................................................................79
1.5.3. PF-06651600 Dose Rationale.....................................................................79
1.5.4. PF-06700841 Dose Rationale.....................................................................80
1.5.5. Summary of Benefits and Risks .................................................................81
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................82
2.1. Objectives and Endpoints during the Induction Period...........................................82
2.2. Objectives and Endpoints during the Chronic Period .............................................84
3. STUDY DESIGN.................................................................................................................86
3.1. Study Overview.......................................................................................................86
3.2. Duration of Subject Participation............................................................................87
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3.3. Approximate Duration of Study..............................................................................88
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................88
4.1. Inclusion Criteria.....................................................................................................88
4.2. Exclusion Criteria....................................................................................................90
4.3. Lifestyle Requirements ...........................................................................................96
4.3.1. Contraception..............................................................................................96
4.3.2. Dietary Restriction......................................................................................97
4.4. Sponsor’s Qualified Medical Personnel..................................................................98
5. STUDY TREATMENTS.....................................................................................................98
5.1. Allocation to Treatment ..........................................................................................98
5.2. Breaking the Blind ..................................................................................................99
5.3. Subject Compliance.................................................................................................99
5.4. Investigational Product Supplies.............................................................................99
5.4.1. Dosage Form(s) and Packaging..................................................................99
5.4.2. Preparation and Dispensing......................................................................100
5.5. Administration.......................................................................................................100
5.6. Investigational Product Storage ............................................................................101
5.7. Investigational Product Accountability.................................................................101
5.7.1. Destruction of Investigational Product Supplies ......................................102
5.8. Concomitant Treatment(s).....................................................................................102
5.8.1. Oral Corticosteroids..................................................................................102
5.8.2. Permitted Medications..............................................................................102
5.8.3. Prohibited Medications.............................................................................103
5.8.4. Vaccinations .............................................................................................104
5.9. Rescue Medication ................................................................................................105
6. STUDY PROCEDURES ...................................................................................................105
6.1. Screening...............................................................................................................105
6.2. Study Period (Induction) .......................................................................................108
6.2.1. Baseline/(Week 0/Day 1)..........................................................................108
6.2.2. Week 2 (±2 Days).....................................................................................110
6.2.3. Week 4 (±2 Days).....................................................................................111
6.2.4. Week 8 (±2 Days).....................................................................................112


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6.3. Study Period (Chronic Therapy) ...........................................................................114
6.3.1. Week 12 (±4 Days)...................................................................................114
6.3.2. Week 16 (±4 Days)...................................................................................115
6.3.3. Week 20 (±4 Days)...................................................................................116
6.3.4. Week 24 (±4 Days)...................................................................................117
6.3.5. Week 32 (±4 Days)/Early Termination Visit............................................118
6.3.6. Follow-up Visit (Week 36±7 Days) .........................................................119
6.4. Subject Withdrawal...............................................................................................120
6.4.1. Withdrawal of Consent.............................................................................120
6.4.2. Lost to Follow-up .....................................................................................121
6.5. Guidelines for Monitoring and Discontinuations..................................................121
7. ASSESSMENTS................................................................................................................124
7.1. Blood Volume .......................................................................................................124
7.2. Safety.....................................................................................................................125
7.2.1. Laboratory.................................................................................................125
7.2.2. Creatinine and Cystatin C.........................................................................126
7.2.3. Estimated Glomerular Filtration Rate.......................................................126
7.2.4. Pregnancy Testing ....................................................................................126
7.2.5. Mantoux/Purified Protein Derivative (PPD) Tuberculin Test..................127
7.2.6. Interferon Gamma Release Assay Tuberculin Test..................................127
7.2.7. Screening for Clostridium Difficile ..........................................................128
7.2.8. Infections ..................................................................................................128
7.2.10. Vital Signs (Blood Pressure, Pulse Rate, and Temperature) ..................129
7.2.11. Medical History, Physical Examination, Height and Weight.................130
7.2.11.1. Dermatology/Skin .................................................................130
7.2.12. Audiogram ..............................................................................................132
7.2.13. Electrocardiogram...................................................................................132
7.2.14. Chest Radiograph....................................................................................133
7.3. Diagnostic and Efficacy Assessments...................................................................133
7.3.1. Endoscopy.................................................................................................133
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7.3.2. Subject Stool Diary...................................................................................135
7.3.3. Mayo Score...............................................................................................135
7.3.4. Partial Mayo Score ...................................................................................137
7.3.6. Patient Reported Outcomes (PRO) for Health Outcomes Assessment ....137
7.3.6.1. Inflammatory Bowel Disease Questionnaire (IBDQ) .............138
7.3.6.2. Short Form – 36, Version 2, Acute (SF-36)............................138
7.3.6.3. Euro Quality of Life Questionnaire 5 Dimensions 
3 Levels and Visual Analog Scale (EQ-5D-3L & VAS).................138
7.4. Pharmacodynamics................................................................................................139
7.4.1. High-Sensitivity C-Reactive Protein (hsCRP)..........................................139
7.4.5. Fecal Calprotectin.....................................................................................140
8. ADVERSE EVENT REPORTING....................................................................................143
8.1. Requirements.........................................................................................................143
8.1.1. Additional Details on Recording Adverse Events on the CRF.................144
8.1.2. Eliciting Adverse Event Information........................................................144
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)..........................................................................144
8.1.4. Time Period for Collecting AE/SAE Information....................................144
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................145
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8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............145
8.1.5. Causality Assessment ...............................................................................145
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................145
8.2. Definitions.............................................................................................................146
8.2.1. Adverse Events.........................................................................................146
8.2.2. Abnormal Test Findings ...........................................................................146
8.2.3. Serious Adverse Events ............................................................................147
8.2.4. Hospitalization..........................................................................................147
8.3. Severity Assessment..............................................................................................149
8.4. Special Situations ..................................................................................................149
8.4.1. Protocol-Specified Serious Adverse Events.............................................149
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................149
8.4.3. Potential Cases of Decreased eGFR .........................................................151
8.4.4. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................152
8.4.4.1. Exposure During Pregnancy....................................................152
8.4.4.2. Exposure During Breastfeeding ..............................................153
8.4.4.3. Occupational Exposure ...........................................................153
8.4.5. Medication Errors .....................................................................................154
8.4.5.1. Medication Errors....................................................................154
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................154
9.1. Sample Size Determination...................................................................................155
9.2. Efficacy Analysis ..................................................................................................155
9.2.1. Analysis of the Primary Endpoint During Induction Period ....................155
9.2.2. Analysis of Secondary Endpoints During Induction Period.....................156
9.2.3. Analysis of Secondary Endpoints During Chronic Period .......................156
9.3. Analysis of Other Endpoints During Induction and Chronic Period ....................156
9.3.1. Pharmacokinetic Analysis During Induction and Chronic Period............156
9.3.2. PK/PD Unblinding Plan............................................................................157
9.3.3. Biomarkers Unblinding Plan ....................................................................157
9.4. Safety Analysis During the Induction and Chronic Period...................................157
9.5. Interim Analysis ....................................................................................................158


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9.6. Data Monitoring Committee .................................................................................158
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................158
11. DATA HANDLING AND RECORD KEEPING ...........................................................159
11.1. Case Report Forms/Electronic Data Record .......................................................159
11.2. Record Retention.................................................................................................160
12. ETHICS............................................................................................................................160
12.1. Institutional Review Board/Ethics Committee....................................................160
12.2. Ethical Conduct of the Study ..............................................................................161
12.3. Subject Information and Consent........................................................................161
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................162
13. DEFINITION OF END OF TRIAL.................................................................................162
13.1. End of Trial in a Member State...........................................................................162
13.2. End of Trial in All Other Participating Countries...............................................162
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................162
15. PUBLICATION OF STUDY RESULTS........................................................................162
15.1. Communication of Results by Pfizer ..................................................................162
15.2. Publications by Investigators ..............................................................................163
16. REFERENCES ................................................................................................................165
LIST OF TABLES
 
 
 
 
 
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Table 6.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06651600 Pharmacokinetic and Pharmacodynamic Parameters 
During the Induction and Chronic Periods of Multiple Dose 
Administration..........................................................................................79
Table 7.
Summary of the Predicted Average Percent In Vitro Signaling 
Inhibition Following Multiple Dose Administration................................80
Table 8.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06700841 Pharmacokinetic and Pharmacodynamic Parameters 
During the Induction and Chronic Periods of Multiple Dose 
Administration..........................................................................................80
Table 9.
Management of Dermatological Events .................................................131
APPENDICES
Appendix 1. Supplementary information for Inclusion Criteria 5.........................................167
Appendix 2. Prohibited Concomitant Medications................................................................169
Appendix 3. Common Terminology Criteria for Adverse Events 
v4.0 (CTCAE)-Dermatology..................................................................171
Appendix 4. Mayo Scoring System for Assessment of Ulcerative Colitis Activity..............172
Appendix 5. Inflammatory Bowel Disease Questionnaire (IBDQ).......................................173
Appendix 6. Short Form -36, version 2, acute (SF-36) .........................................................185
Appendix 7. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and Visual 
Analog Scale (EQ-5D-3L & VAS).........................................................191
Appendix 9. Summary of corticosteroid equivalents.............................................................194
Appendix 10. Alternative Measures During Public Emergencies .........................................195
Appendix 10.1. Eligibility......................................................................................................195
Appendix 10.2. TeleHealth Visits..........................................................................................195
Appendix 10.3. Alternative Facilities for Safety Assessments..............................................196
Appendix 10.3.1. Laboratory Testing....................................................................................196
Appendix 10.4. Investigational Product.................................................................................196
Appendix 10.5. Home Health Visits......................................................................................196
Appendix 10.6. Adverse Events and Serious Adverse Events...............................................197
Appendix 10.7. Patient Reported Outcomes (PROs).............................................................197
Appendix 11. Abbreviations..................................................................................................199
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PROTOCOL SUMMARY
Background and Rationale:
The Janus kinase (JAK) family kinases mediate signal transduction via interactions with 
type I and type II cytokine receptors.  Upon binding of the cytokine to its receptor, the 
associated JAKs are activated, and phosphorylate each other and the receptor.  The 
phosphorylated receptors serve as docking sites for the signal transducers and activators of 
transcription (STAT) family (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and 
STAT6) of transcription factors.  The STATs are then phosphorylated by the co-localized 
JAKs, which stabilize homo- or heterodimeric STAT complexes that translocate the nucleus 
where they bind to specific gene promoters and activate transcription of a range of target 
genes.
PF-06651600 (ritlecitinib) is an orally bioavailable small molecule that selectively inhibits
JAK3 by irreversibly blocking the adenosine triphosphate (ATP) binding site without 
significantly inhibiting the other three JAK isoforms (JAK1, JAK2, and TYK2).  
PF-06651600 also inhibits irreversibly the tyrosine kinase expressed in hepatocellular 
carcinoma (TEC kinase) family (BTK, bone marrow tyrosine kinase on chromosome 
X (BMX), (interleukin-2-inducible T-cell kinase) ITK, TEC, and tyrosine kinase expressed in 
T cells (TXK)), with high selectivity over the broader kinome.  The selective inhibition of 
JAK3 will lead to modulation of -common chain cytokine pathways, such as IL-7, IL-9, 
IL-15 and IL-21, which have been implicated in the pathophysiology of ulcerative colitis 
(UC).  Furthermore, in vivo PF-06651600 will spare signaling of key immunoregulatory 
cytokines, such as IL-10, IL-27 and IL-35, which have been shown to be critical to maintain 
immune homeostasis in the digestive tract.  Finally, TEC kinase inhibition will impact cluster 
of differentiation 8 (CD8)+ T and natural killer (NK) cells cytotoxic functions, which play a 
role in the pathogenesis of Inflammatory Bowel Disease (IBD).  Taken together, it is 
hypothesized that PF-06651600 could be efficacious in the treatment of UC.
PF-06700841 (brepocitinib) is an orally bioavailable, small molecule, potent dual inhibitor of 
human tyrosine-protein kinase 2 (TYK2) and JAK1.  JAK1 inhibition will impact the 
signaling of pro-inflammatory cytokines such as interferon (IFN)-gamma and cytokines 
signaling through the -common chain receptor such as IL-7, IL-9, IL-15 and IL-21, while 
the inhibition of TYK2 will block the production of pro-inflammatory cytokines 
interferon-gamma and IL-17 through upstream inhibition of the IL-12/Th1 and 
IL-23/Th17 pathways.  Taken together, it is hypothesized that dual inhibition of both 
TYK2 and JAK1 could be efficacious in the treatment of UC.
Both PF-06651600 and PF-06700841 are under development as induction and chronic 
therapy for the treatment of inflammatory bowel disease (IBD).


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Objectives and Endpoints:
Objectives and Endpoints during the Induction period.
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 8 in subjects with moderate to 
severe UC.

Total Mayo score at Week 8.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in induction.  

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 
12-lead ECG in the induction period. 

Incidence of serious infections (see Section 7.2.8 for 
definition) in the induction period.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in induction of remission at Week 8 in 
subjects with moderate to severe UC.

Proportion of subjects achieving remission* based on 
total Mayo score of ≤2 with no individual subscore 
>1 and a rectal bleeding subscore of 0 at Week 8.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 8 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in 
endoscopic appearance (defined as a Mayo 
endoscopic subscore of ≤1) at Week 8.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction of other clinical outcomes
in subjects with moderate to severe UC.

Proportion of subjects achieving clinical response at 
Week 8.

Proportion of subjects in endoscopic remission at 
Week 8.

Proportion of subjects in symptomatic remission at 
Week 8.

Proportion of subjects achieving deep remission at 
Week 8.

Partial Mayo scores and change from baseline over 
time at Weeks 2, 4 and 8.

Change from baseline at Week 8 in total Mayo score.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction on patient reported 
outcomes (PRO) in subjects with moderate to severe 
UC.

The scores and change from baseline in 
Inflammatory Bowel Disease Questionnaire (IBDQ) 
Total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and Social 
Function) at Weeks 4 and 8.

The proportion of subjects with IBDQ total score 
≥170 at Weeks 4 and 8.

The proportion of subjects with ≥16 point increase in 
IBDQ total score from baseline at Weeks 4 and 8.

Proportion of subjects with improvement in IBDQ 
bowel symptom domain at Weeks 4 and 8.  The 
improvement is defined as an increase of at least 
1.2 points from baseline in average score among 
IBDQ bowel symptom domain (items 1, 5, 9, 13, 17, 


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20, 22, 24, 26, 29).

The scores and change from baseline in Short 
Form 36 version 2, acute (SF-36v2) (physical and 
mental component summary scores: PCS & MCS, 
and 8 domain scores) at Weeks 4 and 8.

The scores and change from baseline in EuroQoL 
5 Dimensions (EQ-5D-3L & EQ-5D VAS) at 
Weeks 4 and 8.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
 
 

To assess the effect of PF-06651600 and 
PF-06700841 compared to placebo on disease and 
mechanistic biomarkers over time during induction. 

Change from baseline in serum hsCRP levels over 
time.

Change from baseline in fecal calprotectin.
 

Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets, 
.

To explore outcomes based on investigational criteria 
in induction.

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus 
PGA).

Proportion of subjects with partial Mayo score 
≤2 with no individual subscore >1 in response to 
treatment over time.

Proportion of subjects with reduction of ≥2 points 
from baseline in partial Mayo score over time.

Proportion of subjects in endoscopic response at 
Week 8.  Endoscopic response is defined by a 
decrease from baseline in the endoscopic subscore of 
1 point or more.
 
 
 
 
 
 
 
 
*Remission in total Mayo score excludes friability (Refer to Section 7.3.3).
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Objectives and Endpoints during the Chronic period.
Primary Objective(s):
Primary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in the chronic period.

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 
12-lead ECG in the chronic period. 

Incidence of serious infections (see Section 7.2.8 for 
definition) in the chronic period.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 32 in subjects with moderate to 
severe UC.

Total Mayo score at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 for achieving remission at Week 32.

Proportion of subjects in remission* based on total 
Mayo score of ≤2 with no individual subscore >1 and 
a rectal bleeding subscore of 0 at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 32 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in 
endoscopic appearance (defined as a Mayo 
endoscopic subscore of ≤1) at Week 32.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
 
 
 
 

To explore the effect of PF-06651600 and 
PF-06700841 in subjects with moderate to severe UC 
in the chronic dosing period.

Proportion of subjects achieving clinical response at 
Week 32.

Proportion of subjects in endoscopic remission at 
Week 32.
 
 

Change from baseline at Week 32 in total Mayo 
score.

 
 
 
 
 
 
 
 
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
To assess the effect of PF-06651600 and 
PF-06700841 compared to placebo on disease and 
mechanistic biomarkers over time during chronic 
period.

Change from baseline in serum high-sensitivity 
C-reactive protein (hsCRP) levels over time.

Change from baseline in fecal calprotectin.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets, and T-cell, B-cell, 
 
.

To explore outcomes based on investigational criteria 
in the chronic period.

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus 
Physician’s global assessment (PGA)) at Week 32.
 
 
 
 
 
 
 
 
 
 
 
 
 
*Remission in total Mayo score excludes friability (Refer to Section 7.3.3).
Study Design and Treatments:
This is a Phase 2b, randomized, double-blind, placebo-controlled (for induction period and 
not for chronic dosing (ie, chronic therapy)), parallel group, multicenter study in subjects 
with moderate to severe active UC.  The first part of the study is a screening period of up to 
6 weeks followed by an 8 week double-blind induction period.  At Week 8, all subjects will 
continue within their respective treatment cohort (PF-06651600 or PF-06700841) into an 
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additional 24 week active chronic dosing period followed by a 4 week follow up period after 
the last dose of investigational product for a total of 36 weeks.  Total duration of the study 
will be approximately 42 weeks, including screening.  Approximately 318 subjects in total 
will be randomized into the study.  Following the screening period, subjects who meet the 
eligibility criteria at the baseline visit will be randomly assigned to receive one of 
8 treatments.  Three oral dose levels (20, 70, and 200 mg daily) of PF-06651600 plus 
matching placebo in a 4:4:4:1 ratio and three oral dose levels (10, 30, and 60 mg daily) of 
PF-06700841 plus matching placebo in a 4:4:4:1 ratio will be investigated. For analysis of 
the induction period, placebo groups will be combined to yield drug:placebo ratios of 
2:2:2:1 for each drug at Week 8.  See Section 3.1.
During the chronic dosing period, all subjects from the induction period PF-06651600 cohort 
(including subjects who received placebo) will receive 50 mg of PF-06651600, while all 
subjects from the induction period PF-06700841 cohort (including subjects who received 
placebo) will receive 30 mg of PF-06700841 for 24 weeks.  After completion of the chronic 
dosing period, subjects will enter the 4-week follow up period.
Any subject who discontinues early from the induction period prior to the Week 8 visit 
should undergo the procedures for an Early Termination visit on the last day the subject takes 
the investigational product or as soon as possible thereafter, and will not be permitted to enter 
the chronic dosing period.  For subjects who discontinue early from the chronic dosing
period (after the Week 8 visit, but prior to the Week 32 visit), the procedures scheduled for 
an Early Termination visit will be performed on the last day the subject takes the 
investigational product or as soon as possible thereafter.  After completion of the Early 
Termination visit subjects will enter the follow-up period.
Statistical Methods:
The primary efficacy analysis will be conducted on total Mayo score at Week 8. 
Analysis will include data from all active arms and combined placebo.
Analysis details will be outlined in statistical analysis plan.
The primary analysis at Week 8 will be based on constrained Longitudinal Data Analysis 
(cLDA) using Total Mayo score. Other statistical analysis methods will include fitting 
bayesian emax model for dose-response estimation after conducting Bayesian predictive 
checks on monotonicity.
The primary analysis will be conducted on the intention-to-treat (ITT) population, defined as 
all randomized subjects who received at least one dose of investigational product or placebo.  
Sensitivity analysis handling of the missing values (including subjects who are missing due 
to COVID-19) will be outlined in the statistical analysis plan (SAP).


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. Refer to Appendix 10 for Alternative Measures 
During Public Emergencies if applicable.
Study Procedure
Screening Baseline
Induction Period
Chronic Dosing Period
Follow-up
Visit Identifiera
Week -1 to 
-6
Week
0
Week 
2
Week 
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week 32/
Early Terminationb
Week 36
Study Day/Visit Window Day -42 -0
1
15±2
29±2
57±2
85±4
113±4
141±4
169±4
225±4
253±7
Informed consent
X
Medical historyc
X
Complete physical 
examinationd
X
X
X
X
Targeted physical 
examinationd
X
X
X
X
X
X
X
Audiogram
X
Xe
Xe
Xe
Vital signs & temperaturef
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGf
X
X
X
Heightg
X
Weightg
X
X
Chest radiographh
X
Laboratory
Hematology
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
HbA1C
X
Fasting Lipid Paneli
X
X
X
X
X
X
X
X
X
X
X
Cystatin C (and eGFR)
X
X
X
X
X
X
X
X
X
X
Urinalysisj
Xk
X
X
X
X
X
X
X
X
X
X
Stool microbiologyl
X
(HBsAg, HBcAb, HBsAb, 
HCV Ab, HCV RNA)m
X
HIV serology
X
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Study Procedure
Screening Baseline
Induction Period
Chronic Dosing Period
Follow-up
Visit Identifiera
Week -1 to 
-6
Week
0
Week 
2
Week 
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week 32/
Early Terminationb
Week 36
Study Day/Visit Window Day -42 -0
1
15±2
29±2
57±2
85±4
113±4
141±4
169±4
225±4
253±7
Serum -HCGo
X
Urine -HCGo
X
X
X
X
X
X
X
X
X
X
Tuberculosis screeningp
X
hsCRP
X
X
X
X
X
X
Fecal calprotectinq
X
X
X
X
X
X
Contraception check 
X









X
Eligibility assessment
X
X
Randomization
X
X
Study treatment
Investigational product 
dispensing
X
X
X
X
X
X
X
X
Investigational product 
accountability
X
X
X
X
X
X
X
X
Investigational product 
dosing (at site)
X
X
X
X
X
X
X
X
X
Assessments
Endoscopy (flexible 
sigmoidoscopy or 
colonoscopy) and intestinal 
tissue biopsiess
Xt
Xu
Xu
Bowel movement diary, 
instruction/review 
datav
X
X
X
X
X
X
X
X
X
X
Mayo score
Xw
X
X
Partial Mayo score
X
X
X
X
X
X
X
X
X
IBDQ
X
X
X
X
SF-36 v.2, acute
X
X
X
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Study Procedure
Screening Baseline
Induction Period
Chronic Dosing Period
Follow-up
Visit Identifiera
Week -1 to 
-6
Week
0
Week 
2
Week 
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week 32/
Early Terminationb
Week 36
Study Day/Visit Window Day -42 -0
1
15±2
29±2
57±2
85±4
113±4
141±4
169±4
225±4
253±7
EQ-5D-3L & EQ-5D-VAS
X
X
X
X
Prior/Concomitant 
Treatment(s)
X
X








X
Serious and non-serious 
adverse event monitoring
X









X
Abbreviations: = ongoing/continuous event; -HCG = beta human chorionic gonadotropin; ECG = electrocardiogram; eGFR = estimated glomerular filtration 
rate; EQ-5D-3L-VAS = Euro quality of life questionnaire 5 dimensions 3 levels and visual analog scale; 
 
FSH = follicle stimulating hormone; HbA1C = Glycosylated hemoglobin; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface 
antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C antibody; HCV RNA = hepatitis C virus ribonucleic acid; HDL= high-density lipoprotein;
HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; IBDQ = inflammatory bowel disease questionnaire;
 
 LDL=low-density lipoprotein;
 
 SF-36 = short form 36; 
a.
Day relative to start of study treatment (Day 1).
b.
For subjects who discontinue early from either the induction (double-blind period prior to Week 8 visit), or from the chronic dosing period (after Week 8 and
prior to the Week 32 visit), the procedures scheduled for Week 32/ET will be performed on the last day the subject takes the investigational product or as 
soon as possible thereafter before entering the follow-up period.
c.
Medical history includes detailed histories of conditions specified in Study Procedures Section 6.1.
d.
Complete physical examination consists of general appearance, skin, head, eyes, ears, nose and throat (HEENT), heart, lungs, breast (optional), abdomen, 
external genitalia (optional), extremities, neurologic function, back, and lymph nodes.  Targeted physical examination consists of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by the subject.  Full and targeted physical examinations must include a full 
body skin examination.  Skin examinations should include visual inspection of the breasts and external genitalia to assess for rashes, even if a subject does 
not wish to have the examination of breast and/or external genitalia (these are optional) done as a part of the physical examination.
e.
Audiograms may be performed within a ±2 week window relative to study visit.
f.
Vital signs (including temperature) and ECG should be performed before laboratory blood collection and endoscopic procedure. 
g.
Height and weight will be measured without shoes.
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h.
If not performed within the 12 weeks prior to screening.  Copy of the report must be available in the source document if previously performed.  If a subject 
had a CT scan of the chest (with or without IV contrast) within 12 weeks prior to screening, the CT scan results can substitute for chest radiograph results
(see Section 7.2.14).
i.
Includes fasting cholesterol, triglycerides, HDL, and LDL.
j.
Dipstick in all cases; microscopy analysis is indicated if urinalysis is positive for blood, nitrite, leukocyte esterase and/or protein.  Urine culture is performed 
if urinalysis is positive for nitrite and/or leukocyte esterase or if clinically indicated.
k.
Screening urinalysis will include spot urine albumin/creatinine ratio.
l.
Stool microbiology (stool culture for enteric pathogens, ova and parasites, and Clostridium difficile toxin test), if not performed within 6 weeks prior to 
screening, should be prior to administration of any bowel prep for endoscopy.
m. Subjects who are HBsAg negative and HBcAb positive will be reflex tested for HBsAb. Subjects who are HCV Ab positive require further testing with 
HCV RNA. See Section 4.2 for details.
n.
To be done in postmenopausal females only (females who are amenorrheic for at least 12 consecutive months).
o.
Only for women of childbearing potential.  If serum pregnancy test is borderline positive, the central lab will run a FSH test to confirm menopause.
p.
If not performed within 12 weeks prior to screening (see Assessments Section 7.2.5 for details).
q.
Collection of stool for 
 fecal calprotectin analyses should be prior to administration of any bowel prep for endoscopy.
 
 
s.
At each biopsy collection time point, the 7 biopsies should be taken for the analyses described: 6 from abnormally inflamed colonic mucosa and 1 from 
normal appearing colonic mucosa (if possible) in a targeted manner from the most affected area 15-30 cm from the anal verge in the colon.  
 
t.
For subject at risk for colorectal cancer, a colonoscopy is required instead of flexible sigmoidoscopy if not performed within the specified time period (see 
Section 4.2). Only one endoscopy (either colonoscopy or flexible sigmoidoscopy) needs to be done for a subject within 10 days prior to baseline visit. This 
should preferably be done within 5 to 7 days prior to baseline to allow stool data collection for Mayo score calculation and also to obtain endoscopic 
subscore report from the central reader. The centrally read endoscopic subscore will be used to determine eligibility.
u.
Week 8 and Week 32/early withdrawal endoscopy to be performed at the Week 8 and Week 32/early withdrawal visit to site, but may be performed up 
to -7 days prior if necessary (see Section 7.3.1). Colonoscopy should be performed at the Early Termination (ET) visit unless the previous colonoscopy was 
less than 8 weeks prior to this.
v.
Bowel movement diary instructions will be provided at screening.  The bowel movement diary to collect BM frequency and rectal bleeding should be 
collected daily beginning approximately 2 weeks prior to screening endoscopy.
w.
Mayo score at Week 0 will be calculated based on stool frequency, rectal bleeding, and centrally read endoscopic subscores for the endoscopy performed 
during the screening period and the PGA obtained at baseline. 
 
 
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1. INTRODUCTION
IBD is a chronic inflammatory condition of the gastrointestinal tract that affects five million 
people worldwide.  IBD presents as one of two major forms, UC or Crohn’s disease (CD).  
UC is characterized by continuous inflammation that is localized to the colon.  CD is 
characterized by discontinuous inflammation that can affect the entire gastrointestinal tract 
from mouth to anus and may be associated with long-term debilitating sequelae, such as 
fistulae and intestinal strictures.
The incidence of UC reported in the past 20 years varies by location.  Reported rates in North 
America range from about 8-19, in South America from 1.5-2.6, in Asia and the Middle East 
from 0.6-4.4, in Western Europe from 2.3-17.5, in Eastern Europe from 0.8-5.9, and in 
Australia/New Zealand, from 7.6-17.4 per 100,000 person-years.  The prevalence of UC in 
the same time period, by geographic region, ranged from 155.8-248.6 in North America, was 
76.1 in a single report from South America, from 4.9-168.3 in Asia and the Middle East, 
from 4.9-294 in Northern and Western Europe, from 2.42-101 in Eastern Europe and 145 in 
Australia and New Zealand per 1,000,000 persons.  Globally there does not appear to be a 
gender difference in incidence of UC.1
Although UC can occur at any age, the incidence peaks between 15 to 25 years with a second 
peak between 55 to 65 years.2 UC is a lifelong condition with a serious effect on the quality 
of life. 
Current IBD treatments include aminosalicylates, corticosteroids, immunosuppressants, and 
monoclonal antibodies against tumor necrosis factor (TNF)-or 47 integrin.  Despite 
multiple therapies being available, limitations remain in the treatment of IBD, and patients 
continue to have symptoms or develop intolerance to or side effects from their treatment 
regimens.  Because of the significantly reduced risk for immunogenicity and the potential for 
oral administration, small molecule inhibitors have emerged as an attractive therapeutic 
modality.  Tofacitinib is a JAK inhibitor with broad specificity, mainly targeting JAK1 and 
JAK3, with lesser effects on JAK2, and therefore affects multiple cytokine signaling 
pathways.  Tofacitinib has been approved for use in rheumatoid arthritis and has 
demonstrated significant differences in clinical response and remission in comparison to
placebo in subjects with UC.3 Pfizer’s plan is to test multiple selective kinase inhibitor assets 
simultaneously in the UC disease setting, which in this trial will include a JAK3-specific 
inhibitor and a TYK2/JAK1-specific inhibitor in the context of a single clinical study.  Each 
arm of the study will address a biologically distinct question.  The JAK3-specific arm will 
address the involvement of cytokines that signal through JAK3 in UC, and the 
TYK2/JAK1-specific arm will address the involvement of cytokines that signal through 
TYK2 and JAK1 in UC.
Both PF-06651600 and PF-06700841 avoid specific targeting of JAK2, thus reducing the 
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1.1. Background and Rationale
The JAK family kinases mediate signal transduction via interactions with type I and type II 
cytokine receptors.  Upon binding of the cytokine to its receptor, the associated JAKs are 
activated, and phosphorylate each other and the receptor.  The phosphorylated receptors 
serve as docking sites for the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5a, 
STAT5b, and STAT6) of transcription factors.  The STATs are then phosphorylated by the 
co-localized JAKs, which stabilize homo- or heterodimeric STAT complexes that translocate 
the nucleus where they bind to specific gene promoters and activate transcription of a range 
of target genes.
PF-06651600 (ritlecitinib) is a potent, JAK 3 selective, covalent inhibitor.  It is an orally 
bioavailable small molecule that selectively inhibits JAK3 by irreversibly blocking the ATP 
binding site without significantly inhibiting the other three JAK isoforms (JAK1, JAK2, and 
TYK2).  PF-06651600 also inhibits irreversibly the TEC kinase family (BTK, bone marrow 
tyrosine kinase on chromosome X (BMX), ITK, TEC, and tyrosine kinase expressed in T 
cells (TXK)), with high selectivity over the broader kinome.  The selective inhibition of 
JAK3 will lead to modulation of -common chain cytokine pathways, such as IL-7, IL-9, 
IL-15 and IL-21, which have been implicated in the pathophysiology of UC.  Furthermore, 
in vivo PF-06651600 will spare signaling of key immunoregulatory cytokines, such as IL-10, 
IL-27 and IL-35, which have been shown to be critical to maintain immune homeostasis in 
the digestive tract.  Finally, TEC kinase inhibition will impact CD8+T and NK cells 
cytotoxic functions, which play a role in the pathogenesis of IBD.  Taken together, it is 
hypothesized that PF-06651600 could be efficacious in treatment of UC.
PF-06700841 (brepocitinib) is an orally bioavailable, small molecule, potent dual inhibitor of 
human TYK2 and JAK 1.  JAK1 inhibition will impact the signaling of pro-inflammatory 
cytokines such as IFN-gamma and cytokines signaling through the -common chain receptor 
such as IL-7, IL-9, IL-15 and IL-21, while the inhibition of TYK2 will block the production 
of pro-inflammatory cytokines interferon-gamma and IL-17 through upstream inhibition of 
the IL-12/Th1 and IL-23/Th17 pathways.  Taken together, it is hypothesized that dual 
inhibition of both TYK2 and JAK1 could be efficacious in the treatment of UC. 
Both PF-06651600 and PF-06700841 are under development as induction and chronic 
therapy for the treatment of inflammatory bowel disease (IBD).
1.2. Non-Clinical Pharmacokinetics and Metabolism 
 
 
 
 
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1.3. Non-Clinical Safety Studies
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
1.3.2. Non-Clinical Safety Studies with PF-06700841
 
 
 
 
 
 
  
 
  
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1.4. Summary of Clinical Experience 
1.4.1. Summary of Clinical Experience of PF-06651600
PF-06651600 has been explored in seven completed Phase 1 trials in healthy subjects and in 
two Phase 2 trials in subjects with RA (B7981006) and AA (B7931005).  There are 3 
ongoing studies in AA (B7981015, B7981032, B7981037), and 1 each in vitiligo
(B7981019), CD (B7981007), and RA (B7921023). 
1.4.1.1. Summary of Clinical Safety of PF-06651600
1.4.1.1.1. Study B7981001
B7981001 was a Phase 1, randomized, double-blind, third-party open, placebo-controlled, 
single- and multiple-dose escalation, parallel group study to evaluate the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of PF-06651600 in healthy subjects.  This single
ascending dose (SAD) and multiple ascending dose (MAD) study was the first evaluation of 
PF-06651600, a JAK3/TEC inhibitor, in humans.  During the SAD period, a total of 
64 subjects were randomized and received doses of 5, 20, 50, 100, 200, 400 or 800 mg of 
PF-06651600 or placebo in a dose escalation format.  During the MAD period, a total of 
51 subjects were randomized and received doses of 50 mg QD, 100 mg BID (twice a day), 
200 mg QD, 400 mg QD, or 200 mg BID or placebo for 14 days.
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1.4.1.1.2. Study B7981003
B7981003 was a Phase 1, open-label, single-dose, 3-way crossover study to evaluate the 
bioavailability (BA) of a solid dose formulation of PF-06651600 relative to an oral solution 
formulation under fasting conditions and the effect of a high fat meal on the BA of the solid 
dosage formulation of PF-06651600 in healthy subjects.  A total of 14 subjects were 
randomized to study treatment and treated with 50 mg PF-06651600 solution/tablets under 
fasted and fed conditions completed the study.
 
 
 
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1.4.1.1.3. Study B7981008
Study B7981008 is a completed Phase 1, randomized, double-blind, third-party open, 
placebo-controlled study to evaluate the safety, tolerability, PK and pharmacodynamics after 
multiple oral doses of PF-06651600 in healthy Japanese adult subjects.  Four subjects 
received oral PF-06651600 200 mg QD for 10 days, and 2 subjects received the matched 
placebo
 
 
 
 
 
 
 
 
 
 
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1.4.1.1.4. Study B7981006
B7981006 was a Phase 2a, randomized, double-blind, parallel group, placebo-controlled, 
multi-center study to assess the efficacy and safety profile of PF-06651600 in seropositive 
subjects with moderate to severe active Rheumatoid Arthritis (RA) with an inadequate 
response to Methotrexate (MTX). A total of 70 subjects were randomized to study treatment, 
28 subjects received placebo and 42 subjects received PF-06651600.
1.4.1.1.4.1. Analysis of Adverse Events
The majority of all causality TEAEs (28 out of 36) were mild in severity.  Overall, the most 
frequently reported TEAEs were:

Influenza (3 [4.3%] subjects in total: 3 [7.1%] subjects in the PF-06651600 group and 
0 subjects in the placebo group);

Pruritus (3 [4.3%] subjects in total: 2 [4.8%] subjects in the PF-06651600 group and 
1 [3.6%] subject in the placebo group);
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
Lymphopenia (3 [4.3%] subjects in total: 3 [7.1%] subjects in the PF-06651600 group 
and 0 subjects in the placebo group);

Headache (3 [4.3%] subjects in total: 0 subjects in the PF-06651600 group and 
3 [10.7%] subjects in the placebo group).
The majority of all treatment-related TEAEs (9 out of 11) were mild in severity.  Overall, the 
most frequently reported treatment-related TEAE was Lymphopenia (2 [2.9%] subjects in 
total: 2 [4.8%] subjects in the PF-06651600 group and 0 subjects in the placebo group).
1.4.1.1.4.2. Permanent Discontinuations due to Adverse Events
A total of 3 subjects (7.1%) in the PF-06651600 group and 0 subjects in the placebo group 
permanently discontinued due to TEAEs.  One (1) subject discontinued due to suicidal
ideation, 1 subject discontinued due to lymphopenia, and the third subject discontinued due 
to hepatotoxicity.
1.4.1.1.4.3. Deaths
There were no deaths among subjects who participated in Study B7981006.
1.4.1.1.4.4. Serious Adverse Events
There were no SAE in subjects who participated in study B7981006.
1.4.1.1.4.5. Analysis and Discussion of Deaths, Other Serious Adverse Events and Other 
Significant Adverse Events
No deaths occurred in this study.  No SAEs were reported in this study.  A total of 3 subjects 
experienced TEAEs that led to permanent discontinuation due to TEAEs during the study.  
No clinically meaningful differences between the PF-06651600 treatment group and placebo 
were observed with regard to AEs of special interest.
1.4.1.1.4.6. Clinical Laboratory Evaluation
Without regard to baseline abnormality, 70 (100%) of the 70 treated subjects experienced 
laboratory abnormalities.  Overall, the most frequently occurring laboratory abnormality was 
erythrocyte sedimentation rate, reported by 68 (97.1%) subjects.
Three (3) subjects (7.1%) in the PF-06651600 treatment group met the discontinuation 
criterion of hemoglobin <8 g/dL.  One (1) subject (2.4%) in the PF-06651600 treatment 
group met the discontinuation criterion of lymphocytes (absolute) <0.5 × 103/mm3.
By the Week 8 time point (as early as 2 weeks), in the PF-06651600 group, there were 
decreases in the median platelet counts (25% change from baseline), lymphocyte counts 
(21% change from baseline), neutrophil counts (24% change from baseline), and hemoglobin 
(3% change from baseline).  None of these were deemed to be clinically relevant by the 
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1.4.1.1.5. Study B7981007
B7981007 is a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, 
multicenter study to examine the efficacy of PF-06651600 and PF-06700841 in subjects with 
moderate to severe active Crohn’s disease (CD). The entire study consists of: 1) a screening 
period of up to 6-weeks, 2) a 12-week induction period, 3) a 52-week open label extension 
(OLE) period, and 4) a 4-week follow up period. Approximately 250 subjects in total will be 
randomized into the study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.4.1.1.6. Study B7981015
B7981015 is a Phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging study 
to investigate PF-06651600 in AA. The study has a maximum duration of approximately 
57-weeks. This includes an up to 5-week Screening period, a 48-week treatment period, and 
a 4-week follow-up period (for subjects who do not roll over into the open-label, long-term 
study B7981032). The treatment period is comprised of a placebo-controlled period that 
includes a 4-week loading phase and a 20-week maintenance phase, followed by a 24-week 
extension phase. The study will enroll a total of approximately 660 subjects. The study will 
be conducted at approximately 120 sites.
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1.4.1.1.7. Study B7981019 
B7981019 is an ongoing Phase 2b, randomized, double-blind, parallel group, multicenter, 
placebo-controlled, dose-ranging study to investigate different dose/dose regimens of
PF-06651600 in active non-segmental vitiligo with a partially blinded extension period. The 
study has a maximum duration of approximately 60 weeks. This includes an up to 4-week 
Screening period, a 24-week dose ranging period, an up to 24-week extension period, and a 
8-week follow-up period. The 24-week dose ranging period is comprised of a 
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placebo-controlled period that includes a 4-week loading phase and a 20-week maintenance 
phase. The study will enroll a total of approximately 330 subjects. The study will be 
conducted globally at approximately 85 sites.
 
 
 
 
 
 
 
 
 
 
 
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1.4.1.1.8. Study B7981032
Study B7981032 is an ongoing 2-year Phase 3 open-label, multicenter study to evaluate the 
safety and efficacy of PF-06651600 in adult and adolescent subjects ≥12 years of age with 
alopecia areata. The study will have a maximum duration of approximately 26 months. This 
includes up to a 5-week screening period, a 24-month open-label treatment period, and a 
4-week follow up period. Study B7981032 includes eligible subjects who are given the 
opportunity to enroll from the index studies B7931005 and B7981015, as well as de novo 
subjects (ie, those who have not previously received study intervention in Study B7931005 or 
B7981015).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.4.2. Summary of Clinical Experience with PF-06700841
1.4.2.1. Summary of Clinical safety of PF-06700841
This section consists of safety information for PF-06700841 in 7 completed Phase 1 studies 
(Studies B7931001, B7931009, B7931010, B7931014 and B7931029), and 2 completed
Phase 2 studies (B7931004 and B7931005), Two Phase 1 studies (B7931019 and B7931033) 
have completed enrollment (clinical study report is under preparation) and draft data from 
these small studies are included in the IB. Data have not been pooled for the studies 
conducted with brepocitinib. Safety and efficacy data are presented separately for each 
study.
Adverse events (AE) may be reported as all-causality or treatment-related.  Treatment-related
adverse events are those events considered related to the study treatment at least by the
investigator. See IB for adverse events that have been further evaluated and determined by
the sponsor to be expected adverse reactions (ie, events for which there is a reason to 
conclude that the drug caused the event[s]).
1.4.2.1.1. Study B7931001
The B7931001 study was a Phase 1, within cohort, randomized, double-blind, third party 
open, placebo-controlled, parallel group study with single and multiple dose escalation in 
healthy adult subjects, and multiple dosing in subjects with chronic plaque psoriasis. In 
addition, the bioavailability (BA) of a tablet formulation relative to the first in human (FIH) 
solution/suspension formulation, as well as the effect of a high fat meal on the BA of the 
tablet formulation, was determined in a 3 -way crossover study design.
Of the 96 subjects randomized into study B7931001, 74 subjects have received at least one 
active dose of oral PF-06700841, 41 healthy subjects in the single and multiple ascending 
dose period of the trial, 12 healthy subjects in BA and 21 subjects with chronic plaque 
psoriasis. 
In the SAD/MAD period, 41 healthy subjects received doses of 1, 3, 10, 30, 100, or 200 mg 
of PF-06700841 during the SAD period, and doses of 10, 30, 100, or 175 mg QD for 10 days
during the MAD period.  Subjects participating in the 100 mg multiple dose cohort returned 
for a third period to receive 50 mg PF-06700841 BID for 10 days.  Thirty subjects with 
moderate to severe chronic plaque psoriasis were also randomized into study B7931001 to 
receive once daily placebo (n=9), 30 mg (n=14), or 100 mg (n=7) PF-06700841 for 28 days.  
In the BA period, 12 healthy subjects were randomized and received PF-06700841.
1.4.2.1.1.1. Adverse Events
PF-06700841 was generally safe and well tolerated in all cohorts in the Phase 1 clinical study 
B7931001.  There were no deaths in the study.  Subjects reported 11 TEAEs in the SAD 
phase, 22 TEAEs in the MAD phase, 39 TEAEs in the psoriasis phase, and 3 TEAEs in the 
BA phase.  All AEs were mild or moderate in severity; there were no severe or serious 
adverse events, or serious infections in any of the 4 study groups cohorts.  Of the 7 healthy 
volunteers who prematurely discontinued the MAD cohort, 3 discontinuations were due to
AEs. Of the 13 patients in the psoriasis cohort who discontinued prematurely, 7 of the 


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discontinuations were due to AEs. There were no discontinuations due to AEs in the SAD or 
BA cohorts.
1.4.2.1.1.2. Common Adverse Events in Study B7931001
In the SAD cohort, the most commonly reported AEs by System Organ Classes (SOCs) were 
Investigations, reported by 2 participants, and Nervous System Disorders, reported by
3 participants.  The most frequently reported AEs were blood creatinine increased and 
headache, each of which was experienced by 2 participants.  All TEAEs were mild in 
severity.
In the MAD cohort, the most commonly reported AEs by SOCs were Investigations, reported 
by 13 participants, and Nervous System Disorders, reported by 3 participants.  The most 
frequently reported AEs were blood creatinine increased, experienced by 11 participants, and 
neutrophil count decreased, experienced by 3 participants. All TEAEs were mild or 
moderate in severity.
In the psoriasis cohort, the most commonly reported AEs by SOCs were gastrointestinal 
disorders, reported by 7 participants, investigations, reported by 15 participants, and nervous 
system disorders, reported by 4 participants.  The most frequently reported AEs were 
constipation, experienced by 6 participants and blood creatinine increased, experienced by 
14 participants.  All TEAEs were mild in severity.
In the BA cohort, the most commonly reported AEs by SOCs were gastrointestinal disorders, 
injury, poisoning, and procedural complications, and nervous system disorders, each reported 
by 1 participant. The most frequently reported AEs were nausea, contusion, and headache, 
each of which was experienced by 1 participant.  All TEAEs were mild in severity.
 
 
 
 
1.4.2.1.1.4. Clinical Laboratory Evaluations
In the SAD and MAD cohorts, 40 participants (7 in the placebo; 4 each in the 1 and 3 mg;
6 each in the 10, 30 and 100 mg; and 7 in the 200 mg treatment groups) in the SAD group
and 32 participants (6 in the placebo; 5 each in the 10 and 50 mg; 4 in the 30 mg; and 6 each
in the 100 and 175 mg treatment groups) in the MAD group had laboratory abnormalities.
The most frequently reported laboratory abnormalities were elevations of low-density
lipoprotein (LDL) >1.2 × upper limits of normal (ULN), 26 participants during SAD and
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Serum creatinine ≥1.5 × ULN occurred in 1 participant in the PF-06700841 100 mg group 
during SAD, 4 participants (1, 2, and 1 participants in the PF-06700841 10 mg QD,
100 mg QD, and 50 mg BID groups, respectively) in the MAD period. Participants in the 
MAD and psoriasis cohorts that had increased SCr ≥0.3 mg/dL did demonstrate a change in S 
Cystatin-C based estimated glomerular filtration rate (eGFR).
Abnormally low neutrophil counts were observed in 3 participants (1 participant each in the 
1 mg, 200 mg, and placebo groups) in the SAD cohort and 14 participants in the MAD cohort 
(1, 3, 3, 5, and 2 participants in the 10 mg QD, 100 mg QD, 50 mg BID, 175 mg QD, and 
placebo QD groups, respectively). There were no clinically meaningful changes from 
baseline in other hematology parameters during SAD and MAD.
In the SAD group, there was a slight increase in alanine amino transferase (ALT) in the
30 mg group on Day 8.  Overall there were no clinically significant abnormalities in aspartate 
amino transferase (AST), ALT and total bilirubin during SAD and MAD.
In the psoriasis cohort, 27 participants (7 in the Placebo, 13 in the 30 mg and 7 in the 100 mg 
PF-06700841 treatment groups) had laboratory abnormalities.
The most frequently reported laboratory abnormalities during the psoriasis period were LDL 
>1.2 × ULN (16 participants: 5 in Placebo, 7 in the 30 mg and 4 in the 100 mg PF-06700841 
treatment groups) and uric acid >1.2 × ULN (10 participants: 4 in Placebo, 4 in the 30 mg 
and 2 in the 100 mg PF-06700841 treatment groups).
In the psoriasis group, 6 participants (1 and 5 participants in the 30 mg QD and 100 mg QD 
groups, respectively) had neutrophil counts meeting the criteria for abnormally low levels. 
Overall there were no clinical meaningful changes from baseline in other hematology 
parameters during psoriasis period.
In the BA cohort, there were 9 participants that had laboratory abnormalities. The most 
frequently reported laboratory abnormalities during the BA period were total neutrophils
<0.8 × LLN (4 participants) and lymphocytes <0.8 × LLN (3 participants).  There were no 
other clinically significant abnormalities during BA period.
There were no participants with clinically significant laboratory abnormalities during the 
study.
1.4.2.1.1.5. Vital Signs, Physical Findings, Electrocardiogram (ECG) and Other
Observations Related to Safety
There were no clinically meaningful findings in vital signs, and ECG in any of the 4 groups.
1.4.2.1.2. Study B7931009
This study was a Phase 1 randomized, double-blind, third-party open, placebo-controlled, 
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1.4.2.1.3. Study B7931014
This study is a Phase 1, open-label, non-randomized, 2-period, fixed sequence, single-dose 
study of PF-06700841 in healthy male participants to characterize the absorption, 
distribution, metabolism, and excretion (ADME) of 14C PF-06700841; and to evaluate the 
absolute oral bioavailability (F) and fraction absorbed (Fa) of PF-06700841 following oral 
administration of unlabeled PF-06700841 and IV and oral administration of 
14C-PF-06700841 to healthy male participants.  A 2-period design will be used to minimize 
variability and enable within-subject comparison of the urinary excretion of radioactivity
with both routes for the estimation of Fa. Fa will be estimated by comparing total 14C urine 
recovery following IV and oral administration of 14C-PF-06700841. There was a
10- to 17-day washout between the 2 treatment periods.
 
 
 
 
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1.4.2.1.4. Study B7931019
This study was designed to determine the effect of PF-06700841 on QTc interval in healthy 
participants.  This was a Phase 1, 3-way crossover, 3-treatment, 6-sequence, sponsor-open 
study, in which, each participant received single oral doses of PF-06700841 200 mg, placebo 
and moxifloxacin 400 mg, according to one of the treatment sequences they were randomly 
assigned.  Treatment assignments to PF-06700841 and placebo were blinded to the 
participants and investigator but moxifloxacin treatment was unblinded.
 
 
 
 
 
 
 
 
 
1.4.2.1.5. Study B7931029
This is a Phase 1, single center, randomized, vehicle and white petrolatum controlled, 
evaluator blinded study to assess the skin irritation potential with a range of concentrations of 
PF-06700841 cream including vehicle and empty patch with white petrolatum under 
occlusive conditions in adult Japanese healthy participants.
 
 
 
 
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All participants had 6 application sites on the back where 6 patches of investigational 
 
 
 
 
 
 
 
 
 
 
 
1.4.2.1.6. Study B7931033
This was a Phase 1, open-label, fixed-sequence, 2-period study to investigate the effect of
multiple oral doses of itraconazole on a single oral dose of brepocitinib PK in healthy
participants at a single center. Approximately 12 healthy participants were enrolled in the
study. The study has completed enrollment; however, the clinical study report has not been
finalized as of the time of this IB update, and these summarized results are in draft stage.
 
 
1.4.2.1.7. Study B7931010
This was an open-label, single dose, 2-period, 2-sequence crossover study in 8 healthy
participants to characterize the PF-06700841 pharmacokinetic (PK) profile and
bioavailability following single oral dose formulation of immediate release (IR) tablets and
modified release (MR) tablets each administered as 30 mg dose in the fasted state.
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1.4.2.1.8. Study B7931004
This was a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, 
multicenter study in adult participants with moderate to severe plaque psoriasis. Following a 
screening period (up to 6 weeks), the study consisted of a 4-week induction treatment period 
with double-blind daily treatment (PF-06700841 30 mg QD, 60 mg QD or matched placebo). 
At the end of Week 4, all participants switched to their predefined double-blind maintenance 
treatment regimen (PF-06700841 10 mg QD, 30 mg QD, 100 mg once weekly (QW) or 
matched placebo) for Week 5 through Week 12.  Subsequent to the induction and 
maintenance periods, the study had an 8-week safety follow up period.
1.4.2.1.8.1. Disposition and Demographic Characteristics of Phase 2 Study B7931004
A total of 212 participants were randomized and received at least 1 dose of study treatment. 
All treated participants were analyzed for efficacy and safety. Participants randomized to 
treatment received either PF-06700841 60 mg QD or PF-06700841 30 mg QD for the first 
4 weeks of treatment (induction) after which those on 60 mg QD were switched to either 
30 mg QD, 10 mg QD, 100 mg QW or placebo in the maintenance period.  Those who 
received 30 mg QD during the first 4 weeks of induction were switched to either 30 mg, 
10 mg QD, or 100 mg QW in the maintenance period.
Overall, 164 of 212 (77.4%) participants completed the study.  The majority of the treated 
participants were male (69.8%) and white (89.2%).  The mean age was 46.0 years 
(median: 48.0, range: 18 to 75). The mean weight was 94.7 kg (median: 91.6, range: 45.1 to 
204.3), and mean body mass index (BMI) was 31.9 kg/m2 (median: 30.9, range: 18.9 to 
64.7). The mean duration of psoriasis since first diagnosis was 17.9 years, with a mean 
baseline PASI score of 20.8, which was comparable for participants in all treatment groups.
1.4.2.1.8.2. Treatment-Emergent Adverse Events (All-causality and Treatment Related) 
in Phase 2 Study B7931004
The proportion of participants with all-causality TEAEs was comparable across all treatment 
groups but numerically higher in the active treatment groups (64.0% to 76.7%) than the 
placebo group (56.5%).  The majority of participants in all the treatment groups experienced 
mild or moderate all-causality TEAEs, and only 11 (5.2%) out of 212 participants 
experienced severe all-causality TEAEs. Overall, there were no dose dependent increases in 
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the all-causality TEAEs.  The most reported non-serious TEAEs were in the SOC of 
Infections and Infestations with 25.9% of participants. There were more participants
experiencing mild to moderate infections and infestations, such as nasopharyngitis, upper 
respiratory tract infection, bronchitis, sinusitis, or urinary tract infection in the active 
treatment groups relative to the placebo group. Other non-serious TEAEs in SOCs occurring 
>5% of participants were Gastrointestinal Disorders, Musculoskeletal and Connective Tissue 
Disorders, Skin and Subcutaneous Tissue Disorders, and Nervous System Disorders. 
Incidence occurring in other SOCs except Infections and Infestations was comparable 
between all treatment groups.
A total of 13 participants discontinued from the study due to TEAEs.
One participant in the 30 to 10 mg group was found to have a positive urine human chorionic 
gonadotropin test at the Week 6 (Day 42) visit after which confirmation with serum 
pregnancy test led to permanent discontinuation from study on Day 53.  On Day 165, an 
obstetrical ultrasound demonstrated a right-sided cleft lip with a gap of 10 millimeters in the 
fetus, with no definite cleft palate.  The Day 176 obstetrical ultrasound confirmed presence of 
cleft lip in the fetus, with all other findings appearing within normal limits.  This event of 
fetal cleft lip was unexpected in the single reference safety document for the study drug and 
was assessed as related per sponsor.
1.4.2.1.8.3. Serious Adverse Events in Phase 2 Study B7931004
Five (5) participants experienced a total of 6 SAEs during the study; 3 of the SAEs were 
considered to be related to study drug by the investigator, of which 2 SAEs (pneumonia and 
sepsis) reported by 1 participant in the 60 mg QD to 100 mg QW group were considered not 
related to study drug by the sponsor. This participant had 1 dose of PF-06700841 60 mg on 
Day 1 and had 2 SAEs of pneumonia and sepsis on Day 2 before dosing and was 
permanently discontinued from study due to the SAE of pneumonia.
One post-therapy death occurred due to gunshot wound after the participant was discontinued 
from the study due to noncompliance with study drug, which was considered unrelated to the 
study treatment by the investigator.
1.4.2.1.8.4. Laboratory Evaluation, Vital Signs, and ECG in Phase 2 Study B7931004
There were no clinically meaningful dose dependent neutropenia, lymphopenia, 
thrombocytopenia, and anemia among the active treatment groups, except for 1 SAE of 
anemia reported by 1 participant in the 60 to 10 mg QD group.
No participants met the laboratory test discontinuation criteria (laboratory test abnormalities 
confirmed through re-testing within 48 hours) during study treatment. There was no 
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1.4.2.1.8.4.1. Hematology
During the induction period, there was a dose-dependent decrease of in reticulocyte count in 
the active treatment groups compared to the placebo group. During the 8-week maintenance 
period, the reticulocytes levels appeared to rebound for all the active treatment groups, 
except for the 30 to 10 mg QD group.  There were no clinically meaningful changes from 
baseline observed in hemoglobin across treatment groups during the study, except for 1 SAE 
of anemia reported by 1 participant in the 60 to 10 mg QD group.
During the induction period, dose-dependent decreases from baseline in neutrophils were 
observed for the 60 mg QD induction dose group, compared to the 30 mg QD induction dose 
group and the placebo group at Week 4.  During the maintenance period at Week 12, the 
neutrophils levels for all the treatment groups were similar to placebo.
During the induction period and maintenance periods, lymphocyte levels in all active 
treatment groups were similar to placebo at Week 4 and Week 12. A total of 6 participants 
(3 participants in the 60 mg QD to 100 mg QW group and 1 participant each in the 60 to
10 mg QD group, the 60 mg QD to placebo group, and the placebo group, respectively) had 
lymphocyte values meeting the criteria for low levels. There were no clinically meaningful 
changes from baseline observed in lymphocytes across treatment groups during the study.
During the induction period and maintenance periods, platelet levels in all active treatment 
groups were similar to placebo at Week 4 and Week 12.
1.4.2.1.8.4.2. Liver Function Tests
There were no clinically meaningful changes from baseline observed in AST and ALT across 
treatment groups during the study.  Two (2) participants (1 participant each in the 30 mg QD 
group and the 30 mg QD to 100 mg QW group) had AST meeting the criteria of AST 
>3.0 × ULN. One participant in the 30 to 10 mg QD group had ALT meeting the criteria for 
high levels. The participant was permanently discontinued from the study due to a moderate 
AE of liver function test (LFT) abnormal.
1.4.2.1.8.4.3. Creatine Kinase
There were no clinically meaningful changes from baseline observed in creatine kinase (CK) 
during the study. A total of 24 participants (5 participants each in the 60 mg QD to 
100 mg QW and 30 to 10 mg QD groups; 4 participants each in the 60 to 30 QD and 30 QD 
groups; and 3 participants each in the 60 to 10 mg QD and 60 mg QD to placebo groups) had 
CK meeting the criteria of CK >2 ×ULN.  CK levels >10 × ULN were observed in 
2 participants without AE. One moderate AE of CK-MB increased reported by 1 participant 
in the 30 to 10 mg QD group during the induction period, which was considered to be related 
to the study drug by the investigator.  No participant was discontinued from the study due to 
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1.4.2.1.8.4.4. Serum Creatinine, Serum Cystatin-C, and eGFR (serum Cystatin C 
Based)
During the induction period, increases from baseline in SCr were observed in all the active 
treatment groups (range from 10.9% to 25.0%), compared to the placebo group (1.8%) at
Week 4. During the maintenance period, the SCr levels returned close to baseline for all the 
active treatment groups, except for the 60 to 30 mg QD, 60 to 10 mg QD, and 30 mg QD 
groups. A total of 4 participants (1 participant each in the 60 to 30 mg QD, 60 to 10 mg QD, 
30 mg QD and 30 to 10 mg QD groups) had SCr meeting the criteria of SCr 1.3 × ULN.
There were no clinically meaningful changes from baseline observed in serum cystatin C
across treatment groups during the study. Two (2) participants (1 participant each in the 
60 to 30 mg QD and 60 to 10 mg QD groups) had elevated serum cystatin C meeting the 
criteria of serum cystatin C >1.3 × ULN.
There were no clinically meaningful changes from baseline observed in serum cystatin-C 
based eGFR across treatment groups during the study.
1.4.2.1.8.4.5. Lipids
During the induction period, dose-dependent increases from baseline in LDL were observed 
in the active treatment groups (13.5% for the 60 mg QD induction dose group, 5.1% for the 
30 mg QD induction dose group), compared to placebo (-6.0%) at Week 4.
During the induction period, dose-dependent increases from baseline in HDL were observed 
in the active treatment groups (22.5% for the 60 mg QD induction dose group, 15.6% for the 
30 mg QD induction dose group), compared to placebo (-1.44%) at Week 4.
There were no clinically meaningful changes from baseline observed in LDL/High density 
lipoprotein (HDL) ratio across treatment groups during the study.
1.4.2.1.8.5. Vital Signs, ECG, and Suicidal Behavior or Ideation
There were no clinically meaningful findings in vital signs, ECG, and suicidal behavior or 
ideation during the study.
1.4.2.1.9. Study B7931005
This was a Phase 2a, randomized, double blind, placebo-controlled, parallel group, 
multicenter study to investigate the efficacy and safety of both PF-06651600 and PF-
06700841 in treatment of alopecia areata. The study was to have a maximum duration of 
approximately 113 weeks, consisting of 3 periods: a 24-week double-blind treatment period, 
an up to 48-week SBE period, and a 24-week cross over extension (COE) period. The study
included 2 drug holiday periods of 4 weeks each, and 2 follow-up periods of 4 weeks each.
1.4.2.1.9.1. Summary of Adverse Events
There were no deaths reported.  


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In the Initial 24 weeks Treatment Period; There were no deaths during the Initial 24-Week
Treatment Period. A total of 4 participants discontinued from the study due to TEAEs and
5 participants discontinued study drug due to TEAEs and continued in the study. Two (2)
participants in brepocitinib treatment group experienced an SAE of Rhabdomyolysis which
resulted in permanent discontinuation from the study. The most frequently laboratory
abnormality which met retest criterion was total neutrophils (absolute) <2 × 10³/mm³ in 
20 (14.2%) participants: 9 (19.6%) participants in placebo group and 8 (17.0%) participants
in brepocitinib treatment group. Two (2) participants in brepocitinib treatment group
experienced Grade 3 decreased neutrophil count. There were 2 participants in placebo group
and 13 participants in brepocitinib treatment group experienced a decline of ≥30% from
baseline in SCr-based eGFR during the Initial 24-Week Treatment Period but none of these
declines were accompanied by a concomitant decline of ≥30% in serum cystatin C-based
eGFR. Elevated CK levels of at least 3 × ULN were reported in 9 participants in brepocitinib
treatment group. There were no clinically significant findings in ECG and vital signs except
increased diastolic BP in 3 participants (one in each group). There were no clinically 
significant auditory changes in the active treatment groups. A mild TEAE of Deafness
neurosensory was reported in 1 participant in placebo group.
In the SBE Period; There were no deaths during the SBE Period. Two (2) participants 
discontinued from the study due to TEAEs (Abnormal liver function test in 1 active
non-responder on PF-06651600 and Lower limb fracture in 1 retreated brepocitinib
responder). One (1) active non-responder on brepocitinib discontinued from brepocitinib due 
to AE of Proteinuria but completed the study. Five (5) participants (2 placebo non-
responders on brepocitinib, 1 non-retreated PF-06651600 responder, 1 non-retreated
brepocitinib responder, and 1 retreated brepocitinib responder) had temporary
discontinuation due to TEAEs (Increased blood creatine phosphokinase in 2 participants, 
Increased blood creatinine and Decreased glomerular filtration rate in 1 participant, 
Palpitations in 1 participant, and Rhabdomyolysis in 1 participant). One (1) retreated 
brepocitinib responder experienced a treatment-emergent SAE of Lower limb fracture which 
was considered not related to study drug. The most frequently met retest criterion was total 
neutrophils (absolute) <2 × 10³/mm³ which was reported in 11 participants receiving 
brepocitinib and 3 participants receiving placebo. There were no clinically relevant changes 
in lipid profile. Elevated CK levels of at least 3 × ULN were reported in 2 participants 


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receiving brepocitinib and 3 participants receiving placebo. TEAEs of increased blood 
creatine phosphokinase were reported in placebo non-responder on brepocitinib, and 1
retreated brepocitinib responder; none of these TEAEs were considered as treatment-related
by the investigator. There were no clinically significant findings in ECG and vital signs 
except increased diastolic BP in participants. There were no clinically significant changes 
from baseline in auditory tests. There were no increased risks with re-exposure to
brepocitinib.
In the CO period: There were no deaths during the COE Period. No participants 
discontinued from the study or discontinued study drug due to TEAEs. Two (2) participants 
(1 participant in each treatment group) had temporary discontinuation due to TEAEs 
(moderate bronchitis in the brepocitinib CO treatment group; moderate influenza like illness
and moderate torticollis in the PF-06651600 CO treatment group). One (1) participant in the
brepocitinib CO treatment group experienced a treatment-emergent SAE of gastroenteritis 
salmonella which was considered not related to study drug. The most frequently met retest 
criterion was total neutrophils (absolute) <2 × 10³/mm³ which was reported by 6 (26.1%)
participants: 5 (27.8%) participants in the brepocitinib CO treatment group. One (1) 
participant in the brepocitinib CO treatment group experienced Grade 3 decreased neutrophil 
count. There were no clinically relevant changes in lipid profile. Elevated CK levels of at 
least 3 × ULN were reported in 1 participant in brepocitinib CO treatment group. There were 
no clinically significant findings in ECG and vital signs except increased diastolic BP in 
1 participant. There were no clinically significant changes from baseline in auditory tests.
There were no increased risks observed after cross-over to treatment with brepocitinib.
1.4.2.1.10. Study B7931028
This is a Phase 2b, double blind, randomized, placebo controlled, parallel design, 
multicenter, dose ranging study to assess the efficacy and safety of brepocitinib in
participants with active, moderate to severe generalized systemic lupus erythematosus (SLE).
This is the first study of brepocitinib in participants with moderate to severe active, 
generalized SLE that have inadequate response to standard of care. After an up to 5 week 
screening period, eligible participants will be randomized in a 1:2:2:2 ratio such that 
participants will receive either 1 of 3 brepocitinib QD dose levels (15 mg, 30 mg and 45 mg) 
or placebo every day for 52 weeks. All participants will receive blinded dosing throughout 
the study treatment period in order to maintain the study blind.
 
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1.4.2.1.11. Study B7931030
This is a Phase 2B, randomized, double blind, placebo-controlled, dose range, parallel group
study of brepocitinib to evaluate the efficacy of brepocitinib at 16 weeks and to evaluate the
safety and efficacy up to 1 year in participants with active psoriatic arthritis.
As of 20 August 2020, 8 cases reporting a total of 9 treatment emergent SAEs have been 
reported in the ongoing blinded Study B7931030. Six (6) of these SAEs are assessed by the
Investigator as not related to treatment. The SAEs are Appendicitis, Duodenal ulcer,
Cholecystitis chronic, Psoriasis, Synovitis, and Varicella.
There were 2 cases reporting 3 SAEs assessed by the Investigator as treatmentrelated;
1.4.2.1.12. Study B7931023
Study B7931023 is a Phase 2b, randomized, double blind, vehicle-controlled, parallel-group,
dose ranging study to assess efficacy, safety, tolerability and pharmacokinetics of
brepocitinib topical cream applied once or twice daily for 12 weeks in participants with mild
to moderate chronic plaque psoriasis.
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1.4.2.2. Pharmacokinetics of PF-06700841
PK data from single doses of 1, 3, 10, 30, 100 and 200 mg and multiple doses of 10, 30, 
100 and 175 mg QD and 50 mg BID mg administered for 10 days are summarized in 
Table 3 and Table 4, respectively.  Following single oral doses of 1 mg to 200 mg under 
fasted conditions, PF-06700841 was absorbed rapidly with median Tmax of 1 hour or less.  
Following the attainment of Cmax, concentrations appeared to decline in monophasic fashion.  
Mean terminal t½ ranged from 3.8 to 7.5 hours.  In general, both AUCinf and Cmax appeared
to increase proportionally with dose from 1 mg to 100 mg, and there appeared to be a trend 
toward more than proportional increases from 100 mg to 200 mg for AUCinf and Cmax. 
Table 3.
Summary of Plasma PF-06700841 Pharmacokinetic Parameters Following 
Single Oral Doses, Study B7931001
PF-06700841 Parameter Summary Statisticsa by Treatment
Parameter, units
1 mg
3 mg
10 mg
30 mg
100 mg
200 mg
N, n
7, 2
6, 5
6, 6
6, 6
8, 7
8, 8
AUCinf, ng.hr/mL
NR
145.8 (61)
353.8 (31)
1439 (65)
4797 (62)
18410 (46)
AUClast, ng.hr/mL
17.71 (114)
79.18 (239)
340.4 (30)
1431 (65)
5041 (59)
18400 (46)
Cmax, ng/mL
5.138 (52)
18.21 (92)
79.30 (35)
271.3 (21)
748.4 (35)
2460 (37)
Tmax, hr
1.00
(0.500-2.00)
1.00
(0.500-1.00)
0.500
(0.500-1.00)
1.00
(0.500-1.02)
1.00
(0.500-2.00)
1.00
(0.500-2.00)
t½, hr
NR
4.55 ± 1.81
3.85 ± 1.16
4.36 ± 2.41
7.52 ± 2.82
6.81 ± 1.99
a Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic mean ± SD for t½.
N = Number of subjects in the treatment group and contributing to the mean; n= number of subjects where t½, 
AUCinf were determined.
NR = Not reported.  Summary statistics are not presented if fewer than 3 subjects have reportable parameter
values.
On Day 10 of multiple-dose administration, PF-06700841 was absorbed rapidly with median 
Tmax of 1.5 hours or less across the entire range of doses, from a total daily dose of 30 mg up 
to 175 mg.  Following attainment of Cmax, the disposition of PF-06700841 was similar with 
that observed following single-dose administration.  Mean terminal t½ ranged from 4.9 to 
10.7 hours.  In general, both AUCtau and Cmax appeared to increase proportionally with dose 
from 10 mg to 175 mg.  The mean apparent clearance (CL/F) was 10.8 L/hr to 23.7 L/hr, and 
the mean apparent volume of distribution (Vz/F) was 106.2 L to 249.4 L.
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Table 4.
Summary of Steady Sate Plasma and Urine PF-06700841 Pharmacokinetic 
Parameters Following Multiple Dose Administration (10 Days), Study 
B7931001
PF-06700841 Parameter Summary Statisticsa by Treatment
Parameter, units
10 mg (QD)
30 mg (QD)
100 mg (QD)
50 mg (BID)
175 mg (QD)
N, n
5, 5
3, 3
6, 6
4, 4
4, 4
AUC, ng.hr/mL
422.8 (41)
1880 (52)
6089 (38)
3560 (35)
16180 (15)
Cmax, ng/mL
63.4 (11)
286.6 (17)
734.1 (29)
522.0 (31)
2091 (28)
Tmax, hr
1.0 (1.0-1.0)
1.00 (1.00-1.00)
1.5 (1.0-2.0)
1.0 (1.0-2.0)
0.98 (0.50-2.0)
CL/F, L/hr
23.7 (41)
16.0 (51)
16.4 (38)
14.0 (35)
10.8 (16)
t½, hr
5.93 ± 3.33
4.86 ± 1.93
10.67 ± 1.84
9.13 ± 2.26
7.46 ± 2.16
Vz/F, L
177.6 (30)
106.2 (12)
249.4 (45)
180.9 (30)
112.4 (18)
Ae%
11.1 (45)
9.3 (57)
NR
15.5 (57)
8.9 (44)
CLr, L/hr
2.619 (18)
1.486 (15)
NR
2.179 (31)
0.9629 (58)
Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic mean ± SD for t½.
N = Number of subjects in the treatment group and contributing to the mean; n= number of subjects where t½ 
was determined; NR = Not reported.
AUC, = Area under the concentration-time curve from zero to 24 hours (QD) or zero to 12 hours (BID) 
postdose at steady state; QD = Once daily; BID = Twice daily; Cmax = Peak plasma concentration; 
CL/F = apparent total body clearance; Vz/F = apparent volume of distribution; Ae% = Percent of dose 
recovered unchanged in urine over the dosing interval τ; CLr = Renal clearance.
Urinary recovery of PF-06700841 was low, with approximately <16% of the dose recovered 
unchanged in urine on Day 10 across all doses (geometric mean Ae% of 8.9% to 15.5%).  
Renal clearance ranged from 0.96 L/hr to 2.62 L/hr.
The relative BA (B7931001) of 100 mg PF-06700841 tablets compared to 100 mg oral 
suspension was 96.2% for AUCinf and 94.3% for Cmax.  Both of the 90% CIs for the ratio 
were within the 80% to 125% equivalence interval.  When the 100 mg tablets were 
administered under fed conditions, Tmax was delayed with a median value of 4.0 hours, 
compared to a median Tmax 0.5 hours under fasted conditions.  For 100 mg tablets fed vs.
fasted, the ratio (90% CI) of adjusted geometric means for AUCinf and Cmax was 
82.3% (73.5%, 92.3%) and 64.3% (56.0%, 73.8%), respectively.  Tablets will be 
administered with no requirement regarding food in the current study.
Listed in Table 5 are the PK parameters following multiple-dose administration of 
PF-06700841 to psoriasis subjects. PF-06700841 was absorbed rapidly with median Tmax of 
1 hour to 2 hours post dose.  Mean terminal t½ was 16 hours in the 30 mg group and 6 hours 
in the 100 mg group.  The mean t½ value in the 30 mg group included a reported t½ value of 
87.5 hours for one subject with an anomalous data point at 216 hours postdose: all other 
subjects in the dose group had concentrations below the lower limit of quantitation (LLOQ)
after 24 hours, and t½ values of 6.48 hours or less. 


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Table 5.
Summary of Plasma Steady State PF-06700841 Pharmacokinetic 
Parameters Following Multiple Dose Administration (28 Days) in Psoriasis 
Subjects, Study B7931001
Parameter Summary Statisticsa by Treatment
Parameter, units
PF-06700841 30 mg QD (P)
PF-06700841 100 mg QD (P)
N, n
7, 7
5, 5
AUCτ, ng.hr/mL
990.0 (103)
7672 (43)
Cmax, ng/mL
204.7 (43)
924.2 (13)
Tmax, hr
1.00 (0.983-2.00)
2.00 (1.00-2.00)
CL/F, L/hr
30.30 (103)
13.04 (43)
MRT, hr
6.072 (92)
8.534 (36)
PTF
3.414 (44)b
2.654 (42)
t½, hr
16.01 ± 31.58
6.032 ± 1.712
Vz/F, L
245.4 (206)
109.6 (18)
a Geometric mean (geometric %CV) for all except: median (range) for Tmax; arithmetic mean ± SD for t½.
b 4 subjects contributing to the mean in this group.
N = Number of subjects in the treatment group and contributing to the mean; n= number of subjects where t½, 
Vz/F and MRT were determined.
In general, dose normalized exposure was higher in the 100 mg group than in the 30 mg 
group although the highest individual dose normalized values for both AUCand Cmax were 
observed in one subject in the 30 mg group.  Note that the subject in the 30 mg group with 
the highest Cmax and AUCvalues was not the same subject with the anomalous 87.5 hour 
t½ value.
1.5. Rationale
1.5.1. Study Rationale
This multicenter, multiple-arm, dose ranging, placebo-controlled study (in the induction 
period and not the chronic dosing period) will be the first determination of safety and 
efficacy of PF-06651600 and PF-06700841 in subjects with moderate to severe UC.  The 
objectives of this study are to evaluate the efficacy (based on total Mayo score), safety, 
tolerability, 
 and PD of 20, 70, and 200 mg of PF-06651600 and 10, 30, and 60 mg of 
PF-06700841 dosed once daily during an induction period of 8 weeks, followed by a chronic 
dosing period at doses of 50 mg and 30 mg of PF-06651600 and PF-06700841, respectively 
for 24 weeks (Section 2).  The current non-clinical toxicology packages support treatment 
duration ≥6 months.
Dermatologic rashes have been observed in the Phase 1 PF-06651600 studies.  As the more 
severe rashes were associated with twice a day administration, dosing has been limited to 
once a day in this study.  The availability of dermatology consultation in this study is purely 
a precautionary measure.
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  Periodic 
audiogram monitoring is being implemented to detect any clinically-meaningful changes in 
hearing that might occur.  The availability of audiology consultation in this study is purely a 
precautionary measure.
Changes in lipid profile linked to Interleukin-6 (IL-6) inhibition have been observed with
JAK inhibitors.  Therefore, lipid profiles will be assessed in this study.
Simvastatin is highly metabolized in the gut and modeling based on in vitro data suggests 
that PF-06651600 may exhibit time dependent inhibition of CYP3A which could result in a 
clinically relevant increase in simvastatin plasma levels.  Thus, simvastatin use with 
PF-06651600 is currently prohibited.  Since PF-06651600 is metabolized by CYP3A,
moderate to potent inhibitors and inducers of CYP3A are prohibited.
Increases in serum creatinine have been observed in the Phase 1 PF-06700841 studies.  
However, nonclinical data suggest that this could be due to inhibition of creatinine transport 
in the proximal tubule of the nephron rather than being an indication of renal toxicity.  
Parallel cystatin C assessments in the Phase 1 studies were consistent with this hypothesis.  
The availability of nephrology consultation in this study is purely a precautionary measure.
By including two investigational drugs in a single study, the respective placebo groups can 
be combined, resulting in fewer subjects being exposed to placebo and smaller overall study 
size.  The inclusion of these two investigational drugs is appropriate as the target population 
for both is identical, as are the efficacy outcome measures. 
Though clinical remission based on total Mayo score has traditionally been used as a primary 
endpoint in the UC population, total Mayo score at Week 8 is used in this study to maximize 
the value of the information from the statistical inference perspective.  The two scores are 
highly correlated, with total Mayo score being a good predictor of the remission rates, but 
utilization of the total Mayo score in an appropriate model setting allows for a sample size 
reduction, while not compromising the statistical power. 
All endoscopies will be read by a Central Reader who will be blinded to study treatment.  
 
  
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1.5.2. Dose Rationale
The dose selection strategy was designed to balance pharmacology and safety for this study 
with an 8 week induction period followed by a 24 week chronic dosing period in subjects 
with moderate to severe UC.  A population PK model was developed using the data from the 
FIH study for PF-06651600 (Study B7981001) and similarly for PF-06700841 (Study 
B7931001).  PK was assumed to be similar between healthy subjects and subjects with 
moderate to severe UC.  The activity of the JAK inhibitors was assessed by measurement of 
various PD markers and markers of safety that were collected in the FIH studies and 
analyzed using indirect response modeling.  The magnitude of change in these markers 
required for efficacy and/or safety is poorly understood.
1.5.3. PF-06651600 Dose Rationale
The predicted PK parameters for PF-06651600 based on simulations using the global PK 
model are provided in Table 6.
Table 6.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06651600 Pharmacokinetic and Pharmacodynamic Parameters During 
the Induction and Chronic Periods of Multiple Dose Administration
Dose
mg QD
Total Cmax
ng/mL
Total AUCtau
ng.hr/mL
IP-10 %
Reduction from 
Baseline
Induction
20
91.3 (3.3)
209.8 (17)
11 (42)
70
381.0 (3.5)
1015 (21)
23 (35)
200
1254 (2.1)
3712 (14)
42 (19)
Chronic
50
259.5 (3.4)
662.0 (20)
18 (39)
AUCtau = Area under the concentration-time curve from zero to 24 hours postdose at steady state; 
Cmax = Peak plasma concentration; QD = Once daily; ( ) = Coefficient of variation expressed as a 
percent; human unbound fraction (fu) = 0.86; 1 ng/mL= 3.504 nM.
 
 
 
 
 
In human whole blood lymphocytes, PF-06651600 inhibited JAK1/JAK3 dependent 
STAT5 and STAT3 phosphorylation by IL-15 and IL-21 respectively, with IC50 values of 
56.5 ng/mL and 103 ng/mL, respectively.  All other pathways were inhibited at IC50 values 
>571 ng/mL.  The inhibition (11-42%) of IP-10 is indicative of modulation of interferon 
gamma.  The predicted average percent IL-15 and IL-21 in vitro signaling inhibition in 
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human whole blood based on human PK for the selected induction and chronic dosing 
periods are provided in Table 7.
Table 7.
Summary of the Predicted Average Percent In Vitro Signaling Inhibition 
Following Multiple Dose Administration
Cytokine
Average Percent Signaling Inhibition
20 mg
50 mg
70 mg
200 mg
IL-15
20
44
55
81
IL-21
12
30
39
71
Pharmacological modulation of the target can be inferred from the predictions in Table 7.
1.5.4. PF-06700841 Dose Rationale
The predicted PK parameters for PF-06700841 based on simulations using the global PK 
model are provided in Table 8.
Table 8.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06700841 Pharmacokinetic and Pharmacodynamic Parameters During 
the Induction and Chronic Periods of Multiple Dose Administration
Dose
mg 
QD
Total Cmax
ng/mL
Total AUCtau
ng.hr/mL
Percent Reduction from Baseline
hsCRP
IP-10
Neutrophils Reticulocytes
Induction
10
56.6 (36)
435.7 (40)
69 (24)
30 (39)
10 (59)
13 (41)
30
206.7 (27)
1619 (44)
80 (7.5)
44 (29)
23 (66)
33 (40)
60
433.3 (27)
3797 (43)
84 (6.4)
51 (21)
32 (70)
50 (34)
Chronic Dosing
30
202 (30)
1499 (44)
81 (9.6)
45 (29)
28 (50)
34 (40)
AUCtau = Area under the concentration-time curve from zero to 24 hours postdose at steady state; Cmax = Peak 
plasma concentration; QD = Once daily; ( ) = Coefficient of variation expressed as a percentage 
 
 
 
 
 
In study B7931001, mechanistic biomarkers of efficacy, hsCRP and interferon 
gamma-induced protein 10 (IP-10) related to IL-6 and IFN-gamma, respectively, were 
measured in healthy subjects.  Based on indirect response modeling, the predicted percent 
reductions in the hsCRP levels ranged between 69% and 84% over the dose range 10-60 mg.  
Similarly, the reduction of IP-10 levels ranged between 30% and 51% over the same dose
range.  Modeling and simulations predicted maximum reductions during the induction period
in neutrophils and reticulocytes of 32% and 50%, respectively.
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Subjects with moderate to severe psoriasis received doses of 30 mg or 100 mg QD or placebo 
for 28 days (B7931001).  Efficacy was measured by placebo adjusted psoriasis area and 
severity index (PASI) change from baseline.  Significant psoriasis disease modification 
(change >-9) at 30 mg and 100 mg was observed in the patients.
Overall, the doses selected for this study are expected to demonstrate clinically relevant 
efficacy in subjects with moderate to severe UC.
1.5.5. Summary of Benefits and Risks
IBD is a serious and potentially life threatening disease. 
The completed Phase 1 study B7981001 was a randomized, double blind, third party open, 
placebo controlled, single and multiple dose escalation, parallel group study in healthy adult 
subjects.  Based on this study, PF-06651600 appeared to be generally safe and well-tolerated.  
No clinically significant changes in vital signs, electrocardiogram or laboratory data were 
observed.  No dose limiting adverse events (AEs) were reported and no subjects met the 
protocol prescribed individual stopping rules.  There were no deaths in the study. 
The completed RA Phase 2a study was a randomized double-blind, parallel group, placebo 
controlled, multi-center study to assess the efficacy and safety profile of 200 mg QD dose of 
PF-06651600 compared to placebo after 8 week treatment in seropositive subjects with 
moderate to severe active RA and an inadequate response to methotrexate.  
PF-06651600 appeared to be generally safe and well tolerated in this study.  No deaths or 
SAEs were reported.  TEAEs were numerically higher in the active group compared to 
placebo and were generally mild in severity.  The most common TEAEs by SOC were 
Infections and Infestations, Skin and Subcutaneous Tissue Disorders, Blood and Lymphatic 
System Disorders and Gastrointestinal Disorders.  There was one mild case of herpes simplex 
in the PF-06651600 group that was considered to be treatment related with no cases in the 
placebo group.
The Phase 2a study in subjects with AA is ongoing.  However, draft data from an interim 
analysis at 24 weeks has been reported in this IB.  The study is a Phase 2a, randomized, 
double-blind, placebo-controlled, multi-center study with an extension period to evaluate the 
efficacy and safety profile of PF-06651600 and PF-06700841 in subjects with moderate to 
severe active AA.  PF-06651600 appeared generally safe and well tolerated. There were no 
deaths in the study.  There were no subjects with SAEs in the PF-06651600 group.  The 
number of AEs was higher in the placebo group relative to the PF-06651600 group. The 
most common AEs were in the Infections and Infestations, Gastrointestinal Disorders, and 
Skin and Subcutaneous Tissue Disorders categories, and the majority of events were 
mild. No serious infections or cases of herpes zoster were reported in the 
study. Hematological changes were observed in both active groups during the induction and 
maintenance periods, but were not associated with clinically relevant adverse events.


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The safety profile observed during the Phase 1 program for PF-06700841 appears to be 
acceptable at dosages up to 175 mg administered orally as multiple doses over 10 days.  A 
longer dosing duration was explored in psoriasis patients, who received the maximum 
PF-06700841 dose level of 100 mg daily for 28 days.  No serious or severe AEs were 
reported in the Phase 1 study.  However, there was one AE of herpes zoster infection in a 
psoriasis subject treated with 100 mg PF-06700841 for 4 weeks.  As with other 
immunomodulators, the risk of infection is potential concern due to the immunosuppressive 
effects of PF-06700841.  To limit this risk, a maximum daily dose below 100 mg (the dose 
associated with infection in the Phase 1 study B7931001) will be used in this Phase 2 trial.  A 
chronic therapy dose of 30 mg was selected since this dose has demonstrated 
anti-inflammatory activity resulting in clinical efficacy in patients with psoriasis. 
Additional information for these compounds may be found in the single reference safety 
document (SRSD), which for this study is the individual IB for each compound. 
 
 
 
 
 
 
 
 
 
 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives and Endpoints during the Induction Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 8 in subjects with moderate to 
severe UC.

Total Mayo score at Week 8.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in induction.  

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 
12-lead ECG in the induction period. 

Incidence of serious infections (see Section 7.2.8 for 
definition) in the induction period.
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
To evaluate the efficacy of PF-06651600 and 
PF-06700841 in induction of remission at Week 8 in 
subjects with moderate to severe UC.

Proportion of subjects achieving remission* based on 
total Mayo score of ≤2 with no individual subscore 
>1 and a rectal bleeding subscore of 0 at Week 8.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 8 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in 
endoscopic appearance (defined as a Mayo 
endoscopic subscore of ≤1) at Week 8.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction of other clinical outcomes 
in subjects with moderate to severe UC.

Proportion of subjects achieving clinical response at 
Week 8.

Proportion of subjects in endoscopic remission at 
Week 8.

Proportion of subjects in symptomatic remission at 
Week 8.

Proportion of subjects achieving deep remission at 
Week 8.

Partial Mayo scores and change from baseline over 
time at Weeks 2, 4 and 8.

Change from baseline at Week 8 in total Mayo score.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction on patient reported 
outcomes (PRO) in subjects with moderate to severe 
UC.

The scores and change from baseline in 
Inflammatory Bowel Disease Questionnaire (IBDQ) 
Total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and Social 
Function) at Weeks 4 and 8.

The proportion of subjects with IBDQ total score 
≥170 at Weeks 4 and 8.

The proportion of subjects with ≥16 point increase in 
IBDQ total score from baseline at Weeks 4 and 8.

Proportion of subjects with improvement in IBDQ 
bowel symptom domain at Weeks 4 and 8.  The 
improvement is defined as an increase of at least 
1.2 points from baseline in average score among 
IBDQ bowel symptom domain (items 1, 5, 9, 13, 17, 
20, 22, 24, 26, 29).

The scores and change from baseline in Short 
Form 36 version 2, acute (SF-36v2) (physical and 
mental component summary scores: PCS & MCS, 
and 8 domain scores) at Weeks 4 and 8.

The scores and change from baseline in EuroQoL 
5 Dimensions (EQ-5D-3L & EQ-5D VAS) at 
Weeks 4 and 8.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
 
 

To assess the effect of PF-06651600 and 
PF-06700841 compared to placebo on disease and 
mechanistic biomarkers over time during induction. 

Change from baseline in serum hsCRP levels over 
time.

Change from baseline in fecal calprotectin.
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
Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets,
.

To explore outcomes based on investigational criteria 
in induction.

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus 
PGA).

Proportion of subjects with partial Mayo score 
≤2 with no individual subscore >1 in response to 
treatment over time.

Proportion of subjects with reduction of ≥2 points 
from baseline in partial Mayo score over time.

Proportion of subjects in endoscopic response at 
Week 8.  Endoscopic response is defined by a 
decrease from baseline in the endoscopic subscore of 
1 point or more.
 
 
 
 
 
 
 
 
*Remission in total Mayo score excludes friability (Refer to Section 7.3.3).
2.2. Objectives and Endpoints during the Chronic Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in the chronic period.

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 
12-lead ECG in the chronic period. 

Incidence of serious infections (see Section 7.2.8 for 
definition) in the chronic period.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 32 in subjects with moderate to 
severe UC.

Total Mayo score at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 for achieving remission at Week 32.

Proportion of subjects in remission* based on total 
Mayo score of ≤2 with no individual subscore >1 and 
a rectal bleeding subscore of 0 at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 32 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in 
endoscopic appearance (defined as a Mayo 
endoscopic subscore of ≤1) at Week 32.
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Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
 
 
 
 

To explore the effect of PF-06651600 and 
PF-06700841 in subjects with moderate to severe UC 
in the chronic dosing period.

Proportion of subjects achieving clinical response at 
Week 32.

Proportion of subjects in endoscopic remission at 
Week 32.
 
 

Change from baseline at Week 32 in total Mayo 
score.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

To assess the effect of PF-06651600 and 
PF-06700841 compared to placebo on disease and 
mechanistic biomarkers over time during chronic 
period.

Change from baseline in serum high-sensitivity 
C-reactive protein (hsCRP) levels over time.

Change from baseline in fecal calprotectin.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets, and T-cell, B-cell, 
 
CCI
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
To explore outcomes based on investigational criteria 
in the chronic period.

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus 
Physician’s global assessment (PGA)) at Week 32.
 
 
 
 
 
 
 
 
 
 
 
 
 
*Remission in total Mayo score excludes friability (Refer to Section 7.3.3).
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 2b, randomized, double-blind, placebo-controlled (in the induction period and 
not in the chronic dosing period), parallel group, multicenter study in subjects with moderate 
to severe active UC.  The first part of the study is a screening period of up to 6 weeks 
followed by an 8 week double-blind induction period.  The study will not be blinded across 
the PF-06651600 and PF-06700841 cohorts, but will be placebo-controlled during the 
induction phase, and double-blinded within each investigational product. 
At Week 8, all subjects will be assigned to their respective treatment cohort (PF-06651600
or PF-06700841) into an additional 24 week active chronic dosing period followed by a 
4 week follow up period after the last dose of investigational product for a total of 36 weeks.  
The chronic dosing period is in effect open label, with both subjects and Investigators aware 
that they have been assigned to PF-06651600 or PF-06700841, and that there is no placebo 
control.
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Approximately 318 subjects in total will be randomized into the study.  Following the 
screening period, subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive one of 8 treatments.  In the induction period, three oral dose 
levels (20, 70, and 200 mg daily) of PF-06651600 plus matching placebo in a 4:4:4:1 ratio 
and three oral doses (10, 30, and 60 mg daily) of PF-06700841 plus matching placebo in a 
4:4:4:1 ratio will be investigated.  For analysis of the induction period, placebo groups will 
be combined to yield final drug: placebo ratios of 2:2:2:1 for each drug at week 8. 
Following the induction period of the study, all subjects will enter the chronic dosing period
in which there will be no placebo arms (Protocol Amendments 5, 6, 7).  All subjects 
(including placebo subjects) from the double-blind PF-06651600 treatment/placebo induction 
period will receive 50 mg of PF-06651600 for 24 weeks.  All subjects (including placebo 
subjects) from the double-blind PF-06700841/placebo induction period will receive 30 mg of 
PF-06700841 for 24 weeks. Prior to Amendment 5, subjects were assigned to placebo and 
active during the chronic period within their respective treatment using a 2:1 ratio.
Any subject who discontinues early from the induction period prior to the Week 8 visit 
should undergo the procedures for an Early Termination visit on the last day the subject takes 
the investigational product or as soon as possible thereafter, and will not be permitted to enter 
the chronic dosing period.  For subjects who discontinue early from the chronic dosing
period (after the Week 8 visit, but prior to the Week 32 visit), the procedures scheduled for 
an Early Termination visit will be performed on the last day the subject takes the 
investigational product or as soon as possible thereafter.  After completion of the Early 
Termination visit subjects will enter the follow-up period.
3.2. Duration of Subject Participation
The duration of participation for eligible subjects will be approximately 42 weeks.  This 
includes a screening period of up to 6 weeks, an 8 week double-blind induction period 
followed by a 24 week open label chronic dosing period and a 4 week follow up visit after 
the last dose of investigational product. 


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3.3. Approximate Duration of Study
The study is estimated to complete in approximately 50 months, allowing for an estimated 
40 months to complete enrollment with each subject remaining on study for approximately 
10 months. 
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male and/or female subjects ≥18 years to ≤75 years of age at the time of informed 
consent.  For subjects in Korea: Male and/or female subjects ≥19 years to ≤75 years 
of age at the time of informed consent.
2. Diagnosis (endoscopic and histological) of UC for ≥3 months prior to entry into the 
study.  A report supporting disease duration and extent (eg, proctosigmoiditis, 
left-sided colitis, or pancolitis) based upon prior endoscopy including a biopsy report 
must be available in the source documentation.
3. Subjects with moderate to severe active UC as defined by a total Mayo score of ≥6, 
with a rectal bleeding subscore of ≥1 and an endoscopic subscore of ≥2.  Endoscopy 
(colonoscopy or flexible sigmoidoscopy) must be performed within 10 days of 
baseline, preferably 5 to 7 days prior to baseline, to allow calculation of Total Mayo 
Score.  The endoscopic subscore assessed by the Central Reader must be available at 
the baseline visit and will be used to derive the total Mayo score to determine study 
eligibility.
4. Active disease beyond the rectum (>15 cm of active disease from the anal verge at the 
screening endoscopy).
5. Must have inadequate response to, loss of response to, or intolerance to at least one 
conventional therapy for UC:

Steroids;

Immunosuppressants (azathioprine [AZA], 6-MP, or methotrexate [MTX]);

Anti-TNF inhibitors (eg, infliximab, adalimumab, or golimumab);


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
Anti-integrin inhibitors (eg, vedolizumab).
See Appendix 1 for guidance only.  Local standards of care, as well as investigator 
assessment should be considered in any assessment.
6. Subjects currently receiving the following treatment for UC are eligible providing 
they have been on stable doses as described below:

Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline.  If 
oral 5-ASA treatment has been recently discontinued, it must have been stopped 
for at least 2 weeks prior to baseline.

Oral corticosteroids (dose equivalent to prednisone up to 25 mg/day; budesonide 
up to 9 mg/day; See Appendix 9) stable dose for at least 2 weeks prior to baseline.  
If oral corticosteroids have been recently discontinued, they must have been 
stopped at least 2 weeks prior to baseline.  Decreases in steroid use due to AEs are 
allowed. 
7. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
9. Female subjects of childbearing potential (Women of child-bearing potential: 
WOCBP) must test negative for pregnancy at screening visit and baseline visit.
10. Female subjects considered to be of non-childbearing potential must meet at least 1 of 
the following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Female subjects who are pregnant or wish to become pregnant; breastfeeding female 
subjects; male subjects with partners currently pregnant; male subjects able to father 
children and female subjects of childbearing potential who are unwilling or unable to 
use 2 effective methods of contraception (at least 1 highly effective method) as 
outlined in this protocol for the duration of the study and for at least 28 days after the 
last dose of investigational product.
2. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious 
colitis, radiation colitis, and diverticular disease associated with colitis, or clinical 
findings suggestive of Crohn’s disease (eg, fistulae, granulomas on biopsy).
3. Subjects with known colonic stricture and subjects with history of colonic or small 
bowel obstruction or resection.
4. Subjects with significant trauma or major surgery within 4 weeks of screening.
5. Subjects considered in imminent need for surgery or with elective surgery scheduled 
to occur during the study. 
6. Subjects with a history of bowel surgery within 6 months prior to baseline.
7. Subjects displaying clinical signs of fulminant colitis or toxic megacolon. 
8. Subjects with primary sclerosing cholangitis.
9. Subjects with history of colonic or small bowel stoma.
10. Subjects with evidence of colonic dysplasia, adenomas or neoplasia.  However, 
subjects with adenomatous polyps identified on screening endoscopy will be eligible 
if the polyps have been completely removed and follow-up surveillance per local 
guidelines is negative.
11. Subjects who meet either of the 2 criteria below are considered at risk for colorectal 
cancer and must have a colonoscopy prior to randomization.  The colonoscopy and 
pathology reports (if biopsies obtained) must be available in the source 
documentation:

If the subject is ≥50 years of age, a colonoscopy within 10 years of screening is 
required to exclude adenomatous polyps.  Subjects with adenomatous polyps
identified on screening endoscopy will be eligible after complete polypectomy 
and follow-up surveillance per local guidelines is negative.


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
If the subject has had extensive (ie, greater than left sided) colitis for ≥8 years or 
disease limited to left side of colon (ie, distal to splenic flexure) for ≥10 years, 
regardless of age, a colonoscopy within 1 year of screening visit is required to 
survey for dysplasia.  Subjects with dysplasia or cancer identified on biopsies will 
be excluded.
12. Subjects receiving the following therapies within the time period described below or 
expected to receive any of these therapies during the study period:

>9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral 
systemic corticosteroid dose within 2 weeks prior to baseline. 

IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid 
enemas/suppositories within 2 weeks prior to baseline.

Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline.

Anti-TNF inhibitors (or biosimilars thereof) as described below:

Infliximab within 8 weeks prior to baseline;

Adalimumab within 8 weeks prior to baseline;

Golimumab within 8 weeks prior to baseline;

Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.

Interferon therapy within 8 weeks prior to baseline.

Subjects with prior treatment with lymphocyte-depleting agents/therapies within 
1 year prior to baseline (eg, CamPath® [alemtuzumab], alkylating agents 
[eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc).
Subjects who have received rituximab or other selective B lymphocyte-depleting 
agents within 1 year prior to baseline.

Subjects previously receiving leukocyte apheresis, including selective 
lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 
6 months prior to baseline. 

Other marketed immunosuppressants or biologics with immunomodulatory 
properties within 3 months prior to baseline. 

Other investigational procedures(s) or product(s), such as immunosuppressants 
used in transplantation (eg, mycophenolate mofetil, cyclosporine, rapamycin, or 
tacrolimus) or live (attenuated) vaccine within 30 days prior to baseline.


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
Other JAK inhibitors within 3 months prior to baseline. Subjects who have not 
responded to or have been intolerant of other JAK inhibitors.

Participation in other studies involving investigational drug(s) within 30 days, or 
5 half-lives of investigational product (IP) (whichever is greater), prior to study 
entry and/or during study participation.
13. Abnormal findings on the chest x-ray film such as presence of tuberculosis (TB), 
general infections, heart failure, or malignancy.  Chest x-ray examination may be 
performed up to 12 weeks prior to screening.  Documentation of the official reading 
must be located and available in the source documentation. If a subject had a CT 
scan of the chest (with or without IV contrast) up to 12 weeks prior to screening, the 
CT scan results can substitute for the chest radiograph results.
14. Any history of either untreated or inadequately treated latent or active TB infection, 
current treatment for active or latent TB infection, evidence of currently active TB by 
chest x-ray, or residing with or frequent close contact with individual(s) with active 
TB.  Subjects who have a positive Mantoux (PPD) tuberculin skin test or a positive 
Interferon Gamma Release Assay (IGRA to be tested at the site’s local lab where 
feasible) during screening or within 12 weeks prior to randomization, except as noted 
below:

An IGRA is preferred for subjects with a prior BCG vaccination (to be tested by a 
site’s local lab when feasible), but may be used for any subject.  Documentation 
of IGRA product used and the test result must be in the subject’s source 
documentation.

If the results of the IGRA are positive, the test must not be repeated. 

If the results of the IGRA are indeterminate, the test may be repeated, and if a 
negative result is obtained, enrollment may proceed.  A positive test on repeat 
is exclusionary.

Subjects with repeat indeterminate IGRA results may be enrolled after a 
documented evaluation by appropriately qualified personnel (which may 
include a pulmonary or infectious disease specialist, or locally acceptable 
expert as defined by local guidelines), that in their opinion, the probability of 
reactivation is low (ie, subject would be acceptable for immunosuppressant 
treatment without additional action).

Subjects adequately treated (in the opinion of the appropriately qualified 
personnel - which may include a pulmonary or infectious disease specialist, or 
locally acceptable expert as defined by local guidelines) for latent and/or active 
tuberculosis infection may be enrolled regardless of Mantoux or IGRA results 
provided the treatment is well documented in the subject’s medical records and/or 
source documentation prior to enrollment in the study.


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Note:

A positive Mantoux tuberculin skin test is defined as ≥5 mm of induration (or as 
defined by country specific or local standards) at 48-72 hours without 
consideration of prior Bacillus Calmette-Guerin (BCG) vaccination.  
Documentation of the dose and product used for the Mantoux tuberculin test as 
well as the official test reading must be obtained and available in the subject’s 
source documentation.

The following are acceptable assays: QuantiFERON® - TB Gold test (QFT-G), 
QuantiFERON® - TB Gold In-Tube test (QFT-GIT) and T-SPOT® - TB test 
during screening or within 12 weeks prior to screening.
15. Presence of active enteric infections (positive stool culture and sensitivity performed 
at screening or 6 week prior to the screening visit).  The presence of Clostridium 
difficile infection (reference C. diff section) or pseudomembranous colitis.  Known 
active invasive fungal infections such as histoplasmosis or parasitic infections.  
Subject with Clostridium difficile infection may be treated and re-tested or 
re-screened at the discretion of the Investigator.
16. Known history of human immunodeficiency virus (HIV) based on documented 
history with positive serological test, or positive HIV serologic test at screening, 
tested at the site’s local lab (when feasible). 
17. Subjects with Hepatitis B or Hepatitis C viruses.

For Hepatitis B, all subjects will undergo testing for Hepatitis B Surface Antigen 
(HBsAg) and Hepatitis B Core Antibody (HBcAb) during Screening.  Subjects 
who are HBsAg positive are not eligible for the study.  Subjects who are HBsAg 
negative and HBcAb positive will be reflex tested for Hepatitis B Surface 
Antibody (HBsAb) and if HBsAb is positive, may be enrolled in the study; if 
HBsAb is negative, the subject is not eligible for the study. 

For Hepatitis C, all subjects will undergo testing for Hepatitis C antibody
(HCVAb) during Screening.  Subjects with positive HCV Ab tests will be reflex 
tested for HCV ribonucleic acid (HCV RNA).  Only subjects with negative 
HCV Ab or HCV RNA will be allowed to enroll in the study.
18. Clinically significant infections within 6 months of baseline (eg, those requiring 
hospitalization or parenteral antimicrobial therapy, or opportunistic infections), or a 
history of any infection otherwise judged by the investigator to have the potential for 
exacerbation by participation in the study.
19. Cancer or history of cancer or lymphoproliferative disease within the previous 5 years 
(with the exception of subjects with adequately treated or excised non-metastatic
basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ).


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20. Presence of transplanted organ; skin grafts are allowed. 
21. Have a history (single episode) of disseminated herpes zoster or disseminated herpes 
simplex, or a recurrent (more than one episode of) localized dermatomal herpes 
zoster.
22. Have current or recent history of clinically significant severe or progressive hearing 
loss or auditory disease.  Subjects with hearing aids will be allowed to enter the study 
provided their hearing impairment is considered controlled/clinically stable.
23. Significant concurrent medical condition at the time of screening or baseline visit, 
including but not limited to the following:

Any major illness/condition or evidence of an unstable clinical condition 
(eg, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, 
immunologic [eg, Felty’s syndrome], or local active infection/infectious illness) 
that, in the investigator’s judgment will substantially increase the risk to the 
subject if he or she participates in the study.

Active renal disease and/or recent kidney stones.

Severe hepatic impairment (defined as Child-Pugh C).

Acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) 
and any history of cerebrovascular disease within 24 weeks before screening.
24. Prior evidence of liver injury or toxicity due to methotrexate.
25. Abnormality in hematology and/or chemistry profiles during screening:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 
≥1.5 times the upper limit of normal (ULN).

Total bilirubin level ≥1.5 times the ULN; subjects with a history of Gilbert’s 
syndrome may have a direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin in ≤ULN.

Hemoglobin level ≤90 g/L (9.0 g/dL).

Platelet count ≤100 x 109/L (100,000 cells/mm3) or ≥1000 x 109/L 
(1,000,000 cells/mm3).

White blood cell (WBC) count ≤3.0 x 109/L (3000 cells/mm3) or absolute 
neutrophil count (ANC) <1200 cells/mm3 or absolute lymphocyte count of 
<0.8 x 109/L (<800 cells/mm3).

eGFR <60 mL/min/1.73m2 based on the age appropriate calculation.


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
Proteinuria ≥3+.

Glycosylated hemoglobin (HbA1C) >10%.

Subjects with HbA1C > ULN without a diagnosis of diabetes mellitus should 
be evaluated prior to randomization for confirmation of diagnosis.
26. Subjects with any condition possibly affecting oral drug absorption (eg, gastrectomy, 
clinically-significant diabetic gastroenteropathy, or certain types of bariatric surgery 
such as gastric bypass).  Procedures such as gastric banding that simply divide the 
stomach into separate chambers are NOT exclusionary.
27. Subjects receiving prohibited concomitant medications, including moderate to potent 
CYP3A inducers or inhibitors (See Appendix 2) in the time periods described below:

For moderate to potent CYP3A inducers, within 28 days or 5 half-lives,
whichever is longer, prior to baseline.

For moderate to potent CYP3A inhibitors, within 7 days or 5 half-lives, 
whichever is longer, prior to baseline.
Note: Simvastatin or simvastatin-containing products from 5 days prior to baseline.
28. Subjects receiving strong P-gp inhibitors (eg, quinidine) within 5 half-lives prior to 
baseline.
29. Subjects receiving narrow therapeutic index substrates of MDR1 (eg, digoxin), 
OCT2 or MATE (eg, dofetilide) within 5 half-lives prior to baseline.
30. Donation of blood in excess of 500 mL within 8 weeks prior to baseline.
31. History of alcohol or drug abuse with less than 6 months of abstinence prior to 
baseline.
32. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
33. 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 subject inappropriate for entry into this 
study.


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34. History of thrombotic event(s), including deep venous thrombosis (DVT), and known 
inherited conditions that predispose to hypercoagulability.
Screening laboratory tests with abnormal results (if considered by the investigator to be 
transient and inconsistent with the subject’s clinical condition) may be repeated within 
the screening window to confirm abnormal results.  If results return to protocol 
acceptable limits within the screening period, the subject may enter the study. 
Subjects who do not meet eligibility criteria (ie, screen fail) may be re-screened once (with a 
new screening number) at the discretion of the investigator.
4.3. Lifestyle Requirements
4.3.1. Contraception
 
 
 
Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use 2 methods of effective contraception (at least 1 highly 
effective method) throughout the study and for at least 28 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected 2 appropriate methods of contraception for 
the individual subject and his/her partner(s) from the list of permitted contraception methods 
(see below) and will confirm that the subject has been instructed in their consistent and 
correct use.  At time points indicated in the Schedule of Activities, the investigator or 
designee will inform the subject of the need to use 2 methods of effective contraception (at 
least 1 highly effective method) consistently and correctly and document the conversation, 
and the subject’s affirmation, in the subject’s chart.  In addition, the investigator or designee 
will instruct the subject to call immediately if 1 or both of the selected contraception methods
is discontinued or if pregnancy is known or suspected in the subject or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner.
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
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal;

Transdermal;

Injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral;

Injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
Effective method:
1. Male condom or female condom.
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose of investigational product.  Male subjects must refrain from donating sperm during the
study and for 90 days after the last dose of investigational product.
 
4.3.2. Dietary Restriction
It is recommended that subjects avoid consumption of grapefruit juice exceeding 8 ounces
(~240 ml) total in a day while in the study.
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4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study portal.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational product(s) are PF-06651600 and PF-06700841 tablets.
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number assigned.  The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 


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5.2. Breaking the Blind 
The study will be Sponsor, subject, and investigator blinded during the induction phase.
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject. If an investigator believes that 
immediate unblinding is necessary and time and circumstances allows, he/she is encouraged 
to discuss unblinding with a member of the study team.  However, discussion with a member 
of the study team in advance of unblinding is not required. When the blinding code is 
broken, the reason must be fully documented and entered on the case report form (CRF).
5.3. Subject Compliance
IP accountability and compliance will be assessed by the site at each clinic visit starting at 
the visit after the baseline visit up through Week 32.  Subject compliance will be verified by 
the accounting of investigational product at each visit.  When investigational product is 
administered at the research facility, it will be administered under the supervision of study 
personnel.
Compliance of the IP will be monitored by delegated site personnel by the accounting of 
unused IP returned by the subject at study visits.  Compliance will be documented on the 
CRF and source document.  Non-compliance is defined as taking less than 80% or more than
120% of IP during the double-blind study treatment (induction) and/or chronic dosing
period(s) and as directed by the dosing instructions, regardless of reason.  Subjects are to 
bring the blister cards and/or bottles with any remaining study drug to each visit for review.  
The investigator has the discretion to withdraw any subject from the study for reasons of 
non-compliance with the dosing regimen.  Investigators should indicate on appropriate CRF 
page non-compliance with study treatment and provide an explanation.  Inventory control of 
all IP must be rigorously maintained throughout the duration of the study until all IP has been 
accounted for and/or returned to the sponsor.  Any discrepancies noted between drug 
dispensing records and drug inventory must be reported to Pfizer.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded PF-06651600, PF-06700841 and matching placebos will be provided as tablets in 
blister cards for oral administration during the induction period of the study.  For the chronic 
dosing period, PF-06700841 tablets will be supplied in bottles, PF-06651600 tablets will be 
supplied as tablets in blister cards. The designation “PF-06651600-15” and 
“PF-06700841-15” may appear on labeling and indicates a salt.  They are equivalent to 
“PF-06651600” and “PF-06700841” with regard to this protocol. The PF-06651600 10 mg
and 50 mg tablets and their matching placebos will be supplied in separate blister cards and 
labeled according to local regulatory requirements.  The PF-06700841 5 mg and 25 mg 
tablets and their matching placebos will be supplied in separate blister cards and labeled 


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according to local regulatory requirements.  Blinding occurs within investigational products, 
not across investigational products and only for the induction phase.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each 
visit from baseline visit through Week 24. A qualified staff member will dispense the 
investigational product via unique container numbers in the blister cards or bottles provided, 
in quantities appropriate for the study visit schedule. The subject should be instructed to 
maintain the product in the blister cards or bottles provided throughout the course of dosing 
and return the blister cards or bottles to the site at the next study visit. Refer to Appendix 10
for investigational drug dispensing during public emergencies if applicable.
5.5. Administration
PF-06651600 and PF-06700841 tablets and matching placebo for oral administration will be 
dispensed in blister cards or bottles as described above in Section 5.4.1.  Subjects will be 
dispensed an appropriate number of blister cards or bottles sufficient for administration until 
the next dispensing visit and given clear dosing instructions. 
Sites will be trained on how subjects should take tablets at home through an IP manual and/or 
other vehicle(s).  Sites are responsible for communicating this information and site staff 
should review the dosing instructions with subjects at every study visit through Week 24. 
Subjects should take the IP orally for 8 weeks during the induction period and an additional 
24 weeks during the chronic dosing period for a total of 32 weeks.  Subjects should swallow 
the tablets with ambient temperature water to a total volume of approximately 240 mL.  
Subjects should swallow the IP whole, and will not manipulate or chew the IP prior to 
swallowing.  Subjects will be instructed to take the IP in the morning after breakfast 
whenever possible even though IP may be taken with or without food; however, for study 
visit days (ie, baseline, Weeks 2, 4, 8, 12, 16, 20, and 24), subjects are to be instructed to 
refrain from dosing at home, bring their blister cards or bottles to the site.  Subjects are to 
take the dose in the clinic from their current blister card or bottle.  If a subject 
administers the morning dose prior to the visit, the subject may be rescheduled within the 
permitted window or the visit may be conducted 
 
If a dose is missed and the interval to the next dose is less than 8 hours, the missed dose 
should not be administered.
During the induction phase, if subjects require discontinuation of investigational product for 
medically mandated reasons (eg, following instructions from investigator) for more than 
7 consecutive days at any time during the study, they will be discontinued from treatment and
should undergo the procedures for an Early Termination visit on the last day the subject takes 
the investigational product or as soon as possible thereafter before entering the follow-up 
period, and will not be permitted to enter the chronic dosing period.  During the chronic 
dosing period, if dosing is missed for more than 7 consecutive days, the subject should be 
considered for discontinuation following consultation with the Sponsor.
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5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
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All blister cards and/or bottles of study drug must be returned to the investigator by the 
subject at every visit.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
For all blisters and/or bottles returned to the investigator by the subject, the investigator will 
maintain the returned supply until destruction is authorized. Pfizer will provide instructions 
as to the disposition of any unused investigational product.
5.8. Concomitant Treatment(s)
All concomitant medication(s) and treatment(s) administered/taken during the study must be 
recorded with indication, daily dose, and start and stop dates of administration.  All subjects 
will be questioned about concomitant medication at each site visit.
A subject who is receiving metformin as concomitant medication must allow at least two 
hours after taking either medication and before taking investigational product.
Medication(s) administered/taken following the first dose of IP will be documented as 
concomitant medication(s).
Treatments taken within 42 days before the first dose of study drug will be documented as 
prior treatment.  Treatments taken after the first dose of study drug will be documented as 
concomitant treatment. 
5.8.1. Oral Corticosteroids
Any oral corticosteroids taken during the screening and treatment periods of the study will be 
captured on the appropriate CRF.
5.8.2. Permitted Medications
Subjects will be allowed to use the following medications as detailed below:

Concomitant use of oral 5-ASA or sulfasalazine.  Dose must be stable for at least 
4 weeks prior to baseline and through end of study (Week 36).  If oral 5-ASA 
treatment has been recently discontinued, it must have been stopped for at least 
2 weeks prior to baseline.

A stable dose of oral corticosteroids (dose equivalent to prednisone up to 25 mg/day; 
budesonide up to 9 mg/day; See Appendix 9) for at least 2 weeks prior to baseline and 
through end of the induction period (Week 8, except for the case of subjects 
undergoing optional steroid tapering in the chronic dosing period).


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
If oral corticosteroids have been recently discontinued, they must have been stopped 
at least 2 weeks prior to baseline.  Rectal steroids are prohibited.  Decreases in steroid 
use due to AEs are allowed.

Upon a subject achieving remission during the chronic dosing period, steroids may be 
slowly tapered per local guidelines.  Steroid tapering is allowed only in the chronic 
dosing period.  Subjects may reduce the daily dose of prednisone or equivalent by 
2.5 to 5 mg weekly (based on their symptoms) until the dose of prednisone or 
equivalent is 10 mg/day, then reduce the daily dose of prednisone or equivalent by 
2.5 mg weekly until the dose is 0 mg.  If a subject experiences worsening of UC
symptoms during the corticosteroid taper that in the opinion of the investigator are 
attributable to the corticosteroid taper, then the investigator may instruct the subject 
to revert back to the preceding dose in the taper schedule (ie, “step up”).  The signs or 
symptoms leading to this change (eg, increased stool frequency, increased rectal 
bleeding) must be recorded on the CRF.  Study subjects with signs or symptoms 
attributed to corticosteroid taper are permitted to step up their corticosteroid dosage 
one time during study participation and then resume corticosteroid taper to achieve 
steroid-free status. See Appendix 9 for guidance on steroid equivalency.
5.8.3. Prohibited Medications
The following medications are prohibited for the specified time periods as described below:

Oral budesonide (>9 mg/day) or prednisone (>25 mg/day) or equivalent oral systemic 
corticosteroid within 2 weeks prior to baseline and through end of study (Week 36).

IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid 
enemas/suppositories within 2 weeks prior to baseline and through end of study 
(Week 36).

Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline and 
through end of study (Week 36).

Biologics including anti-TNF inhibitors (eg, infliximab, adalimumab, golimumab), or 
biosimilars thereof, within 8 weeks prior to baseline and through end of study 
(Week 36).

Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline and 
through end of study (Week 36).

Interferon therapy within 8 weeks prior to baseline and through end of study 
(Week 36).

Lymphocyte-depleting agents/therapies within 1 year prior to baseline and through 
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
Leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte 
apheresis, or plasma exchange within 6 months prior to baseline and through end of 
study (Week 36). 

Rituximab or other selective B lymphocyte-depleting agents within 1 year prior to 
baseline and through end of study (Week 36).

Other marketed immunosuppressants or biologics with immunomodulatory properties 
within 3 months prior to baseline and through end of study (Week 36).

Use of immunosupressants used in transplantation (eg, mycophenolate mofetil, 
cyclosporine, rapamycin, or tacrolimus) within 30 days prior to baseline and through 
end of study (Week 36).

Any live (attenuated) vaccines from 30 days prior to baseline and through the end of 
study (Week 36).

Anti-motility agents for control of diarrhea (eg, diphenoxylate hydrochloride with 
atropine sulfate or loperamide) from 5 days prior to baseline through end of study 
(Week 36).

Moderate to potent CYP3A inducers or inhibitors as listed in Appendix 2 through end 
of the study (Week 36) (unless as in an emergency as outlined in Appendix 2).

Simvastatin or simvastatin-containing products from 5 days prior to baseline and 
through end of study (Week 36).

Strong P-gp inhibitors (eg, quinidine) within 5 half-lives prior to baseline and through 
end of study (Week 36).

Narrow therapeutic index substrates of MDR1 (eg, digoxin), OCT2 or MATE 
(eg, dofetilide) within 5 half-lives prior to baseline and through end of study 
(Week 36).
5.8.4. Vaccinations
Vaccination with live virus, attenuated live virus, or any live viral components is prohibited 
within the 30 days prior to the first dose of study drug and through the end of the study 
(Week 36).  Similarly, current routine household contact with individuals who have been 
vaccinated with live vaccine components should be avoided during treatment and through the 
end of the study. 
Such vaccines include but are not limited to FluMist® (intranasal influenza vaccine), 
attenuated rotavirus vaccine, varicella (chickenpox) vaccine, attenuated typhoid fever 
vaccine, oral polio vaccine, MMR (measles, mumps, rubella) vaccine and vaccinia 
(smallpox) vaccine.  Following vaccination with live component vaccines, the virus may be 


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shed in bodily fluids, including stool, and there is a potential risk that the virus may be 
transmitted. 
5.9. Rescue Medication
Subjects requiring rescue medication prior to the end of study (Week 36) visit will be 
discontinued from treatment should undergo the procedures for an Early Termination visit on 
the last day the subject takes the investigational product or as soon as possible thereafter and 
then enter the follow up period.  Subjects requiring rescue medication after the Week 32 visit 
should complete the follow-up visit.
6. STUDY PROCEDURES 
Refer to Appendix 10 for Alternative Measures During Public Emergencies if applicable.
6.1. Screening
After informed consent has been obtained, subjects have up to 6 weeks of a screening period 
to complete all of the screening procedures.  Subject’s eligibility for the study will be 
evaluated during this period based on medical history, physical examination, laboratory 
values, bowel movement diary data and additional tests.  To prepare for study participation, 
subjects will be instructed on the use of Lifestyle Requirements (see Section 4.3) and
Concomitant Medications (see Section 5.8).
Screening laboratory tests with abnormal results may be repeated to confirm abnormal 
results; the last value will be used to determine eligibility.  If results return to protocol 
accepted limits within the 6-week screening period, the subject may enter the study. 
Subjects who do not meet eligibility criteria (ie, screen fail) may be re-screened once (with a 
new screening number) at the discretion of the investigator. 
The study investigator, or appropriate delegate at the site, will discuss with each subject the 
nature of the study, its requirements, risks and restrictions.  Written informed consent must 
be obtained prior to performing any protocol-specific procedures, including washout of 
prohibited medications.
The following procedures will be performed:

Informed consent and Eligibility Assessment.

Complete medical history including:

History of UC, including duration of disease, extent of disease, extra-intestinal 
manifestations, duration of current flares, number of flares in the preceding year, 
and UC related hospitalizations; 

History of chicken pox and shingles;


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
History of skin rash, skin infection and any abnormalities that may predispose the 
subject to infection; 

Reasons for previous UC medication intolerance (eg, discontinuation of 
medication due to an AE as determined by the investigator); 

History of previous vaccinations, specifically influenza, pneumococcal, varicella,
and zoster; 

History of illegal drug use; 

Smoking status;

Average weekly alcohol consumption; 

Family history of premature coronary heart disease (CHD).  Premature coronary 
heart disease is defined as CHD in a male first-degree relative first observed at 
<55 years or CHD in female first-degree relative first observed <65 years; 

Family history of colorectal cancer.

Assessment of prior concomitant medications, including a complete history of all 
therapies for UC received since diagnosis (including treatment response), and detailed 
UC medications (including dose, frequency, and route) taken within 3 months prior to 
the screening visit.  Complete history of all drugs (including nonprescription drugs, 
vitamins, and dietary or herbal supplements), taken within 4 weeks prior to screening 
procedures.

Complete physical examination (including height and weight).

Vital signs including temperature.

12-lead electrocardiogram (ECG).

Audiogram.

Laboratory tests including (see Section 7): 

Hematology;

Serum chemistry;

Fasting lipid panel (at least 8 hour fast);

HbA1C;


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
HBsAg, HBcAb, HCVAb.  Subjects who are HCV Ab positive require further 
testing with HCV RNA;

HIV-1/HIV-2 serology;

-hCG blood test will be performed for women of childbearing potential;

Urinalysis, including spot urine albumin/creatinine ratio;

FSH should be done in postmenopausal women (females who are amenorrheic for 
at least 12 consecutive months);

Stool microbiology (stool culture for enteric pathogens, ova and parasites, and 
Clostridium difficile toxin test), if not performed within 6 weeks prior to 
screening, should be prior to administration of any bowel prep for endoscopy.

Tuberculosis Screening (Refer to Sections 7.2.5 and 7.2.6).

Chest radiograph (posteroanterior and lateral), if not performed and documented 
within 12 weeks prior to screening.  Negative results must be documented prior to 
Baseline (Day 1) randomization.

Stool sample for fecal calprotectin analysis (should be prior to initiation of any bowel 
preparation for endoscopy).
 

Subjects will be instructed on daily collection of bowel movement diary data.  The 
bowel movement diary to collect BM frequency and rectal bleeding should be 
collected daily beginning approximately 2 weeks prior to screening endoscopy.

Endoscopy: 
Colonoscopy is required for the following subjects:

Who are at least 50 years old and have not had a colonoscopy performed within 
10 years; OR

Who have extensive colitis for ≥8 years or disease limited to left side of colon for 
≥10 years and have not had a colonoscopy within 1 year.
Flexible sigmoidoscopy: All other subjects may undergo a flexible sigmoidoscopy at 
the discretion of the investigator. Subjects who undergo colonoscopy do not require a 
separate sigmoidoscopy.
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
Endoscopy (colonoscopy or flexible sigmoidoscopy) should be performed (during the 
screening period and preferably after all other eligibility criteria have been verified)
within 10 days of baseline, preferably 5 to 7 days prior to the baseline to allow stool 
diary data collection for Mayo score calculation and to obtain endoscopic subscore 
report from the central reader.  The stool frequency, rectal bleeding and centrally-read 
endoscopic subscores for the endoscopy performed during the screening period and 
the PGA obtained at baseline will be used to determine eligibility.

Contraception check (Refer to Section 4.3).

Serious and non-serious adverse event monitoring.
6.2. Study Period (Induction)
6.2.1. Baseline/(Week 0/Day 1)
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
baseline visit.  This is required for fasting lipid profile and fasting glucose sample collection.
Eligibility assessment will be performed based on all available data collected during the 
screening period and at baseline visit. 
The following procedures will be performed:

Review study data collected during screening and perform initial eligibility 
assessment before proceeding to the other procedures below.

Assessments (Bowel Movement and 
 IBDQ, SF-36, EQ-5D-3L,
EQ-5D-VAS).

Complete physical examination.

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum chemistry;

Lipid profile (fasting);

hsCRP;
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
Cystatin C (and eGFR);

Urinalysis;

Urine pregnancy test for women of childbearing potential.

Prior/concomitant medication assessment.

Serious adverse event and adverse event monitoring.

Contraception check.

Mayo (total and partial) scores at Week 0 will be calculated based on stool frequency, 
rectal bleeding, and centrally read endoscopic subscores for the endoscopy performed 
during the screening period and the PGA obtained at baseline.

Assessment of eligibility.

Randomization.
 
 
 

Study drug dispensing.

Administration of the first dose of IP.

Provide and review dosing instruction.
C
C
I
C
C
C
C
I


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6.2.2. Week 2 (±2 Days)
There is a ±2 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

Cystatin C (and eGFR);
 

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Administration of one dose of IP.

Provide and review dosing instruction.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.
C
C
C
C
I
CCI


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
Contraception check.
6.2.3. Week 4 (±2 Days)
There is a ±2 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score, IBDQ, 
SF-36, EQ-5D-3L, EQ-5D-VAS).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

Cystatin C (and eGFR);

hsCRP;
 

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Stool sample for fecal calprotectin analysis;
 

Provide and review dosing instruction.
C
C
I
C
C
I
CCI


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
Administration of one dose of IP.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
6.2.4. Week 8 (±2 Days)
There is a ±2 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 IBDQ, SF-36, EQ-5D-3L,
EQ-5D-VAS).

Complete physical examination.

Audiogram.

Vital signs including temperature.

12-lead ECG.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

hsCRP;

Cystatin C (and eGFR);
C
C
C
C
CCI
C
C


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
Urinalysis;

Urine pregnancy test for women of childbearing potential;

Stool sample for fecal calprotectin analysis;
 
 

Administration of one dose of IP.

Provide and review dosing instruction for the chronic dosing period.
 

Endoscopy (colonoscopy or flexible sigmoidoscopy):

Mayo score.

Partial Mayo Score calculation.

Re-Randomization to chronic dosing period.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
C
C
C
C
C
C
I
C
C
I
C
C
I


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6.3. Study Period (Chronic Therapy)
Subjects will begin the chronic dosing period after assessments at week 8 are complete. 
6.3.1. Week 12 (±4 Days)
There is a ±4 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel;

Cystatin C (and eGFR);

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Administration of one dose of IP.

Provide and review dosing instruction.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
C
C
CCI


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6.3.2. Week 16 (±4 Days)
There is a ±4 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Audiogram.

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

Cystatin C (and eGFR);

hsCRP;
 

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Stool sample for fecal calprotectin analysis;

Administration of one dose of IP.

Provide and review dosing instruction.

IP accountability and dispensing.
C
C
C
C
I
CCI


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
Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
6.3.3. Week 20 (±4 Days)
There is a ±4 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel;

Cystatin C (and eGFR);

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Administration of one dose of IP.

Provide and review dosing instruction.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.
C
C
CCI


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
Contraception check.
6.3.4. Week 24 (±4 Days)
There is a ±4 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Partial Mayo score).

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

Cystatin C (and eGFR);

hsCRP;

Urinalysis;

Urine pregnancy test for women of childbearing potential;

Stool sample for fecal calprotectin analysis;

Administration of one dose of IP.

Provide and review dosing instruction.

IP accountability and dispensing.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.
C
C
CCI


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
Contraception check.
6.3.5. Week 32 (±4 Days)/Early Termination Visit
For subjects who discontinue early during the chronic dosing period (after Week 8 and prior 
to Week 32 visit), the procedures scheduled for Week 32 will be performed on the last day 
the subject takes the investigational product or as soon as possible thereafter.
There is a ±4 day window for this study visit.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
The following procedures will be performed:

Assessments (Bowel Movement and 
 Diary Data, IBDQ, SF-36, EQ-5D-3L,
EQ-5D-VAS).

Complete physical examination (including weight).

Audiogram.

Vital signs including temperature.

12-lead ECG.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel; 

Cystatin C (and eGFR);

hsCRP;
C
C
I
CCI


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
Urinalysis;

Urine pregnancy test for women of childbearing potential;

Stool sample for fecal calprotectin analysis;
 

Administration of final dose of IP.

Endoscopy (colonoscopy or flexible sigmoidoscopy):

Mayo score.

Partial Mayo Score calculation.

IP accountability.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
6.3.6. Follow-up Visit (Week 36±7 Days)
There is a ±7 day window for this study visit.
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see Section 8.1.4) and to confirm appropriate contraception usage (see Section 4.3.1).
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to the 
visit.  This is required for fasting lipid profile and fasting glucose sample collection.
C
C
C
C
C
C
I
C
C
I


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The following procedures will be performed:

Targeted physical examination (consisting of examination of skin, heart, lungs, 
abdomen, and examination of body systems where there are symptom complaints by 
the subject).

Vital signs including temperature.

Laboratory tests including:

Hematology;

Serum Chemistry;

Fasting lipid panel (at least 8 hours fast);

Cystatin C (and eGFR);

Urinalysis;

Urine pregnancy test for women of childbearing potential.

Serious adverse event and adverse event monitoring.

Concomitant medication assessment.

Contraception check.
6.4. Subject Withdrawal
6.4.1. Withdrawal of Consent
Subjects who request to discontinue receipt of study treatment will remain in the study and 
continue to be followed for protocol specified follow-up procedures; the follow-up visit 
should occur 4 weeks after their last dose whenever possible.  The procedures scheduled for 
Week 32 will be performed on the last day the subject takes the investigational product or as 
soon as possible thereafter.  The only exception to this is when a subject specifically 
withdraws consent for any further contact with him or her or persons previously authorized 
by the subject to provide this information. Subjects should notify the investigator in writing 
of the decision to withdraw consent from future follow-up, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is only from further receipt of investigational 
product or also from study procedures and/or post treatment study follow-up, and entered on 
the appropriate CRF page. In the event that vital status (whether the subject is alive or dead) 
is being measured, publicly available information should be used to determine vital status 
only as appropriately directed in accordance with local law.


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6.4.2. Lost to Follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing
status. This includes follow-up with persons authorized by the subject as noted above. Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational
product(s), request that the subject return for a final visit, if applicable, and follow up with 
the subject regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor. 
6.5. Guidelines for Monitoring and Discontinuations
The following laboratory abnormalities require monitoring and re-testing ideally within 
3-5 days, except as noted below when a shorter re-testing period is required:

Absolute neutrophil counts <1.2 x 109/L (<1200/mm3).

Hemoglobin <9.0 g/dL.


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
Platelet counts <100 x 109/L (<100,000/mm3).

Lymphocytes <800/mm3; <0.8 x 109/L.

CK > 3x ULN.

Any single AST and/or ALT elevation ≥3 times the upper limit of normal (repeat 
laboratory testing should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, GGT, PT [prothrombin time] with INR [international normalized 
ratio], and alkaline phosphatase), regardless of the total bilirubin.  (Please note that 
3 times the upper limit of normal increases in ALT, AST need confirmation on 
separate blood draw before undertaking thorough evaluation for liver injury).

For women of child-bearing potential with any positive urine -hCG test, the subject 
will have study drug interrupted and a serum sample submitted to the central 
laboratory for -hCG testing.
Additional individual subject safety monitoring in addition to these guidelines is at the 
discretion of the investigator and dependent on any perceived safety concerns.  Unscheduled 
laboratory testing through the central laboratory may be obtained at any time during the study 
to assess such concerns, and a subject may be withdrawn at any time at the discretion of the 
investigator.
Treatment with investigational product will be discontinued and the subject withdrawn from 
this study for:

Serious infections (See Section 7.2.8).

Two sequential absolute neutrophil counts <1.0 x 109/L (<1000/mm3); repeat testing 
must be performed as soon as feasible and within 3 days of the initial absolute 
neutrophil count <1.0 x 109/L (<1000/mm3).

Two sequential platelet counts <75 x 109/L (<75,000/mm3); repeat testing must be 
performed as soon as feasible and within 3 days of the initial platelet count 
<75 x 109/L (<75,000/mm3).

Two sequential lymphocyte counts <500/mm3; <0.5x109/L; repeat testing must be 
performed as soon as feasible and within 3 days of the initial lymphocyte count 
<500/mm3; <0.5x109/L.

Two sequential hemoglobin values of <8.0 g/dL; <4.96 mmol/L; <80 g/L.

Symptomatic anemia with hemoglobin <7.0 g/dL; <70 g/L or any anemia requiring a 
blood transfusion.


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
If an individual subject demonstrates CONCOMITANT serum creatinine-based 
AND serum cystatin C-based eGFR decline of ≥30% compared to the subject’s 
baseline eGFR, then the subject should not be dosed further and adequate, immediate
supportive measures including evaluation by a nephrologist (preferably within 
24 hours) for appropriate management.  If the subject cannot be seen by a 
nephrologist within 24 hours, then the subject should be sent to a local emergency 
room for assessment of renal function.  Results should be repeated as indicated by the 
nephrologist or weekly at a minimum until the eGFR returns to baseline ±15% or the 
renal parameters are deemed to be stable by the nephrologist and/or principal 
investigator (PI).

AST or ALT elevation >8 times the upper limit of normal.

Two sequential AST or ALT elevation ≥3 times the upper limit of normal with at 
least one total bilirubin value ≥2 times the upper limit of normal.

Two sequential AST or ALT elevation ≥3 times the upper limit of normal 
accompanied by signs or symptoms consistent with hepatic injury.

Two sequential AST or ALT elevation ≥5 times the upper limit of normal, regardless 
of total bilirubin or accompanying signs or symptoms.

AST or ALT elevation ≥3 times the upper limit of normal with an INR >1.5.
In each of the 5 cases above, there is a need for additional investigations, such as review of 
ethanol, recreational drug and dietary supplement consumption; testing for acute hepatitis A, 
B or C infection and biliary tract imaging should be promptly discussed with the Pfizer 
medical monitor or designee.

Female subjects found to be pregnant during the study.

At the discretion of the PI, initiation of any new treatment for UC for disease 
progression.

Subjects who are inadequately responding to investigational product in the opinion of 
the investigator.

Surgery for UC.

Clinically meaningful, treatment related decline in hearing from baseline.

Thrombotic or thromboembolic event occurs(even if not categorized as serious or 
severe in intensity), unless clearly unrelated to study drug.

Other treatment related serious or severe AEs, after consultation with the Pfizer 
medical monitor or designee.


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site via the 
laboratory manual provided to the site prior to initiation of the study.
Refer to Appendix 10 for Alternative Measures During Public Emergencies if applicable.
7.1. Blood Volume
Total planned blood sampling for an individual subject that completes all currently scheduled 
assessments through the Week 36 visit is approximately 430 mL.  Additional blood samples 
may need to be collected at times not specified in the protocol (eg, replacement of clotted or 
compromised specimens or repeat of clinically significant out of range laboratory results).


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7.2. Safety
7.2.1. Laboratory
The following safety laboratory tests will be performed at times defined in the Schedule of 
Activities. 
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
PT/INR/PTT
Reticulocytes (% and 
Abs)
BUN/Urea and 
Creatinine
Cystatin C
Glucose 
Calcium
Sodium
Potassium
Chloride
AST, ALT
Total Bilirubin
Direct bilirubina
Alkaline phosphatase
Uric acid
Albumin
Total protein
Creatine kinase (CK)
CK fractionationb
Total Cholesterolc
Triglyceridesc
HDLc
LDLc
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Microscopyd
Spot urine 
albumin/creatinine ratioe
FSHf,g
-hCGh
HbA1C
Hepatitis B, C and HIVg
QFT-G or other IGRAg
hsCRP
IP-10
Stool sampleg to detect 
enteric infections and C. 
difficile toxins A and B
 
Stool sample for fecal 
calprotectin 
 
 
Skin biopsies/swabsi
a.
Only if total bilirubin is elevated. 
b.
Only if CK is elevated.
c.
Fasting.
d.
Microscopy analysis is indicated if urinalysis is positive for blood, nitrite, leukocyte esterase and/or 
protein.  Urine culture is performed if urinalysis is positive for nitrite and/or leukocyte esterase or if 
clinically indicated.
e.
At screening only.
f.
In females who are amenorrheic for at least 12 consecutive months. 
g.
Complete at screening.
h.
Serum/Urine for women of childbearing potential.  Serum pregnancy test must be performed at 
screening.  If serum pregnancy test is borderline positive, the central lab will run a FSH test to confirm 
menopause.
i.
When required in cases of skin rash adverse events.
CCI
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7.2.2. Creatinine and Cystatin C
Serum creatinine is the best known standard test for monitoring renal function.  However, 
serum creatinine based estimates of glomerular filtration rate (eGFR) may be affected by 
factors other than renal function, including chronic and acute illness.  Cystatin C is a test that 
can be used either as an adjunct to or as a replacement for serum creatinine.  The most 
reliable estimates of GFR use both test results.5
Cystatin C is a low molecular weight protein that is used as an alternative to serum creatinine 
for monitoring of renal function.  It seems to correlate more closely with GFR than does 
serum creatinine concentration and may be a more sensitive detector of early renal 
dysfunction.6,7 While use of cystatin C has been limited, its independence of demographic 
factors (eg, race) has made it an interesting means of determining changes in renal function 
in clinical settings and it is included in the 2012 Kidney Disease: Improving Global 
Outcomes (KDIGO) guidelines.  Estimated GFR may be calculated via the 2012 CKD-EPI 
creatinine, cystatin C, or creatinine-cystatin C equations.8
Serum creatinine will be measured and creatinine based eGFR will be calculated at times 
specified in the Schedule of Activities. Serum cystatin C will be measured and cystatin C 
based eGFR will be calculated at times specified in the Schedule of Activities.
7.2.3. Estimated Glomerular Filtration Rate
Serum creatinine and serum cystatin-C based estimated GFR (eGFR) will be calculated at 
times specified in the Schedule of activities, in order to facilitate calculation of eGFR at these 
time points.  Corresponding serum creatinine and cystatin-C based eGFR will be determined 
to assess renal function. 
The estimated GFR (eGFR) will be calculated using the 2 sets of equations developed by the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), which utilize serum 
creatinine (SCr) and serum Cystatin C (S Cystatin C) respectively.9
7.2.4. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory.  For female subjects of 
childbearing potential, 2 negative pregnancy tests are required before receiving 
investigational product (1 negative pregnancy test at screening and 1 at the baseline visit 
immediately before investigational product administration).  Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and the second 
negative pregnancy test result will then be required at the baseline visit before the subject 
may receive the investigational product.  In the absence of regular menstrual bleeding, the 
study candidate should have used 2 forms of contraception for at least 1 month before the 
second pregnancy test.  Pregnancy tests will also be repeated at all visits and at the end of the 
study to confirm that the subject has not become pregnant during the study.  Pregnancy tests 
will also be done whenever 1 menstrual cycle is missed and when potential pregnancy is 
otherwise suspected, and may be repeated if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations.  In the case of a positive 


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confirmed pregnancy, the subject will be withdrawn from administration of investigational 
product but will remain in the study in follow-up.
7.2.5. Mantoux/Purified Protein Derivative (PPD) Tuberculin Test
Subjects may be screened for TB using the PPD Tuberculin Test per local guidelines.  The 
test consists of an intracutaneous injection of 5 Tuberculin Units (5 TU) PPD in 0.1 mL of 
solution on the volar aspect of the forearm, using a short beveled 26- or 27- gauge needle 
(Mantoux test).  After the tuberculin test is administered, the test area will be evaluated by a 
qualified healthcare professional, per local guidelines, 48 to 72 hours later.  The test is 
positive if the induration diameter is ≥5 mm at 48 to 72 hours post injection. 
To be eligible for this study, a negative test response is required during screening unless the 
test was performed and documented negative within 12 weeks prior to screening.  If a subject 
had a CT scan of the chest (with or without contrast) within 12 weeks prior to screening, the 
CT scan results can substitute for chest radiograph results.  Subjects with suspected false 
positive PPD results, eg, results from suspected BCG vaccination, should be further tested 
with an Interferon Gamma Release Assay (IGRA) assay during screening.
7.2.6. Interferon Gamma Release Assay Tuberculin Test
Subjects may be screened for TB using an IGRA per local guidelines.  IGRA will be tested 
locally (where feasible) during screening or within 12 weeks prior to screening.  The
following are acceptable assays: QuantiFERON®-TB Gold test (QFT-G), 
QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT® TB test.  Central lab used 
for the study may replace these tests with other acceptable QFT tests. Blood sampling may 
include 3 mL up to 10 mL of blood.  Site personnel should follow the processing and 
analyses steps based on the assay chosen.  Ensure incubation steps are followed as 
appropriate.
An IGRA is preferred for subjects with a prior BCG vaccination, but may be used for any 
subject.  Documentation of IGRA product used and the test result must be in the subject’s 
source documentation.
If the results of the IGRA are indeterminate, the test may be repeated, and if a negative result 
is obtained, enrollment may proceed.  A positive test on repeat is exclusionary. 
Subjects with repeat indeterminate IGRA results may be enrolled after a documented 
evaluation by appropriately qualified personnel (which may include a pulmonary or 
infectious disease specialist, or locally acceptable expert as defined by local guidelines), to 
rule out the possibility of low risk of infection (ie, subject would be acceptable for 
immunosuppressant treatment without additional action).
Subjects adequately treated (in the opinion of the appropriately qualified personnel - which 
may include a pulmonary or infectious disease specialist, or locally acceptable expert as 
defined by local guidelines) for latent and/or active tuberculosis infection may be enrolled 
regardless of Mantoux or IGRA results provided the treatment is well documented in the 
subject’s medical records and/or source documentation prior to enrollment in the study.


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The sample(s) will be analyzed by the site’s local laboratory.  Refer to local lab for any 
additional processing information and shipping instructions.
7.2.7. Screening for Clostridium Difficile
C.difficile testing is performed at screening (if not performed 6 weeks prior to screening) and 
during the study when there is a suspected disease flare or gastroenteritis.  C. difficile
infection in these settings requires treatment as determined by the PI.  Subjects with 
Clostridium difficile infection may be treated and re-tested or re-screened at the discretion of 
the Investigator.
Highly sensitive screening tests, with high negative predictive value, should be employed in 
evaluating subjects for eligibility for the study.  The detection of C. difficile by toxigenic 
stool culture (stool culture followed by detection of toxin) is considered the gold standard for 
the diagnosis of the colonization or infection with pathogenic C. difficile.  Comparable 
sensitivity may be achieved by direct testing of stool via point of use rapid membrane 
enzyme immunoassay card for both C. difficile toxin A and B and glutamate dehydrogenase 
(GDH) antigen on a card.  Use of the card for point of care screening is encouraged where 
permitted by local regulation.  Molecular techniques such as polymerase chain reaction 
(PCR) for detection of toxin RNA are also acceptable alternatives. 
Refer to the lab manual for further guidance and instruction for C. difficile screening.
7.2.8. Infections
Subjects will be monitored for development of any infection (viral, bacterial, and fungal).  
Infections will be classified as either treated or non-treated infections.  All treated infections 
occurring during the study should be cultured if feasible and the results (eg, any identified 
organisms or absence of growth) recorded in the CRF.
Treated infections are infections that:

Require antimicrobial therapy by any route of administration or; 

Require any surgical intervention (eg, incision and drainage).
Treated infections will be further classified as serious or non-serious.  Serious infections are 
treated infections that:

Require parenteral antimicrobial therapy and present with positive pre-treatment 
culture;
AND EITHER

Require hospitalization for treatment;
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
Meet other criteria that require the infection to be classified as a SAE.
A subject who experiences a serious infection should be discontinued from the study.  A 
serious infection should be reported as a SAE and should be listed as the reason for 
discontinuation in the CRF.  All serious infections occurring during the study should undergo 
appropriate laboratory investigations, including culture, and the results (eg, any identified 
organisms or absence of growth) be recorded in the CRF.
Subjects who experience non-serious infections that require treatment may have their study 
drug temporarily discontinued during treatment at the investigator’s discretion.  Consultation 
with the Pfizer medical monitor is available.  Temporary discontinuation of study drug
should be recorded in the CRF.
 
 
 
7.2.10. Vital Signs (Blood Pressure, Pulse Rate, and Temperature)
Single sitting blood pressure (BP), pulse rate, and temperature will be measured at times 
specified in the Schedule of Activities.  Additional collection times or changes to collection 
times will be permitted, as necessary to ensure appropriate collection of safety data. 
Vital signs (including temperature) should be performed before laboratory blood collection 
and endoscopic procedure.
Sitting blood pressure will be measured with the subject’s arm supported at the level of the 
heart, and recorded to the nearest mmHg.  It is preferred that the same arm (preferably the
dominant arm) be used throughout the study. 
The same size BP cuff, which has been properly sized and calibrated, will be used to measure 
BP each time.  The use of automated devices for measuring BP and pulse rate is acceptable, 
although, 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, 
it is preferred that vital signs be obtained prior to the nominal time of blood collection. 
It is preferred that body temperature be collected using tympanic, oral, or axillary methods 
and that the same method be used consistently throughout the study.
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7.2.11. Medical History, Physical Examination, Height and Weight
Medical history, including UC history, history of illegal drug, alcohol, tobacco use, skin rash, 
skin infection, and any abnormalities that may predispose the subject to infection will be 
collected at the Screening visit.  Smoking status and average weekly alcohol consumption 
(units/week) will also be collected.
Complete physical examinations must be performed by the investigator, sub-investigator, or 
a qualified healthcare professional per local guidelines.  Complete physical examinations 
consist of assessments of general appearance; skin, head, eyes, ears, nose and throat 
(HEENT); heart, lungs; breast (optional); abdomen; and external genitalia (optional); 
extremities; neurologic function; back; and lymph nodes.
Targeted physical examinations must be performed by the investigator, sub-investigator, or a 
qualified healthcare professional per local guidelines and should include skin, heart, lungs, 
abdomen and examination of body systems where there are symptom complaints by the 
subject. 
Both full and targeted physical examinations must include a full body skin examination.  
Skin examinations should include a visual inspection of the breasts and external genitalia to 
assess for rashes, even if a subject does not wish to have examination of the breast and/or 
external genitalia (these are optional) done as a part of the physical examination.
Complete and Targeted physical examinations are performed at specified timepoints 
(See Schedule of Activities).
Height and weight will be measured without the subject wearing shoes.  Height (inches or 
centimeters) will be measured and recorded at the Screening visit only and weight (lbs or kg) 
will be measured and recorded at various timepoints (See Schedule of Activities).
7.2.11.1. Dermatology/Skin
As part of the physical examination, all subjects will have a dermatological full body exam at 
times specified in the Schedule of Activities.  Skin lesions will be evaluated as defined in the 
National Cancer Institute Common Toxicity Criteria for Adverse Events v4.0 (See 
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Table 9.
Management of Dermatological Events
Dermatologic Event (CTCAE v 4.0)*
Course of Management
Acne/Acneiform Rash/Maculopapular Rash
Grade ½
1. Investigator’s discretion for withdrawing IP.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3
1. Discontinue IP.
2. Monitor to resolution (defined as a Return to Baseline 
status).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Pruritus
Grade 1 Mild or localized
1. Investigator’s discretion for withdrawing IP.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 2 Intense or widespread
1. Discontinuation of the IP may not be required unless 
condition is sustained >4 days or at the investigator’s 
discretion.
2. Execute reasonable monitoring.
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
Grade 3 Intense or widespread and interfering 
with activities of daily living
1. Permanently discontinue IP.
2. Monitor to resolution (Return to Baseline).
3. Consider treatment with topical agents such as 
clindamycin or corticosteroids.
* Refer to Appendix 3 for clarification.
All reports of potential drug-related rash will be followed up until resolution or clinically 
stable or following agreement with Pfizer. 
Upon resolution of a Grade 1 or 2 rash/pruritus, including confirmed herpes zoster, subjects 
may be re-challenged with IP at the discretion of the investigator.  Re-challenge is not 
permitted with Grade 3 rash/pruritus.
All events of rash should be treated according to International and local guidelines for the 
treatment of rash, eg, where appropriate, topical corticosteroids and/or agents such as 
antibiotics or antivirals could be prescribed.
 
 
  Also, a swab (for microbiological assessment) of the 
affected area will be taken for culture and sensitivity to assess for any bacterial or fungal 
pathogens. 
 
 
Investigators will complete a questionnaire and take appropriate photographs of the rash in 
order to provide information necessary for a dermatologist’s assessment of the event. 
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All subjects reporting an unexplained skin rash should be referred to a local dermatologist 
according to local guidelines for formal comprehensive dermatologic evaluation.  A 4 mm 
punch biopsy should be taken and sent to the local laboratory for histological investigation of 
the rash in order to gain insight into potential etiology of the rash.  If the rash is present on 
the face or other cosmetically exposed area, biopsy can be at the discretion of the 
dermatologist. 
All de-identified dermatologic consultation reports, biopsy results, culture results, 
photographs, and any additional relevant test results will be forwarded to Pfizer/designee for 
review within 30 days of receipt by the PI.
An independent dermatologist contracted by Pfizer will review all relevant data and 
summarize the data at the end of the study. 
7.2.12. Audiogram
All subjects will have an audiogram at times specified in the Schedule of Activities.  
Audiograms may be performed within a ±2 week window relative to the study visit.  When 
possible, the subject should have the audiogram performed at the same evaluation center 
during the study.
Audiogram testing at screening must be completed and results available by the baseline visit 
(Week 0). Audiogram testing at each time specified in the Schedule of Activities must be 
completed and results available by the next scheduled visit. For subjects that terminate early 
from the study, if possible, efforts must be made to complete the audiology testing and obtain 
the results.
If there is a clinically meaningful, treatment related decline in hearing from baseline, the 
subject will be followed off treatment with appropriate testing at regular intervals, until 
hearing returns to baseline or is determined to be clinically stable.
The information from the audiogram will be entered into the data collection tool.
Any de-identified audiogram results/reports and any additional relevant test results 
(if applicable) may be requested to be forwarded to Pfizer (and/or designee) at any time 
during the study.
Audiogram results may be reviewed by an external audiologist.
7.2.13. Electrocardiogram
Twelve (12)-lead ECGs should be collected at times specified in the Schedule of Activities.
ECGs should be performed before laboratory blood collection and endoscopic procedure.


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All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position.  When the timing of these measurements coincides with a 
blood collection, the ECG should be obtained prior to the nominal time of the blood 
collection, BP, and pulse rate. 
To ensure safety of the subjects, a qualified individual (eg, sub-investigator) at the 
investigator site will make comparisons to baseline studies taken at screening.  A copy of the 
ECG should be available as source documents for review.  ECGs will be read locally during 
the dosing period. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, repeat measurements may not be necessary if a qualified physician’s 
interpretation determines that the QTc values are in the acceptable range.  QTc prolongations 
are defined as a QTc ≥480 msec or an absolute change in QTc >60 msec.
7.2.14. Chest Radiograph
Chest x-ray (posterior-anterior and lateral views are recommended however local guidelines 
should be followed) with no current evidence of untreated latent or active TB infection or 
evidence of currently active TB, general infections, heart failure or malignancy taken at 
screening or within the 12 weeks prior to screening and read by a qualified radiologist.  If a 
subject had a CT scan of the chest (with or without IV contrast) within 12 weeks prior to 
screening, the CT scan results can substitute for chest radiograph results. Documentation of 
the official reading must be located and available in the source documentation.
7.3. Diagnostic and Efficacy Assessments
7.3.1. Endoscopy
Endoscopy (colonoscopy or flexible sigmoidoscopy) should be performed (during the 
screening period and preferably after all other eligibility criteria have been verified) within 
10 days of baseline, preferably 5 to 7 days prior to the baseline to allow total Mayo score 
calculation. 
The endoscopic subscore by the Central Reader must be available at the baseline visit.  The 
assessment by the Central Reader will be used to derive the total Mayo score for study 
eligibility.  The stool frequency, rectal bleeding and centrally-read endoscopic subscores for 
the endoscopy performed during the screening period and the PGA obtained at baseline will 
be used to determine eligibility.  The endoscopic report and pathology report must be 
available in the source documents.
Endoscopy is also performed during the Week 8 and Week 32/early withdrawal visit where 
possible, but may be performed up to – 7 days prior to the site visit if necessary.  If it is 
necessary, a bowel prep should be conducted as per local routine.  The position of the 
endoscope will be based on the length of the instrument at various levels of insertion as well 
as the morphological features of the intestine as seen during screening endoscopy.  The 


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endoscopy report and any photographs and/or video recordings taken during the procedure 
should be filed in the subject’s chart. Colonoscopy should be performed at the Early 
Termination (ET) visit unless the previous colonoscopy was less than 8 weeks prior to this.
Endoscopy subscores will be reported per Mayo score based on Central Reader, and for 
Mayo endoscopy subscore of 1, presence or absence of friability will be noted.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3.2. Subject Stool Diary
Subjects will use a diary in order to record on a daily basis the following information during 
the study:

‘Normal’ number of stools per day (eg, pre-UC diagnosis/when not having a flare).  
This question will be asked only at the screening visit. 

Number of times needed to visit the toilet to have a bowel movement (per day).

Presence of blood in the stools (if any).

Description of blood in the stools (if any), ONLY if presence is noted.
In order to encourage consistent diary recording, subjects should enter diary data 
continuously throughout the study. Instructions for completing the diary will be provided to 
subjects at screening and reviewed at subsequent visits.
7.3.3. Mayo Score
The Mayo Score is a tool designed to measure disease activity for UC.  The Mayo scoring 
system ranges from 0 to 12 points and consists of 4 subscores, each graded 0 to 3 with the 
higher score indicating more severe disease activity (See Appendix 4).

Stool frequency (Subscore 0-3).

Rectal bleeding (Subscore 0-3).

Findings on endoscopy (Subscore 0-3).

Physician’s global assessment (Subscore 0-3).
Calculation of the Mayo Score requires an assessment of the subject’s stool frequency and 
any amount of blood in the stool.  The Mayo scores will be calculated based on the subject’s 
stool diary recorded over 3 consecutive days prior to the visit (for visits where endoscopy is 
not done) or endoscopy bowel preparation procedure (for visits where endoscopy is done 
ie, Screening, Week 8, Week 32/ET).  Investigator sites will be trained on the diary usage 
and will train subjects on use of the diary.  Diary data entered by the subject will be reviewed 
by the site at each visit. 
If there are missing stool diary data, the average will be taken from the 3 most recently 
available days reported within 5 days prior to the endoscopy preparation (for visits where 
endoscopy is done ie, Screening, Week 8, Week 32/ET) or 5 days prior to the visit (for visits 
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If there only 2 available days reported within the 5 days prior to the study visit (for visits 
where endoscopy is not done) or endoscopy bowel preparation procedure (for visits where 
endoscopy is done ie, Screening, Week 8, Week 32/ET), the average will be taken from the 
limited available data unless there is no diary data reported within 5 days.  In this case, stool 
frequency and rectal bleeding subscores will be considered as missing.
Note that if there is 1 day of diary data or no diary data recorded prior to the baseline 
endoscopy preparation, then the patient cannot be randomized into the study.
Values used for Mayo score calculation should exclude any day when a bowel prep or 
endoscopy is performed.
The endoscopic appearance will be read by the Central Reader.
The physician’s global assessment (PGA) acknowledges the other three criteria, the subject’s 
abdominal discomfort and sense of general well-being.  In addition, the investigator should 
consider other observations (eg, physical findings) and subject’s performance status when 
making the PGA assessment.  In consequence, the PGA should be recorded after all other 
components of the Mayo score and relevant interval medical history and physical 
examination have been completed.  The PGA assessment should take into account the
centrally read endoscopy score at baseline, Week 8, and Week 32/early withdrawal visits, 
however the locally read endoscopy score is an acceptable alternative at Week 8 and 
Week 32/early withdrawal visits when the endoscopic subscore by the Central Reader are not 
available prior to the conduct of the Week 8 or Week 32/ET PGA collection timepoint. It is 
preferred that the same physician performs all such assessment for a given subject throughout 
the study.
The Mayo score at the screening visit must be ≥6 with an endoscopic subscore of ≥2 and 
rectal bleeding subscore ≥1 and meet all other eligibility criteria to be eligible for the study.  
The duration of the time between the Mayo endoscopic subscore assessment and baseline 
should not exceed 10 days. 
Endpoints based on the total Mayo scores are defined below:

Remission: total Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a rectal bleeding subscore of 0 and excluding any friability.

Clinical response: decrease from baseline in total Mayo score of at least 3 points and 
at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at 
least 1 point or absolute subscore for rectal bleeding of 0 or 1.

Deep remission: total Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a 0 on both endoscopic and rectal bleeding subscore.

Symptomatic remission: total Mayo score of 2 points or lower, with no individual 
subscore exceeding 1 point, and both rectal bleeding and stool frequency subscores 
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
Improvement in endoscopic appearance: endoscopic subscore of 0 or 1.

Endoscopic remission: endoscopic subscore of 0.

Endoscopic response is defined by a decrease from baseline in the endoscopic 
subscore of 1 point or more.
Remission* based on modified Mayo score (Total Mayo score minus PGA): endoscopic 
subscore = 0 or 1 AND stool frequency = 0 or 1 AND rectal bleeding = 0.
7.3.4. Partial Mayo Score
A partial Mayo Score (Mayo Score without endoscopic subscore, ranging from 0 to 9) will be 
assessed at the times specified in the Schedule of Activities.  On dosing days, the partial 
Mayo Score should be assessed prior to administration of investigational product.  Response 
based on change in partial Mayo score is defined as a decrease from baseline of at least 
2 points, while remission is defined as an absolute value of partial Mayo score <2 points with 
no individual subscore >1.10
 
 
7.3.6. Patient Reported Outcomes (PRO) for Health Outcomes Assessment
Patient reported outcomes (PRO) assessments are self-administered during the study. Refer 
to Appendix 10 for Alternative Measures During Public Emergencies if applicable.
It is important to note that the PRO measurements are collected and evaluated in a different
manner than the observed or volunteered adverse events.  Given those differences, no attempt 
will be made to resolve any apparent discrepancies between observed or volunteered adverse 
events and PRO data collected from subjects.  Adverse event incidence rates will not be 
calculated from these solicited data but rather from the information recorded on the AE pages 
on the CRF.
The following PROs will be completed as specified in the Schedule of Activities.  Subjects 
should be encouraged to complete the PROs at the clinic at the beginning of the study visit 
prior to any clinical assessments.  A member of the staff should be available if a subject 
requires further instruction and to review the PRO questionnaires for completeness prior to
leaving the clinic. 

Inflammatory Bowel Disease Questionnaire (IBDQ).

Short Form-36, version 2, acute (SF-36).
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
European Quality of Life Questionnaire – 5 Dimensions-3 Levels (EQ-5D-3L) & 
Visual Analog Scale (EQ-5D VAS).
7.3.6.1. Inflammatory Bowel Disease Questionnaire (IBDQ)
IBDQ is a psychometrically validated PRO instrument for measuring the disease-specific 
quality of life in subjects with IBD, including UC.  The IBDQ is comprised of 32-items, 
which are grouped into 4 dimensions: bowel function, emotional status, systemic symptoms 
and social function.11 The 4 domains are scored as follows:

Bowel symptoms: 10 to 70.

Systemic symptoms: 5 to 35.

Emotional function: 12 to 84.

Social function: 5 to 35.
The total IBDQ score ranges from 32 to 224.  For the total score and each domain, a higher 
score indicates better quality of life.  A score of at least 170 corresponds to clinical remission 
and an increase of at least 16 points is considered to indicate a clinically meaningful 
improvement.11,12 See Appendix 5.
7.3.6.2. Short Form – 36, Version 2, Acute (SF-36)
The SF-36 v2 Acute is a psychometrically valid and reliable health status questionnaire that 
assesses 8 domains of functional health and well-being: Physical Functioning, Role 
Limitations due to Physical Health Problems, Bodily Pain, Social Functioning, Mental 
Health, Role Limitations due to Emotional Problems, Vitality, and General Health 
Perceptions.  A physical health component summary score (PCS) and mental health 
component summary score (MCS) are calculated from the 8 domain scores.  The acute form 
uses a recall period of one week.  Higher scores indicate a better health-related quality of life.  
See Appendix 6.
7.3.6.3. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and Visual Analog 
Scale (EQ-5D-3L & VAS)
The EQ-5D 3L and EQ-5D VAS is a patient completed questionnaire designed to assess 
impact on health related quality of life in five domains: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Additionally, scores from the five domains may be 
used to calculate a single index value, also known as a utility score.  The validity and 
reliability of the EQ-5D-3L has been established in a number of disease states, including 
UC.13 The EQ-5D/VAS records the respondent’s self-rated health on a scale from 0 (worst 
imaginable health state) to 100 (best imaginable health state).  See Appendix 7.
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7.4. Pharmacodynamics
The pharmacodynamics (PD) samples must be processed and shipped as indicated in the 
laboratory manual to maintain sample integrity.  Any deviations from the PD processing 
steps, including any actions taken, must be documented and reported to the sponsor.  On a 
case-by-case basis, the sponsor may make a determination as to whether sample integrity has 
been compromised.  Depending on sampling and transport constraints, it is possible that not 
all biomarker samples will be collected in all study regions.
All efforts will be made to obtain the PD samples at the exact nominal time relative to
dosing.  Please consult the laboratory manual(s) for final instructions on sample collection, 
storage, and shipping requirements.  These manual(s) supersede the instructions listed in the 
applicable protocol sections.  Samples that are handled according to the respective manual 
guidance are considered “per protocol”.
Samples will be analyzed using fit for purpose or validated analytical methods in compliance 
with Pfizer standard operating procedures.
 
 
7.4.1. High-Sensitivity C-Reactive Protein (hsCRP)
Blood samples for determination of hsCRP will be obtained at the times specified in the 
Schedule of Activities. 
 
 
 
 
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7.4.5. Fecal Calprotectin
A stool sample for determination of fecal calprotectin will be obtained at the times specified
in the Schedule of Activities
The study site personnel will provide appropriately labeled containers and instructions to the 
subject on how best to collect a sufficient fecal sample.  A sample collected on the day of the 
visit is preferred, however if this is not possible, a sample from the day before or day after 
the visit should be collected, but should be prior to the subject initiating the bowel 
preparation for endoscopy.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
CCI


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This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.


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For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.


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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
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8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
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.


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The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 


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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Potential Cases of Decreased eGFR
In the PF-06700841 FIH study B7931001, serum creatinine elevation was reported across
dose levels in both healthy volunteers and psoriasis patients.  The proposed mechanism for 
the observed serum creatinine increases in study B7931001 is inhibition of creatinine 
transport in the kidney (ie, transporter-mediated rather than direct nephrotoxicity) (See 
Section 1.4.2.1.2).
All subjects will have serum creatinine based and serum cystatin-C based eGFR calculated at 
times specified in the Schedule of Activities.Abnormal values in serum creatinine concurrent 
with absence of increase in blood urea nitrogen (BUN) that meet the below criteria, in the 
absence of other causes of kidney injury, are considered important medical events. 
Based on these measurements, estimated GFR using serum creatinine (2009 CKD-EPI 
eGFR14) and serum cystatin C (2012 CDK-EPI eGFR8) will be determined at the time of 
elevation in serum creatinine above ULN. If an individual subject demonstrates a 
CONCOMITANT serum creatinine based AND serum cystatin C based eGFR decline
of ≥30% compared to the subject’s baseline eGFR, then the subject should not be further 
dosed and adequate, immediate, supportive measures including immediate evaluation by a 
nephrologist (preferably within 24 hours) with appropriate management.  If the subject 
cannot be seen by a nephrologist within 24 hours, then the subject should be sent to a local 
emergency room for assessment of renal function.  Results should be repeated as indicated by 
the nephrologist or weekly at a minimum until the eGFR returns to baseline ±15% or the 
renal parameters are deemed to be stable by the nephrologist and/or PI.
eGFR results will be communicated to the treating physician. 
Subjects should return to the investigational site and be evaluated as soon as possible, 
preferably within 24 to 48 hours from awareness of the abnormal eGFR (CONCOMITANT 
serum creatinine based AND serum cystatin C based eGFR decline of ≥30% compared to the 
subject’s baseline eGFR) result for a safety follow-up visit.  This evaluation should include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating serum 
creatinine and serum cystatin C, laboratory tests should also include: serum BUN, serum CK, 
serum electrolytes (including at a minimum potassium, sodium, phosphate/phosphorus, 
calcium), in addition to urine dipstick, urine microscopic examination, and urinary indices.  
All cases confirmed on repeat testing as meeting the above pre-set laboratory criteria, with no 
other cause(s) of laboratory abnormalities identified should be considered as important 


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medical event irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal serum creatinine. 
All relevant test results will be forwarded to Pfizer immediately by the PI.
This requirement applies to all subjects, all cohorts.
8.4.4. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.4.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product:

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
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 


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


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8.4.5. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.5.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a 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 and/or secondary endpoint 
definitions or their analyses will also be reflected in a protocol amendment.
The information from the two placebo arms in the induction stage will be combined for the 
statistical analysis.  It will be further combined with the historical database using Bayesian 
statistical methodology.  The historical study data base will include the data obtained from 
Phase 3 tofacitinib trials available to the Sponsor.  The integration details and historical data 


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specifications will be detailed in the SAP.  The integration with historical data will involve 
application of statistical procedures attempting maximization of the commensurability 
between the current trial and the subgroup of the historical data used for synthesizing the 
prior distribution. 
9.1. Sample Size Determination
The primary endpoint for the study is based on total Mayo score at Week 8.  The study is 
powered for the induction stage. 
The study will enroll approximately 318 subjects with the expected number of completers of 
286 assuming an estimated drop out rate of ~10%.  The table below represents the 
approximate number of expected completers per arm in the induction phase:
PF-06651600 Pla
cebo
PF-06651600
200 mg
PF-06651600 70
mg
PF-06651600 2
0 mg
PF-06700841 P
lacebo
PF-06700841 60
mg
PF-06700841 30
mg
PF-06700841 10
mg
11
44
44
44
11
44
44
44
For induction phase analysis purposes, the combined placebo group is thus expected to have 
approximately 22 completers.
Using a between-group comparison at Week 8 (end of induction), assuming estimated 
standard deviation of the total Mayo score equal to 3, Type 1 error = 10% (2-sided)) and 
assuming a true difference between drug and placebo to be 2.1, planned sample size of 
44 completers in the active and 22 completers in the placebo will provide 84.3% power. The 
delta of 2.1 is based on what has been seen in Tofacitinib Phase 3 studies for this endpoint. 
9.2. Efficacy Analysis
9.2.1. Analysis of the Primary Endpoint During Induction Period
Primary efficacy analysis will be conducted based on total Mayo score at Week 8.
The primary analysis at Week 8 will be based on constrained Longitudinal Data Analysis 
(cLDA) model15,16 using Total Mayo score. The constraint in cLDA is that the expected 
baseline values of Total Mayo score are identical in all of the treatment groups as a result of 
randomization. The model will include baseline and week 8 values of the Total Mayo Score 
as the response vector. The model will include treatment (6 active dose and pooled placebo), 
visit (baseline and Week 8) and treatment by visit interaction as fixed effects. An 
unstructured variance-covariance matrix will be allowed. Other statistical analysis methods 
will include fitting bayesian emax model for dose-response estimation after conducting 
Bayesian predictive checks on monotonicity. The Bayesian emax model will estimate the 
dose response and will be supportive to the primary analysis.
The primary analysis will be conducted on the intention-to-treat (ITT) population, defined as 
all randomized subjects who received at least one dose of investigational product or placebo.
Sensitivity analysis handling of the missing values (including subjects who are missing due 
to COVID-19) will be outlined in the SAP.


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9.2.2. Analysis of Secondary Endpoints During Induction Period
Analysis of the secondary endpoints, including the endpoints collected during the 24 week 
chronic dosing period, will be outlined in the SAP.  For the binary endpoints such as 
remission, improvement in endoscopic appearance, and so on, missing data will be treated as 
non-responders and the risk differences between treatment and placebo will be computed 
along with exact confidence intervals. Continuous and discrete modelling techniques will be 
applied whenever applicable.  The statistical summaries will be presented by dose groups.  
The correlations between the endpoints will be analyzed.
9.2.3. Analysis of Secondary Endpoints During Chronic Period
Total Mayo score at Week 32 is one of the secondary endpoint during the chronic period. 
The analysis model will be similar to the primary analysis using cLDA. 
The model will include treatment (active doses and placebo), visit (baseline, Week 8 and 
Week 32) and treatment by visit interaction as fixed effects. An unstructured variance-
covariance matrix will be allowed. This model will not include the data from the chronic 
period for the subjects assigned to placebo during this period. For the remaining secondary 
endpoints of Remission and, improvement in endoscopic appearance, missing data will be 
treated as non-responders and and the risk differences between treatment and placebo will be 
computed along with exact CI. Additional details will be described in the SAP.
9.3. Analysis of Other Endpoints During Induction and Chronic Period
Analysis of other endpoints will be conducted as deemed appropriate.  Continuous and 
discrete modelling techniques will be applied whenever applicable.  Distribution summaries 
will be presented by means of summary tables and data visualization methods.
9.3.1. Pharmacokinetic Analysis During Induction and Chronic Period
The PK concentration population is defined as all enrolled subjects who received at least one 
dose of PF-06651600 or PF-06700841 and in whom at least one concentration value is 
reported.
PK concentrations will be summarized and presented with summary statistics and, if 
appropriate, non-compartmental PK parameter estimates will be provided.  A population PK 
model may be developed for the purpose of estimating PK parameters.  Any population PK 
model developed to characterize the PK data will be reported separately.
Data permitting, the relationship between exposure and clinical responses (efficacy, safety
and pharmacodynamic) from the 8 week induction period of treatment in subjects with 
moderate to severe active UC may be explored using either observed or modeled exposures.  
Similar analyses may be conducted with data collected from the chronic dosing period.  Any 
population analyses conducted will not be part of the clinical study report (CSR) and may be 
reported separately.


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9.3.2. PK/PD Unblinding Plan
A PK/PD unblinding plan approved by the clinical lead, clinical pharmacology lead and 
statistical lead will be in place to describe the procedures to be employed in safeguarding the 
study blind for members of the study team.  These procedures will be in accordance with 
applicable Pfizer SOPs for releasing randomization codes and breaking the study blind.  
Under this plan a group of statisticians, PK/PD data provider, PK/PD analyst and PK/PD 
support would be unblinded in order to initiate the building of statistical models of the PK, 
dose/response as well as exposure/response analysis models and conduct associated 
simulations.  The aim of this work would be to facilitate a fuller interpretation of the study 
upon completion (at appropriate interim milestone).  This group will not serve on the study 
team during the period of early unblinding.  The unblinding may occur after the last subject 
has been randomized.  The details of the procedures will be described in the PK/PD 
Unblinding Plan for Modelling and Simulation for study B7981005 which will be finalized 
prior to the start of the PK/PD unblinding. 
9.3.3. Biomarkers Unblinding Plan
In order to expedite the analyses of the biomarkers, an unblinded team may review the 
biomarker data (including exploratory biomarkers) [excluding any biomarker data that is or 
contributes to a primary endpoint] and exposure data on an ongoing basis.  This group will 
minimally be comprised of a bioanalyst and statistician, but may also include 
clinicians/precision medicine personnel, clinical pharmacologist and PK/PD analyst/support 
staff.  This group will be unblinded when needed in order to conduct the analyses of the 
biomarkers in accordance with a biomarker data analysis plan, and will be independent of the 
study team.  This unblinding process will be in accordance with Pfizer SOPs related to 
Releasing Randomization Codes and Breaking the Blind and will not have any impact on the 
conduct of the study.  The biomarker plan, approved by the clinical lead, clinical 
pharmacology lead and statistical lead, will be in place to describe the procedures to be 
employed in safeguarding the study blind for members of the study team.  The biomarker 
plan will outline the range of possible analyses and provide details of the decision-making 
process regarding unblinding.
9.4. Safety Analysis During the Induction and Chronic Period
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects. 
The safety analysis set will include all subjects who have received at least one dose of IP.  
Safety data will be presented in tabular and/or graphical format for both the induction and 
chronic period and summarized descriptively, where appropriate.  All safety endpoints will 
be listed and summarized in accordance with Pfizer Data Standards.  Categorical outcomes 
(eg, AEs) will be summarized by subject counts and percentage.  Continuous outcome 
(eg, BP, heart rate, etc) will be summarized using N, mean, median, standard deviation, etc.  
Change from baseline in laboratory data, ECGs and vital signs will also be summarized.  
Subject listings will be produced for these safety endpoints accordingly. 


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9.5. Interim Analysis
At least one interim analysis for futility may be performed.  The final number and timing of 
the IA(s) will be defined by the Sponsor, but a preliminarily one may be conducted 
approximately 6 months after the randomization of the first subject and/or after at least 
50% of the planned subjects, ie, approximately 160 subjects, have completed the 8 week 
induction period.  An active arm may be stopped for futility if the posterior probability of the 
given active arm being better than the placebo is less than 20%.
Further details related to the interim analysis will be outlined in the SAP. 
9.6. Data Monitoring Committee
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of subjects 
in the study according to the charter.  The E-DMC will review accumulating renal safety data 
and propose changes to the protocol as needed to ensure subject safety.  The 
recommendations made by the E-DMC to alter the conduct of the study will be forwarded to 
Pfizer for final decision.  Pfizer will forward such decisions, which may include summaries 
of aggregate analyses of endpoint events and of safety data that are not endpoints, to 
regulatory authorities, as appropriate. 
Additional information can be obtained in the E-DMC charter.
 
 
 
 
 
 
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
CCI


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During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any
reports, publications, or other disclosures, except where required by applicable laws.
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single specific numerical 
code based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH Good Clinical Practice (GCP), local regulatory requirements, and legal 
requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection. 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study, the sharing of data relating to the study and possible risks associated 
with participation, including the risks associated with the processing of the subject’s personal 
data.  The investigator further must ensure that each study subject is fully informed about his 
or her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her personal data. 


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
PF-06651600 and/or PF-06700841 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 28 days.  As directed by Pfizer, all study materials must be collected
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 


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In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.


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The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al.  
“Increasing incidence and prevalence of the inflammatory bowel diseases with time,
based on systematic review.”  Gastroenterology. 2012:142(1):46-54 e42: quiz e30. 
2.
Basson, MD, Ulcerative Colitis [http://emedicine, Medscape Web site]. June 28, 2010. 
Available at http://emedicine.medscape.com/article/183084- overview.
3.
Sandborn WJ, et. al. Tofacitinib as induction and maintenance therapy for Ulcerative 
Colitis. NEJM 2017 376:1723-1736.
4.
Olaharski, A.J., et al. (2009) “Identification of a kinase profile that predicts 
chromosome damage induced by small molecule kinase inhibitors.” PLoS 
computational biology 5:e1000446.
5.
Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma 
creatinine and the Cockcroft and Gault formula for the estimation of glomerular 
filtration rate. Nephrol Dial Transplant. 2003;18(10):2024-31.
6.
Newman DJ, Thakkar H, Edwards RG, Wilkie M, White T, Grubb AO, et al. Serum 
cystatin C measured by automated immunoassay: a more sensitive marker of changes in 
GFR than serum creatinine. Kidney international. 1995;47(1):312-8. 
7.
Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine 
as a marker of kidney function: a meta-analysis. Am J Kidney Dis. 2002;40(2):221-6.
8.
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. 
Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J 
Med. 2012;367(1):20-9.
9.
Zhu Y, Ye X, Zhu B, et al. Comparisons between the 2012 New CKD-EPI (Chronic 
Kidney Disease Epidemiology Collaboration) Equations and Other Four Approved 
Equations. PLoS ONE 9(1): e84688. doi: 10.1371/journal.pone.0084688.
10.
Lewis JD, Chuai S, Nessel L, et al. Use of the Non-invasive Components of the Mayo
Score to Assess Clinical Response in Ulcerative Colitis. Inflammatory Bowel Disease 
2008 December; 14(12): 1660-1666. doi 10.1002/ibd20520.
11.
Irvine EJ, Feagan B, Rochon J, Archambault A, Fedorak RN, Groll A, Kinnear D, Saibil 
F, McDonald JW.  Quality of life: a valid and reliable measure of therapeutic efficacy in 
the treatment of IBD.  Canadian Crohn’s Relapse Prevention Trial Study Group.  
Gastroenterology 1994; 106:287-296.
12.
Feagan B, Reinisch, W Rutgeerts P, et al. The Effects of Infliximab Therapy on Health-
Related Quality of Life in Ulcerative Colitis Patients. American Journal of 
Gastroenterology 2007; 102:794-802.


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13.
Konig HH, Ulshofer A, Gregor M, et al. Validation of the EuroQol questionnaire in 
patients with inflammatory bowel disease. European Journal of Gastroenterology & 
Hepatology 2002, 14:1205-1215.
14.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009 May 5; 150(9):604-12.
15.
Fitzmaurice GM, Laird NM, Ware JH Applied Longitudinal Data Analysis, Second 
Edition, 2011, Published by John Wiley and Sons, 2011, section 5.7, pp.156-162.
16.
Mallinckrodt C, Lipkovich I Analyzing Longitudinal Clinical Trials Data. A Practical 
Guide. CRC Press, 2017, pp. 100-110.


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Appendix 1. Supplementary information for Inclusion Criteria 5
Note: The information below is provided for guidance only.  Local standards of care, as well 
as investigator assessment should be considered in any assessment.
Inadequate response to, loss of response to, or intolerance to corticosteroid treatment (See 
Appendix 9 for steroid equivalency) may be defined as one or more of the following:

Steroid refractory: Persistent symptoms of active disease despite treatment with at 
least one 4-week induction regimen that included a dose equivalent to ≥30 mg 
prednisone (oral) daily for at least 2 weeks or IV for at least 1 week within the 
previous 5 years; 

Steroid dependent: Two failed attempts to taper steroids below a dose equivalent to 
10 mg prednisone (oral) daily; 

Steroid intolerant: History of intolerance to corticosteroids (including but not limited 
to Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection) 
within the previous 5 years.
Inadequate response to, loss of response to, or intolerance to prior immunosuppressant
treatment is defined by one or more of the following:

Persistent signs and symptoms of active disease despite a history of at least one 
12-week regimen of oral AZA (≥2-2.5 mg/kg/day) or 6-MP (≥1-1.5 mg/kg/day) 
and/or MTX (≥25 mg/week) within the previous 5 years; 

History of intolerance to AZA, 6-MP, or MTX (including but not limited to 
nausea/vomiting, abdominal pain, pancreatitis, liver function testing (LFT) 
abnormalities, lymphopenia, TPMP [thiopurine methyltransferase] genetic mutation, 
infection) within the previous 5 years.
Inadequate response to, loss of response to, or intolerance to prior anti-TNF inhibitors and 
anti-integrin inhibitors (within the previous 5 years) is defined as one or more of the 
following:

Persistent signs and symptoms of active disease despite at least one 8-week regimen 
of adalimumab (subcutaneous doses of 160 mg at Week 0 and 80 mg at 
Week 2 followed by a dose of ≥40 mg every 2 weeks) or golimumab (subcutaneous 
doses of 200 mg at Week 0 and 100 mg at Week 2, followed by 50 mg or 100 mg 
every 4 weeks), or one 14-week regimen of infliximab (3 intravenous doses 
≥5 mg/kg), or one 10-week regimen of vedolizumab (intravenous doses of 300 mg at 
Weeks 0, 2, and 6).


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
Intolerance is defined as: Clinically significant side effect(s) [including 
hypersensitivity (eg, signs/symptoms including rash, flushing, anaphylaxis, serum 
sickness) and development of anti-drug antibodies] to at least 1 treatment regimen 
with an anti-TNF inhibitor.


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Appendix 2. Prohibited Concomitant Medications
This is not an all-inclusive list.  Study personnel should stay current and consult with their 
pharmacy to exclude all concomitant medications that are either moderate to potent CYP3A 
inhibitors or inducers.
Moderate to Potent CYP3A 
Inhibitors*
Moderate to Potent CYP3A Inducers**
Amprenavir
Avasimibe#
Amiodarone 
Bosentan
Aprepitant
Barbiturates
Atazanavir
Carbamazepine#
Boceprevir
Efavirenz 
Casopitant
Etravirine
Cimetidine
Mitotane#
Ciprofloxacin
Modafinil
Clarithromycin#
Nafcillin
Cobicistat#
Phenobarbital#
Conivaptan#
Phenytoin#
Darunavir
Rifabutin#
Diethyldithiocarbamate
Rifampin #
Diltiazem
St. John’s Wort#
Dronedarone
Talviraline
Elvitegravir#
Erythromycin
Fluconazole
Fluvoxamine
Imatinib
Indinavir#
Itraconazole#
Ketoconazole#
Lopinavir#
Mibefradil#
Mifepristone (RU486)
Nefazodone#
Nelfinavir#
Norfloxacin
Posaconazole#
Ritonavir#
Saquinavir#
Schisandra sphenanthera
Telaprevir
Telithromycin#
Tipranavir#
Tofisopam
Troleandomycin#
Verapamil
Voriconazole#
* 
All prohibited drugs that are CYP3A inhibitors require at least a 7 day or 5 half-lives (whichever is longer) 
washout prior to the first dose of study drug.  Note: Amiodarone requires discontinuation at least 290 days 
(~5 half-lives, half-life averages ~58 days) prior to the first dose of study drug.
** All prohibited drugs that are CYP3A inducers require at least a 28 day or 5 half-lives (whichever is longer) 
washout prior to the first dose of study drug.


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# 
Noted as potent inhibitors or inducers. 
It is recommended that subjects avoid consumption of grapefruit juice exceeding 8 ounces (~240 ml) total in a 
day while in the study.
In a situation where appropriate medical care of a subject requires the use of a prohibited CYP3A 
inhibitor or inducer:
Moderate to potent inhibitors and inducers of CYP3A are not permitted in the study EXCEPT in emergency 
situations requiring no more than one day of administration.  Note: Amiodarone and mitotane are not 
permitted for any duration due to their long half-lives.  Topical (including skin or mucous membranes) 
application of antimicrobial and antifungal medications is permitted.


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Appendix 3. Common Terminology Criteria for Adverse Events 
v4.0 (CTCAE)-Dermatology
The NCI Common Terminology Criteria for Adverse Events v4.0 is a descriptive 
terminology that can be utilized for Adverse Event (AE) reporting.  A grading (severity) 
scale is provided for each AE term.  One page of the Dermatology/Skin Category is 
presented, which contains listings for Pruritus, Rash/Desquamation, and Rash: 
Acne/acneiform.
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Pruritus
Mild or localized; topical 
intervention indicated
Intense or widespread; 
intermittent; skin 
changes from scratching 
(eg, edema, papulation, 
excoriations, 
lichenification, 
oozing/crusts); oral 
intervention indicated; 
limiting instrumental 
ADL
Intense or widespread; 
constant; limiting 
self-care ADL or sleep; 
oral corticosteroid or 
immunosuppressive 
therapy indicated
-
-
Definition: A disorder characterized by an intense itching sensation.
Purpura
Combined area of lesions 
covering <10% BSA
Combined area of lesions 
covering 10 - 30% BSA; 
bleeding with trauma
Combined area of lesions 
covering >30% BSA; 
spontaneous bleeding
-
-
Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane.  Newer lesions appear reddish in color.  Older 
lesions are usually a darker purple color and eventually become a brownish-yellow color.
Rash acneiform
Papules and/or pustules 
covering <10% BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness
Papules and/or pustules 
covering 10 - 30% BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness; associated 
with psychosocial 
impact; limiting 
instrumental ADL
Papules and/or pustules 
covering >30% BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness; limiting 
self-care ADL; 
associated with local 
superinfection with oral 
antibiotics indicated
Papules and/or pustules 
covering any % BSA, 
which may or may not be 
associated with 
symptoms of pruritus or 
tenderness and are 
associated with extensive 
superinfection with IV 
antibiotics indicated; 
life- threatening 
consequences
Death
Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back.
Skin and subcutaneous tissue disorders
Grade
Adverse Event
1
2
3
4
5
Rash maculo-papular
Macules/papules 
covering
<10% BSA with or 
without symptoms 
(eg, pruritus, burning, 
tightness)
Macules/papules 
covering 10
- 30% BSA with or 
without symptoms 
(eg, pruritus, burning, 
tightness); limiting 
instrumental ADL
Macules/papules 
covering
>30% BSA with or 
without associated 
symptoms; limiting 
self-care ADL
-
-
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated).  Also known as morbillform rash, it is one of 
the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally and associated with pruritus.
Rash/desquamation and erythema multiforme progressing to Grade 2, acne/acneiform rash or 
pruritus progressing to Grade 3 are the severity levels for permanently discontinuing a 
subject from IP.
Pruritus progressing to Grade 2 sustained (>4 days) is cause to permanently discontinue IP.


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Appendix 4. Mayo Scoring System for Assessment of Ulcerative Colitis Activity
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  
Data are from Schroeder et al.
Stool frequency†:
0 = Normal no. of stools for this subject
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleeding‡:
0 = No blood seen
1 = Streaks of blood with stools less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy:
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
Subscore, 0 to 3
Physician’s global assessment§:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3
† Each subject serves as his or her own control to establish the degree of abnormality of the 
stool frequency.
‡ The daily bleeding score represents the most severe bleeding of the day.
§ The physician’s global assessment acknowledges the three other criteria, the subject’s daily 
recollection of abdominal discomfort and general sense of wellbeing, and other observations, 
such as physical findings and the subject’s performance status.


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Appendix 5. Inflammatory Bowel Disease Questionnaire (IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 2 weeks.
You will be asked about symptoms you have been having as a result of your inflammatory 
bowel disease, the way you have been feeling in general, and how your mood has been.
1. How frequent have your bowel movements been during the last two weeks?  Please 
indicate how frequent your bowel movements have been during the last two weeks by 
picking one of the options from:
A. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE 
EVER BEEN
B. EXTREMELY FREQUENT
C. VERY FREQUENT
D. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
E. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
F. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
G. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2. How often has the feeling of fatigue or of being tired and worn out been a problem for 
you during the last 2 weeks?  Please indicate how often the feeling of fatigue or tiredness 
has been a problem for you during the last 2 weeks by picking one of the options from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless?  Please 
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
5. How much of the time during the last 2 weeks have your bowel movements been loose?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME


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G. NONE OF THE TIME
6. How much energy have you had during the last 2 weeks?  Please choose an option from:
A. NO ENERGY AT ALL
B. VERY LITTLE ENERGY
C. A LITTLE ENERGY
D. SOME ENERGY
E. A MODERATE AMOUNT OF ENERGY
F. A LOT OF ENERGY
G. FULL OF ENERGY
7. How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME


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G. NONE OF THE TIME
9. How often during the last 2 weeks have you been troubled by cramps in your abdomen?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
10. How often during the last 2 weeks have you felt generally unwell?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
11. How often during the last 2 weeks have you been troubled because of fear of not finding 
a washroom?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME


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F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
12. How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks?  Please 
choose an option from:
A. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
B. A LOT OF DIFFICULTY
C. A FAIR BIT OF DIFFICULTY
D. SOME DIFFICULTY
E. A LITTLE DIFFICULTY
F. HARDLY ANY DIFFICULTY
G. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES
13. How often during the last 2 weeks have you been troubled by pain in the abdomen?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or 
been troubled by waking up during the night?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME


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E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
15. How often during the last 2 weeks have you felt depressed or discouraged?  Please 
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
16. How often during the last 2 weeks have you had to avoid attending events where there 
was no washroom close at hand?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of gas?  Please choose an option from:
A. A MAJOR PROBLEM
B. A BIG PROBLEM
C. A SIGNIFICANT PROBLEM


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D. SOME TROUBLE
E. A LITTLE TROUBLE
F. HARDLY ANY TROUBLE
G. NO TROUBLE
18. Overall, in the last 2 weeks, how much a problem have you had maintaining or getting to, 
the weight you would like to be at?  Please choose an option from:
A. A MAJOR PROBLEM
B. A BIG PROBLEM
C. A SIGNIFICANT PROBLEM
D. SOME TROUBLE
E. A LITTLE TROUBLE
F. HARDLY ANY TROUBLE
G. NO TROUBLE
19. Many patients with bowel problems often have worries and anxieties related to their 
illness.  These include worries about getting cancer, worries about never feeling any 
better, and worries about having a relapse.  In general, how often during the last 2 weeks 
have you felt worried or anxious?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME


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C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
21. How often during the last 2 weeks have you felt relaxed and free of tension?  Please 
choose an option from:
A. NONE OF THE TIME
B. A LITTLE OF THE TIME
C. SOME OF THE TIME
D. A GOOD BIT OF THE TIME
E. MOST OF THE TIME
F. ALMOST ALL OF THE TIME
G. ALL OF THE TIME
22. How much of the time during the last 2 weeks have you had a problem with rectal 
bleeding with your bowel movements?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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23. How much of the time during the last 2 weeks have you felt embarrassed as a result of 
your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
24. How much of the time during the last 2 weeks have you been troubled by a feeling of 
having to go to the bathroom even though your bowels were empty?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
25. How much of the time during the last 2 weeks have you felt tearful or upset?  Please
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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26. How much of the time during the last 2 weeks have you been troubled by accidental 
soiling of your underpants?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
27. How much of the time during the last 2 weeks have you felt angry as a result of your 
bowel problem? Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks? 
Please choose an option from:
A. NO SEX AS A RESULT OF BOWEL DISEASE
B. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
C. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
D. SOME LIMITATION AS A RESULT OF BOWEL DISEASE
E. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
F. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE


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G. NO LIMITATION AS A RESULT OF BOWEL DISEASE
29. How much of the time during the last 2 weeks have you been troubled by nausea or 
feeling sick to your stomach?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
30. How much of the time during the last 2 weeks have you felt irritable?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
31. How often during the past 2 weeks have you felt a lack of understanding from others?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME


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G. NONE OF THE TIME
32. How satisfied, happy, or pleased have you been with your personal life during the past 
2 weeks?  Please choose one of the following options from:
A. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
B. GENERALLY DISSATISFIED, UNHAPPY
C. SOMEWHAT DISSATISFIED, UNHAPPY
D. GENERALLY SATISFIED, PLEASED
E. SATISFIED MOST OF THE TIME, HAPPY
F. VERY SATISFIED MOST OF THE TIME, HAPPY
G. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
PLEASED


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Appendix 6. Short Form -36, version 2, acute (SF-36)
Please answer every question.  Some questions may look like others, but each one is different.  
Please take the time to read and answer each question carefully by filling in the bubble that 
best represents your response.


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Appendix 7. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and Visual 
Analog Scale (EQ-5D-3L & VAS)
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (eg, work, study, housework, family or leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



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To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0.
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion.  Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst
imaginable
health state
0
Best 
imaginable
health state
Example
Your own
health state
today


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CCI


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Appendix 9. Summary of corticosteroid equivalents
Compound
Equivalent Dose (mg)
Prednisone
10
Prednisolone
10
6-methylprednisolone
8
Triamcinolone
8
Betamethasone
1.2
Dexamethasone
1.5
Hydrocortisone
40
Cortisone
50
Deflazacort
12
Cloprednol
5
Prednylidene
12


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Appendix 10. Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer.
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
All procedures should be performed per protocol Schedule of Activities to monitor the safety 
of the partcipant. 
If the sponsor determines that the impact of COVID-19 on protocol visits and procedures and 
associated timeframe needs to be reported on a CRF, this will be requested. 
In situations where participants are quarantined, self-isolating or unable to visit the study site, 
the participant verbal consent must be documented in the site’s source documents prior to 
performing any protocol procedures or shipping study intervention.
Appendix 10.1. Eligibility
Not Applicable.
Appendix 10.2. TeleHealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study participants at scheduled visits per the Schedule of Activities
or unscheduled visits. 
Telehealth visits may be used to continue to assess participant safety and collect data points, 
(if permitted by law or local guidance). Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, 
video-conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Section 4.3.1 and Section 7.2.4.


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Study participants must be reminded to promptly notify site staff about any change in their 
health status. 
Appendix 10.3. Alternative Facilities for Safety Assessments
Appendix 10.3.1. Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local regulations. 
The local laboratory may be a standalone institution or within a hospital. The following 
safety laboratory evaluations may be performed at a local laboratory: See SoA.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible.  The local laboratory reports should be filed in the 
participant’s source documents/medical records. Relevant data from the local laboratory 
report should be recorded on the CRF.
If a participant requiring pregnancy testing cannot visit a local laboratory for pregnancy 
testing, a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be 
used by the participant to perform the test at home, if compliant with local regulatory 
requirements. The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol.
Appendix 10.4. Investigational Product
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention (investigational product) must be considered. 
Investigational product may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the 
investigational product. Pfizer does not permit the shipment of investigational product by 
mail. The tracking record of shipments and the chain of custody of investigational product 
must be kept in the participant’s source documents/medical records.
Appendix 10.5. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the participant’s location, rather than an in-person study visit at the site. The 
following may be performed during a home health visit: See SoA.


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Appendix 10.6. Adverse Events and Serious Adverse Events 
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse events (SAE) and appropriate medical intervention provided. 
Temporary discontinuation of the study intervention (investigational product) may be 
medically appropriate until the participant has recovered from COVID-19.  See Section 6.5
guidelines for monitoring and discontinuations.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention (investigational product) with the study medical monitor.
For participant discontinuation reporting in the CRF, select the most appropriate status for 
discontinuation; if the discontinuation is associated with the current COVID-19 pandemic, 
enter “COVID-19” in the “Specify Status” field. 
Appendix 10.7. Patient Reported Outcomes (PROs)
Patient-Centered Outcome Assessments (PCOAs) that were to be administered (via a 
provisioned site-based device) at the site per protocol may be administered by qualified site 
personnel via telehealth, if permitted by local regulations, laws, and guidance from 
regulatory authorities.

To avoid influencing the study participants’ responses, it is recommended that the 
PCOA questionnaires be administered via telehealth prior to any site staff interactions 
for other reasons.

Site staff performing the PCOA administration via telehealth should:

Conduct this telehealth interaction in a quiet, private area and ask the study
participant also to go to a similar setting in which the study participant’s safety,
privacy and ability to complete the assessment and provide accurate data without
interruption or 3rd party input or influence is adequate;

Read the full text including all instructions, questions, and response choices
verbatim and mark the response choice selected by the participant; site staff can
read the PCOA from the paper source or provisioned site-based device, but the
site staff must read exactly as that specific PCOA appears on the paper source or
site provisioned device;

Speak clearly and at a comfortable pace;

Let the study participant know that the instructions, question, or response options
can be re-read at any time if needed.


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
Not interpret any part of the questionnaire for the study participant. If the study
participant does not understand, the site staff should repeat the question and response 
choices verbatim and ask the participant to select the response that they feel best
represents his/her experience.

Encourage the study participant to answer based on his/her first instincts and remind 
the study participant that there are no right or wrong answers. If needed, use a 
prompt such as “Which answer most closely matches what you are thinking or 
feeling?”

Confirm the study participant’s response selection before you record the answer 
(eg, you would like me to select “moderate pain,” is that right?

Indicate that the PCOA was administered via telehealth.

For the telehealth administration of a paper PCOA, indicate this on the participant 
worksheet (ie, the participant facing source document). Include the name of the site 
staff administering the PCOA and confirm that the study participant was the one to 
answer the questions.

For PCOAs that are collected via telehealth, the PCOA CRF must be completed. 
Document the administration and completion date in the CRF.


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Appendix 11. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
AA 
Alopecia
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
AST
aspartate aminotransferase
AT3
Antithrombin III 
ATP
adenosine triphosphate
AUC
Area under the concentration-time profile
AUCtau
Area under the concentration-time profile from time 0 to time 
tau () the dosing interval
AUC24
area under the concentration-time curve from time 0 to time 
24 hours
Aetau
Cumulative amount of drug recovered unchanged in urine up to 
24 hours
BA
Bioavailability
BCG
Bacillus Calmette-Guerin
BCRP
breast cancer resistant protein 
BID
bis in die (twice daily)
BMI
Body mass index
BMX
bone marrow tyrosine kinase on chromosome X
BTK
Bruton Tyrosine Kinase
BSEP
bile salt export pump
14C
Carbon-14
CD
Crohn’s disease
CD8
Cluster of differentiation 8
CFB
Change from baseline
CHD
Coronary heart disease
CK
creatine kinase
CK-MB
Creatinine kinase, myocardial band
CL
Clearance
CO
Cross-Over
COE
Cross over extension
COVID-19
Corona virus disease 2019
Cmax
maximum plasma concentration 
cLDA
constrained Longitudinal Data Analysis
CL/F
Apparent clearance
CLr
Renal clearance
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Abbreviation
Term
CNS
Central nervous system
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
CYP450
cytochrome P450
DDI
Drug drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DU
dispensable unit
EC
ethics committee
ECG
Electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EFD
Embryo fetal development
eGFR
Estimated glomerular filtration rate
Emax
Maximal effect model
EU
European Union
EudraCT
European Clinical Trials Database
FIH
First in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GST
glutathione-S-transferase 
HbA1C
Glycosylated hemoglobin
HBsAg
Hepatitis B Surface Antigen 
HBcAb
Hepatitis B Core Antibody 
HBsAb
Hepatitis B Surface Antibody 
HCVAb
Hepatitis C antibody 
HCV RNA
HCV ribonucleic acid
HDL
High density lipoprotein
HEENT
head, eyes, ears, nose and throat
HIV
human immunodeficiency virus
HRQL
health-related quality of life
IB
Investigators brochure
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Abbreviation
Term
IBD
Inflammatory bowel disease
IBDQ
Inflammatory bowel disease questionnaire 
ICH
International Conference on Harmonisation
IC50
50% inhibitive concentration
ID
Identification
IFN
Interferon
IGA
Immunoglobulin A
IGG
Immunoglobulin G
IGM
Immunoglobulin M
IGRA
Interferon gamma release assay
IL-6
Interleukin 6
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
ITK
IL-2 inducible T-cell kinase
ITT
Intent to treat
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWR
interactive web response
JAK
Janus kinase
KDIGO
Kidney Disease: Improving Global Outcomes
LDL
Low density lipoprotein
LFT
liver function test
LLN
lower limit of normal
LLOQ
Lower limit of quantification
LOAEL
Lowest Observed Adverse Effect Level
LSLV
last subject last visit 
MAD
Multiple ascending dose
MATE
multidrug and toxin extrusion
MCS
Mental component summary
MDR
Multi drug resistant
MedDRA
Medical Dictionary for Regulatory Activities
MMR
Measles, Mumps, Rubella
MnB
meningitidis serogroup B
mRNA
messenger ribonucleic acid
MRA
Magnetic Resonance Angiography
MTX
Methotrexate
N/A
not applicable
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Abbreviation
Term
NADPH
nicotinamide adenine dinucleotide phosphate 
NK
Natural Killer
NOAEL
No observed adverse effect level
OAT
organic anion transporting
OATP
organic anion transporting polypeptide
OCT
Organic cation transporter
PCD
primary completion date
PCOA
Patient-Centered Outcome Assessments
PCS
Physical component summary
PD
Pharmacodynamics(s)
PFS
prefilled syringe
P-gp
P-glycoprotein
PGA
Physician’s global assessment
PGx
Pharmacogenomics(s)
PI
principal investigator
PK
Pharmacokinetic
PO
Oral
PPD
Purified protein derivative
PRO
Patient reported outcome
PT
prothrombin time
QD
Once daily
QFT-G
QuantiFERON-TB Gold
QFT-GIT
QuantiFERON-TB Gold In-Tube
RA
Rheumatoid Arthritis
Rac
Observed accumulation ratio
Rss
Steady state accumulation ratio
RNA
ribonucleic acid
rGST
Recombinant Glutatione-S-Transferase
SAD
Single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SBE
Single-Blind Extension Period
SLE
Systemic Lupus Erythematosus
SC
Subcutaneous
SCr
Serum creatinine
SF-36
Short form 36
SOC
System organ class
SOP
standard operating procedure
SRSD
single reference safety document
STAT
signal transducers and activators of transcription
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Term
T-cell
T lymphocyte
t1/2
Terminal half life
TB
Tuberculosis
TBili
total bilirubin
TEAE
Treatment emergent adverse event
TEC
tyrosine kinase expressed in hepatocellular carcinoma (TEC)
Tmax
Time at which Cmax occurred
TNF
Tumor necrosis factor
TPMP
thiopurine methyltransferase
TXK
tyrosine kinase expressed in T cells
TYK
tyrosine-protein kinase
UC
Ulcerative colitis
UDP
uridine 5'-diphospho
ULN
upper limit of normal
URI
upper respiratory tract infection
US
United States
UV
Ultraviolet
Vss
volume of distribution at steady state
Vz/F
Apparent volume of distribution
WBC
White blood cells
WOCBP
Women of child bearing potential
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SAP_001.pdf: 
Protocol B7981005 (PF-06651600 and PF-06700841) Statistical Analysis Plan
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Protocol B7981005
A PHASE 2B, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PARALLEL GROUP, DOSE RANGING STUDY OF ORAL PF-06651600 AND 
PF-06700841 AS INDUCTION AND CHRONIC THERAPY IN SUBJECTS WITH 
MODERATE TO SEVERE ULCERATIVE COLITIS
Statistical Analysis Plan 
(SAP)
Version:
4.0
Date:
05 May 2021


Protocol B7981005 (PF-06651600 and PF-06700841) Statistical Analysis Plan
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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
3. STUDY OBJECTIVES AND ENDPOINTS.........................................................................6
Study Objectives and Endpoints During the Induction Period..................................6
Objectives and Endpoints During the Chronic Period ..............................................8
Timing of the Efficacy Evaluations
 
...........................................................10
4. STUDY DESIGN.................................................................................................................12
Initial (Pre-Amendment 5 Protocol) Study Design .................................................12
Amendment 7 Protocol............................................................................................13
5. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................15
Efficacy and Patient Reported Endpoints................................................................15
Baseline Variables...................................................................................................15
Safety Endpoints .....................................................................................................15
5.3.1. Adverse Events ...........................................................................................16
5.3.2. Laboratory Data..........................................................................................16
5.3.3. Vital Signs, Including Height and Weight and ECG..................................16
5.3.4. Physical Examinations................................................................................16
PD Endpoints...........................................................................................................17
6. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................17
Intent-to-Treat Analysis Sets...................................................................................17
Safety Analysis Set..................................................................................................18
7. GENERAL METHODOLOGY AND CONVENTIONS....................................................18
Hypotheses and Decision Rules ..............................................................................18
Analyses for Continuous Endpoints........................................................................18
Analyses for Binary Endpoints ...............................................................................19
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Analyses for Categorical Endpoints........................................................................20
Analyses for Time-to-Event Endpoints...................................................................20
Methods to Manage Missing Data ..........................................................................20
8. ANALYSES AND SUMMARIES ......................................................................................20
Treatment Groups....................................................................................................20
8.1.1. Induction Period..........................................................................................21
8.1.2. Chronic Dosing Period ...............................................................................21
Efficacy, PRO and 
 Analyses for 
the Induction and Chronic Therapy Period ...............................................................21
8.2.1. Analyses for Induction Period Observations ..............................................21
8.2.2. Primary Efficacy Analysis..........................................................................22
8.2.3. Analysis of Observations in the Chronic Therapy Period ..........................22
8.4.1. Induction Period..........................................................................................24
8.4.2. Chronic Dosing Period ...............................................................................24
Baseline and Other Summaries and Analyses.........................................................24
8.5.1. Baseline Summaries....................................................................................24
8.5.2. Study Conduct and Participant Disposition................................................24
8.5.3. Study Treatment Exposure .........................................................................25
8.5.4. Concomitant Medications and Nondrug Treatments..................................25
Safety Summaries and Analyses .............................................................................25
8.6.1. Adverse Events ...........................................................................................25
8.6.2. Laboratory Data..........................................................................................25
8.6.3. Vital Signs ..................................................................................................26
8.6.4. Electrocardiograms.....................................................................................26
8.6.5. Physical Examination .................................................................................26
9. INTERIM ANALYSES.......................................................................................................26
10. REFERENCES ..................................................................................................................27
11. APPENDICES ...................................................................................................................28
Appendix 1 Mayo Scoring System for Assessment of Ulcerative Colitis 
Activity and Outcomes Based on Subscores of Mayo Score ....................................28
11.1.1. Subscores of Total Mayo Score................................................................28
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11.1.2. Endpoints Based on the Subscores of Total Mayo Score, Partial 
Mayo Score and Modified Mayo Scores .........................................................29
11.1.3. Endpoints Based on Partial Mayo and Modified Score............................30
Appendix 2 Inflammatory Bowel Disease Questionnaire (IBDQ) .......................31
Appendix 3 Short Form -36, version 2, acute (SF-36)..........................................42
Appendix 4. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and 
Visual Analog Scale (EQ-5D-3L & VAS) ................................................................48
Appendix 7 Definition and Use of Visit Windows in Reporting ..........................53
Appendix 8 Sample SAS Code for cLDA.............................................................54
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................5
Table 2.
Objectives and Endpoints During the Induction Period .............................6
Table 3.
Objectives and Endpoints During the Chronic Therapy Period .................8
Table 4.
Continuous Outcomes. Scores and Changes from Baseline will be 
Reported....................................................................................................11
Table 5.
Binary outcomes. Proportion of Responders will be Reported. 
Definition of Responder is Given Below..................................................11
Table 6.
Treatment Sequences................................................................................20
Table 7.
Treatment Groups in the Induction Period (ITT data set) ........................21
Table 8.
Analysis of Continuous Outcomes During Induction Period ...................21
Table 9.
Analysis of Binary Outcomes During the Induction Period.....................22
Table 10.
Treatment Groups in the Induction and Chronic Period (mITT data 
set).............................................................................................................23
Table 11.
Analysis of Continuous Outcomes During Chronic Period (main)..........23
Table 12.
Analysis of Binary Outcomes During the Chronic Period .......................23
Table 13.
Endpoints Based on the Subscores of Total Mayo Score.........................30
LIST OF FIGURES
Figure 1
Study Design Schematic – Pre-Amendment 5 Protocol...........................13
Figure 2
Study Design Schematic – Amendment 7 Protocol..................................14
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1. VERSION HISTORY
This SAP for Study B7981005 is based on the protocol Amendment 7 dated 10NOV2020.
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable.
2
The endpoints in 
the chronic and 
induction periods 
were separated. 
Addition of some 
statistical methods
for all variables.
Major updates were required as a result of protocol 
amendment (version 7, Nov 17, 2020).
 
 
 
 
 
 
 
 
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study B7981005.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
This study was designed before the estimands terminology was incorporated into the 
protocols and SAPs. Therefore, discussion of the estimands and intercurrent events is not 
included into the document. 
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3. STUDY OBJECTIVES AND ENDPOINTS
Study Objectives and Endpoints During the Induction Period
Table 2.
Objectives and Endpoints During the Induction Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 8 in subjects with moderate to 
severe UC.

Total Mayo score at Week 8.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in induction.  

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 12-lead 
ECG in the induction period. 

Incidence of serious infections (see Section 7.2.8. of 
Protocol for definition) in the induction period.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in induction of remission at Week 8 in 
subjects with moderate to severe UC.

Proportion of subjects achieving remission based on 
total Mayo score of ≤2 with no individual subscore 
>1 and a rectal bleeding subscore of 0 at Week 8.  

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 8 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in
endoscopic appearance (defined as a Mayo endoscopic 
subscore of ≤1) at Week 8.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction of other clinical outcomes 
in subjects with moderate to severe UC.

Proportion of subjects achieving clinical response at 
Week 8.

Proportion of subjects in endoscopic remission at 
Week 8.

Proportion of subjects in symptomatic remission at 
Week 8.

Proportion of subjects achieving deep remission at 
Week 8.

Partial Mayo scores and change from baseline over 
time at Weeks 2, 4 and 8.

Change from baseline at Week 8 in total Mayo score.

To evaluate the effect of PF-06651600 and 
PF-06700841 in induction on patient reported 
outcomes (PRO) in subjects with moderate to severe 
UC.

The scores and change from baseline in Inflammatory 
Bowel Disease Questionnaire (IBDQ) Total score and 
domains (Bowel Symptoms, Systemic Symptoms, 
Emotional Function and Social Function) at 
Weeks 4 and 8.

The proportion of subjects with IBDQ total score 
≥170 at Weeks 4 and 8.

The proportion of subjects with ≥16 point increase in 
IBDQ total score from baseline at Weeks 4 and 8.

Proportion of subjects with improvement in IBDQ 
bowel symptom domain at Weeks 4 and 8.  The 
improvement is defined as an increase of at least 
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IBDQ bowel symptom domain (items 1, 5, 9, 13, 17, 
20, 22, 24, 26, 29).

The scores and change from baseline in Short 
Form 36 version 2, acute (SF-36v2) (physical and 
mental component summary scores: PCS & MCS, and 
8 domain scores) at Weeks 4 and 8.

The scores and change from baseline in EuroQoL 
5 Dimensions (EQ-5D-3L & EQ-5D VAS) at 
Weeks 4 and 8.
 
 
 
 

Change from baseline in serum hsCRP levels over 
time.

Change from baseline in fecal calprotectin.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets, 
.

To explore outcomes based on investigational criteria 
in induction.
 

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus PGA).

Proportion of subjects with partial Mayo score ≤2 with 
no individual subscore >1 in response to treatment 
over time.

Proportion of subjects with reduction of ≥2 points 
from baseline in partial Mayo score over time.

Proportion of subjects in endoscopic response at 
Week 8.  Endoscopic response is defined by a 
decrease from baseline in the endoscopic subscore of 
1 point or more.
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives and Endpoints During the Chronic Period
Table 3.
Objectives and Endpoints During the Chronic Therapy Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 in subjects with 
moderate to severe UC in the chronic period.

Incidence and severity of laboratory abnormalities, 
adverse events, serious adverse events and 
withdrawals due to adverse events, vital signs, 12-lead 
ECG in the chronic period. 

Incidence of serious infections (see Section 7.2.8 for 
definition) in the chronic period.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 at Week 32 in subjects with moderate 
to severe UC.

Total Mayo score at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 for achieving remission at Week 32.

Proportion of subjects in remission based on total 
Mayo score of ≤2 with no individual subscore >1 and 
a rectal bleeding subscore of 0 at Week 32.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 in improvement of endoscopic 
appearance at Week 32 in subjects with moderate to 
severe UC.

Proportion of subjects achieving improvement in 
endoscopic appearance (defined as a Mayo endoscopic 
subscore of ≤1) at Week 32.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):
 
 
 
 

To explore the effect of PF-06651600 and 
PF-06700841 in subjects with moderate to severe UC 
in the chronic dosing period.

Proportion of subjects achieving clinical response at 
Week 32.

Proportion of subjects in endoscopic remission at 
Week 32.
 
 

Change from baseline at Week 32 in total Mayo score.
 
 
 
 
 
 
 
 
 
 
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
Change from baseline in serum high-sensitivity 
C-reactive protein (hsCRP) levels over time.

Change from baseline in fecal calprotectin.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, neutrophils, 
platelets,
 

To explore outcomes based on investigational criteria 
in the chronic period.
 

Proportion of subjects in remission* based on 
modified Mayo score (Total Mayo score minus 
Physician’s global assessment (PGA) at Week 32.
 
 
 

Proportion of subjects in endoscopic response at 
Week 32.  Endoscopic response is defined by a 
decrease from baseline in the endoscopic subscore of 
1 point or more.
 
 
 
 
 
 
 
 
 
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Timing of the Efficacy Evaluations and
 
The tables in Section 3.1-3.2 were copied from the most Version 7 (Nov 18, 2020) version of 
the protocol. Tables 4 and 5 provide an additional insight to the programmer/data analyst. 
They present separately continuous and binary outcomes of interest and show the analysis 
times based on the observations required by the schedule of activity in the protocol. The 
definition of the outcomes is discussed in the Section 5.
The BL characters in the tables denote baseline observations (either day 1 or screening visits)
and IND and CHR characters denote observations during the induction and chronic periods 
of the study respectively.
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Table 4.
Continuous Outcomes. Scores and Changes from Baseline will be Reported
N
Definition
BL
w2
w4
w8
w12
w16
w20
w24
w32
1
Total Mayo score      
BL
IND
CHR
2
Partial Mayo score (PM)  
BL
IND
IND
IND
CHR
CHR
CHR
CHR
CHR
3
IBDQ
A.
Total score
B.
Bowel symptoms, 
C.
Systemic symptoms
D.
Emotional function 
E.
Social function
BL
    
IND
IND
CHR
4
Scores and changes from baseline 
(based on SF-36v2)
A.
PCS
B.
MCS
C.
8 domain scores
BL
IND
IND
CHR
6
Euro Quality of Life Questionnaire
Scores
A.
EQ-5D-3L
B.
EQ-5D-VAS
BL
IND
IND
CHR
7
Biomarkers
A.
hsCRP
B.
fecal calprotectin
E.
hematological values 
(includes reticulocytes, 
hemoglobin, 
neutrophils,platelets, 
BL
BL
BL
IND
IND
IND
IND
CHR
CHR
CHR
CHR
CHR
CHR
BL = Baseline or Screening as per schedule of Activities in the protocol. IND= Induction. CHR= Chronic
Table 5.
Binary outcomes. Proportion of Responders will be Reported. Definition of 
Responder is Given Below
N
Definition
BL
w2
w4
w8
w12
w16
w20
w24
w32
1
Remission based on total Mayo 
score
BL
IND
CHR
 
4
Endoscopic remission based on 
endoscopic subscore of total Mayo 
score
BL
IND
CHR
5
Clinical response based on total
Mayo score
BL
IND
CHR
6
Endoscopic response based on 
endoscopic subscore of total Mayo 
score
BL
IND
CHR
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N
Definition
BL
w2
w4
w8
w12
w16
w20
w24
w32
7
Improvement in endoscopic 
appearance based on endoscopic 
subscore of total Mayo score
BL
IND
CHR
8
Remission based on modified
Mayo score
BL
IND
CHR
 
 
 
11
IBDQ total score ≥170
BL
IND
IND  
CHR
12
≥16 point increase in IBDQ total 
score from baseline
BL
IND
IND
CHR
13
Improvement in IBDQ bowel 
symptom domain
IND
IND
CHR
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
The study design was modified after an enrollment of the initial cohort of subjects. In the 
initial design (Pre-Amendment 5 protocol) subjects who enrolled into the chronic period of 
the study were randomized to the active and control treatment arms with the randomization 
ratio of 2:1. After the modification of the protocol by the Amendment 5 the randomization to 
placebo in the chronic therapy period was no longer allowed and each subject in the chronic 
therapy period was assigned to the active arm only. The change in the protocol occurred at 
the time when approximately 52 subjects were enrolled into the chronic therapy period and 
therefore limited number of subjects were randomized to the placebo arm during the chronic 
therapy period.
Initial (Pre-Amendment 5 Protocol) Study Design
This is a Phase 2b, randomized, double-blind, placebo-controlled, parallel group, multicenter 
study in subjects with moderate to severe active UC.  The first part of the study is a screening 
period of up to 6 weeks followed by an 8-week duration double-blind induction period.  The 
study will not be blinded across the PF-06651600 and PF-06700841 cohorts but will be 
placebo-controlled double-blinded within each investigational product.  At Week 8, all 
subjects will be re-randomized within their respective treatment cohort (PF-06651600 or 
PF-06700841) or placebo into an additional 24 week double blind chronic therapy period 
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followed by a 4 week follow up period after the last dose of investigational product for a total 
of 32 weeks.
Figure 1
Study Design Schematic – Pre-Amendment 5 Protocol
50 mg
70 mg
20 mg
200 mg
Induction
(8 weeks)
Chronic Therapy
(24 weeks)
30 mg
PF-06651600
PF-06700841
Powered for induction only
N = 360 total  (55/cohort with total induction placebo = 30)
PBO
PBO
30 mg
10 mg
60 mg
PBO
PBO
For analysis, placebo groups will be combined to yield final 
drug:placebo ratios of 2:2:2:1.
Screening
(Up to 6 weeks)
Follow Up
(4 weeks)
Approximately 360 subjects in total will be randomized into the study.  In the induction 
period, three oral dose levels (20, 70, and 200 mg daily) of PF-06651600 plus matching 
placebo in a 4:4:4:1 ratio and three oral doses (10, 30, and 60 mg daily) of PF-06700841 plus 
matching placebo in a 4:4:4:1 ratio will be investigated.  For analysis placebo groups will be 
combined to yield final drug: placebo ratios of 2:2:2:1 for each drug.  Following the 
screening period, subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive one of 8 treatments. 
Following the induction period of the study, all subjects, including those on placebo, will be 
re-randomized within their respective treatment cohort to enter the chronic therapy period.  In 
the chronic therapy period, 50 mg of PF-06651600 and 30 mg of PF-06700841 given daily 
(or matching placebos) will be investigated.  Subjects re-randomized to chronic therapy will 
be stratified according to their responder status. Responder status will be determined by the 
use of a decrease from baseline greater than or equal to 2 in the partial Mayo score as a 
stratification variable.  The re-randomization will be conducted using a 2:1 ratio for both 
PF-06651600 (50 mg):placebo and PF-06700841 (30 mg):placebo.
Amendment 7 Protocol
This is a Phase 2b, randomized, double-blind, placebo-controlled (in the induction period and 
not in the chronic dosing period), parallel group, multicenter study in subjects with moderate 
to severe active UC.  The first part of the study is a screening period of up to 6 weeks 
followed by an 8 week double-blind induction period.  The study will not be blinded across 


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the PF-06651600 and PF-06700841 cohorts, but will be placebo-controlled during the 
induction phase, and double-blinded within each investigational product.  At Week 8, all 
subjects will be assigned to their respective treatment cohort (either PF-06651600 or 
PF-06700841 as during the induction phase) into an additional 24 week active chronic dosing 
period followed by a 4 week follow up period after the last dose of investigational product
for a total of 36 weeks.  The chronic dosing period is in effect open label; with both subjects 
and Investigators aware that they have been assigned to PF-06651600 or PF-06700841, and 
that there is no placebo control.
Figure 2
Study Design Schematic – Amendment 7 Protocol
50 mg
70 mg
20 mg
200 mg
Induction
(8 weeks)
Chronic Therapy
(24 weeks)
30 mg
PF-06651600
PF-06700841
•Powered for induction period only
•N = 360 total (55/cohort with total induction placebo = 30)
•Randomization into induction period with 4:4:4:1 ratio of actives and a placebo
•For analysis of induction period, placebo groups will be combined to yield 2:2:2:1 ratio of actives and a placebo.
PBO
PBO
30 mg
10 mg
60 mg
Screening
(Up to 6 weeks)
Follow Up
(4 weeks)
Approximately 360 subjects in total will be randomized into the study.  Following the 
screening period, subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive one of 8 treatments. In the induction period, three oral dose 
levels (20, 70, and 200 mg daily) of PF-06651600 plus matching placebo in a 4:4:4:1 ratio 
and three oral doses (10, 30, and 60 mg daily) of PF-06700841 plus matching placebo in a 
4:4:4:1 ratio will be investigated. For analysis of the induction period, placebo groups will 
be combined to yield final drug: placebo ratios of 2:2:2:1 for each drug at Week 8.
Following the induction period of the study, all subjects will enter the chronic dosing period 
in which there will be no placebo arms (Protocol Amendment 5).  All subjects (including 
placebo subjects) from the double-blind PF-06651600 treatment/placebo induction period 
will receive 50 mg of PF-06651600 for 24 weeks.  All subjects (including placebo subjects) 
from the double-blind PF-06700841/placebo induction period will receive 30 mg of 
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Any subject who discontinues early from the induction period prior to the Week 8 visit 
should undergo the procedures for an Early Termination visit on the last day the subject takes 
the investigational product or as soon as possible thereafter, and will not be permitted to enter 
the chronic dosing period. For subjects who discontinue early from the chronic dosing 
period (after the Week 8 visit, but prior to the Week 32 visit), the procedures scheduled for 
an Early Termination visit will be performed on the last day the subject takes the 
investigational product or as soon as possible thereafter. After completion of the Early 
Termination visit subjects will enter the follow-up period.
5. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Efficacy and Patient Reported Endpoints
The tables with the listing of the endpoints for induction and chronic periods are presented in
Section 3. The details of the calculations for efficacy endpoints are discussed in the 
Appendices 1-5.
Baseline Variables
Unless specifically stated otherwise, the baseline value for the induction and chronic periods
is defined as the last non-missing measurement collected prior to the first administration of 
study drug at Day 1. Baseline value will be used as a covariate in statistical models for 
change from baseline in efficacy endpoints to adjust for baseline disease severity (except for 
cLDA models).
Baseline data collected/measured at Screening visit are:

Medical history, prior concomitant medications height, weight, Mayo score (Total), 
 and FCP.
Baseline data collected/measured at Baseline (Day 1) are listed below:
a.
Complete physical examination, and vital signs & temperature.
b. hsCRP, 
 Mayo score (Partial), 
 IBDQ, 
EQ-5D-3L + VAS, and SF-36.
c.
Labs (Hematology and serum chemistry (including fasting lipid panel), Cystatin C, 
GFR, urine analysis, 
).
Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs (including rashes and hearing), 
physical examinations, and clinical laboratory results in all subjects who receive at least one 
dose of the investigational product.  Unscheduled safety assessments may be performed at 
any time during the study to assess any perceived safety concerns.
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5.3.1. Adverse Events
An adverse event is considered treatment-emergent adverse event (TEAE) to a given 
treatment if the event started during the effective duration of treatment regardless of whether 
a similar event of equal or greater severity existed in the baseline period.
Safety endpoints will be assessed by the spontaneous reporting of:

Incidence of TEAEs.

Incidence of SAEs and AEs leading to discontinuation.

Incidence of serious infections.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.
5.3.2. Laboratory Data
Below is a list of hematology and serum chemistry test parameters.

Hematology: Hemoglobin, hematocrit, red blood cell count, platelet count, white 
blood cell count, total neutrophils (Abs), eosinophils (Abs), monocytes (Abs), 
basophils (Abs), lymphocytes (Abs), prothrombin time (PT)/international normalized 
ratio (INR)/partial thromboplastin time (PTT), and reticulocytes (% and Abs).

Serum chemistry: Blood urea nitrogen, creatinine, cystatin C, glucose, calcium, 
sodium, potassium, chloride, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, direct bilirubin, alkaline phosphatase, uric 
acid, albumin, total protein, creatine kinase (CK), CK fractionation, total cholesterol, 
triglycerides, high-density lipoproteins (HDL), and low-density lipoprotein (LDL).

CRP.
5.3.3. Vital Signs, Including Height and Weight and ECG
Vital sign measurements are respiratory rate, oral or tympanic temperature or axillary 
methods, respiratory rate, pulse rate, and blood pressures.
Height and weight are collected at screening and post-treatment (only weight).
5.3.4. Physical Examinations
Complete physical examination consists of general appearance, skin, head, eyes, ears, nose
and throat (HEENT), heart, lungs, breast (optional), abdomen, external genitalia (optional),
extremities, neurologic function, back, and lymph nodes. Targeted physical examination
consists of skin, heart, lungs, abdomen, and examination of body systems where there are
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symptom complaints by the subject. Full and targeted physical examinations must include a
full body skin examination. Skin examinations should include visual inspection of the breasts
and external genitalia, even if a subject does not wish to have breast and/or external genitalia
examined as part of the physical examination.
PD Endpoints

High sensitivity C-reactive protein (hsCRP).

Fecal calprotectin.
 
6. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Intent-to-Treat Analysis Sets
An intent-to-treat (ITT) analysis set will include all randomized subjects who received at 
least one dose of PF-06651600, PF-06700841, or placebo. The intent to treat dataset (ITT) 
will be used for primary efficacy analysis. 
As a result of discontinuation in the randomization to placebo during chronic period of the 
study the number of subjects that are randomized to placebo treatment for each of the 
treatment arms in induction period will be small. The observations (during both induction 
and randomization periods for these subjects will not be used in the analysis (see also 
Section 8.2.3).  We will call the corresponding dataset a modified intent-to treat dataset 
(mITT). 
At the time of interim analysis only the incomplete versions of ITT and mITT datasets will 
be available as the observations for some of the subjects who did not dropped out of the 
study will be missing. For the continuous outcomes all available data will be used in the 
corresponding analyses. No imputation of binary outcomes will be done for the binary 
outcomes and missing values will be excluded from the analyses.
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Safety Analysis Set
The safety (SAF) analysis set is defined as those subjects who received at least one dose of 
PF-06651600, PF-06700841, or placebo.
7. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Subject Last Visit (LSLV).
Hypotheses and Decision Rules
For any given active arm, the null hypothesis is that the there is no difference between the 
distributions of the total Mayo score at Week 8 between the pooled placebo group and active 
arm.  This hypothesis is equivalent to the hypothesis that there is no difference between the 
distributions of the change from baseline of total Mayo score at Week 8 between the pooled 
placebo group and active arm. The equivalence of the two formulation is caused by the 
equality of the expected values of total Mayo score at the baseline caused by randomization.
The placebo-adjusted treatment effect for a particular group can therefore be defined as the 
difference between the expected values of total Mayo Scores (ie, expected total Mayo score 
at Week 8 in the active treatment group minus the expected total Mayo score at Week 8 in 
the placebo treatment group) or difference between the expected values  of change from 
baseline in total Mayo Scores (ie, expected change from baseline in total Mayo score at 
Week 8 in the active treatment group minus the expected change from baseline in total Mayo 
score at Week 8 in the placebo treatment group), A successful treatment should decrease
total Mayo score and therefore the desired treatment effect is negative.  The treatment arm is 
declared efficacious if an upper limit of 2-sided 90% confidence interval for the treatment 
effect is below zero.
Analyses for Continuous Endpoints

Descriptive statistics will provide estimates (with confidence intervals based on 
Wald’s method) of expected continuous outcome for each treatment group and 
difference between the expected values of outcomes in the treatment group of interest 
and reference treatment group. There will be no imputation of the missing data. This 
method will be applied to all continuous endpoints and all visits.

The constrained Longitudinal Data Analysis (eg, Fitzmaurice, Laird and Ware (2011) 
and Malincrodt and Lipkovich (2017)) is expected to provide improved estimates in 
comparison to the ones provided by the descriptive statistics. The modeling approach 
explicitly uses the equality of the expected baseline values of continuous outcomes at 
different treatment groups caused by randomization. The model will include baseline 
and post-baseline values as the response vector and will form fixed effects using 
treatment andvisit (see SAS code in Appendix 8). An unstructured 
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variance-covariance matrix will be allowed. If there are convergence issues, a 
compound-symmetry structure will be used. 

The longitudinal Mixed Model Repeated Measures (MMRM) modeling 
(eg, Fitzmaurice, Laird and Ware (2011)6 and Malincrodt and Lipkovich (2017)7) will 
provide an alternative and qualitatively similar estimates to the estimates provided by
the cLDA method. The MMRM model uses the change from baseline as an outcome
and the baseline value as a covariate.  The model includes treatment, baseline, 
treatment by visit and baseline by visit interactions for post-baseline visits as fixed 
effects. An unstructured variance-covariance matrix will be allowed. While the 
MMRM model is similar in spirit to the cLDA the estimates provided by these 
models may be slightly different and could be viewed as complementary.
 
 
 
 
Analyses for Binary Endpoints

Chan and Zhang method (1999)8 provides confidence intervals of proportions of 
response for each treatment group and difference between the response in the 
treatment group of interest and reference treatment group. The confidence intervals 
for one sample proportions will be based on Blyth Still Casella. The analysis will be 
applied to the ITT dataset without imputation and with non-responder imputation 
(NRI) of missing data. These analyses will be applied to all binary outcomes at all 
visits.

Bayesian emax modeling (as described in the Appendix 6) will be used for the analysis 
of dose dependence of the probability of remission based on total Mayo score. The 
analysis will be applied to the ITT dataset of observations at Week 8 with 
non-responder imputation.  Note that this analysis needs to be done separately for two 
datasets. The first dataset contains observations for pooled placebo data and 
observations for active treatment groups exposed to the PF-06651600 (JAK3 
inhibitor) and the second dataset contains pooled placebo data and PF-06700841 
(JAK1-TYK2 inhibitor).

The stratum-adjusted difference in probabilities of remission based on total Mayo 
score between the treatment group of interest and reference treatment group will be 
based on the approach described by Mehrotra and Railkar (2000).9 The 
non-responder imputation will be done before the analysis. The analysis will be 
applied to the ITT dataset of observations at Week 8. The definition of the strata will 
be given in the Section 8.4.1.
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Analyses for Categorical Endpoints
The frequency and percentage for each category will be presented.
Analyses for Time-to-Event Endpoints
None.
Methods to Manage Missing Data
Non-responder imputation (NRI) will be used for the missing binary data.  For the 
continuous outcomes observed data will be used for the analysis. The subjects with the data 
that have data missing due to COVID 19 will be removed from the analysis (eg, not included 
into numerator and denominator in the calculation of proportion of responders).  
8. ANALYSES AND SUMMARIES
Analyses of efficacy, PRO 
 endpoints will be based on the ITT population.  
Safety analyses will be based on the SAF population.
Treatment Groups
In the initial design of the trial subjects in the chronic therapy were randomized to the active 
and placebo group. Table 6 shows the possible sequences of treatment assignments.
Table 6.
Treatment Sequences
N
Compound
Dose in the induction 
period
Dose in the chronic 
therapy period
1
PF-06651600(JAK3)
200 mg
50 mg
2
PF-06651600(JAK3)
70 mg
50 mg
3
PF-06651600(JAK3)
20 mg 
50 mg
4
Placebo
Placebo 
50 mg
5
PF-06700841 (JAK1-TYK2)
60 mg
30 mg
6
PF-06700841 (JAK1-TYK2)
30 mg
30 mg
7
PF-06700841 (JAK1-TYK2)
10 mg
30 mg
8
Placebo
Placebo 
30 mg
9
PF-06651600(JAK3)
200 mg
Placebo
10
PF-06651600(JAK3)
70 mg
Placebo
11
PF-06651600(JAK3)
20 mg 
Placebo
12
Placebo
Placebo 
Placebo
13
PF-06700841 (JAK1-TYK2)
60 mg
Placebo
14
PF-06700841 (JAK1-TYK2)
30 mg
Placebo
15
PF-06700841 (JAK1-TYK2)
10 mg
Placebo
The total number of subjects (about 17) who were randomized to placebo in the chronic 
therapy period (sequences 9-15) is very small. 
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8.1.1. Induction Period
In the analysis of the data observed up to the end of the induction treatment there are 6 active 
treatment groups and pooled placebo groups.
Table 7.
Treatment Groups in the Induction Period (ITT data set)
N
Compound
Dose in the induction 
period
1
PF-06651600(JAK3)
200 mg
2
PF-06651600(JAK3)
70 mg
3
PF-06651600(JAK3)
20 mg 
4
PF-06700841 (JAK1-TYK2)
60 mg
5
PF-06700841 (JAK1-TYK2)
30 mg
6
PF-06700841 (JAK1-TYK2)
10 mg
7
Placebo (pooled)
Placebo (pooled)
The active treatment groups will be compared to the combined placebo group. 
8.1.2. Chronic Dosing Period
The descriptive summaries for all the 15 treatment groups corresponding to the treatment 
sequences presented in the Table 6 will be provided. A statistical modeling will be used for 
the analysis of the 8 groups corresponding to the treatment sequences that are assigned into 
the active treatment group during the chronic therapy period.
Efficacy, PRO and 
Analyses for the 
Induction and Chronic Therapy Period
8.2.1. Analyses for Induction Period Observations
The endpoints of interest and time of observations characterization are presented in the
Sections 3.1 and 3.3. All the efficacy, PRO 
 outcomes 
will be analyzed based on the ITT data set. The details of approaches are shown in the 
Tables 8 and 9.  
Table 8.
Analysis of Continuous Outcomes During Induction Period
Method
Imputation
Application
Descriptive Statistics
None
All endpoints and all visits
cLDA
None
All endpoints and all visits*
MMRM
None
All endpoints and all visits
*The cLDA analysis is not needed for changes from baseline.
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Table 9.
Analysis of Binary Outcomes During the Induction Period
Method
Imputation
Application
Descriptive Statistics
None
All endpoints and all visits
Chang and Zhang
NRI
All endpoints and all visits
Adjustment for strata
NRI
Remission, modified remission and 
endoscopic improvement at Week 8 
only
Bayesian emax modeling 
NRI
Remission based on Total Mayo
score at Week 8 only
The goal of the analysis adjusted for strata is to evaluate robustness of the main analysis. 
The stratification analysis will be performed for remission, modified remission and 
endoscopic improvement. The stratification analyses will be based on the baseline exposure
to the following treatments:
1. Anti-TNF: experienced/naïve.
2. Anti-integrin: experienced/naïve.
3. Anti-IL12/23 experienced/naïve.
4. Biologic: experienced/naïve.
5. Steroid exposure at baseline: y/n.
6. 5-ASA at baseline: y/n.
8.2.2. Primary Efficacy Analysis  
Primary efficacy analysis will be conducted based on total Mayo score at Week 8.  The 
Clda-based analysis will provide estimate of the treatment effect. The placebo-adjusted 
treatment effect for a particular group is defined as the difference between the expected 
values of total Mayo Scores (ie, expected total Mayo score at Week 8 in the active treatment 
group minus the expected total Mayo score at Week 8 in the placebo treatment group).  A 
successful treatment should decrease total Mayo score and therefore the desired treatment 
effect is negative.  The treatment arm is declared efficacious if an upper limit of 2-sided 
90% confidence interval for the treatment effect is below zero.
8.2.3. Analysis of Observations in the Chronic Therapy Period
The endpoints of interest and time of observations characterization are presented in the
Sections 3.2 and 3.3. All the efficacy, PRO 
 outcomes 
will be analyzed based on the modified ITT data set.
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Table 10.
Treatment Groups in the Induction and Chronic Period (mITT data set)
N
Compound
Dose in the induction 
chronic/periods
1
PF-06651600(JAK3)
200 mg/50 mg
2
PF-06651600(JAK3)
70 mg/50 mg
3
PF-06651600(JAK3)
20 mg/50 mg
4
Placebo
Placebo/50 mg
5
PF-06700841 (JAK1-TYK2)
60 mg/30 mg
6
PF-06700841 (JAK1-TYK2)
30 mg/30 mg
7
PF-06700841 (JAK1-TYK2)
10 mg/30 mg
8
Placebo
Placebo/30 mg
The details of approaches are shown in the Table 11 and Table 12.  
Table 11.
Analysis of Continuous Outcomes During Chronic Period (main)
Method
Imputation
Application
Descriptive Statistics
None
All endpoints and all visits
cLDA
None
All endpoints and all visits*
MMRM
None
All endpoints and all visits
*The cLDA analysis is not needed for changes from baseline.
Table 12.
Analysis of Binary Outcomes During the Chronic Period
Method
Imputation
Application
Descriptive Statistics
None
All endpoints and all visits
Chang and Zhang
NRI
All endpoints and all visits
 
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Baseline and Other Summaries and Analyses
8.5.1. Baseline Summaries
Demographics and medical history will be summarized by treatment group according to 
Pfizer standards.
8.5.2. Study Conduct and Participant Disposition
Subjects evaluation, disposition, discontinuation will be summarized, separately for induction 
and chronic dosing periods by treatment, according to Pfizer standards.
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8.5.3. Study Treatment Exposure
A summary of compliance and the number of doses received as well as the median total dose 
by visit and treatment group will be provided for each period.
The exposure to study drug will be summarized by the total number of days of dosing, and 
number and percentage of subjects who are compliant with the dosing regimen.
8.5.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
Safety Summaries and Analyses
Safety analysis will be based on the SAF analysis set.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs, vital signs and safety 
laboratory data will be reviewed and summarized on an ongoing basis during the study to 
evaluate the safety of subjects.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards.  Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage.  Continuous outcome (eg, blood pressure, pulse rate, etc) will 
be summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, ECGs and vital signs will also be summarized.  Subject listings will be 
produced for these safety endpoints accordingly.
8.6.1. Adverse Events
The safety data will be summarized in accordance with Pfizer Data Standards.  All safety 
data will be summarized descriptively through appropriate data tabulations, descriptive 
statistics, categorical summaries, and graphical presentations.  Safety endpoints for the study 
include:

Treatment-emergent AEs and SAEs;

Withdrawals from active treatment due to AEs;

Serious infections, defined as any infection (for eg, viral, bacterial, and fungal) 
requiring hospitalization or parenteral antimicrobials. This definition 
programmatically should be consistent with 7.2.8 in the protocol.
8.6.2. Laboratory Data
Laboratory data will be summarized, for induction period and chronic dosing period, in 
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8.6.3. Vital Signs
Vital signs including will be summarized for each period, in accordance with the Pfizer 
reporting standards.
8.6.4. Electrocardiograms
ECG data will be summarized for each period, in accordance with the Pfizer reporting 
standards.
8.6.5. Physical Examination
Physical examination data will be summarized for each period, in accordance with the Pfizer 
reporting standards.
9. INTERIM ANALYSES
At least one interim analysis (IA) for futility will be performed. The final number and timing 
of the IA(s) will be defined by the Sponsor, but a preliminarily one will be conducted 
approximately 6 months after the randomization of the first subject and/or after at least 
50% of the planned subjects, ie, approximately 160 subjects, have completed the 8 week 
induction period.
The interim analysis is based on the remission endpoint. The futility analysis of remission at 
Week 8 will be utilizing the Bayesian framework outlined in the interim analysis plan.  
Informative prior distribution model for the placebo arm, will be used for the interim analysis 
data.  The futility might be declared if the posterior probability of the treatment effect of the 
highest dose for each asset meets a specified criterion as outlined in the Interim analysis plan.
The interim analysis will not have an option to stop the trial early for efficacy.


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10. REFERENCES
 
 
 
 
 
 
 
 
6. Fitzmaurice GM, Laird NM, Ware JH (2011) Applied Longitudinal Data Analysis, 
Second Edition, Published by John Wiley and Sons, section 5.7, pp.156-162. 
7. Mallinckrodt C, Lipkovich I (2017) Analyzing Longitudinal Clinical Trials Data. A 
Practical Guide. CRC Press, pp. 100-110. 
8. Chan I, Zhang Z (1999) Test‐Based Exact Confidence Intervals for the Difference of 
Two Binomial Proportions Biometrics, Volume 55, Issue 4, pp 1202-1209.
9. Mehrotra DV and Railkar R (2000) Minimum risk weights for comparing treatments 
in strati"ed binomial trials, Statistics in Medicine, 19, pp. 811- 825.
CCI


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11. APPENDICES
Appendix 1 Mayo Scoring System for Assessment of Ulcerative Colitis Activity
and Outcomes Based on Subscores of Mayo Score
11.1.1. Subscores of Total Mayo Score
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  
Data are from Schroeder et al.
Stool frequency:
0 = Normal no. of stools for this subject
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
Subscore, 0 to 3
Rectal bleeding:
0 = No blood seen
1 = Streaks of blood with stools less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
Subscore, 0 to 3
Findings on endoscopy (END) :
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, mild friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration) Subscore, 0 to 3
The scoring denoted by the END incorporates evaluation of friability into the scoring. The 
END definition is used in all definitions of the outcomes used in the study.
Physician’s global assessment:
0 = Normal
1 = Mild disease
2 = Moderate disease
3 = Severe disease
Subscore, 0 to 3


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11.1.2. Endpoints Based on the Subscores of Total Mayo Score, Partial Mayo Score and
Modified Mayo Scores
Total Set of Subscores of Total Mayo Score consists of four subscores: 

Stool frequency (SFR);

Rectal bleeding (RBL);

Finding on endoscopy (END);

Physician’s global assessment (PGA).
Each of the subscores has value within 0-3 range where a higher value indicates a more 
severe disease symptom. The total score TM (t) at each time is calculated as the sum of the 
subscores so that:

TM(t)= SFR(t)+RBL(t)+END(t)+PGA(t).
The partial Mayo score PM(t) does not incorporate the endoscopy score so that:

PM(t)= SFR(t)+RBL(t)+ PGA(t).
The modified Mayo score MM (t) does not include PGA components so that:

MM(t)= SFR(t)+RBL(t)+END(t).
The following definitions of binary outcomes are based on the subscores of the total Mayo 
Score:
1. Remission: total Mayo score of 2 points or lower, with no individual subscore exceeding 
1 point and a rectal bleeding subscore of 0. The calculation of the remission status is 
based on the endoscopy score END (see Appendix 3). The friability status is 
incorporated into evaluation of END.  
2. Deep r emission: total Mayo score of 2 points or lower, with no individual subscore 
exceeding 1 point and a 0 on both endoscopic and rectal bleeding subscore.
3. Symptomatic remission: total Mayo score of 2 points or lower, with no individual 
subscore exceeding 1 point, and both rectal bleeding and stool frequency subscores of 0.
4. Endoscopic remission: endoscopic subscore of 0.
5. Clinical response: decrease from baseline in total Mayo score of at least 3 points and at 
least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 
1 point or absolute subscore for rectal bleeding of 0 or 1.
6. Endoscopic response: a decrease from baseline in the endoscopic subscore of 1 point or 
more.
7. Improvement in endoscopic appearance: Mayo endoscopic subscore of ≤1.


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These definitions are summarized in the Table 13.
Table 13.
Endpoints Based on the Subscores of Total Mayo Score
N
Outcome at time t
TM
SFR
RBL
END
PGA
1
Remission
TM(t) ≤2
SFR(t) ≤1
RBL(t)=0
END(t) ≤1
PGA (t) ≤1
  
 
4
Endoscopic 
remission
Any
Any 
Any 
END(t) =0
Any 
5
Clinical response 
TM(0)-TM(t) ≥3
and
100x(TM(0)-
TM(t)/TM(0)≥30%
Any 
RBL(0)-
RBL(t) ≥1 
or 
RBL(t) ≤1
Any 
Any 
6
Endoscopic
response
Any
Any 
Any 
END(0)-
END(t) ≥1
Any 
7
Improvement in 
endoscopic 
appearance
Any
Any 
Any 
END(t) ≤ 1
Any 
11.1.3. Endpoints Based on Partial Mayo and Modified Score
 
 
3. Remission based on modified Mayo Score: (Total Mayo score minus PGA): 
endoscopic subscore = 0 or 1 AND stool frequency = 0 or 1 AND rectal bleeding = 0.
4. Response based on modified Mayo Score (Total Mayo score minus PGA): Decrease 
from baseline in modified total Mayo score of at least 2 points and at least 30%, with 
an accompanying decrease in the subscore for rectal bleeding of at least 1 point or 
absolute subscore for rectal bleeding of 0 or 1.
C
C
I
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Appendix 2 Inflammatory Bowel Disease Questionnaire (IBDQ)
This questionnaire is designed to find out how you have been feeling during the last 2 weeks.
You will be asked about symptoms you have been having as a result of your inflammatory 
bowel disease, the way you have been feeling in general, and how your mood has been.
1. How frequent have your bowel movements been during the last two weeks?  Please 
indicate how frequent your bowel movements have been during the last two weeks by 
picking one of the options from:
A. BOWEL MOVEMENTS AS OR MORE FREQUENT THAN THEY HAVE 
EVER BEEN
B. EXTREMELY FREQUENT
C. VERY FREQUENT
D. MODERATE INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
E. SOME INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
F. SLIGHT INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
G. NORMAL, NO INCREASE IN FREQUENCY OF BOWEL MOVEMENTS
2. How often has the feeling of fatigue or of being tired and worn out been a problem for 
you during the last 2 weeks?  Please indicate how often the feeling of fatigue or tiredness 
has been a problem for you during the last 2 weeks by picking one of the options from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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3. How often during the last 2 weeks have you felt frustrated, impatient, or restless? Please 
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
4. How often during the last 2 weeks have you been unable to attend school or do your work 
because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
5. How much of the time during the last 2 weeks have your bowel movements been loose?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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6. How much energy have you had during the last 2 weeks?  Please choose an option from:
A. NO ENERGY AT ALL
B. VERY LITTLE ENERGY
C. A LITTLE ENERGY
D. SOME ENERGY
E. A MODERATE AMOUNT OF ENERGY
F. A LOT OF ENERGY
G. FULL OF ENERGY
7. How often during the last 2 weeks did you feel worried about the possibility of needing to 
have surgery because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
8. How often during the last 2 weeks have you had to delay or cancel a social engagement 
because of your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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9. How often during the last 2 weeks have you been troubled by cramps in your abdomen?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
10. How often during the last 2 weeks have you felt generally unwell?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
11. How often during the last 2 weeks have you been troubled because of fear of not finding 
a washroom?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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12. How much difficulty have you had, as a result of your bowel problems, doing leisure or 
sports activities you would have liked to have done during the last 2 weeks?  Please 
choose an option from:
A. A GREAT DEAL OF DIFFICULTY; ACTIVITIES MADE IMPOSSIBLE
B. A LOT OF DIFFICULTY
C. A FAIR BIT OF DIFFICULTY
D. SOME DIFFICULTY
E. A LITTLE DIFFICULTY
F. HARDLY ANY DIFFICULTY
G. NO DIFFICULTY; THE BOWEL PROBLEMS DID NOT LIMIT SPORTS OR 
LEISURE ACTIVITIES
13. How often during the last 2 weeks have you been troubled by pain in the abdomen?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
14. How often during the last 2 weeks have you had problems getting a good night’s sleep, or 
been troubled by waking up during the night?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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15. How often during the last 2 weeks have you felt depressed or discouraged?  Please 
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
16. How often during the last 2 weeks have you had to avoid attending events where there 
was no washroom close at hand?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
17. Overall, in the last 2 weeks, how much of a problem have you had with passing large 
amounts of gas?  Please choose an option from:
A. A MAJOR PROBLEM
B. A BIG PROBLEM
C. A SIGNIFICANT PROBLEM
D. SOME TROUBLE
E. A LITTLE TROUBLE
F. HARDLY ANY TROUBLE
G. NO TROUBLE


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18. Overall, in the last 2 weeks, how much a problem have you had maintaining or getting to, 
the weight you would like to be at?  Please choose an option from:
A. A MAJOR PROBLEM
B. A BIG PROBLEM
C. A SIGNIFICANT PROBLEM
D. SOME TROUBLE
E. A LITTLE TROUBLE
F. HARDLY ANY TROUBLE
G. NO TROUBLE
19. Many patients with bowel problems often have worries and anxieties related to their 
illness.  These include worries about getting cancer, worries about never feeling any 
better, and worries about having a relapse.  In general, how often during the last 2 weeks 
have you felt worried or anxious?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
20. How much of the time during the last 2 weeks have you been troubled by a feeling of 
abdominal bloating?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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21. How often during the last 2 weeks have you felt relaxed and free of tension?  Please 
choose an option from:
A. NONE OF THE TIME
B. A LITTLE OF THE TIME
C. SOME OF THE TIME
D. A GOOD BIT OF THE TIME
E. MOST OF THE TIME
F. ALMOST ALL OF THE TIME
G. ALL OF THE TIME
22. How much of the time during the last 2 weeks have you had a problem with rectal 
bleeding with your bowel movements?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
23. How much of the time during the last 2 weeks have you felt embarrassed as a result of 
your bowel problem?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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24. How much of the time during the last 2 weeks have you been troubled by a feeling of 
having to go to the bathroom even though your bowels were empty?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
25. How much of the time during the last 2 weeks have you felt tearful or upset?  Please 
choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
26. How much of the time during the last 2 weeks have you been troubled by accidental 
soiling of your underpants?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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27. How much of the time during the last 2 weeks have you felt angry as a result of your 
bowel problem? Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks? 
Please choose an option from:
A. NO SEX AS A RESULT OF BOWEL DISEASE
B. MAJOR LIMITATION AS A RESULT OF BOWEL DISEASE
C. MODERATE LIMITATION AS A RESULT OF BOWEL DISEASE
D. SOME LIMITATION AS A RESULT OF BOWEL DISEASE
E. A LITTLE LIMITATION AS A RESULT OF BOWEL DISEASE
F. HARDLY ANY LIMITATION AS A RESULT OF BOWEL DISEASE
G. NO LIMITATION AS A RESULT OF BOWEL DISEASE
29. How much of the time during the last 2 weeks have you been troubled by nausea or 
feeling sick to your stomach?  Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME


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30. How much of the time during the last 2 weeks have you felt irritable?  Please choose an 
option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
31. How often during the past 2 weeks have you felt a lack of understanding from others?  
Please choose an option from:
A. ALL OF THE TIME
B. MOST OF THE TIME
C. A GOOD BIT OF THE TIME
D. SOME OF THE TIME
E. A LITTLE OF THE TIME
F. HARDLY ANY OF THE TIME
G. NONE OF THE TIME
32. How satisfied, happy, or pleased have you been with your personal life during the past 
2 weeks?  Please choose one of the following options from:
A. VERY DISSATISFIED, UNHAPPY MOST OF THE TIME
B. GENERALLY DISSATISFIED, UNHAPPY
C. SOMEWHAT DISSATISFIED, UNHAPPY
D. GENERALLY SATISFIED, PLEASED
E. SATISFIED MOST OF THE TIME, HAPPY
F. VERY SATISFIED MOST OF THE TIME, HAPPY
G. EXTREMELY SATISFIED, COULD NOT HAVE BEEN MORE HAPPY OR 
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Appendix 3 Short Form -36, version 2, acute (SF-36)
Please answer every question.  Some questions may look like others, but each one is 
different.  Please take the time to read and answer each question carefully by filling in the 
bubble that best represents your response.


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Appendix 4. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and Visual 
Analog Scale (EQ-5D-3L & VAS)
Please note that the US-based weights will be used for the calculation of EQ-5D-3L & VAS 
as per the Pfizer data standards.
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (eg, work, study, housework, family or leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



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To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0.
We would like you to indicate on this scale how good or
bad your own health is today, in your opinion.  Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
9 0
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst
imaginable
health state
0
Best 
imaginable
health state
Example
Your own
health state
today


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CCI


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CCI


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CCI


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Appendix 7 Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety data that 
display/summarize by study visit.  For other endpoints (eg, ECG, vital signs), visit windows 
will be applied for summary statistics by study visits if required.
Visit Label
Target Day
Definition [Day window]
Screening
Days -42 to Day 0
Induction Period Weeks 0-8
Week 0
Day 1, Baseline
Day 1
Week 2
15
Days 2 to 21
Week 4
29
Days 22 to 42
Week 8
57
Days 43 to 70
Chronic Dosing Period Weeks 8-24
Week 12
85
Day 71 to 98
Week 16
113
Days 99 to 126
Week 20
141
Days 127 to 154
Week 24
169
Days 155 to 196
Week 32/Early Termination
225
Days 197 to 238
Follow-up
Week 36
253
Day 239 to -
For the lab values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls within 28 days before the start of the study dosing, then that data should 
be used for the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should 
be used.


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Appendix 8 Sample SAS Code for cLDA
Id = subject ID, avisit = visit, trtpn = treatment group, y=response  
data ds (keep= id avisitn week trtpn y treatment); 
set admy;
treatment = trtpn;
if week = 0 then treatment = 1;
run;
proc mixed data = ds;
class id week (ref='0') treatment (ref='1');
model y = week treatment*week / solution cl vciry ddfm = kr outpm=fit3;
repeated week / subject = id type = un R Rcorr;
lsmeans treatment*week /pdiff;
run;