Clinical trial NCT03395184
Conditions: Crohn's Disease
Sponsor: Pfizer
Start date: 2018-02-02; Completion date: 2023-10-19
Enrollment: 244 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this study are to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06651600 (200 mg for 8 weeks followed by 50 mg for 4 weeks) dosed once daily and PF-06700841 (60 mg for 12 weeks) dosed once daily during an induction period of 12 weeks, followed by an open label extension period at doses of 50 mg and 30 mg of PF 06651600 and PF 06700841, respectively, for 52 weeks.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: PF-06651600 Placebo intervention 2: PF-06651600 intervention 3: Placebo PF-06700841 intervention 4: PF-06700841
Intervention descriptions: intervention 1: 12 weeks, followed by PF-06651600, 50 mg once daily (QD) for 52 weeks intervention 2: 200 mg QD for 8 weeks, followed by 50 mg QD up to 56 weeks intervention 3: 12 weeks, followed by PF-06700841, 30 mg QD for 52 weeks intervention 4: 60 mg QD for 12 weeks followed by 30 mg QD for up to 52 weeks

Protocol documents:
Prot_000.pdf: 
PF-06651600, PF-06700841
B7981007
Final Protocol Amendment 5, 27 July 2021 
PFIZER CONFIDENTIAL
Page 1
A PHASE 2A, DOUBLE -BLIND, RANDOMIZED, PLACEBO -CONTROLLED, 
PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
ORAL PF-06651600 AND PF-06700841 AS INDUCTION AND OPEN LABEL 
EXTENSION TREATMENT IN SUBJECTS WITH MODERATE TO SEVERE
CROHN’S DISEASE
Investigational Product Number:
PF-06651600, PF-06700841
Investigational Product Name:
ritlecitinib, brepocitinib
United States (US) Investigational New 
Drug (IND) Number:
136177 PF-06651600
136173 PF-06700841
European Clinical Trials Database 
(EudraCT) Number:
2017-003359-43
Protocol Number:
B7981007
Phase:
2a
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 5
27 July 2021

Sections Summary, 1, 1.3.2, 1.4.2, 1.5.3, 
1.6, 1.6.2.2, 2.1, 3.1, 4.3, 5.4.1: updated to 
eliminate the PF-06700841 (brepocitinib)
active and corresponding (brepocitinib)
placebo arms. Section 9.1: updated to 
provide power for comparison of PF-
06651600 (ritlecitinib) to combined placebo
only. 
Rationale: A strategic decision on the part of 
the sponsor to prioritize future development 
of PF-06651600 (ritlecitinib), a JAK3/TEC 
inhibitor currently in development for a 
number of additional autoimmune diseases 
namely ulcerative colitis, alopecia areata and 
vitiligo. The decision to eliminate the 
PF-06700841 (brepocitinib) cohort from this 
study B7981007 is not due to any specific 
safety, efficacy or quality concerns that 
would negatively affect the overall 
benefit/risk for patients in this trial or in
other trials.

Protocol Summary, Section 2, 9.1 and 9.2.1 
and 9.2.2: updated to change the primary 
endpoint during induction from CMEI to 
SES-CD 50.
Rationale: to enable efficient comparison 
with contemporary and emerging trials in 
Crohn’s disease.

Section 1.5.1: updated the clinical overview 
summary.
Rationale: to align with the PF-06651600
(ritlecitinib) Dec 2020 Investigator’s 
Brochure.


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
Section 4.4.1: deleted “injectable” from 
contraception highly effective methods that 
are user dependent.
Rationale: to align with Pfizer May 2020 
protocol template updates.

Sections 7.2.5: added clarification when the 
investigator should assess CDAI parameters 
in the clinic. 
Rationale: procedure clarification. 

Appendix 3, CDAI sub-component 2 text: 
updated to replace “Sum of the number of 
liquid or very soft stools” with the “sum of 
the abdominal pain ratings”.
Also added “0 = none, 1 = mild, 
2 = moderate, 3 = severe”.
Rationale: text clarification.

Appendix 4 and section 7.1.10: added elbow 
circumference measurement. 
Rationale: to allow frame determination (for 
the weight item in Crohn’s Disease Activity 
Index [CDAI] for only randomized male 
subjects with height ≤163 cm (only 
1 subject at the time of this amendment). 
This does not impact the CDAI calculation 
for subjects with height >163 cm.

All protocol sections updated: added 
Investigational product names (brepocitinib, 
ritlecitinib) and replaced JAK3 with 
JAK3/TEC.
Rationale: Generic names assigned to 
Investigational products and PF-06651600 
(ritlecitinib) is a potent inhibitor of 
JAK3/TEC not JAK3.


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Amendment 4
20 November 2020

Title Page, Protocol Summary and 
Sections 1 and 1.1: Investigational product 
names (brepocitinib, ritlecitinib) added.
Rationale: Generic names assigned to 
Investigational products.

Schedule of Activities, Section 5.5, 
Section 6, Section 7 and Section 7.2.6: 
Reference to Appendix 12 regarding
Alternative Measures during Public 
Emergencies added.
Rationale: To provide guidance on study 
conduct during public emergencies 
including COVID-19.

Schedule of Activities Footnote “g”
(Induction Period), “d” (Open label period) 
and Section 7.1.10 are updated to clarify 
that breast and external genitalia 
examination as a part of physical exam are
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 and evaluated early.

Schedule of Activities footnote “bb”
(Induction Period), “p” (Open label period)
and Section 7.3.2 are updated to add the 
timing of IP-10 sample collection. 
Rationale: To clarify that IP-10 samples 
must be collected prior to dosing (PACL 
16 Oct 2019).

Section 1.4: Non-clinical safety studies 
updated to include rat fertility studies.
Rationale: To align with Investigator 
Brochure update.


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
Section 1.5: Summary of Clinical 
Experience with PF-06651600 and 
PF-06700841 is updated.
Rationale: To align with the updated 
Investigator Brochure.

Section 4.1 Inclusion criterion #6 and 
Section 5.9.2 are updated to reference 
Summary of corticosteroid Equivalents table 
in Appendix 11.
Rationale: To provide guidance on steroid 
conversions.

Section 4.2 and 7.1.5 are updated to allow
central lab to replace QuantiFERON®TB
Gold test (QFTG), QuantiFERON®TB Gold 
InTube test (QFTGIT) and TSPOT® TB test
with other acceptable QFT tests. 
Rationale: To permit central lab to replace 
the above tests with new ones (PACL 
16 Oct 2019).

Section 4.2, exclusion #37 is added to 
exclude subjects with history of thrombotic 
event(s) including DVT and known 
inherited conditions that predispose to 
hypercoagulability.
Rationale: Per regulatory request. 

Section 4.4.1 is revised to include “tubal 
ligation” to the list of highly effective 
methods of contraception.
Rationale: To clarify that tubal occlusion or 
tubal ligation are both highly effective 
methods of contraception.

Section 4.4.1 is updated to indicate that the 
protocol specified contraception language is 
in alignment with the recommendations 
received from European regulatory 
authorities for the B7981018 study.


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Rationale: To align with the Investigator 
Brochure update.

Section 6.4 is updated to replace Week “52” 
with Week “68”.
Rationale: To correct a discrepancy in the 
protocol (PACL 16 Oct 2019).

Section 6.5 is updated to add Lymphocytes
<800/mm3; <0.8 x 109/L and CK > 3x ULN
as additional labs to monitor.
Rationale: To ensure decreased 
lymphocytes <0.8 x 109 /L or increased CK 
>3x ULN are followed up in a timely 
manner and appropriate actions taken
(PACL 04 March 2020).

Section 6.5 is updated to clarify the 
definition of serious infections by 
referencing Section 7.1.7.
Rationale: To clarify definition of serious 
infections.

Section 6.5: Guidelines for monitoring and 
discontinuations are updated to include 
discontinuation of study drug for thrombotic 
or thromboembolic events.
Rationale: Per regulatory request. 

Section 7.2.2 is updated to clarify that in 
South Africa, 18 tissue samples will be 
collected instead of the protocol defined 
19 samples. 
Rationale: Due to the rejection of the Import 
License for the Fetal Bovine Serum required 
for the processing of 1 tissue sample for 
cytometry, this sample will not be collected 
for subjects in South Africa (PACL 17 May 
2019).


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
Section 7.1.11 is updated to indicate that 
audiogram results maybe reviewed by an 
external audiologist.
Rationale: To provide clarification on the 
review of the audiology results.

Sections 7.2.4 and 7.2.5 are updated to add 
the following sentence: for any visit that 
has an endoscopy, stool frequency (SF) and 
abdominal pain (AP) must be collected 
prior to administration of any bowel prep 
for endoscopy. 
Rationale: Clarification of text regarding 
endoscopies (PACL 16 Oct 2019).

Sections 7.3.5 and 7.3.6 are updated to 
clarify that during Screening period, 
collection of stool MUST be prior to 
administration of any bowel prep for 
endoscopy. 
Rationale: To clarify that during Screening,
stool samples must be collected prior to the 
start of diet change for bowel preparation 
and endoscopy PACL 11 Nov 2018).  

Section 9.1: The power has been updated.
Rationale: The power was updated to take 
into account the frequentist rule for futility 
and also incorporation of the frequentist 
stopping rule for efficacy.

Section 9.2.1: The alpha adjustment 
statement has been removed.
There is no alpha adjustment for primary 
and secondary endpoints described in the 
SAP, hence this statement has been 
removed. 

Section 9.6: Interim Analysis section has 
been updated to incorporate possibility of 
additional interims. 


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Rationale: The sponsor would like to have 
the possibility of additional interims 
including the possibility of stopping the 
study early due to efficacy.

Section 9.7 is updated to include an internal 
review committee (IRC) to assess the 
interim analyses.
Rationale: They will be assessing the IA. 

Section 9.8: added adjudication committees 
for opportunistic infections, cardiovascular 
and neuroaudiometry events.
Rationale: three adjudication committees
added based on known mechanism of 
action of JAK inhibitors.

Appendix 11 is added to include steroid 
conversion table.
Rationale: to provide guidance on steroid 
conversions.

Appendix 12 is added to include Alternative 
Measures During Public Emergencies.
Rationale: To provide guidance on study 
conduct during public emergencies 
including COVID-19.

Appendix 1 is updated to include the 
abbreviation for brainstem auditory evoked 
potential (BAEP).

Section 16 References are updated to add a 
new reference.
Amendment 3
24 August 2018

Protocol summary, Section 1.2, 
Section 1.3.1, Section 1.4.1, Section 1.5.1.1, 
Section 1.5.2, Section 1.5.3.1, 
Section 1.5.3.2 and Section 1.6.3 are being 
updated to align with PF0665100
Investigator Brochure updated in 2018.


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
SoA footnote “n” is being updated to align 
the OLE 0.5 hr post dose PK sample 
collection window with the induction phase 
0.5 hr post dose PK collection window 
(±15 min).

Section 4.2, exclusion criteria 11 is being 
updated to clarify that subjects with 
adenomatous polyps finding at screening 
will be eligible if the polyps have been 
completely removed and subjects are free of 
polyps at baseline.

Section 4.2, Exclusion criterion 14 and 
Section 7.1.6 Screening for Clostridium 
Difficile are revised to permit treatment and 
re-testing or re-screening of subjects and to 
allow subjects with appropriately resolved 
infection to enter the study. 

Section 4.2, Exclusion criterion 16 is 
revised to allow subjects adequately treated 
for latent and/or active tuberculosis 
infection to enter the study.

Section 4.2, Exclusion criterion 33 is 
revised to lower the eGFR requirement from 
<80 mL/min/1.73m2 to <60 mL/min/1.73m2
because there is no increased risk to include 
subjects with eGFR >60 and <80 based on 
the available nonclinical and clinical data to 
date.  The exclusion of subjects with serum 
creatinine levels > ULN has also been 
removed form Exclusion criterion 33. 
Reference to subjects with serum creatinine 
> ULN has also been removed from 
Section 7.1.2 Creatinine and Cystatin C and 
Section 8.4.3 Potential Cases of Decreased 
eGFR.

Section 4.2, Exclusion criterion 33 is 
revised to correct that “ALT or AST 
≥1.5 times > ULN” not “ALT and AST 
≥1.5 times ULN “will be exclusionary. 


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
Section 4.4.1 and Exclusion criterion 27 are 
being updated to align with the Clinical 
Trials Facilitation Group (CTFG) European 
guidance of the Heads of Medicines 
Agencies (HMA) and TransCelerate 
initiative across Pharma.

Section 5.9.3, is updated to clarify the
timeframe in which the listed medications 
are not permitted for those for which the 
information is not already stated.

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.
Amendment 2
15 March 2018

The SOA is revised to reflect the wrist 
measurement at the screening visit that will 
be used to determine frame size as it relates 
to question 8 of the CDAI.

To address the VHP (Voluntary 
Harmonization Procedure) request, the 
protocol summary, Section 2.2, and 
Section 9.5.2 are updated to add a secondary 
objective and endpoint to assess the 
proportion of patients who maintain 
response after the induction period. 

To address the VHP request, Section 4.1 is 
updated to clarify that inclusion criterion 
number 5 should be met only after the usual 
clinical practice in each center has been 
fulfilled, which may involve administration 
of more than one line of previous treatment.

To address the VHP request, Section 4.2 is 
updated to exclude subjects with heart 
failure (NYHA III, NYHA IV).

To address the VHP request, Section 5.9.2 is 
updated to clarify that subjects requiring a 


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second step up in corticosteroid usage will 
be required to discontinue the study.

Section 4.1, 4.2 and 5.9.3 are revised to 
correct a discrepancy and remove 
Golimumab from the list of antiTNF
inhibitors, as Golimumab is not approved 
for Crohn’s disease.

To address the VHP request, Section 4.4.1 is 
updated to add that male subject must 
refrain from donating sperm during the 
study and for 90 days after the last dose of 
investigational product. 

To address the VHP request, Section 5.9.2 is 
updated to add that subjects requiring a 
second step up in corticosteroid usage will 
be required to discontinue the study.

Section 7.2.5 is updated to correct a 
discrepancy that the wrist measurement 
value will be recorded on the appropriate 
CRF page instead of the source document. 

Section 7.2.5 is revised to clarify that Hct 
test will only be performed by the central 
and not the local lab.

To address VHP request, Section 9.1 is 
revised to clarify the sample size rationale.

Section 9.2.1 is revised to update the term 
remission to CMEI response.
Amendment 1
27 November 2017

(EudraCT) Number added.

To address the FDA request for additional 
auditory testing, the induction and OLE 
SOAs are revised to add an auditory testing 
at Week 48 and to shift the auditory testing 
from Week 12 to Week 16. These changes 
together result in audiograms being 


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conducted at screening and at Weeks 16, 32, 
48, 64 and Early Termination.

The induction and OLE SOAs are revised to 
add weight measurements at baseline, 
Weeks 2, 4, 8, 16 and 32 to facilitate CDAI 
calculation (which is also collected at these 
time points).

The OLE SOA is being updated to add ECG 
monitoring at Weeks 32, 48 and 64.  This 
update is to ensure subject safety during the 
study.

The induction SOA is being revised to 
clarify that PGIS will be collected 
continuously for 12 weeks throughout the 
induction phase (including at Week 2). 

The induction SOA, footnote j, is being 
revised to clarify that fasting lipid profile 
will be assessed from Baseline visit. 

The OLE SOA, footnote m, is being revised 
to clarify that SF and AP will be collected 
continuously for 12 weeks throughout the 
induction phase.

The OLE SOA, footnote n, is being revised 
to add a window of ±30 min to post dose PK 
sample collection.

The induction and OLE SOAs are being 
updated to add: Review and report to the 
Sponsor of any incidental endoscopic 
findings reported by Robarts that are 
deemed clinically significatby the PI/sites. 

Section 2.2 and protocol summary are being 
updated to correct a discrepancy that during 
the OLE period the proportion of subjects 
achieving IBDQ symptom domain is being 
analyzed at Weeks 16, 32 and 64 instead of 
Weeks 4, 8 and 12.


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
Section 4.1 is being revised to correct a 
discrepancy and remove Golimumab from 
the list of antiTNF inhibitors, as Golimumab 
is not approved for Crohn’s disease.

Section 4.2, exclusion criteria 33 and 
Section 7.1.1 are being updated to add the 
exclusion of subjects with CK >3 x ULN 
and positive urine myoglobin. This update 
is to ensure subject safety is fully evaluated 
prior to study entry.

Section 4.3 is being updated to clarify that 
the baseline SES CD stratification factor 
reflects the isolated ileal disease as a 
separate strata.

Section 4.4, Lifestyle Requirements, is 
being updated to add the requirement for 
subjects to avoid excessive exercise during 
the study, and maintain adequate hydration, 
if possible. This update is to ensure subject 
safety during the study.

Section 4.4.1 is being revised to clarify that 
male or female condom used with a separate 
spermicide product is not appropriate or 
accepted in the EU Union.

Section 5.9.2 is being revised to clarify that 
steroid tapering is allowed in the OLE 
period.

Section 7.1.4 and the induction SOA are 
being 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). This requirement is not 
required by any EU or FDA guidance and 
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.


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
Section 7.2.1, induction SOA (footnote t) 
and OLE SOA (footnote l) are being revised 
to clarify that ET colonoscopy should be 
performed unless the previous colonoscopy 
is less than 8 weeks prior.

Section 7.2.3 is being revised to correct a 
discrepancy that study drug administration 
will not be reported in the subject Diary and 
will not be reconciled against the drug 
accountability inventory form.
Original protocol
26 July 2017
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 
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................21
LIST OF FIGURES .................................................................................................................21
APPENDICES .........................................................................................................................21
PROTOCOL SUMMARY.......................................................................................................23
SCHEDULE OF ACTIVITIES (INDUCTION PERIOD) ......................................................32
SCHEDULE OF ACTIVITIES (OPEN LABEL EXTENSION PERIOD).............................36
1. INTRODUCTION ...............................................................................................................39
1.1. Mechanism of Action/Indication.............................................................................39
1.2. Background and Rationale ......................................................................................39
1.3. Non-Clinical Pharmacokinetics and Metabolism....................................................41
1.3.1. Non-Clinical Pharmacokinetics and Metabolism of PF-06651600 
(ritlecitinib) ......................................................................................................41
1.3.2. Non-Clinical Pharmacokinetics and Metabolism of PF-06700841 
(brepocitinib)....................................................................................................43
1.4. Non-Clinical Safety Studies....................................................................................43
1.4.1. Non-Clinical Safety Studies with PF-06651600 (ritlecitinib) ....................43
1.4.2. Non-Clinical Safety Studies with PF-06700841 (brepocitinib)..................44
1.5. Summary of Clinical Experience ............................................................................45
1.5.1. Summary of Clinical Experience with PF-06651600 (ritlecitinib).............45
1.5.1.1. Summary of Clinical Safety of PF-06651600 (ritlecitinib).......46
1.5.1.2. Study B7981003........................................................................48
1.5.1.3. Study B7981008........................................................................49
1.5.1.4. Study B7981016........................................................................51
1.5.1.5. Study B7981017........................................................................52
1.5.1.6. Study B7981018........................................................................52
1.5.1.7. Study B7981021........................................................................53
1.5.1.8. Study B7981022........................................................................53
1.5.1.9. Study B7981023........................................................................53
1.5.1.10. Study B7981024......................................................................54
1.5.1.11. Study B7981035......................................................................55
1.5.1.12. Study B7981006......................................................................55


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1.5.1.13. Study B7931005......................................................................57
1.5.1.14. Study B7981005......................................................................58
1.5.1.15. Study B7981015......................................................................59
1.5.1.16. Study B7981019......................................................................60
1.5.1.17. Study B7981032......................................................................61
1.5.2. Pharmacokinetics of PF-06651600 (ritlecitinib) ........................................62
1.5.3. Summary of Clinical Experience with PF-06700841 (brepocitinib)..........65
1.5.3.1. Summary of Clinical Safety of PF-06700841 
(brepocitinib) .....................................................................................65
1.5.3.2. Pharmacokinetics of PF-06700841 (brepocitinib) ....................81
1.6. Rationale..................................................................................................................83
1.6.1. Study Rationale...........................................................................................83
1.6.2. Dose Rationale............................................................................................85
1.6.2.1. PF-06651600 (ritlecitinib) Dose Rationale ...............................85
1.6.2.2. PF-06700841 (Brepocitinib) Dose Rationale............................86
1.6.3. Summary of Benefits and Risks .................................................................87
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................89
2.1. Objectives and Endpoints during the Induction Period...........................................89
2.2. Objectives and Endpoints during the Open Label Extension Period ......................91
3. STUDY DESIGN.................................................................................................................93
3.1. Study Overview.......................................................................................................93
3.2. Duration of Subject Participation............................................................................95
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................96
4.1. Inclusion Criteria.....................................................................................................96
4.2. Exclusion Criteria....................................................................................................98
4.3. Randomization Criteria .........................................................................................104
4.4. Lifestyle Requirements .........................................................................................105
4.4.1. Contraception............................................................................................105
4.4.2. Dietary Restriction....................................................................................106
4.5. Sponsor’s Qualified Medical Personnel................................................................107
5. STUDY TREATMENTS...................................................................................................107
5.1. Allocation to Treatment ........................................................................................107


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5.2. Breaking the Blind ................................................................................................108
5.3. Subject Compliance...............................................................................................108
5.4. Investigational Product Supplies...........................................................................108
5.4.1. Dosage Form(s) and Packaging................................................................108
5.5. Preparation and Dispensing...................................................................................109
5.6. Administration.......................................................................................................109
5.7. Investigational Product Storage ............................................................................110
5.8. Investigational Product Accountability.................................................................110
5.8.1. Destruction of Investigational Product Supplies ......................................111
5.9. Concomitant Treatment(s).....................................................................................111
5.9.1. Oral Corticosteroids..................................................................................111
5.9.2. Permitted Medications..............................................................................111
5.9.3. Prohibited Medications.............................................................................112
5.9.4. Vaccinations .............................................................................................113
5.10. Rescue Medication ..............................................................................................114
6. STUDY PROCEDURES ...................................................................................................114
6.1. Screening...............................................................................................................115
6.2. Induction Period ....................................................................................................115
6.3. Open Label Extension Period................................................................................115
6.3.1. Follow-up Contact ....................................................................................116
6.4. Subject Withdrawal...............................................................................................116
6.5. Guidelines for Monitoring and Discontinuations..................................................117
7. ASSESSMENTS................................................................................................................119
7.1. Safety.....................................................................................................................120
7.1.1. Clinical Laboratory Tests .........................................................................120
7.1.2. Creatinine and Cystatin C.........................................................................121
7.1.3. Estimated Glomerular Filtration Rate.......................................................121
7.1.4. Pregnancy Testing ....................................................................................121
7.1.5. Interferon Gamma Release Assay Tuberculin Test..................................122
7.1.6. Screening for Clostridium Difficile ..........................................................122
7.1.7. Infections ..................................................................................................123
7.1.8. Viral Surveillance .....................................................................................124


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7.1.9. Vital Signs (Blood Pressure, Pulse Rate, and Temperature) ....................124
7.1.10. Medical History, Physical Examination, Height and Weight.................124
7.1.10.1. Dermatology/Skin .................................................................125
7.1.11. Audiogram ..............................................................................................127
7.1.12. Electrocardiogram...................................................................................127
7.1.13. Chest Radiograph....................................................................................128
7.2. Diagnostic and Efficacy Assessments...................................................................128
7.2.1. Endoscopy.................................................................................................128
7.2.2. Biopsy Collection from Ileocolonic Mucosa for Histology, RNA, 
Epigenetic, Tissue microbiome and Tissue Protein.......................................128
7.2.3. Subject eDiary ..........................................................................................129
7.2.4. Stool Frequency (SF) and Abdominal Pain (AP) .....................................130
7.2.5. Crohn’s Disease Activity Index (CDAI) ..................................................130
7.2.6. Patient Reported Outcomes (PRO) for Health Outcomes Assessment ....131
7.2.6.1. Inflammatory Bowel Disease Questionnaire (IBDQ) .............131
7.2.6.2. Short Form – 36, Version 2, Acute (SF-36)............................132
7.2.6.3. Euro Quality of Life Questionnaire 5 Dimensions 3 
Levels and Visual Analog Scale (EQ-5D-3L & VAS)....................132
7.2.6.4. Patient Global Impression of Severity (PGIS) ........................132
7.3. Pharmacodynamics................................................................................................133
7.3.1. High-Sensitivity C-Reactive Protein (hsCRP)..........................................133
7.3.2. Interferon Gamma-Induced Protein 10 (IP-10) ........................................133
7.3.3. FACS Analysis (TBNK Cells)..................................................................133
7.3.4. Exploratory Serum Protein Biomarkers....................................................133
7.3.5. Fecal Calprotectin.....................................................................................133
7.3.6. Stool Samples for Microbiome Analysis..................................................134
7.4. Pharmacokinetics ..................................................................................................134
7.4.1. Plasma for PK Analysis of Investigational Product .................................134
7.4.2. Shipment of Plasma Samples for PK Analysis.........................................135
7.5. Pharmacogenomics................................................................................................135
7.5.1. Gene Expression Analysis ........................................................................135
7.6. Banked Biospecimens ...........................................................................................135
7.6.1. Additional Research..................................................................................136


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8. ADVERSE EVENT REPORTING....................................................................................137
8.1. Requirements.........................................................................................................137
8.1.1. Additional Details On Recording Adverse Events on the CRF................138
8.1.2. Eliciting Adverse Event Information........................................................138
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal Section) .........................................................................138
8.1.4. Time Period for Collecting AE/SAE Information....................................138
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................139
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............139
8.1.5. Causality Assessment ...............................................................................139
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................139
8.2. Definitions.............................................................................................................140
8.2.1. Adverse Events .........................................................................................140
8.2.2. Abnormal Test Findings ...........................................................................140
8.2.3. Serious Adverse Events ............................................................................141
8.2.4. Hospitalization..........................................................................................141
8.3. Severity Assessment..............................................................................................143
8.4. Special Situations ..................................................................................................143
8.4.1. Protocol-Specified Serious Adverse Events.............................................143
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................143
8.4.3. Potential Cases of Decreased eGFR .........................................................145
8.4.4. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................146
8.4.4.1. Exposure During Pregnancy....................................................146
8.4.4.2. Exposure During Breastfeeding ..............................................147
8.4.4.3. Occupational Exposure ...........................................................147
8.4.5. Medication Errors .....................................................................................147
8.4.5.1. Medication Errors....................................................................148
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................148
9.1. Sample Size Determination...................................................................................148
9.2. Efficacy Analysis During Induction......................................................................149
9.2.1. Analysis of the Primary Endpoint During Induction................................149
9.2.2. Analysis of Secondary Endpoints During Induction ................................150


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9.3. Analysis of Other Endpoints During Induction.....................................................150
9.3.1. Pharmacokinetic Analysis ........................................................................150
9.3.2. PK/PD Unblinding Plan............................................................................150
9.3.3. Analysis of Exploratory Biomarkers ........................................................151
9.3.4. Unblinding for Biomarkers.......................................................................151
9.3.5. Analysis of Health Outcomes Endpoints..................................................151
9.4. Safety Analysis During Induction.........................................................................151
9.5. Analysis During the Open Label Extension Period ..............................................152
9.5.1. Secondary Efficacy Analysis....................................................................152
9.5.2. Exploratory Efficacy Analysis..................................................................152
9.5.3. Pharmacokinetic Analysis ........................................................................152
9.5.4. Exploratory Pharmacodynamic Analysis .................................................153
9.5.5. Safety Analysis .........................................................................................153
9.6. Interim Analysis ....................................................................................................153
9.7. Data Monitoring Committee .................................................................................154
9.8. Safety Adjudication Committees ..........................................................................154
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................154
11. DATA HANDLING AND RECORD KEEPING ...........................................................155
11.1. Case Report Forms/Electronic Data Record .......................................................155
11.2. Record Retention.................................................................................................156
12. ETHICS............................................................................................................................156
12.1. Institutional Review Board/Ethics Committee....................................................156
12.2. Ethical Conduct of the Study ..............................................................................156
12.3. Subject Information and Consent........................................................................157
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................158
13. DEFINITION OF END OF TRIAL.................................................................................158
13.1. End of Trial in a Member State...........................................................................158
13.2. End of Trial in All Other Participating Countries...............................................158
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................158
15. PUBLICATION OF STUDY RESULTS........................................................................158
15.1. Communication of Results by Pfizer ..................................................................158


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15.2. Publications by Investigators ..............................................................................159
16. REFERENCES ................................................................................................................161
LIST OF TABLES
Table 1.
Summary of Plasma PF-06651600 (ritlecitinib) Pharmacokinetic 
Parameters Following Single Oral Doses, Study B7981001....................62
Table 2.
Summary of Steady State Plasma and Urine PF-06651600 
(ritlecitinib) Pharmacokinetic Parameters Following Multiple Dose 
Administration for 14 Days, Study B7981001 .........................................63
Table 3.
Summary of Plasma PF-06700841 (brepocitinib) Pharmacokinetic 
Parameters Following Single Oral Doses, Study B7931001....................81
Table 4.
Summary of Steady State Plasma and Urine PF-06700841 
(brepocitinib) Pharmacokinetic Parameters Following Multiple 
Dose Administration (10 Days), Study B7931001...................................82
Table 5.
Summary of Plasma Steady State PF-06700841 (brepocitinib)
Pharmacokinetic Parameters Following Multiple Dose 
Administration (28 Days) in Psoriasis Subjects, Study B7931001 ..........83
Table 6.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06651600 (ritlecitinib) Pharmacokinetic and Pharmacodynamic 
Parameters During the Induction and Chronic Periods of Multiple 
Dose Administration.................................................................................86
Table 7.
Summary of Predicted Steady State Total Plasma PF-06700841 
(brepocitinib) Pharmacokinetic and Pharmacodynamic Parameters ........87
Table 8.
Management of Dermatological Events .................................................126
LIST OF FIGURES
Figure 1.
Original Study Schematic.........................................................................95
Figure 2.
Study Schematic Post Implementation of Protocol Amendment 5 ..........95
APPENDICES
Appendix 1. Abbreviations....................................................................................................163
Appendix 2. Simplified Endoscopic Activity Score for Crohn’s Disease (SES-CD)............169
Appendix 3. Crohn’s Disease Activity Index17......................................................................170
Appendix 4. Frame Determination (for the Crohn’s Disease Activity Index [CDAI]) .........174
Appendix 5. Inflammatory Bowel Disease Questionnaire (IBDQ).......................................175


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Appendix 6. Short Form -36, version 2, acute (SF-36) .........................................................186
Appendix 7. Euro Quality of Life Questionnaire 5 Dimensions 3 Levels and Visual 
Analog Scale (EQ-5D-3L & VAS).........................................................192
Appendix 8. Patient Global Impression of Severity (PGIS)..................................................194
Appendix 9. Common Terminology Criteria for Adverse Events v4.0 
(CTCAE)-Dermatology..........................................................................195
Appendix 10. Prohibited Concomitant Medications..............................................................196
Appendix 11. Summary of Corticosteroid Equivalents.........................................................198
Appendix 12. Alternative Measures During Public Emergencies .........................................199
Appendix 12.1. Eligibility......................................................................................................199
Appendix 12.2. TeleHealth Visits..........................................................................................199
Appendix 12.3. Alternative Facilities for Safety Assessments..............................................200
Appendix 12.3.1. Laboratory Testing....................................................................................200
Appendix 12.6. Adverse Events and Serious Adverse Events...............................................201
Appendix 12.7. Patient Reported Outcomes (PROs).............................................................201


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PROTOCOL SUMMARY
Background and Rationale:
The Janus kinase (JAK) family of kinases mediates 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 to the 
nucleus where they bind to specific gene promoters and activate transcription of a range of 
target genes.
PF-06651600 (ritlecitinib) is a potent, selective, covalent inhibitor of JAK3/TEC.  It is an 
orally bioavailable small molecule that selectively inhibits JAK3/TEC by irreversibly 
blocking the adenosine triphosphate (ATP) binding site, without significantly inhibiting the 
other three JAK isoforms (JAK1, JAK2, and tyrosine-protein kinase 2 (TYK2)).  
PF-06651600 (ritlecitinib) also inhibits irreversibly the tyrosine kinase expressed in 
hepatocellular carcinoma (TEC) kinase family (BTK, bone marrow tyrosine kinase on 
chromosome X (BMX), ITK (IL-2 inducible T-cell kinase), TEC, and tyrosine kinase 
expressed in T cells (TXK)), with high selectivity over the broader kinome. The selective 
inhibition of JAK3/TEC will lead to modulation of -common chain cytokine pathways, such 
as interleukin-7 (IL-7), IL-9, IL-15 and IL-21, which have been implicated in the 
pathophysiology of Crohn’s disease (CD).  Furthermore, in vivo PF-06651600 (ritlecitinib)
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 gastrointestinal
tract.  Finally, TEC kinase inhibition will impact CD8+ T and natural killer (NK) cells 
cytotoxic functions, which play a role in the pathogenesis of intestinal bowel disorder (IBD).
Taken together, it is hypothesized that selective inhibition of JAK3/TEC could be efficacious 
in treatment of CD.
PF-06700841 (brepocitinib) is an orally bioavailable, small molecule, potent dual inhibitor of
human 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 such as IFN and IL-17 through upstream 
inhibition of the IL-12/T helper 1 (Th1) and IL-23/Th17 pathways.  Taken together, it is 
hypothesized that selective and combined inhibition of TYK2 and JAK1 could be efficacious 
in treatment of CD.
Both PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) are under development as 
induction and long-term therapy for the treatment of CD.


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The original objectives of this study were to evaluate the efficacy [(based on clinically 
meaningful endoscopic improvement (reduction of ≥3 points from baseline in SES-CD score)
at Week 12 as assessed by central reading], safety, tolerability, PK, and PD of 200 mg for 
8 weeks followed by 50 mg for 4 weeks of PF-06651600 (ritlecitinib) dosed once daily and 
60 mg of PF-06700841 (brepocitinib) dosed once daily during an induction period of 
12 weeks, followed by an open label extension period at doses of 50 mg and 30 mg of 
PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib), respectively, for 52 weeks.  
Amendment 5 of Protocol B7981007 revises the original design to eliminate the 
PF-06700841 (brepocitinib) and placebo arms and to change the primary endpoint during 
induction from CMEI to SES-CD 50 (to enable efficient comparison with contemporary and 
emerging trials in Crohn’s disease). Therefore, upon approval of Amendment 5 by regional 
Regulatory Authorities and Ethics Committees, Protocol B7981007 will be conducted as a 
Phase 2a, randomized, double-blind, placebo-controlled, parallel group study focused on the 
evaluation of the efficacy and safety profile of the PF-06651600 (ritlecitinib) in subjects with 
moderate to severe active CD. All eligible participants that have been randomized to 
PF-06700841 (brepocitinib)/PF-06700841 (brepocitinib) placebo or currently actively 
receiving PF-06700841 (brepocitinib)/PF-06700841 (brepocitinib) placebo under previous 
protocol amendments will continue to receive PF 06700841 (brepocitinib) through to 
completion. This study modification is solely a strategic decision on the part of the sponsor 
to prioritize future development of PF-06651600 (ritlecitinib), a JAK3/TEC inhibitor 
currently in development for a of number of additional autoimmune diseases namely 
ulcerative colitis, alopecia areata and vitiligo. The decision to eliminate the PF-06700841 
(brepocitinib) cohort from this study B7981007 is not due to any specific safety, efficacy or 
quality concerns that would negatively affect the overall benefit/risk for patients in this trial 
or in other trials.
OBJECTIVES AND ENDPOINTS
Objectives and Endpoints during the Induction Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo at Week 12 in subjects with 
moderate to severe CD.

Proportion of subjects achieving SES-CD 50 
(≥50% reduction in SES-CD from baseline) at 
Week 12.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 (ritlecitinib) and PF-06700841
(brepocitinib) compared to placebo in subjects 
with moderate to severe CD over 12 weeks.

Incidence and severity of laboratory 
abnormalities, vital signs, 12lead ECG, adverse 
events, serious adverse events and withdrawals 
due to adverse events.

Incidence of serious infections.

To evaluate the efficacy of PF-06651600
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo during induction of 

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 


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additional endoscopic endpoints in subjects with 
moderate to severe CD.
(reduction of ≥3 points from baseline in 
SES-CD score) at Week 12.

Mean change from baseline in SES-CD score 
at Week 12.

Proportion of subjects achieving SES-CD 25 
(≥25% reduction in SES-CD from baseline) at 
Week 12.

Proportion of subjects achieving endoscopic 
remission (SES-CD ≤2) at Week 12.

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 12.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):

To evaluate the effect of PF-06651600
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on outcomes based on 
additional clinical criteria.

Proportion of subjects achieving clinical 
response and remission using stool frequency 
(SF), and abdominal pain (AP) measures at 
Weeks 2, 4, 6, 8, 10 and 12.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD
and clinical remission by SF and AP) at 
Week 12.

Proportion of subjects with a Crohn’s Disease 
Activity Index (CDAI)100 response (defined 
by a decrease in CDAI score of at least 
100 points from baseline) and proportion of 
subjects who are remitters (defined as
CDAI <150) at Weeks 2, 4, 8 and 12.

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, 8, 
and 12.

The proportion of subjects with IBDQ total 
score ≥170 at Weeks 4, 8, and 12.

The proportion of subjects with ≥16 point 
increase in IBDQ total score from baseline at 
Weeks 4, 8, and 12.

Proportion of subjects achieving IBDQ 
symptom domain response at Weeks 4, 8, 
and 12. 

The scores and change from baseline in Euro 
Quality of Life Questionnaire 5 Dimensions 3 


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Levels (EQ5D3L) + Visual Analog Scale 
(VAS) at Weeks 4, 8, and 12.

The scores and change from baseline in Short 
Form-36, Version 2 Acute (SF-36 v2): physical
and mental component summary scores (PCS 
& MCS), and 8 domain scores at Weeks 4, 8, 
and 12.

Mean change from baseline in Patient Global 
Impression of Severity (PGIS) score at 
Weeks 4, 8 and 12.

To evaluate the effect of PF06651600
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on histopathology score.

Change from baseline in Global Histologic 
Disease Activity (GHAS) score at Week 12.

Proportion of subjects achieving histologic 
remission at Week 12 (defined as GHAS
score ≤4).

To assess the effect of PF-06651600 (ritlecitinib)
and PF-06700841 (brepocitinib) compared to 
placebo on disease and mechanistic biomarkers 
over time.

Change from baseline in serum high sensitivity 
C-reactive protein (hsCRP) levels over time.

Change from baseline in fecal calprotectin
over time.

Change from baseline in serum interferon 
gamma-induced protein 10 (IP-10) levels over 
time.

Change from baseline in (B-cell lymphoma 2)
BCL-2 gene expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and T, B and NK 
(TBNK) cells.

To describe the PK of PF-06651600 (ritlecitinib)
and PF-06700841 (brepocitinib) compared to 
placebo in subjects with moderate to severe CD.

PF-06651600 (ritlecitinib) concentrations at 
Weeks 2, 4, 8 and 12.

PF-06700841 (brepocitinib) concentrations at 
Weeks 2, 4, 8 and 12.

To collect non-banked samples (eg, intestinal 
biopsies, stool for microbiome analysis, serum and 
plasma for analysis of proteins and a whole blood 
tube for RNA analysis) for exploratory research, 
unless prohibited by local regulations or ethics 
committee decision. 

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples
unless prohibited by local regulations or ethics 
committee decision. 

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section.


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Objectives and Endpoints during the Open Label Extension Period
Primary Objective(s):
Primary Endpoint(s):

To assess the safety and tolerability of 
PF-06651600 (ritlecitinib) and PF-06700841
(brepocitinib) therapy during open label 
extension period for subjects with moderate to 
severe CD.

Incidence and severity of laboratory 
abnormalities, vital signs, 12-lead ECG,
adverse events, serious adverse events and 
withdrawals due to adverse events.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib) as 
maintenance therapy in subjects with moderate 
to severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement (CMEI 
response) at Week 64 among subjects who 
achieved CMEI response at Week 12.

Proportion of subjects achieving SES-CD 25 
and SES-CD 50 at Week 64 among subjects 
who achieved SES-CD 25 and SES-CD 50 at 
week 12 respectively.
Exploratory Objective(s):
Exploratory Endpoint(s):

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
therapy during the open label extension period
for subjects with moderate to severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 
(reduction of ≥3 points from baseline in 
SES-CD) at Week 64.

Proportion of subjects achieving SES-CD 25 
and SES-CD 50 (≥25% and ≥50% reduction in 
SES-CD from baseline) at Week 64.

Proportion of subjects achieving endoscopic 
remission (SES-CD ≤2) at Week 64.

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 64.

To evaluate the effect of PF-06651600
(ritlecitinib) and PF-06700841 (brepocitinib) on 
outcomes based on additional clinical criteria.

Proportion of subjects achieving clinical 
response and remission as defined by SF and 
AP endpoints at Weeks 16, 20, 24, 32, 40, 48, 
56 and 64.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD 
and clinical remission by SF, AP) at Week 64.

Proportion of subjects with a CDAI100
response or CDAI remission (CDAI <150) at 
Weeks 16, 32 and 64.

The scores and change from baseline in IBDQ
Total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and 
Social Function) at Weeks 16, 32 and 64.


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
The proportion of subjects with IBDQ total 
score ≥170 at Weeks 16, 32 and 64.

The proportion of subjects with ≥16 point 
increase in IBDQ total score from baseline at 
Weeks 16, 32 and 64.

Proportion of subjects achieving IBDQ 
symptom domain response at Weeks 16, 32 
and 64. 

The scores and change from baseline in 
EQ5D3L + VAS at Weeks 16, 32 and 64.

The scores and change from baseline in SF-36
v2: PCS & MCS, and 8 domain scores at 
Weeks 16, 32 and 64.

Mean change from baseline in PGIS score at 
Weeks 16, 32 and 64.

To evaluate the effect of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on histopathology score.

Change from baseline in GHAS score at 
Week 64.

Proportion of subjects achieving histologic 
remission (GHAS ≤4) at Week 64.  

To describe the PK of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib) in 
subjects with moderate to severe CD.

PF-06651600 (ritlecitinib) concentrations at 
Weeks 16, 20, 32, 56 and 64.

PF-06700841 (brepocitinib) concentrations at 
Weeks 16, 20, 32, 56 and 64.

To explore the relationship between PK, PD, 
and clinical endpoints.

Change from baseline in serum hsCRP levels 
over time.

Change from baseline in fecal calprotectin.

Change from baseline in serum IP-10 levels 
over time.

Change in baseline in BCL-2 gene expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and TBNK cells.

To collect non-banked samples (eg, intestinal 
biopsies, stool for microbiome analysis, serum
and plasma for analysis of proteins and a whole 
blood tube for RNA analysis) for exploratory 
research, unless prohibited by local regulations 
or ethics committee decision. 

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples
unless prohibited by local regulations or ethics 
committee decision. 

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section.


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Study Design and Treatments:
This is a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, multicenter 
study in subjects with moderate to severe active 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 230-250 subjects 
in total will be randomized into the study. 
The 12-week induction period will be placebo-controlled and double-blind within each 
investigational product.  Subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive either active or placebo treatments.  In the induction period, 
200 mg QD (one a day) for 8 weeks followed by 50 mg QD for 4 weeks of PF-06651600 
(ritlecitinib) and matching placebo in a 2:1 ratio and for subjects enrolled prior to 
implementation of PA5, 60 mg QD for 12 weeks of PF-06700841 (brepocitinib) and 
matching placebo in a 2:1 ratio will be investigated.  The hybrid dosing regimen for 
PF-06651600 (ritlecitinib) during the 12-week induction period is a consequence of available 
nonclinical long-term toxicity data supporting 200 mg treatment for only up to 8 weeks.  For 
analysis, placebo groups will be combined.
After the completion of the induction period, subjects will enter the 52-week OLE period.  
There will be no re-randomization at the beginning of the OLE period.  Subjects will receive 
the same study drug that they were randomized to receive during the induction period, and 
there will be no placebo arms.  Placebo subjects from the induction period will also receive 
active drug in the OLE period. The matching placebo subjects from the double-blind 
PF-06651600 (ritlecitinib) treatment/placebo induction period will receive 50 mg of 
PF-06651600 (ritlecitinib), while the corresponding placebos from the double-blind 
PF-06700841 (brepocitinib)/placebo induction period will receive 30 mg of PF-06700841
(brepocitinib) for 52 weeks. 
After completion of the OLE period, subjects will enter the 4-week follow up period.  Any 
subjects, who discontinues early from the double-blind period prior to theWeek 12 visit,
should undergo the procedures for an Early Termination (Induction) visit on the last day the 
subject takes the investigational product or as soon as possible thereafter.  For subjects who 
discontinue early from the OLE period (after the Week 12 visit, but prior to the Week 52 
visit), the procedures scheduled for an Early Termination (OLE) visit will be performed on 
the last day the subject takes the investigational product or as soon as possible thereafter.
These early withdrawal subjects, along with subjects who complete the induction period but 
are not willing to participate in the OLE period, will be asked to complete the Follow-up visit 
approximately 4 weeks after the last dose of study drug.




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The primary efficacy endpoint is the proportion of subjects achieving SES-CD 50 defined as 
≥50%reduction from baseline in SES-CD score at Week 12, as assessed by central reading.  
The safety analysis set will include all subjects who have received at least one dose of the 
study drug or placebo.  Pharmacokinetic (PK) concentrations in treatment period will be 
summarized and presented with summary statistics.  Details regarding the analysis 
procedures to be used for the interim analysis may be provided in the interim analysis plan 
(IAP).  An interim analysis will be performed when approximately 60% of planned subjects 
have completed or had the chance to complete the Week 12 visit for possible futility or early 
efficacy. In case the study fails to stop at this interim, another interim analysis may be
performed when approximately 80% of the subjects have completed or had the chance to 
complete Week 12 visit.
Efficacy endpoints are exploratory in the extension period.  Details of the analysis are 
described in Section 9 and in the SAP.
This study will use an external data monitoring committee (E-DMC).  The E-DMC will be 
responsible for ongoing monitoring of safety of subjects in the study according to the charter.  
The E-DMC will also be responsible for any interim analysis as specified in the protocol and 
interim analysis plan.








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k.
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.
l.
Screening urinalysis will include spot urine albumin/creatinine ratio.
m. Stool microbiology (stool culture for enteric pathogens, ova and parasites, and Clostridium difficile toxin test), if not performed within 6 weeks prior to 
screening.
n.
Subjects who are HBsAg negative and HBcAb positive must have further testing for HBsAb.  Subjects who are HCV Ab positive require further testing with 
HCV RNA PCR. 
o.
If not performed within 12 weeks prior to screening (see Assessments Section 7.1.5 for details).
p.
To be done in postmenopausal females only (females who are amenorrheic for at least 12 consecutive months).
q.
Only for women of childbearing potential. 
r.
Collection of stool for microbiome and fecal calprotectin analyses MUST be prior (within 1 week) to administration of any bowel prep for endoscopy.
s.
Viral surveillance to include analysis of viral load for CMV, EBV, HSV1, HSV2 and VZV.  In addition to time points specified, a plasma sample for viral 
surveillance may also be taken at the time of an adverse event, as clinically appropriate.
t.
At each biopsy collection time point 19 biopsies should be taken for the analyses described: 12 biopsies spanning six segments (rectum, sigmoid, left colon, 
transverse colon, right colon, and ileum), 6 biopsies from inflamed colonic mucosa in the most affected segment, and 1 biopsy from normal adjacent mucosa.  
See Section 7.2.2 for additional details. ET colonoscopy should be performed unless the previous colonoscopy is less than 8 weeks prior. 
u.
Endoscopy should be performed within 10 days prior to baseline visit, preferably within 5 to 7 days prior to baseline.  The centrally read endoscopic 
subscore will be used to determine eligibility.
v.
Stool frequency (SF) and abdominal pain (AP) diary will be provided at screening. 
w.
The PGIS will be assessed daily beginning approximately 2 weeks prior to screening endoscopy.
x.
PK (PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) samples will be collected pre-dose at Weeks 0, 2, 8.  On Week 4, PK (PF-06651600 
(ritlecitinib) or PF-06700841 (brepocitinib) samples will be collected prior to dosing, and 0.5 hour (±15 min) post dose.  On Week 12 PK (PF-06651600 
(ritlecitinib) or PF-06700841 (brepocitinib) samples will be collected prior to dosing, and 0.5 hour (±15 min), 1 hour (±30 min), 2 hour (±30 min) and 4 hour 
(±30 min) post dose. 
y.
If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a 
subject visit.
z.
Urine myoglobin will be measured at Screening and in case of CK >3x ULN during the study (up to week 68). Additional tests may be performed during the 
study at the investigator’s discretion, as indicated by signs and symptoms of ongoing AEs.
aa. Incidental endoscopic findings reported by Robarts that are deemed clinically significant by the principal investigator must be reported as an AE or SAE, as 
appropriate.
bb. IP-10 samples will be collected prior to dosing. 






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a.
Day relative to start of study treatment (Day 1).  Subjects who complete the 12-week induction period will enter the second part of the study which is a 
52 week OLE period and will be asked to complete the Follow-up visit approximately 4 weeks after the last dose of study drug.
b.
For subjects who discontinue early from OLE period (after the Week 12 visit, but prior to the Week 52 visit), the procedures scheduled for Early Term 
(OLE) will be performed on the last day the subject takes the investigational product or as soon as possible thereafter and will be asked to complete the 
Follow-up visit approximately 4 weeks after the last dose of study drug.
c.
Weight will be measured without shoes.
d.
Additional targeted PE may be performed during the study at the investigator’s discretion.  Complete 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 want to have an examination of breast and/or external genitalia (these are optional) done as a part of the physical examination.
e.
Vital signs (including blood pressure, pulse rate and temperature) should be performed before laboratory blood collection and endoscopic procedure. 
f.
Audiograms may be performed within a ±2 week window relative to study visit.
g.
Subjects are required to fast (no food or drink except water) for at least 8 hours prior to study visit, as required for fasting lipid profile and fasting glucose 
sample collection.
h.
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.
i.
Only for women of childbearing potential. 
j.
During screening period collection of stool for microbiome and fecal calprotectin sample collection MUST be prior (within 1 week) to administration of any 
bowel prep for endoscopy. For example, subject can collect their sample one week prior to bowel prep. One week is not a set time period; subject may 
collect the stool sample sooner than 1 week too.
k.
Viral surveillance to include analysis of viral load for CMV, EBV, HSV1, HSV2 and VZV.  In addition to time points specified, a plasma sample for viral 
surveillance may also be taken at the time of an adverse event, as clinically appropriate.
l.
At each biopsy collection time point 19 biopsies should be taken for the analyses described: 12 biopsies spanning six segments (rectum, sigmoid, left colon, 
transverse colon, right colon, and ileum), 6 biopsies from inflamed colonic mucosa in the most affected segment, and 1 biopsy from normal adjacent mucosa.  
See Section 7.2.2 for additional details. ET colonoscopy should be performed unless the previous colonoscopy is less than 8 weeks prior.
m. The PGIS, SF and AP will be assessed daily from Visit 12 to 16, Visit 24 to 32 and from Visit 56 to 64.
n.
PK (PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) samples will be collected pre-dose at Weeks 16, 20, 56.  On Week 32 and 64 PK 
(PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) samples will be collected at predose and 0.5 hour (±15 min) post dose. 
o.
Incidental endoscopic findings reported by Robarts that are deemed clinically significant by the principal investigator must be reported as an AE or SAE, as 
appropriate.
p.
IP-10 samples will be collected prior to dosing. 


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1. INTRODUCTION
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal 
tract that affects five million people worldwide.  IBD presents as one of two major forms, 
ulcerative colitis (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.
Despite multiple therapies being available, there still remains a significant unmet medical 
need, as subjects can suffer from primary or secondary non-responses, as well as, 
development of intolerance to 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/TEC, 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 between tofacitinib and placebo in subjects with UC (NEJM, 2017).1  Pfizer
plans to test multiple selective kinase inhibitor assets simultaneously in the CD setting, which 
in this trial will include a JAK3/TEC-sp ecific inhibitor and a TYK2/JAK1-specific inhibitor
(enrollment into the TYK2/JAK1 arm will conclude upon implementation of PA5) in the
context of a single clinical study.  Each arm of the study will address a biologically distinct 
question.  The JAK3/TEC -specific arm will address the involvement of cytokines that signal 
through JAK3/TEC in CD, and the TYK2/JAK1-specific arm address the involvement of 
cytokines that signal through TYK2 and JAK1 in CD.
Both PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) avoid specific targeting of 
JAK2, thus reducing the risks of undesired side effects, such as anemia.
1.1. Mechanism of Action/Indication
PF-06651600 (ritlecitinib) is a potent, selective, covalent inhibitor of JAK3/TEC that is 
currently being investigated in patients with rheumatoid arthritis, alopecia areata, UC, and 
CD. 
PF-06700841 (brepocitinib) is a potent dual inhibitor of human TYK2 and JAK1 that is 
currently being investigated in patients with psoriasis, alopecia areata, UC, and CD. 
1.2. Background and Rationale
The JAK family of kinases mediates 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
to the nucleus where they bind to specific gene promoters and activate transcription of a 
range of target genes.


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PF-06651600 (ritlecitinib) is a potent, selective, covalent inhibitor of JAK3/TEC.  It is an 
orally bioavailable small molecule that selectively inhibits JAK3/TEC by irreversibly 
blocking the ATP binding site without significantly inhibiting the other three JAK isoforms 
(JAK1, JAK2, and TYK2).  PF-06651600 (ritlecitinib) 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/TEC 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 CD.  Furthermore, in vivo PF-06651600 (ritlecitinib) 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 gastrointestinal 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 selective inhibition of 
JAK3/TEC could be efficacious in treatment of CD.
PF-06700841 (brepocitinib) is an orally bioavailable, small molecule, potent dual inhibitor of 
human TYK2 and JAK1.  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 such as interferon-gamma and IL-17 through upstream 
inhibition of the IL-12/Th1 and IL-23/Th17 pathways.  Taken together, it is hypothesized 
that selective and combined inhibition of TYK2 and JAK1 could be efficacious in treatment 
of CD.
Both PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) are under development as 
induction and long-term therapy for the treatment of CD.
Additional information for these compounds may be found in the single reference safety 
document (SRSD), which for this study is the individual Investigational Brochure (IB) for
each compound. 
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. 
Banked biospecimens retained in the BBS also can be used in research on IBD and other 
inflammatory diseases.


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Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision. 
1.3. Non-Clinical Pharmacokinetics and Metabolism 
1.3.1. Non-Clinical Pharmacokinetics and Metabolism of PF-06651600 (ritlecitinib)
Single dose pharmacokinetic (PK) studies with PF-06651600 (ritlecitinib) were conducted 
after intravenous (IV) and oral (PO) administration to mice, rats, and dogs. Absorption was 
rapid and bioavailability ranged from 61-100%. PF-06651600 (ritlecitinib) exhibited a 
clearance (CL) of 45 mL/min/kg in mice, 69 mL/min/kg in rats, and 13 mL/min/kg in dogs.  
The steady-state volume of distribution (Vss) was 0.8 L/kg in mice, 1.4 L/kg in rats, and 
1.1 L/kg in dogs, resulting in terminal half-lives (t½) of 1.3, 0.3, and 1.1 hours, respectively.
Systemic exposures of PF-06651600 (ritlecitinib) as measured by maximum concentration 
(Cmax) and area under the concentration-time curve (AUC24) in repeat dose oral pivotal 
toxicology studies increased with dose in rats, rabbits, and dogs. No sex-related differences 
and no significant accumulation was observed. In vitro, PF-06651600 (ritlecitinib) showed 
high apparent passive permeability and preliminary studies indicated that PF-06651600 
(ritlecitinib) was a substrate for P-glycoprotein (P-gp; also known as multidrug resistance 
(MDR)1) and breast cancer resistant protein (BCRP) efflux transporters.  However, oral 
bioavailability was high in rat and dog and a dose proportional Cmax was observed in clinical 
studies (between 5 and 800 mg) indicating minimal influence of efflux transporters on 
intestinal absorption. 
Fraction unbound of PF-06651600 (ritlecitinib) to plasma proteins was 0.22 (mouse), 
0.67 (rat), 0.29 (rabbit), 0.82 (dog), and 0.86 (human) across species.  Given the 
species-related differences in plasma protein binding, in vivo exposure-based safety margins 
were calculated using unbound concentrations.  Following an oral dose of [14C]PF-06651600 
(ritlecitinib) to rats, radioactivity was widely distributed throughout the body with the highest 
concentrations in the uveal tract of the eyes, blood, and aorta.  The brain to plasma AUC 
from zero to the last timepoint (AUCt) ratio of [14C]PF-06651600 (ritlecitinib) was 0.04, 
indicating minimal distribution of [14C]PF-06651600 (ritlecitinib) -related radioactivity to the 
brain, consistent with the drug being a substrate for P-gp/BCRP.  Elimination of radioactivity 
was nearly complete, since the majority of tissues were below the limit of quantitation at 
332 or 672 hours post-dose.  [14C]PF-06651600 (ritlecitinib) showed high recovery (98.4%) 
when incubated for 4 hours with human hepatocytes in vitro, indicating limited nonspecific 
interaction.
In vitro and in vivo metabolite profiling indicated that the primary clearance mechanisms for 
PF-06651600 (ritlecitinib) were glutathione related conjugation and cytochrome (CYP) 
450-mediated oxidation.  Renal excretion of parent PF-06651600 (ritlecitinib) was limited in 
the rat and dog. Biliary excretion of parent PF-06651600 (ritlecitinib) was limited in the rat.
No unique human metabolites were observed clinically compared to metabolite profiles in 
mouse, rat, and dog.  Initial metabolite profiling in steady-state first in human (FIH) human 
samples based on ultraviolet (UV) absorption indicated PF-06651600 (ritlecitinib) as the 
major circulating species at ~64%, with 3 glutathione remnant metabolites detected 
(~21% cysteine-, ~9.1% N-acetyl cysteine-, and ~6.3% N-acetyl cysteine 


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sulfoxide-conjugates), indicating glutathione conjugation as the primary clearance 
mechanism.  The respective ratio of circulating cysteine, N-acetylcysteine, and 
N-acetylcysteine sulfoxide in rat:human was estimated at ~28:1, 22:1, and 0.74:1 comparing 
the 6-month good laboratory practice (GLP) toxicity study no-observed-adverse effect 
(NOAEL) level of 200 mg/kg/day to a top human daily dose of 200 mg.  The respective 
urinary rat:human ratios of excreted cysteine, N-acetylcysteine, and N-acetylcysteine 
sulfoxide were ~2.7:1, 19:1, and 6.4:1 indicating exposures of these metabolites in rats 
exceeded those in humans.  No evidence of chiral inversion of PF-06651600 (ritlecitinib) was 
detected in human plasma following oral administration.  Reaction phenotyping in 
recombinant enzyme systems identified CYP3A4 as the predominant CYP450 isoform 
responsible for the oxidative metabolism of PF-06651600 (ritlecitinib), with minor 
contributions from CYP2C19 and CYP3A5. In addition, Glutathione-S-Transferase
(GST)-conjugate was formed in a time dependent manner in Recombinant 
Glutatione-S-Transferase (rGST) Mu 1-1 (M1-1) and Pi 1-1 (P1-1) incubations. 
PF-06651600 (ritlecitinib) showed a low risk of causing a drug-drug interaction (DDI) due to 
reversible inhibition of the major CYP450 enzymes (unbound Cmax/50% inhibitive 
concentration [IC50] ≤0.04) as well as the major uridine 5'-diphospho-glucuronosyltransferase 
(UDP)-glucuronosyltransferase (UGT) enzymes (unbound Cmax/IC50 ≤0.07) at a maximum 
clinical daily dose of 200 mg (unbound Cmax 3.8 µM).  However, in the presence of 
nicotinamide adenine dinucleotide phosphate (NADPH), PF-06651600 (ritlecitinib) showed 
evidence of weak time-dependent inhibition of CYP3A4.  PF-06651600 (ritlecitinib) (caused 
>4-fold induction of CYP3A4 messenger ribonucleic acid (mRNA) levels and >2-fold 
induction of CYP2B6 mRNA levels at 50 to 100 µM, while no CYP1A2 induction was 
noted.  Clinically, PF-06651600 (ritlecitinib) showed no significant changes in 
4-hydroxycholesterol/cholesterol ratio relative to baseline controls following 14 days of 
dosing up to 400 mg once daily (QD), indicating the lack of potent CYP3A modulation.  
Further clinical studies are planned to better understand DDI risk. 
Based on in vitro transporter DDI assessments compared to exposure following a maximum 
clinical dose of 200 mg daily, PF-06651600 (ritlecitinib) showed a low potential to inhibit 
organic anion transporting polypeptide (OATP)1B1, OATP1B3, bile salt export pump 
(BSEP), organic cation transporter (OCT)2, organic anion transporter (OAT)1, and OAT3 at 
clinically relative concentrations.  However, PF-06651600 (ritlecitinib) has the potential to 
inhibit P-glycoprotein (P-gp) (systemically and in the gastrointestinal (GI) tract), breast 
cancer resistance protein (BCRP) (systemically and in the GI tract), organic cation 
transporter (OCT)1, multidrug and toxin extrusion (MATE)1, and MATE2K at clinically 
relative concentrations. Clinically, no significant changes in creatinine clearance 
(OCT2/MATE1/2K) from baseline were noted in multiple dose studies at doses up to 
800 mg. PF-06651600 (ritlecitinib) is not a substrate for OATP1B1 or OATP1B3.
Please refer to the Investigator’s Brochure (IB) for more details on the non-clinical PK and 
metabolism of PF-06651600 (ritlecitinib).


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1.3.2. Non-Clinical Pharmacokinetics and Metabolism of PF-06700841 (brepocitinib)
This Section is no longer applicable to newly enrolled participants under PA5.
A single-dose PK study with PF-06700841 (brepocitinib) was conducted after per os (PO)
and intravenous (IV) administration to male rats.  PF-06700841 (brepocitinib) was rapidly 
absorbed with high oral bioavailability (approximately 100%).  After IV administration, 
PF-06700841 (brepocitinib) demonstrated a steady state volume of distribution (Vss) of 
approximately 1.7 L/kg and a moderate plasma CL (approximately 31 mL/min/kg), relative 
to rat liver blood flow.  Systemic exposures (Cmax and AUC24) of PF-06700841 (brepocitinib)
after repeat oral dosing in the pivotal toxicity studies increased with increasing dose.  In 
vitro, PF-06700841 (brepocitinib) showed high apparent passive permeability and 
preliminary studies indicated that PF-06700841 (brepocitinib) was a substrate for MDR1.  
The mean fraction unbound values in plasma for PF-06700841 (brepocitinib) were 0.51 in 
mouse, 0.69 in rat, 0.36 in rabbit, 0.73 in monkey, and 0.61 in human. 
In vitro and in vivo metabolite profiling suggested that the primary clearance mechanisms for 
PF-06700841 (brepocitinib) were through CYP450-mediated oxidation.  Renal and biliary 
excretion of parent drug was limited in the rat.  No unique human metabolites were observed 
in vitro compared to metabolite profiles in rat and monkey.  In vitro studies using human 
recombinant CYP450 enzymes suggested that CYP3A4 was the primary enzyme responsible 
for clearance of PF-06700841 (brepocitinib), with minor contributions from CYP1A2, 2C19, 
and 2D6. PF-06700841 (brepocitinib) did not significantly inhibit the major CYP450 
enzymes by competitive inhibition or time-dependent inhibition in the presence or absence of 
NADPH (IC50 values >100 µM).  PF-06700841 (brepocitinib) did not cause significant 
induction of CYP1A2, 2B6, or 3A4 enzyme activity or mRNA expression at concentrations 
up to 100 µM.  PF-06700841 (brepocitinib) also did not inhibit the major 
UDP-glucuronosyltransferase (UGT) enzymes (IC50 values >100 µM).  These results 
indicated that the risk of PF-06700841 (brepocitinib) to mediate a CYP450 and/or UGT drug 
interaction at clinically relevant exposures was low (steady state Cmax, u 722 nM at 
60 mg QD).  PF-06700841 (brepocitinib) did not significantly inhibit the organic anion 
transporting polypeptide (OATP) 1B1 (IC50 159 µM) or OATP1B3 (IC50 >300 µM).  
However, PF-06700841 (brepocitinib) did inhibit MDR1 (IC50 7.8 µM), organic cation 
transporter (OCT) 2 (IC50 1.1 µM), multidrug and toxin extrusion (MATE) 1 (IC50 7.7 µM) 
and MATE2K (IC50 17 µM).  SimCYP® modeling indicated a low/small risk of a transporter 
mediated drug interaction with digoxin (MDR1; Cmax/AUC ratios: 1.17/1.08) or metformin 
(OCT/MATE1; Cmax/AUC ratios: 1.19/1.21) following a top dose of 60 mg PF-06700841
(brepocitinib) QD at steady state. 
1.4. Non-Clinical Safety Studies 
1.4.1. Non-Clinical Safety Studies with PF-06651600 (ritlecitinib)
In nonclinical toxicity studies following once daily oral administration of PF-06651600
(ritlecitinib) in rats and dogs up to 6 and 9-months duration respectively, key target organs 
included effects in bone marrow, and the immune and hematolymphopoietic systems 
(pharmacology-related effects) in both species and axonal dystrophy (swelling) in the 
nervous system along with auditory threshold and brainstem auditory evoked potential


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(BAEP) waveform deficits in dogs only.  The NOAELs in the pivotal toxicity studies were 
200 mg/kg/day in rats (mean unbound Cmax of 16,800 ng/mL and AUC24 of 53,700 ng•h/mL) 
and 10 mg/kg/day in dogs (mean unbound Cmax of 1910 ng/mL and unbound AUC24 of 
7940 ng•h/mL). In embryofetal development studies, fetal skeletal and visceral 
malformations, skeletal variations, and decreased fetal weights were observed in rats and 
rabbits; the developmental NOAEL in rats was 75 mg/kg (unbound Cmax of 7770 ng/mL; 
unbound AUC24 of 17,000 ng•h/mL) and in rabbits was 25 mg/kg/day (unbound Cmax of 
4470 ng/mL; AUC24 of 13,200 ng•h/mL).  PF-06651600 (ritlecitinib) was not mutagenic or 
clastogenic, but was aneugenic in vitro.  In vitro aneugenicity is a common observation with 
kinase inhibitors.  PF-06651600 (ritlecitinib) did not induce micronuclei in vivo in rats.  
There was no evidence of cutaneous or ocular phototoxicity following once daily oral 
administration of PF-06651600 (ritlecitinib) in rats. 
In the rat fertility study, adverse effects were limited to higher preimplantation loss and lower 
implantation sites in naïve untreated female rats mated with male rats administered 
200 mg/kg/day. These effects occurred in the absence of any effects on spermatogenesis 
(sperm counts, sperm motility, sperm production rate, or sperm morphology). There were no 
adverse effects in females at 200 mg/kg/day (mean unbound Cmax of 17,800 ng/mL and 
AUC24 of 58,600 ng•h/mL) or in males at the NOAEL of 60 mg/kg/day (mean unbound
Cmax of 7,240 ng/mL and AUC24 of 14,700 ng•h/mL).
Details of the nonclinical safety program are provided in the current Investigator’s Brochure.
1.4.2. Non-Clinical Safety Studies with PF-06700841 (brepocitinib)
This Section is no longer applicable to newly enrolled participants under PA5.
No adverse findings were observed in oral repeat-dose toxicity studies with PF-06700841
(brepocitinib) in rats and monkeys up to 6 and 9 months in duration, respectively.  Test 
article-related, nonadverse, target organs identified include the immune and hemolymphatic 
systems (thymus, spleen, lymph nodes, and bone marrow), gastrointestinal tract (body weight 
and weight gain effects), and adrenal gland (vacuolation).  The findings in the thymus, 
spleen, lymph nodes, and bone marrow are consistent with the pharmacological activity of 
PF-06700841 (brepocitinib). The NOAELs in the pivotal 6-and 9-month toxicity studies 
were 45 mg/kg/day in rats (unbound Cmax of 8280 ng/mL and AUC24 of 69,700 ng•h/mL) and 
20 mg/kg/day in monkeys (unbound Cmax of 2260 ng/mL and AUC24 of 10,700 ng•h/mL).  
Adverse findings in the central nervous system (decreased activity, mortality, prostration, 
convulsions) were observed at high exposures in pregnant, but not nonpregnant, rabbits. In 
pivotal embryo-fetal development studies adverse PF-06700841 (brepocitinib)-related
developmental effects occurred (lower embryo-fetal viability and mean fetal body weights, 
fetal skeletal malformations, external malformations).  
The developmental NOAEL in rats and rabbits was 1.5 or 1 mg/kg/day with unbound AUC24
exposure of 1820 or 608 ng•h/mL), respectively.  In oral rat fertility studies PF-06700841
(brepocitinib)-related adverse effects in females (lower number of viable embryos due to 
higher early resorptions) occurred.  There were no adverse findings in males.  The NOAEL 
for male fertility or female fertility and early embryonic development was 55 or 3 mg/kg/day,


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resulting in unbound AUC24 exposures of 70,400 or 2890 ng•h/mL, respectively. No effects 
on female reproductive organs, as assessed by histopathologic examination, were noted in 
either the rat or monkey repeat-dose toxicity studies.  
PF-06700841 (brepocitinib) is not mutagenic in bacterial reverse mutation assays.  Although 
PF-06700841 (brepocitinib) was positive for micronuclei formation in vitro (through an 
aneugenic mechanism), it did not induce micronuclei in vivo in rats at 55 mg/kg/day 
(unbound Cmax = 7730 ng/mL and AUC24 = 88,300 ng•h/mL), the highest dose tested in the 
1-month oral toxicity study.  
Please refer to Section 4.4.1 for the contraception requirements for participation in this study.
Further details of the nonclinical safety program are provided in the current Investigator’s 
Brochure. 
1.5. Summary of Clinical Experience 
1.5.1. Summary of Clinical Experience with PF-06651600 (ritlecitinib)
PF-06651600 (ritlecitinib) has been explored in 7 completed Phase 1 trials in healthy subjects 
and in 3 Phase 2 trials in subjects with RA (B7981006), AA (B7931005) and vitiligo 
(B7981019).  There are 3 ongoing studies in AA (B7981015, B7981032, B7981037), and 
1 each in CD (B7981007), and RA (B7921023). 
As of 31 August 2020, PF-06651600 (ritlecitinib) has been explored in 3 Phase 1 trials in 
healthy participants, and in 2 completed Phase 2 trials, in participants with RA and AA. 
There are ongoing Phase 2 studies in ulcerative colitis, Crohn’s disease, alopecia areata, and 
vitiligo; a Phase 2b/3 study in alopecia areata, and a Phase 3 study in alopecia areata.
Based on the current clinical and nonclinical experience with PF-06651600 (ritlecitinib) and 
other information from other JAK inhibitors (eg, Xeljanz® [tofacitinib], Jakafi® [ruxolitinib],
baricitinib, GLPG0634, and VX-509), the potential risks for PF-06651600 (ritlecitinib)
include: (1) viral reactivation; (2) serious infections and opportunistic infections;
(3) malignancy and lymphoproliferative disorders; (4) decreased lymphocyte counts; 
(5) change in neutrophil counts; (6) decreased platelet count; (7) alterations in the lipid 
profile; and (8) dermatologic effects (rash/acne); and (9) thromboembolism.  Increased 
incidences of deep vein thrombosis (DVT) and pulmonary embolism (PE) have recently been 
identified as potential risks for these other JAK inhibitors. To date, no adverse drug 
reactions for PF-06651600 (ritlecitinib) have been identified.
Additional information on the safety, tolerability, and efficacy of PF-06651600 (ritlecitinib), 
including information about ongoing Phase 2/3 studies in other indications may be found in 
the current version of the PF-06651600 (ritlecitinib) IB.


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1.5.1.1. Summary of Clinical Safety of PF-06651600 (ritlecitinib)
1.5.1.1.1. 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 (ritlecitinib) in healthy subjects.  
This single ascending dose (SAD) and multiple ascending dose (MAD) study was the first 
evaluation of PF-06651600 (ritlecitinib), 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 (ritlecitinib) 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.
1.5.1.1.1.1. Brief Summary of Adverse Events
1.5.1.1.1.1.1. SAD Period
During the SAD period, 31 subjects had a total of 42 treatment-emergent adverse events 
(TEAEs), 30 of which were considered to be treatment-related.  There were no deaths, severe 
adverse events (AEs), temporary discontinuations, or dose reductions due to AEs reported in 
this study.
1.5.1.1.1.1.2. MAD Period 
During the MAD period, 35 subjects had a total of 90 TEAEs, 75 of which were considered 
to be treatment-related.  The treatment groups with the most AEs were the PF-06651600
(ritlecitinib) 400-mg QD (39 AEs in 17 subjects), 200-mg BID (16 AEs in 6 subjects), and 
100-mg BID treatment groups (14 AEs in 4 subjects). There were no deaths, temporary 
discontinuations, or dose reductions due to AEs reported in the study.
1.5.1.1.1.2. Incidence of Adverse Events
1.5.1.1.1.2.1. SAD Period
The System Organ Classes (SOC) with the greatest number of subjects reporting AEs in the 
SAD period were Infections and infestations (8 subjects); Nervous system disorders 
(7 subjects); Gastrointestinal disorders (5 subjects); Musculoskeletal and connective tissue 
disorders (5 subjects); and Respiratory, thoracic, and mediastinal disorders (5 subjects).  
Most TEAEs reported in the SOCs of Gastrointestinal disorders, Musculoskeletal and 
connective tissue disorders, and Nervous system disorders were treatment-related.
There were generally few TEAEs in the SAD period, most of which occurred in a single 
subject, with the exception of headache and nasopharyngitis (experienced by 5 subjects each) 
and oropharyngeal pain (experienced by 4 subjects).  Most of the TEAEs were mild in 
severity, except for the following AEs that were moderate in severity: 1 adverse event (AE)
each in the PF-06651600 (ritlecitinib) 5-mg (oropharyngeal pain), 20-mg (musculoskeletal 
pain), and 200-mg (subcutaneous abscess) treatment groups, respectively; 2 AEs in the 
placebo group (dry skin and limb injury); 3 AEs in the PF-06651600 (ritlecitinib) 400-mg 
treatment group (nasopharyngitis, pilonidal cyst, and headache); and 5 AEs in the 


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PF-06651600 (ritlecitinib) 100-mg treatment group (abdominal pain, arthralgia, rash 
maculo-papular, and 2 AEs of headache).
1.5.1.1.1.2.2. MAD Period
The SOCs with the greatest number of subjects reporting AEs in the MAD period were Skin 
and subcutaneous tissue disorders (21 subjects); Gastrointestinal disorders (18 subjects); 
Nervous system disorders (12 subjects); Musculoskeletal and connective tissue disorders 
(6 subjects); and Respiratory, thoracic, and mediastinal disorders (5 subjects).  Most TEAEs 
reported in the SOCs of Skin and subcutaneous tissue disorders, Gastrointestinal disorders, 
and Nervous system disorders were treatment-related.  The most frequently reported TEAEs 
across all treatment groups were diarrhea and headache, which were experienced by 8 and 
7 subjects, respectively.
1.5.1.1.1.3. Analysis of Adverse Events
All TEAEs reported in the SAD period were mild except for the following AEs that were 
moderate in severity: 1 AE each in the PF-06651600 (ritlecitinib) 5-, 20-, and 200-mg 
treatment groups; 2 AEs each in the placebo group; 3 AEs in the PF-06651600 (ritlecitinib)
400-mg treatment group; and 5 AEs in the PF-06651600 (ritlecitinib) 100-mg treatment 
group.
All TEAEs reported in the MAD period were mild or moderate in intensity, except for 1 AE 
each in the PF-06651600 (ritlecitinib) 400-mg QD and 200-mg BID treatment groups, which 
were severe in intensity.
1.5.1.1.1.4. Permanent Discontinuations Due to Adverse Events
1.5.1.1.1.4.1. SAD Period
Four (4) subjects discontinued from the study due to AEs, including 1 subject each in the 
placebo and PF-06651600 (ritlecitinib) 100-, 200-, and 400-mg treatment groups.  
Subject
 experienced an AE of erythema after receiving placebo; the AE was 
considered to be treatment-related by the investigator and mild in severity.  
Subject
 experienced an AE of rash maculo-papular after receiving PF-06651600
(ritlecitinib) 100 mg; the AE was considered to be treatment-related by the investigator and 
moderate in severity.  Subject
 experienced an Serious Adverse Event (SAE) of 
subcutaneous abscess after receiving PF-06651600 (ritlecitinib) 200 mg; the SAE was 
considered to be treatment-related by the investigator and moderate in severity.  
Subject
 experienced an SAE of pilonidal cyst after receiving PF-06651600 
(ritlecitinib) 400 mg; the AE was considered to be treatment-related by the investigator and 
moderate in severity.
1.5.1.1.1.4.2. MAD Period
Two (2) subjects discontinued from the study due to AEs, including 1 subject each in the
PF-06651600 (ritlecitinib) 200-mg BID and 400-mg QD treatment groups. 
Subject
 experienced an AE of rash maculo-papular after receiving PF-06651600
(ritlecitinib) 200 mg BID; the AE was considered to be treatment-related by the investigator 
PPD
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and severe in severity.  Subject
 experienced an AE of herpes zoster after receiving 
PF-06651600 (ritlecitinib) 400-mg QD; the AE was considered to be treatment-related by the 
investigator and moderate in severity.
1.5.1.1.1.5. Deaths
There were no deaths among subjects who participated in Study B7981001.
1.5.1.1.1.6. Serious Adverse Events
1.5.1.1.1.6.1. SAD Period
Two (2) treatment-emergent SAEs occurred in 2 subjects in the SAD period; both were 
considered to be treatment-related by the investigator.
1.5.1.1.1.6.2. MAD Period
A treatment-emergent SAE occurred in 1 subject in the PF-06651600 (ritlecitinib) 
400-mg QD treatment group.  The SAE, naïve varicella, was considered to be 
treatment-related by the investigator.
1.5.1.1.1.7. Analysis and Discussion of Deaths, Other Serious Adverse Events, and 
Other Significant Adverse Events
No deaths occurred during the conduct of this study.  Six (6) subjects discontinued from the 
study due to AEs, while 3 subjects experienced SAEs.  Other significant non-serious AEs 
included rash maculo-papular, erythema, and rash pruritic; these events were considered to 
be moderate in severity.
1.5.1.1.1.8. Clinical Laboratory Evaluation
None of the laboratory abnormalities (without regard to baseline abnormality) were reported 
as AEs, and none were considered clinically significant. There was little median % change 
in neutrophil count (1% increase).  Four (4) subjects (doses >200 mg daily) in the 
PF-06651600 (ritlecitinib) treatment developed a lymphocyte count <500 cells/mm3. 
Overall, 36 and 42 subjects had laboratory abnormalities during the SAD and MAD periods, 
respectively.  The most frequently reported laboratory abnormalities in the SAD period were 
high low-density lipoprotein (LDL) cholesterol concentrations (12 subjects), high numbers of 
absolute monocytes (11 subjects), and positive urine blood tests (8 subjects).  The most 
frequently reported laboratory abnormalities in the MAD period were high LDL cholesterol 
concentrations (20 subjects), low lymphocyte percentages (10 subjects), and high numbers of 
absolute monocytes (10 subjects).
1.5.1.2. 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 (ritlecitinib) 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 (ritlecitinib) in healthy subjects.  A total of 
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14 subjects were randomized to study treatment and treated with 50 mg PF-06651600 
(ritlecitinib) solution/tablets under fasted and fed conditions completed the study.
No temporary discontinuations were reported in the study.
1.5.1.2.1. Analysis of Adverse Events
A total of 20 TEAEs were reported in the study of which 14 were reported as 
treatment-related.  All AEs were mild or moderate in severity.
1.5.1.2.2. Permanent Discontinuations Due to Adverse Events
Subject
, while having treatment with 50 mg PF-06651600 (ritlecitinib) oral 
solution under fasted condition, permanently discontinued from treatment due to an AE 
(urethritis) that was considered unrelated to study treatment.  The AE was moderate in 
severity and resolved.
1.5.1.2.3. Deaths
There were no deaths among subjects who participated in Study B7981003.
1.5.1.2.4. Serious Adverse Events
There were no serious adverse events in subjects who participated in Study B7981003.
1.5.1.2.5. Analysis and Discussion of Deaths, Other Serious Adverse Events, and Other 
Significant Adverse Events
No deaths occurred during the conduct of this study.  One (1) subject discontinued from the 
study due to an AE.  There were no SAEs or other significant non-serious AEs in subjects 
who participated in Study B7981003.
1.5.1.2.6. Clinical Laboratory Evaluation
None of the laboratory abnormalities were considered to be clinically significant or reported 
as AEs by the Investigator.
1.5.1.3. 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 (ritlecitinib) in healthy Japanese adult subjects.  Four 
subjects received oral PF-06651600 (ritlecitinib) 200 mg QD for 10 days, and 2 subjects 
received the matched placebo.
1.5.1.3.1. Safety Data
One (1) TEAE was reported by 1 subject treated with placebo.  This AE was mild in severity 
and was considered treatment-related. A total of 2 TEAEs were reported by 1 subject treated 
with PF-06651600 (ritlecitinib).  Both AEs were mild in severity, of which 1 AE was 
considered treatment-related.
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No death, SAEs, severe AEs, permanent or temporary discontinuations or dose reductions 
due to AE were reported during this study.
In the placebo treatment group, dry skin was reported by 1 subject and was considered 
treatment-related by the investigator.  In the PF-06651600 (ritlecitinib) treatment group, 
musculoskeletal stiffness and oropharyngeal pain were experienced by 1 subject, with 
musculoskeletal stiffness considered treatment-related.  None of the AEs were considered 
clinically significant.
1.5.1.3.2. Analysis of Adverse Events
There were generally few TEAEs in both treatment groups, with a total of 3 TEAEs reported 
in this study. All TEAEs were mild in severity.  There were no deaths or SAEs in this study 
and no subjects discontinued from the study.
1.5.1.3.3. Permanent Discontinuations Due to Adverse Events (None)
There were no permanent discontinuations due to AEs reported in this study.
1.5.1.3.4. Dose Reductions or Temporary Discontinuations Due to Adverse Events
(None)
There were no dose reductions or temporary discontinuations due to AEs.
1.5.1.3.5. Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
(None)
There were no deaths among subjects who participated in this study.
1.5.1.3.6. Other Serious Adverse Events (None)
There were no other SAEs in this study.
1.5.1.3.7. Clinical Laboratory Evaluation
No subjects had laboratory abnormalities in the placebo treatment group.  Two (2) subjects in 
the PF-06651600 (ritlecitinib) 200 mg treatment group were reported to have laboratory 
abnormalities).  One (1) subject met abnormal criterion of lymphocytes/leukocytes 
(<0.8 × Lower Limit of Normal (LLN)) and 1 subject met abnormal criteria of 
lymphocytes/leukocytes (<0.8 × LLN) and monocytes (>1.2 × Upper Limit of Normal 
(ULN)). None of laboratory abnormalities were reported as AEs or considered to be 
clinically significant by the investigator.
1.5.1.3.8. Electrocardiogram (ECG)
Only 1 subject treated with placebo was reported to meet the maximum QT interval 
>450 msec and <480 msec and maximum QT interval increase from baseline ≥30 msec and 
<60 msec in this study.  Additionally, there were no subjects meeting the criteria of QT 
values >500 msec.  No ECG values and changes from baseline were considered clinically 
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1.5.1.3.9. Vital Signs
No absolute values or change from baseline in vital signs were considered to be clinically 
significant and reported as AEs by the investigator.
1.5.1.4. Study B7981016
Study B7981016 was a non-randomized, open-label, multiple-dose, parallel-cohort study to 
investigate the effect of hepatic impairment on the plasma PK, safety and tolerability of 
PF-06651600 (ritlecitinib). According to the protocol, 2 parts (Part 1 and Part 2) were 
planned, and Part 2 was to be conducted only if PF-06651600 (ritlecitinib) AUC24 geometric
mean ratio for moderate hepatic impairment group compared to normal group was ≥2.0 (the 
decision criterion to proceed to Part 2). This study was completed after Part 1 since the 
criterion to proceed to Part 2 was not met. Starting on Day 1, participants received 
PF-06651600 (ritlecitinib) 30 mg once daily (QD) up to Day 9. On Day 10 the participants 
received PF-06651600 (ritlecitinib) 30 mg QD after an 8-hour fast.
1.5.1.4.1. Safety Data
Overall, 7 all-causality AEs were reported in 6 (33.3%) participants, of whom 5 (27.8%) 
participants experienced treatment-related AEs (severe, moderate, and mild treatment-related 
AEs were reported in 1, 1, and 3 participants, respectively), 1 (5.6%) participant experienced 
an SAE, and 2 (11.1%) participants discontinued the study drug due to AEs (1 due to 
thrombocytopenia and the other due to hepatic enzyme increased).  In participants with 
moderate hepatic impairment and in participants with normal hepatic function, all-causality 
AEs were reported in 4 (40.0%) and 2 (25.0%) participants, respectively, and 
treatment-related AEs were reported in 4 (40.0%) and 1 (12.5%) participant, respectively. 
Among all-causality AEs, thrombocytopenia, diarrhoea, cholestasis, arthropod bite, and 
hepatic enzyme increased were reported in 1 participant each, and there were 2 participants 
who developed headache.
The SAE, severe AE, and discontinuations from study drug due to AEs were reported only in 
participants with moderate hepatic impairment while there were none in participants with 
normal hepatic function (1 [10.0%] versus 0, 1 [10.0%] versus 0, and 2 [20.0% vs 0], 
respectively). 
One participant with moderate hepatic impairment developed an SAE of cholestasis (total 
bilirubin, ALT, AST, and alkaline phosphatase were 22.8 mg/dL, 51 U/L, 74 U/L, and 
267 U/L relative to 1.6 mg/dL, 45 U/L, 60 U/L, and 215 U/L at Baseline, respectively) 
29 days after the last dose of PF-06651600 (ritlecitinib). The event was considered as 
treatment related by the investigator. The event was reported as resolved on Day 111. 
There were 2 AEs resulting in permanent discontinuation from study drug, both of which 
were reported in participants with moderate hepatic impairment. One participant experienced 
thrombocytopenia (platelet count 95×109 /L relative to 124×109 /L at Baseline), which was 
considered mild in severity and treatment related by the investigator. The second participant 
experienced hepatic enzyme increased (ALT and AST: 204 U/L and 126 U/L, relative to 
69 U/L and 51 U/L at Baseline, respectively), which was considered moderate in severity and 


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treatment related by the investigator. In both cases the study drug was permanently 
discontinued due to those events and the events were later reported as resolved.
1.5.1.5. Study B7981017
This was a Phase 1, randomized, 2-way cross-over, multiple dose, open-label study of the 
effect of PF-06651600 (ritlecitinib) on midazolam and efavirenz pharmacokinetics (PKs) in 
healthy participants. Participants were planned to be randomized to 1 of 2 treatment 
sequences. A total of approximately 12 healthy male and/or female participants were 
planned to be enrolled in the study so that approximately 6 participants were enrolled in each 
treatment sequence. Each treatment sequence consisted of 2 periods in a single fixed 
sequence.
1.5.1.5.1. Safety Data
PF-06651600 (ritlecitinib), midazolam and efavirenz were safe and well-tolerated in the 
healthy participants evaluated in this study, when midazolam and efavirenz administered 
alone and coadministered with multiple doses of PF-06651600 (ritlecitinib). There were no 
deaths in the study. No SAEs or severe AEs were reported. No participants discontinued 
from study or study drug due to an AE. No dose reduction or temporary discontinuation due 
to an AE was reported.
1.5.1.6. Study B7981018
B7981018 was a Phase 1, randomized, 2-way cross-over, multiple dose, open-label study of 
the effect of multiple dose PF-06651600 (ritlecitinib) (200 mg QD) on single dose OC PK in 
healthy post-menopausal female volunteers. The OC evaluated was levonorgestrel (LN) and 
ethinyl estradiol (EE) at doses of 150 µg and 30 µg, respectively.
1.5.1.6.1. Safety Data
A total of 4 participants reported at least 1 AE during the treatment. Six all-causalities 
TEAEs by preferred term were reported. None of these TEAEs were considered treatment 
related. All the TEAEs were mild in severity. The most commonly reported TEAE by 
preferred term was constipation, which was reported by 4 participants administered with 
multiple doses of PF-06651600 (ritlecitinib) 200 mg QD, and by 1 participant administered 
with multiple doses of PF-06651600 (ritlecitinib) 200 mg QD and single-dose OC. All the 
participants with TEAE of constipation were treated with prune juice. TEAE of arthralgia 
was reported by 1 participant administered with multiple doses of PF-06651600 (ritlecitinib)
200 mg QD and single-dose OC.
No deaths, SAEs, severe AEs, discontinuations from the study due to AEs, temporary 
discontinuations or dose reduction due to AEs, or medication errors were reported in any 
treatments. None of laboratory abnormalities were reported as an AE. None of the 
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1.5.1.7. Study B7981021
B7981021 was a single-blind, randomized, 5-period, cross-over study in healthy male and/or 
female adult participants to assess the sensory characteristics, overall palatability and 
preference of different prototype active formulations of PF-06651600 (ritlecitinib) to support 
the selection of an age appropriate dosage form for PF-06651600 (ritlecitinib).
1.5.1.7.1. Safety Data
There were no deaths, SAEs, severe AEs, temporary discontinuations or dose reductions due 
to AEs reported in this study. One all-causality TEAE of gingival bleeding was reported by 
1 participant following Treatment A (API in water), which resulted in permanent 
discontinuation from the study. The event was mild in severity and not considered as 
treatment related. No abnormalities or clinically significant findings of the laboratory data, 
vital signs values and ECG data were reported in this study.
1.5.1.8. Study B7981022
Study B7981022 was a Phase 1, open-label, single dose, randomized, 4-period, cross-over 
design in a single cohort of approximately 12 healthy male or female participants at a single 
center.
1.5.1.8.1. Safety Data
For each PF-06651600 (ritlecitinib) treatment (Tablet, Capsule, Large API particle size 
capsule, and Overencapsulated capsule), all 12 participants were evaluated for AEs. The 
greatest number of AEs was reported for PF-06651600 (ritlecitinib) treatment with 
Over-encapsulated capsule. Two participants reported 2 TEAEs for PF-06651600 
(ritlecitinib) treatment with Tablet, of which none was determined by the investigator as 
treatment related. One participant reported 1 TEAE for PF-06651600 (ritlecitinib) treatment 
with Capsule, which was determined by the investigator as treatment related. No TEAEs 
were reported for PF-06651600 (ritlecitinib) treatment with Large API particle size capsule. 
Four participants reported 5 TEAEs for PF-06651600 (ritlecitinib) treatment with 
Overencapsulated capsule, of which 2 TEAEs reported by 1 participant were determined by 
the investigator as treatment related.
There were no deaths in the study. No SAEs or severe AEs were reported. No participants 
discontinued from study or study drug due to an AE. No dose reduction or temporary 
discontinuation due to an AE was reported.
1.5.1.9. Study B7981023
Study B7981023 was a Phase 1, open-label, fixed sequence 2-period study to investigate the 
effect of multiple doses of itraconazole on the pharmacokinetic of a single dose of 
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1.5.1.9.1. Safety Data
Seven participants reported 11 TEAEs, 6 participants reported 15 TEAEs, and 4 participants 
reported 5 TEAEs after receiving PF-06651600 (ritlecitinib) 30 mg, itraconazole 200 mg, and 
co-administration of PF-06651600 (ritlecitinib) and itraconazole, respectively. Among these 
TEAEs, 7, 14, 2 were considered as treatment-related, respectively. The majority of the 
TEAEs (8/11, 15/15 and 4/5 after receiving PF-06651600 (ritlecitinib) 30 mg, itraconazole 
200 mg, and co-administration of PF-06651600 (ritlecitinib) and itraconazole, respectively) 
were mild. In general, each TEAE was reported by single participants. The most commonly 
reported TEAEs by system organ class (SOC) across 3 treatments was Gastrointestinal 
Disorders, reported by 3, 5, and 2 participants after receiving PF-06651600 (ritlecitinib)
30 mg, itraconazole 200 mg, and co-administration of PF-06651600 (ritlecitinib) and 
itraconazole, respectively. All the TEAEs under “Gastrointestinal Disorders” were 
considered as treatment-related. No death, SAEs, severe AEs, permanent or temporary 
discontinuations or dose reductions due to AE were reported during this study. None of the 
laboratory findings were considered as clinically significant.
1.5.1.10. Study B7981024
B7981024 was a Phase 1, 2-period fixed sequence, multiple dose, open-label study to 
estimate the effect of PF-06651600 (ritlecitinib) on rosuvastatin pharmacokinetics in healthy 
participants. A total of 12 participants were treated with PF-06651600 (ritlecitinib) multiple 
dose of 200 mg QD for 10 days.
1.5.1.10.1. Safety Data
Single oral dose of rosuvastatin when administered alone or concomitantly with multiple 
doses of PF-06651600 (ritlecitinib) was safe and well-tolerated in healthy participants. All of 
TEAEs were mild in severity with the exception of a single AE of moderate back pain in the 
rosuvastatin 10 mg treatment group, considered as treatment-related by the investigator. 
There were no SAEs, severe AEs, dose reductions or discontinuations due to AEs during the 
study. None of the laboratory abnormalities were reported as adverse events or considered to 
be clinically significant by investigator.
Study B7981028
B7981028 was a Phase 1, open-label, fixed sequence study to evaluate the steady state 
pharmacokinetic drug-drug interaction between PF-06650833 and PF-06651600) ritlecitinib 
in healthy adult participants. A total of 15 participants were treated with multiple doses of 
PF-06650833 400 mg QD and multiple doses of PF-06651600 (ritlecitinib) 100 mg.
1.5.1.10.2. Safety Data
Five TEAEs were reported in 5 (33.3%) participants following administration of 
PF-06650833 400 mg QD alone. Two (2) of these TEAEs reported in 2 (13.3%) participants 
were considered treatment related. Fourteen TEAEs were reported in 8 (53.3%) participants 
following the administration of PF-06651600 (ritlecitinib) 100 mg QD as monotherapy. Four 
of these TEAEs reported in 4 (26.7%) participants were considered treatment related.


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Eleven TEAEs were reported in 4 (26.7%) participants following the co-administration of 
PF-06650833 400 mg QD and PF-06651600 (ritlecitinib) 100 mg QD. One of these TEAEs 
was considered treatment related. The most frequently reported all-causality TEAEs by SOC 
were Nervous System Disorders after receiving PF-06651600 (ritlecitinib) 100 mg QD 
monotherapy, which were reported in 4 (26.7%) participants. Regardless of SOC, the most 
commonly reported TEAE by preferred term (PT) was somnolence after receiving 
PF-06651600 (ritlecitinib) 100 mg QD monotherapy, which was reported in 3 (20%) 
participants. All TEAEs were considered mild in severity. All treatment-related TEAEs 
occurred in 1 participant each except for nausea (after receiving PF-06651600 (ritlecitinib)
100 mg QD monotherapy), which occurred in 2 participants. There were no SAEs, severe 
AEs, discontinuations due to AEs, or dose reductions or temporary discontinuations from 
treatment due to the AEs. None of the laboratory abnormalities were considered clinically 
significant.
1.5.1.11. Study B7981035
B7981035 was a Phase 1, randomized, 2-way cross-over, multiple-dose, open-label study of 
the effect of multiple doses PF-06651600 (ritlecitinib) on single dose combination OC 
pharmacokinetics (PK) in healthy female participants. Twenty-eight participants were 
treated with both Treatments A (single dose of combination OC in the form of 1 Portia 
(ethinyl estradiol [EE] and levonorgestrel [LN] or equivalent oral tablet, containing EE 30 µg 
and LN 150 µg) and B (single dose of combination OC in the form of 1 Portia (EE and LN) 
or equivalent oral tablet, containing of EE 30 µg and LN 150 µg on the morning of Day 10 
following 9 days of PF-06651600 (ritlecitinib) dosed at 50 mg po QD. On Day 10, the 
morning dose of PF-06651600 (ritlecitinib) and the single OC dose were administered 
simultaneously. Dosing with PF-06651600 (ritlecitinib) at 50 mg po QD continued through 
until Day 13). One participant was only treated with Treatment B.
1.5.1.11.1. Safety Data
All AEs occurred during the treatment period of repeated doses of PF-06651600 (ritlecitinib)
(before coadministration of PF-06651600 (ritlecitinib) and OC), except 1 AE of headache 
which occurred following the single dose of OC. The incidence of TEAEs was low and the 
severity of TEAEs was mild or moderate in this study. Two participants permanently 
discontinued from study treatment due to AE(s) following repeated doses of PF-06651600 
(ritlecitinib) (before co-administration of PF-06651600 (ritlecitinib) and OC). There were no 
temporary discontinuations and dose reductions resulting from AEs. There were no SAEs or 
severe AEs reported in this study. No laboratory abnormalities, vital signs observations or 
physical findings were clinically significant.
1.5.1.12. 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 (ritlecitinib) in 
seropositive subjects with moderate to severe active Rheumatoid Arthritis (RA) with an 
inadequate response to methotrexate.  A total of 70 subjects were randomized to study 
treatment, 28 subjects received placebo and 42 subjects received PF-06651600 (ritlecitinib).


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1.5.1.12.1. 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 
(ritlecitinib) group and 0 subjects in the placebo group);

Pruritus (3 [4.3%] subjects in total: 2 [4.8%] subjects in the PF-06651600 
(ritlecitinib) group and 1 [3.6%] subject in the placebo group);

Lymphopenia (3 [4.3%] subjects in total: 3 [7.1%] subjects in the PF-06651600 
(ritlecitinib) group and 0 subjects in the placebo group);

Headache (3 [4.3%] subjects in total: 0 subjects in the PF-06651600 (ritlecitinib) 
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 (ritlecitinib) group and 0 subjects in the placebo 
group).
1.5.1.12.2. Permanent Discontinuations due to Adverse Events
A total of 3 subjects (7.1%) in the PF-06651600 (ritlecitinib) 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.
1.5.1.12.3. Deaths
There were no deaths among subjects who participated in Study B7981006.
1.5.1.12.4. Serious Adverse Events
There were no SAE in subjects who participated in study B7981006.
1.5.1.12.5. 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 (ritlecitinib) treatment group 
and placebo were observed with regard to AEs of special interest.
1.5.1.12.6. 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.


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Three (3) subjects (7.1%) in the PF-06651600 (ritlecitinib) treatment group met the 
discontinuation criterion of hemoglobin <8 g/dL.  One (1) subject (2.4%) in the PF-06651600 
(ritlecitinib) 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 (ritlecitinib) 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 
investigator and values returned to near baseline by the 12-week follow-up visit.
1.5.1.13. Study B7931005
B7931005 was a Phase 2a, randomized, double-blind, parallel-group, multicenter study to 
investigate the safety and efficacy of PF-06651600 (ritlecitinib) and PF-06700841
(brepocitinib) compared to placebo in adult participants with AA with scalp hair loss of more 
than 50%. The study consisted of 3 periods: a 24-week double-blind treatment period, an up 
to 48-week SBE period, and a 24-week COE period. The study included 2 drug holiday 
periods of 4 weeks each, and 2 follow-up periods of 4 weeks each. A total of 
142 participants were randomized to study treatment: 47 participants received placebo, 
48 received PF-06651600 (ritlecitinib) for an induction dose of 200 mg QD for 4 weeks 
followed by maintenance dosing of 50 mg QD for 20 weeks, and 47 received PF-06700841
(brepocitinib) for an induction dose of 60 mg QD for 4 weeks followed by maintenance 
dosing of 30 mg QD for 20 weeks during the first 24-week treatment period.
1.5.1.13.1. Safety Data
The most frequently (≥5%) reported all causalities TEAEs were Nasopharyngitis and 
Headache (12.5% each), Acne (10.4%), Diarrhoea and Upper respiratory tract infection 
(8.3% each), Dermatitis atopic, Folliculitis, and Nausea (6.3% each). The majority of 
treatment-related TEAEs (67 out of 84) were mild. The most commonly reported treatment 
related- TEAEs for PF-06651600 (ritlecitinib) by preferred term were upper respiratory tract 
infection (6.3%), and acne, nausea, and headache (each at 4.2%).
Two participants discontinued PF-06651600 (ritlecitinib) due to AEs and continued in the 
study; the AEs were angioedema and blood creatine phosphokinase increased. A total of 
5 participants had a temporary discontinuation of study drug due to AEs: due to diarrhoea 
and due to gastroenteritis in PF-06651600 (ritlecitinib) treatment group; and due to increased 
transaminases, due to headache, and due to abdominal discomfort in PF-06700841
(brepocitinib) treatment group. All these AEs resolved and were mild in severity. Only
abdominal discomfort was considered treatment-related by the investigator. 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. There were no SAEs 
or deaths reported with PF-06651600 (ritlecitinib) in Study B7931005.


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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 3 (6.3%) participants in PF-06651600 (ritlecitinib) treatment group. One participant in 
PF-06651600 (ritlecitinib) treatment group experienced Grade 3 decreased lymphocyte 
count. There were no clinically relevant changes in lipid profile. Elevated CK levels of at 
least 3 × ULN were reported in 1 participant in PF-06651600 (ritlecitinib) treatment group.
During the induction period, when participants received PF-06651600 (ritlecitinib)
200 mg QD for 4 weeks, decreases in mean platelet and lymphocyte counts (-17.89% 
and -17.30% mean CFB, respectively) were observed in the PF-06651600 (ritlecitinib) group 
at Week 2. During the maintenance period, when participants received 50 mg QD for 
20 weeks, there was improvement in the platelet and lymphocyte counts in the PF-06651600 
(ritlecitinib) group. In both groups, hemoglobin level remained comparable to baseline value 
throughout the Initial 24-Week Treatment Period. No participants met the laboratory 
abnormality criterion of hemoglobin <0. .8 × LLN.
There were no clinically significant findings in ECG and vital signs except one increased 
diastolic BP in PF-06651600 (ritlecitinib) treatment group and one in placebo group.
1.5.1.14. Study B7981005
B7981005 is an ongoing Phase 2b, randomized, double-blind, placebo-controlled (in the 
induction period and not in the chronic dosing period), parallel group, multicenter study 
examining the efficacy of PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) in 
participants 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 is 
not be blinded across the PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) cohorts, 
but is placebo-controlled during the induction phase, and double-blinded within each 
investigational product. At Week 8, all participants are re-randomized within their respective 
treatment cohort (PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) 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 participants and Investigators aware that they have been assigned to 
PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib), and that there is no placebo 
control.
1.5.1.14.1. Safety Data
As of 31 August 2020, a total of 316 patients were evaluable for AEs, of whom 197 have 
reported 562 AEs. The most frequently (≥5%) reported AEs were Colitis ulcerative (10.1%), 
Nasopharyngitis (7.9%), Anaemia (5.4%), Arthralgia, and Headache (5.1% each). 
As of 31 August 2020, a total of 35 SAEs have been reported in 33 participants. Thirteen 
SAEs were reported pre-randomization in 13 participants. Twenty-two treatment emergent 
SAEs (TE-SAEs) were reported in 21 participants, of which 6 events were considered 
treatment related and 16 events were not considered treatment related by the investigator. 


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The events considered treatment-related (blinded study treatment) by the Investigator are 
Urticaria (1 participant) and Colitis ulcerative (4 events in 4 participants). The event of acne 
occurred in a participant receiving blinded therapy with PF-06651600 (ritlecitinib)/placebo 
and the outcome for the events of Urticaria and Colitis ulcerative (worsening of ulcerative 
colitis [UC]/UC flare) was recovered/recovering. 
The remaining treatment-emergent SAEs (blinded study treatment) assessed as not related to 
study treatment by the Investigator are as follows (all single events unless otherwise 
specified): Peripheral artery thrombosis, Thrombocytosis, Pyrexia, Anaemia, Interstitial lung 
disease, Large intestinal perforation, Colitis ulcerative (4 events), Condition aggravated 
(exacerbation of UC), Viral infection, Pneumonia, Haemorrhoid operation, Femur fracture, 
Myocardial ischaemia (post-procedural myocardial ischaemia), Myocardial infarction, Ankle 
fracture, Ligament injury, Listeria encephalitis, Pneumonia viral and COVID-19. 
One death has been reported in the study; a 
-year-old 
 participant receiving blinded 
therapy (PF-06651600 (ritlecitinib)/placebo group) experienced a SAE of myocardial 
infarction on study Day 49 (post-randomization) which resulted in death. Relevant medical 
history included ongoing 
 
. The Investigator considered there was not a reasonable possibility that the 
event of myocardial infarction was related to the study drug, a concomitant drug or to a 
clinical trial procedure. The sponsor considered that the ongoing chronic obstructive 
pulmonary disease and the ongoing hypertension in this participant could provide alternate 
explanations for the reported event.
Efficacy Results
The study is blinded and ongoing.
1.5.1.15. Study B7981015
B7981015 is an ongoing Phase 2b/3, randomized, double-blind, placebo-controlled, 
dose-ranging study to investigate PF-06651600 (ritlecitinib) in Alopecia Areata (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 718 subjects. The study will be conducted at approximately 120 sites.
To be eligible to enroll in this study, adolescent (≥12 to <18 years of age) and adult subjects 
must have moderate to severe AA with >50% hair loss of the scalp (Severity of Alopecia 
Tool [SALT] score >50) at both Screening and baseline visits, without evidence of terminal 
hair regrowth within the previous 6 months and with the current episode of hair loss 
<10 years.
PPD
PPD
PPD


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Eligible subjects are randomized to blinded PF-06651600 (ritlecitinib) and matching placebo 
in a 2:2:2:2:1:1:1 (200 mg/50 mg; 200 mg/30 mg; 50 mg; 30 mg; 10 mg; 
placebo/200 mg/50 mg; placebo/50 mg) manner for a total of 7 treatment sequences. All 
subjects begin dosing during the loading phase according to their assigned sequence.
Following the 4-week loading phase, subjects continue dosing according to their assigned 
sequence in the 20-week maintenance phase. At the end of the maintenance phase, 
placebo-treated subjects are advanced in a prespecified, blinded manner to 1 of 2 active 
treatment sequences for the remainder of the study (through Week 48). Investigators, 
subjects, and the sponsor study team are blinded to treatment throughout the duration of the 
study. Following the last dose of study intervention, both discontinued and completed 
subjects enter into a 4-week follow-up period for safety monitoring. Subjects who complete 
treatment may be eligible for enrollment in an open-label, long-term study (Phase 3 study 
B7981032). Subjects who enroll immediately into the B7981032 study are not required to 
complete the 4-week follow-up period in this study.
1.5.1.15.1. Safety Results 
1.5.1.15.1.1. Discontinuations
As of 31 August 2020, 14 subjects discontinued due to a TEAE.
1.5.1.15.2. Adverse Events
SAEs were reported for 11 subjects in the B7981015 study as of 31 August 2020; 2 of these 
11 cases were subsequently determined to be not serious by the investigator (while these 
cases were updated in the safety database prior to 31 August 2020, this change was not 
reflected in the clinical database until after 31 August 2020). The remaining 9 cases were: 
sepsis and empyema, conversion disorder, infected eczema, invasive lobular breast 
carcinoma, spontaneous abortion, diverticulitis, menorrhagia, pulmonary embolism, and 
breast cancer.
There were no deaths reported.
Of 701 subjects evaluable for AEs, 506 (72.2%) experienced TEAEs. The total number of 
TEAEs reported were 1443. Twenty-four subjects experienced severe AEs (3.4%).
The most frequently reported (≥5% of subjects) by MedDRA preferred terms were
Nasopharyngitis (12.8%), Headache (10.1%), Upper Respiratory Tract Infection (7.0%), 
Acne (5.8%), and Nausea (5.3%).
1.5.1.16. 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 (ritlecitinib) in active non-segmental vitiligo with a partially blinded extension 
period. The study includes an up to 4-week Screening period, a 24-week dose ranging 
period, an up to 24-week extension period, and an 8-week follow-up period. The 24-week 
dose ranging period is comprised of a placebo-controlled period that includes a 4-week 
loading phase and a 20-week maintenance phase. An induction dose of 200 mg QD of 


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PF-06651600 (ritlecitinib) for 4 weeks followed by maintenance dosing of 50 mg QD of 
PF-06651600 (ritlecitinib) for 20 weeks (n=60), an induction dose of 100 mg QD of 
PF-06651600 (ritlecitinib) for 4 weeks followed by maintenance dosing of 50 mg QD of 
PF-06651600 (ritlecitinib) for 20 weeks (n=60), a dose of 50 mg QD of PF-06651600 
(ritlecitinib) for 24 weeks (n=60), a dose of 30 mg QD of PF-06651600 (ritlecitinib) for 
24 weeks (n=45), a dose of 10 mg QD of PF-06651600 (ritlecitinib) for 24 weeks (n=45), 
and matching placebo for 24 weeks (n=60) will be investigated during the 24-week dose 
ranging period. 
1.5.1.16.1. Safety Results
1.5.1.16.1.1. Safety Data
As of 31 August 2020, 269 (73.9%) of the 364 evaluable participants experienced at least 
1 AE. There were a total of 743 AEs (all causalities). The most frequently (≥5%) reported 
AEs were Nasopharyngitis (15.9%), Upper respiratory tract infection (10.2%), Headache 
(8.5%), and Urinary tract infection (5.2%). There were 4 participants with SAEs reported in 
B7981019 study as of 31 August 2020. SAEs reported were Migraine in 2 participants, 
Neurogenic bladder, and Oesophageal spasm and Complication associated with device in 
1 participant each. There were no deaths reported in B7981019 study
1.5.1.17. Study B7981032
Study B7981032 is an ongoing 2-year Phase 3 open-label, multicenter study to evaluate the 
safety and efficacy of PF-06651600 (ritlecitinib) in adult and adolescent subjects ≥12 years 
of age with AA. 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).
To be eligible to enroll in this study, subjects enrolling from Study B7931005 or B7981015 
must not have had any events meeting the B7981032 discontinuation criteria or discontinued 
for safety-related events. In addition, subjects enrolling from Study B7931005 must have 
taken their last dose of PF-06700841 (brepocitinib) (a TYK2/JAK1 inhibitor) in Study 
B7931005 >12 weeks prior to the B7981032 Day 1 visit. There is no necessary washout 
period for participants who took PF-06651600 (ritlecitinib) in Study B7931005 or B7981015. 
Participants enrolling from B7981015 must have completed ≥34 weeks of study intervention. 
De novo participants and participants originating from Study B7931005 or B7981015 with 
>30 days between the last dose in Study B7931005 or B7981015 and their first visit in Study 
B7981032 must have a clinical diagnosis of AA with no other etiology of hair loss other than 
androgenetic alopecia, with ≥25% hair loss of the scalp due to AA at both the screening and 
Day 1 visits which, in the opinion of the investigator, is appropriate for systemic therapy.


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Subjects enrolling from B7931005 and B7981015 studies, receive open-label 50 mg 
PF-06651600 (ritlecitinib) QD and de novo subjects receive open-label 200 mg PF-06651600 
(ritlecitinib) QD for 4 weeks followed by open-label 50 mg PF-06651600 (ritlecitinib) QD. 
Following the last dose of study drug, both discontinued and completed subjects enter into a 
4 week follow-up period for safety monitoring.
1.5.1.17.1. Safety Results
As of 31 August 2020, a total of 369 participants were evaluable for AEs, of whom 127 had 
reported 246 TEAEs. The most frequently (≥2% of participants) reported TEAEs were 
headache (4.3%), acne (3.8%), nasopharyngitis (2.7%), and urticaria (2.2%). No TEAEs 
were reported in ≥5% of participants.
As of 31 August 2020, 1 participant discontinued due to a TEAE.
As of 31 August 2020, SAEs were reported for 2 participants. Please refer to the IB for more 
details on the clinical safety information with PF-06651600 (ritlecitinib).
1.5.2. Pharmacokinetics of PF-06651600 (ritlecitinib)
The PK parameters from the 5, 20, 50, 100, 200, 400 and 800 mg single dose levels are 
summarized below in Table 1.  PF-06651600 (ritlecitinib) was absorbed rapidly following 
single doses of 5 mg to 200 mg with median Tmax values ≤0.75 hours, and more slowly at the 
higher doses with a median Tmax of 1.0 and 1.5 hours for the 400 mg and 800 mg doses, 
respectively. 
Table 1.
Summary of Plasma PF-06651600 (ritlecitinib) Pharmacokinetic Parameters 
Following Single Oral Doses, Study B7981001
PF-06651600 (ritlecitinib) Parameter Summary Statisticsa by Treatment
Parameter, 
units
5 mg
20 mg
50 mg
100 mg
200 mg
400 mg
800 mg
N, n
6,6
6,6
6,6
6,6
6,6
12,12
6,6
AUCinf, 
ng.hr/mL
43.86 (26)
211.7 (39)
384.1 (47)
1085 (23)
2464 (42)
7824 (34)
16760 (18)
AUClast, 
ng.hr/mL
42.42 (26)
209.3 (40)
382.6 (47)
1081 (23)
2461 (42)
7821 (34)
16760 (18)
Cmax, 
ng/mL
27.02 (29)
120.9 (54)
253. 3 (45)
647.7 (24)
1039 (40))
2691 (26)
4992 (11)
Tmax, hr
0.5 
(0.5-0.5)
0.5 (0.5-1)
0.5 (0.5-1)
0.5 (0.5-0.6) 0.75 (0.5-2)
1(0.5-2)
1.5 (1-2)
t½, hr
1.20 
(0.107)
1.2 (0.174)
1.13 (0.166) 1.48 (0.176) 1.75 (0.434) 2.18 (0.337)
2.48 
(0.460)
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.


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Following attainment of Cmax, the disposition of PF-06651600 (ritlecitinib) generally showed 
a monophasic decline at the lower doses of 5 to 200 mg (mean t½ of 1.1 to 1.8 hours) while a 
biphasic decline was observed at doses of 400 and 800 mg (mean t½ of 2.2 and 2.5 hours, 
respectively).  An apparent trend toward longer t½ values at higher doses (400 and 800 mg) is 
probably due to concentrations remaining above the quantifiable limit for a longer period of 
time at the higher doses and defining a later terminal phase.  In general, PF-06651600 
(ritlecitinib) AUCinf increased in a dose related manner over the 5 to 800 mg dose range with 
a slightly greater than proportional increase observed over the 200 mg to 400 mg dose range.  
Cmax increased with dose in an apparent dose proportional manner. 
The PK parameters following administration of 50, 200 and 400 QD and 100 mg and 
200 mg BID for 14 days are summarized below in Table 2.
On Day 14 of multiple-dose administration, PF-06651600 (ritlecitinib) was absorbed rapidly 
with median Tmax values of 1 hour or less across the entire range of doses, from a total daily 
dose of 50 mg (50 mg QD) up to 400 mg (200 mg BID or 400 mg QD).  Following 
attainment of Cmax, the disposition of PF-06651600 (ritlecitinib) was consistent with that 
observed following single-dose administration, showing a monophasic decline for the lowest 
doses and a biphasic decline following the 200 mg BID and 400 mg QD dosing regimens and 
a mean terminal t½ of about approximately 1.3 to 2.3 hours.  In general, plasma PF-06651600 
(ritlecitinib) AUCand Cmax increased with dose across the 50 mg to 400 mg total daily dose 
range in a dose related manner based on visual comparison of individual and dose normalized 
geometric mean Cmax and AUCvalues.  Steady-state generally appears to have been reached 
by Day 4 for the QD regimens and Day 6 for the BID regimens based on similar median 
trough (predose) concentrations on Days 6, 8, 10, 12 and 14.
Table 2.
Summary of Steady State Plasma and Urine PF-06651600 (ritlecitinib) 
Pharmacokinetic Parameters Following Multiple Dose Administration for 
14 Days, Study B7981001
PF-06651600 (ritlecitinib) Parameter Summary Statisticsa by Treatment
Parameter, units
50 mg (QD)
100 mg (BID)
200 mg (QD)
400 mg (QD)
200 mg (BID)
N, n
6, 6
4,4
5, 5
15, 14
5, 5
AUC, ng.hr/mL
540.1(38)
1984 (15)
4069 (22)
10040 (19)
5207 (24)
Cmax, ng/mL
315.2 (38)
663.0 (35)
1422 (28)
3136 (26)
1903 (27)
Tmax, hr
0.5 (0.5- 1)
0.75 (0.5- 2)
1 (0.5- 1)
1 (0.5- 2)
1 (0.5- 1)
CL/F, L/hr
92.56 (38)
50.43 (15)
49.14 (22)
39.85 (19)
30.41 (24)
t½, hr
1.3 (0.241)
2.11 (0.341)
1.84 (0.409)
2.16 (0.100)
2.27 (0.212)
Vz/F, L
170.6 (26)
151.4 (27)
128.0 (29)
126.1 (18)
125.3(18)
Ae%
4.09 (23)
6.46 (4)
5.47 (31)
6.46 (19)
7.04 (20)
CLr, mL/min
63.06 (28)
54.33 (12)
44.76 (38)
42.90 (18)
45.46 (17)
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 
was determined.


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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 ; CLr = Renal clearance.
Urinary recovery of PF-06651600 (ritlecitinib) was low, with approximately <8% of the dose 
recovered unchanged in urine on Day 14 across all doses (geometric mean Ae% of 4.1% to 
7.0%).  Renal clearance ranged from 42.9 mL/min to 63.1 mL/min.
The relative bioavailability of 50 mg PF-06651600 (ritlecitinib) tablets was compared to 
50 mg oral suspension in Study B7981003.  The ratio (90% CI) of adjusted geometric mean 
was 93.4% (87.8, 100) for AUCinf and 90.4% (72.2, 113) for Cmax under fasted conditions.  
When the 50 mg tablets were administered under fed conditions, Tmax was slightly delayed 
with a median value of 1.0 hours, compared to a median Tmax 0.5 hours under fasted 
conditions.  For the 50 mg tablets fed vs. fasted, the ratio of adjusted geometric means for 
AUCinf and Cmax was 102% (95.2, 109) and 61.5% (48.5, 77.8), respectively.
Pharmacodynamic biomarkers response was best described by an indirect response PK/PD 
model indicating that AUC rather than Cmax is the important parameter to modulate disease 
response hence the recommendation is to administer the IP with no requirement regarding 
food in the current study. 
Following the first morning oral dose of PF-06651600 (ritlecitinib) 200 mg to healthy 
Japanese subjects (B7981008) under fasted conditions on Day 1, PF-06651600 (ritlecitinib) 
absorption was rapid with a median Time at which Cmax occurred (Tmax) of 0.525 hours and a 
range of 0.500-1.00 hours. Overall, exposures as measured by Area under the 
concentration-time profile from time 0 to time tau (AUCtau) based on geometric mean were 
3779 ng•hr/mL and for Cmax of 1803 ng/mL on Day 1 after a single dose. Mean t½ was 
1.69 hours and it was calculated based on a 24-hour sampling. Mean appearanT clearance
(CL/F) was 53.0 L/hr and apparent volume of distribution (Vz/F) was 129 L.
Trough (predose) concentrations on Days 4, 6, 8 and 10 for all subjects were below the lower 
limit of quantification (LLOQ) (<1.00 ng/mL).
Following multiple oral dosing on Day 10, AUCtau increased slightly while Cmax was similar 
to Day 1. The geometric mean values for AUCtau and Cmax were 4983 ng•hr/mL and 
1790 ng/mL, respectively. Median Tmax was similar to Day 1 with a value of 0.500 hours 
with no range for Day 10. Following the attainment of Cmax, concentrations appeared to 
decline in monophasic fashion.  A short mean t½ was observed with an estimate of 1.8 hours. 
Based on AUCtau calculation, mean CL/F was 40.1 L/hr and mean Vz/F was 103 L.
Plasma PF-06651600 (ritlecitinib) accumulation was 1.3–fold for AUCtau (observed 
accumulation ratio (Rac)) and 0.99–fold for Cmax (observed accumulation ratio for Cmax
[Rac,Cmax]).  The steady state accumumation ratio (Rss) compares AUCtau for multiple-dose 
administration to AUCinf for single-dose administration.  The geometric mean Rss was 
1.3 (close to 1), suggesting linear increases in PF-06651600 (ritlecitinib) exposure with 
multiple-dose administration. 


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Between-subject variability in plasma PF-06651600 (ritlecitinib) exposure on Day 1 and 
Day 10 based on geometric percent coefficient of variation (%CV), ranged from 35% to 
43% for Cmax and from 23% to 25% for AUCtau. 
Urinary recovery of PF-06651600 (ritlecitinib) was low, with <7% of the dose recovered 
unchanged in urine on Day 10 (geometric mean percent of dose recovered unchanged in 
urine up to 24 hours [cumulative amount of drug recovered unchanged in urine up to 
24 hours (Aetau%)] of 6.89%).  Renal clearance was approximately 46.1 mL/min.
Study B7981017 is a Phase 1, randomized, open label, 2-way crossover study to estimate the 
effect of multiple dose PF-06651600 (ritlecitinib) on the pharmacokinetics of single dose 
midazolam and efavirenz in healthy participants. Co-administration of multiple doses of 
PF-06651600 (ritlecitinib) increased midazolam exposure (AUCinf) and peak exposure (Cmax) 
by 2.7 and 1.8 fold, respectively. Efavirenz exposure (AUC0-72) and peak exposure (Cmax) 
were similar following coadministration with multiple doses of PF-06651600 (ritlecitinib) 
and single dose of midazolam and when administered with midazolam only.
Study B7981018 is a Phase 1, randomized, 2-way crossover, multiple dose, open-label study
of the effect of multiple dose PF-06651600 (ritlecitinib) (200 mg QD) on single dose OC PK 
in healthy post-menopausal female volunteers. PF-06651600 (ritlecitinib) decreased the 
adjusted geometric mean AUC and Cmax of ethinyl estradiol around 18% and 12%, 
respectively. Systemic exposure of levonorgestrel did not show any clinically significant 
changes. The clinical significance of this decrease in ethinyl estradiol is unknown; however, 
efficacy of estrogen-containing contraceptives may be decreased, and the concurrent use of 
an additional barrier method of contraception is required.  Female subjects who participate in 
clinical studies with PF-06651600 (ritlecitinib) must agree to use contraception as defined in 
each protocol (Section 4.4.1).
Study B7981023 is a Phase 1, open-label, fixed sequence 2-period study to investigate the 
effect of multiple doses of itraconazole on the pharmacokinetics of a single dose of 
PF-06651600 (ritlecitinib) in healthy participants. Co-administration of multiple 200 mg 
doses of itraconazole increased PF-06651600 (ritlecitinib) total exposure (AUCinf) by 
approximately 15% while peak exposure (Cmax) was similar relative to a single 30 mg 
PF-06651600 (ritlecitinib) dose given alone.
1.5.3. Summary of Clinical Experience with PF-06700841 (brepocitinib)
This Section is no longer applicable to newly enrolled participants under PA5.
1.5.3.1. Summary of Clinical Safety of PF-06700841 (brepocitinib)
This section consists of safety and efficacy information for PF-06700841 (brepocitinib) 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 and draft data from these 
small studies are included in the IB. Data have not been pooled for the studies conducted 
with PF-06700841 (brepocitinib). Safety and efficacy data are presented separately for each 
study.


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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 the 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]).
1.5.3.1.1. 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 
1 active dose of oral PF-06700841 (brepocitinib),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-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 (brepocitinib) 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
(brepocitinib) for 28 days. In the BA period, 12 healthy subjects were randomized and 
received PF-06700841 (brepocitinib).
Whereas additional studies with PF-06700841 brepocitinib are underway, none of these 
studies have been completed to date and the data remain blinded.
1.5.3.1.1.1. Adverse Events
PF-06700841 (brepocitinib) 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 
discontinuations were due to AEs. There were no discontinuations due to AEs in the SAD or 
BA cohorts.


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1.5.3.1.1.2. 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, confusion, and headache, 
each of which was experienced by 1 participant.  All TEAEs were mild in severity.
1.5.3.1.1.3. Other Significant Adverse Events in Study B7931001
One participant in the study B7931001 experienced an AE of herpes zoster after completing 
28-day treatment (Psoriasis period of the study) with PF-06700841 (brepocitinib)
100 mg QD.  The participant presented with non-disseminated, herpetiform rash on the upper 
left side of the back and left arm on Day 30.  The AE was mild in severity, had a reported 
duration of 13 days, and was treated with acyclovir and vicodin by the Investigator.
1.5.3.1.1.4. 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 
22 participants during MAD.


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Serum creatinine ≥1.5 × ULN occurred in 1 participant in the PF-06700841 (brepocitinib)
100 mg group during SAD, 4 participants (1, 2, and 1 participants in the PF-06700841
(brepocitinib) 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 (brepocitinib) 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
(brepocitinib) 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 (brepocitinib) 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.
1.5.3.1.1.5. 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.
1.5.3.1.2. Study B7931009
This study was a Phase 1 randomized, double-blind, third-party open, placebo-controlled, 
multiple dose study in healthy Japanese adult participants.


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1.5.3.1.2.1. Safety Summary of Phase 1 Study B7931009
Eight (8) male Japanese participants were assigned to the study treatment with PF-06700841
(brepocitinib) and all participants completed the study.  Of the 8 participants, 6 participants 
received treatment with 100 mg of PF-06700841 (brepocitinib) and 2 participants received 
matching placebo.
A total of 7 AEs were reported by 3 participants following oral administration of 100mg of 
PF-06700841 (brepocitinib), including flatulence, fatigue, viral upper respiratory tract 
infection, headache, somnolence, nocturia, and hematoma.  Among these, flatulence, 
headache, somnolence, and nocturia were considered treatment-related by the investigator.  
One AE of abdominal pain in the placebo treatment group was moderate and the others were 
considered mild in severity.
No laboratory abnormalities were identified in the placebo group.  Four participants 
experienced laboratory abnormalities following the administration of 100 mg of 
PF-06700841 (brepocitinib). None of the laboratory abnormalities were considered clinically 
significant or reported as AEs by the investigator.
Oral administration of PF-06700841 (brepocitinib) at multiple doses of 100 mg QD was 
well-tolerated in healthy Japanese participants investigated in this study.  There were no 
deaths, SAEs, severe AEs, discontinuations due to AEs, or dose reductions or temporary 
discontinuations due to AEs during this study. There were no clinically significant findings 
observed in laboratory parameters, vital signs, ECG parameters.
1.5.3.1.3. Study B7931014
This study is a Phase 1, open-label, non-randomized, 2-period, fixed sequence, single-dose 
study of PF-06700841 (brepocitinib) in healthy male participants to characterize the 
absorption, distribution, metabolism, and excretion (ADME) of 14C PF-06700841
(brepocitinib); and to evaluate the absolute oral bioavailability (F) and fraction absorbed (Fa) 
of PF-06700841 (brepocitinib) following oral administration of unlabeled PF-06700841
(brepocitinib) and IV and oral administration of 14C- PF-06700841 (brepocitinib) 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 (brepocitinib). There was a 10- to 17-day 
washout between the 2 treatment periods.
1.5.3.1.3.1. Safety Summary of Phase 1 Study B7931014
Six participants were assigned to open-label study treatment, and all were treated and 
completed the study.  All participants received 2 regimens (A and B).  Regimen A is an oral 
dose of 60 mg radiolabeled PF-06700841 (brepocitinib) containing approximately 300 nCi 
14C.  Regimen B is an oral dose of 60 mg unlabeled PF-06700841 (brepocitinib) followed by 
an IV dose of radiolabeled PF-06700841 (brepocitinib).


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Seventeen AEs were reported by 5 participants during the study, including dizziness, 
headache, nasopharyngitis, cough, epistaxis, flatulence, dry skin, diarrhea, dyspepsia and 
respiratory tract irritation.  Two events of headache were considered treatment related by the 
investigator.  All AEs were considered mild except 3 events in 1 participant graded as 
moderate (headache (2) and common cold).  No laboratory abnormalities were considered 
clinically significant.
Oral administration of PF-06700841 (brepocitinib) was well-tolerated in this ADME study.  
There were no deaths, SAEs, severe AEs, discontinuations due to AEs, or dose reductions or 
temporary discontinuations due to AEs during this study.  There were no clinically 
significant findings observed in laboratory parameters, vital signs, or ECG parameters.
1.5.3.1.4. Study B7931019
This study was designed to determine the effect of PF-06700841 (brepocitinib) 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 (brepocitinib) 200 mg, placebo and moxifloxacin 400 mg, according to 1 of the 
treatment sequences they were randomly assigned.  Treatment assignments to PF-06700841
(brepocitinib) and placebo were blinded to the participants and investigator but moxifloxacin 
treatment was unblinded.
1.5.3.1.4.1. Safety Summary of Phase 1 Study B7931019
In this study, 33 participants were enrolled in the study with 32 completers.  Overall 
PF-06700841 (brepocitinib) 200 mg and moxifloxacin 400 mg were well tolerated with no 
deaths, SAE, severe AEs, discontinuation due to AE, or clinically significant findings in 
laboratory parameters, vital signs or ECG parameters.  A total of 24 TEAE (all causalities) 
were reported in 15 participants after PF-06700841 (brepocitinib) treatment.  There were 
11 and 12 TEAEs reported in 10 and 8 participants after moxifloxacin and placebo treatment 
respectively. All AEs were mild to moderate in severity. Despite QTc increases observed 
after single doses of PF-06700841 (brepocitinib) 200 mg and moxifloxacin 400 mg, there 
were no clinically significant findings in ECG categorical analyses including no changes in 
QTcF>60 msec or an absolute value >500 msec.
1.5.3.1.5. 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 (brepocitinib) cream including vehicle and empty patch with white petrolatum 
under occlusive conditions in adult Japanese healthy participants.
Six investigational products PF-06700841 (brepocitinib) cream 0% [vehicle], 0.1%, 0.3%, 
1%, 3%, and empty patch with white petrolatum) were applied topically once using occlusive 
patches to the infrascapular area of the back on Day 1 and remained under occlusive 
conditions for 48 hours at which time the patches were removed.  The skin irritancy was 
evaluated approximately 30 minutes after removal of the patches and 24 hours after removal 
of the patches.


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All participants had 6 application sites on the back where 6 patches of investigational 
products were randomly assigned to determine irritation potential.  Dermal reactions at the 
application sites were assessed using a visual grade rating for erythema, edema, and other 
signs of skin irritation. One participant experienced a total of 3 TEAEs including 
nasopharyngitis, asthma and upper-airway cough syndrome; all of which were of moderate 
intensity, which were not considered treatment-related.
1.5.3.1.5.1. Disposition, and Demographic Characteristics Treatment-Emergent
Adverse Events (All-causality and Treatment Related) and Laboratory Values 
Twenty Japanese male participants were enrolled into the study and 20 participants 
completed treatment and safety follow-up.  None of the participants discontinued the study.  
No patients had skin irritation grade equal to or greater than 2 plus (≥++) were 0% on either 
Day 3 or Day 4 and on both assessment days for any of the 6 treatment groups.
One participant experienced a total of 3 TEAEs including nasopharyngitis, asthma and 
upper-airway cough syndrome; all of which were of moderate intensity, which were not 
considered treatment-related.
There were no deaths, SAEs or discontinuations in the study.  There were no clinically 
significant changes in laboratory values, vital signs or ECG.
1.5.3.1.6. 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 PF-06700841 (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 was not 
been finalized as of the time of this IB update, and these summarized results are in draft 
stage.
1.5.3.1.6.1. Safety Summary of Phase 1 Study B7931033
In this study, 12 healthy participants were enrolled in the study with 12 completers. In 
Period 1, a single oral dose of 30 mg PF-06700841 (brepocitinib) tablets was given alone, in 
Period 2, itraconazole 200 mg was administered as oral solution QD on Days 1-7 and 30 mg 
PF-06700841 (brepocitinib) co-administered on Day 4. There was no required washout 
between the last dose of PF-06700841 (brepocitinib) in Period 1 and the first dose of 
itraconazole in Period 2. Overall PF-06700841 (brepocitinib) 30 mg and itraconazole 
200 mg were well tolerated with no deaths, SAE, severe AEs, discontinuation due to AE, or 
clinically significant findings in laboratory parameters, vital signs or ECG parameters.
1.5.3.1.7. Study B7931010
This was an open-label, single dose, 2-period, 2-sequence crossover study in 8 healthy 
participants to characterize the PF-06700841 (brepocitinib) 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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1.5.3.1.7.1. Safety Summary of Phase 1 Study B7931010
All 8 participants received at least 1 dose of study medication and were included in the safety 
analysis.  Two participants reported 2 TEAEs when receiving PF-06700841 (brepocitinib)
30 mg IR and 2 participants reported 3 TEAEs when receiving PF-06700841 (brepocitinib)
30 mg MR. One participant experienced a treatment-related TEAE of headache and 1 
participant experienced throat irritation following the administration of PF-06700841
(brepocitinib) 30 mg IR.  In the MR treatment group, 1 participant experienced treatment 
related TEAEs of dry mouth and abdominal pain and 1 participant experienced a TEAE of 
dizziness.
All the TEAEs were of mild severity.  There were no deaths, SAEs, severe AEs, permanent 
discontinuations, dose reductions or temporary discontinuations due to AEs during the study.
1.5.3.1.8. 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 (brepocitinib) 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 (brepocitinib) 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 follow up 
period.
1.5.3.1.8.1. 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 (brepocitinib) 60 mg QD or PF-06700841
(brepocitinib) 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.


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1.5.3.1.8.2. 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 
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.
1.5.3.1.8.3. Serious Adverse Events in Phase 2 Study B7931004
Five 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
(brepocitinib) 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.
1.5.3.1.8.4. 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.


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No participants met the laboratory test discontinuation criteria (laboratory test abnormalities 
confirmed through re-testing within 48 hours) during study treatment.  There was no 
potential Hy’s Law case reported during the study.
1.5.3.1.8.4.1. 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.
1.5.3.1.8.4.2. Liver Function Tests
There were no clinically meaningful changes from baseline observed in AST and ALT across 
treatment groups during the study.  Two 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.
1.5.3.1.8.4.3. 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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1.5.3.1.8.4.4. 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 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.
1.5.3.1.8.4.5. 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.
1.5.3.1.8.5. 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.
1.5.3.1.9. 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 (ritlecitinib) and 
PF-06700841 (brepocitinib) 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 COE period. The study
included 2 drug holiday periods of 4 weeks each, and 2 follow-up periods of 4 weeks each.


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1.5.3.1.9.1. Summary of Adverse Events
There were no deaths reported.  During initial 24 weeks, 2 participants (
 
) experienced SAEs of rhabdomyolysis when receiving PF-06700841
(brepocitinib) 30 mg which resulted in permanent discontinuation from the study. Both 
SAEs were considered unrelated to the study drug.
There was 1 SAE during SBE period. One retreated PF-06700841 (brepocitinib) responder
(Participant
) permanently discontinued from PF-06700841 (brepocitinib) and 
discontinued from study due to a severe SAE of lower limb fracture in the Retreatment 
Segment, which was caused by an accident and was determined by the investigator and 
sponsor as not treatment-related.
One participant in PF-06700841 (brepocitinib) cross-over (CO) treatment group 
(Participant
) experienced an SAE of gastroenteritis salmonella which was 
considered not related to study drug and did not result in discontinuation from study or from 
study drug.
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 
participants in PF-06700841 (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 PF-06700841 (brepocitinib) treatment group. Two participants in 
PF-06700841 (brepocitinib) treatment group experienced Grade 3 decreased neutrophil
count. There were 2 participants in placebo group and 13 participants in PF-06700841
(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 PF-06700841 (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 participants 
discontinued from the study due to TEAEs (abnormal liver function test in 1 active
non-responder on PF-06651600 (ritlecitinib) and lower limb fracture in 1 retreated 
PF-06700841 (brepocitinib) responder). One active non-responder on PF-06700841 
(brepocitinib) discontinued from PF-06700841 (brepocitinib) due to AE of proteinuria but 
completed the study. Five participants (2 placebo non-responders on PF-06700841
(brepocitinib), 1 non-retreated PF-06651600 (ritlecitinib) responder, 1 non-retreated
PF-06700841 (brepocitinib) responder, and 1 retreated PF-06700841 (brepocitinib)
responder) had temporary discontinuation due to TEAEs (increased blood creatine 
phosphokinase in 2 participants, increased blood creatinine and decreased glomerular 
PPD
PPD
PPD


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filtration rate in 1 participant, palpitations in 1 participant, and rhabdomyolysis in 1 
participant). One retreated PF-06700841 (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 PF-06700841 (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 receiving 
PF-06700841 (brepocitinib) and 3 participants receiving placebo. TEAEs of increased blood 
creatine phosphokinase were reported in placebo non-responder on PF-06700841
(brepocitinib), and 1 retreated PF-06700841 (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 PF-06700841 (brepocitinib).
In the CO period: There were no deaths during the CO Period. No participants discontinued
from the study or discontinued study drug due to TEAEs. Two participants (1 participant in 
each treatment group) had temporary discontinuation due to TEAEs (moderate bronchitis in 
the PF-06700841 (brepocitinib) CO treatment group; moderate influenza like illness and
moderate torticollis in the PF-06651600 (ritlecitinib) CO treatment group). One participant 
in the PF-06700841 (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 PF-06700841 (brepocitinib)
CO treatment group. One participant in the PF-06700841 (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 
PF-06700841 (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 PF-06700841 (brepocitinib).
1.5.3.1.10. 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 PF-06700841
(brepocitinib) in participants with active, moderate to severe generalized SLE. This is the 
first study of PF-06700841 (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 PF-06700841 (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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1.5.3.1.12. Study B7931022
Study B7931022 was a Phase 2b, POC, randomized, double-blind, vehicle-controlled,
parallel group, dose ranging study to assess the efficacy, safety and PK of PF-06700841
(brepocitinib) cream applied topically once or twice daily in participants with mild or
moderate atopic dermatitis. Participation in this study was for approximately 16 
weeks which included up to a 6-week screening period, a 6-week treatment period, and a
4-week follow-up period.  Blood for determination of PF-06700841 (brepocitinib) plasma 
concentrations was collected prior to dosing at each visit.  In order to observe at least
224 participants with 6 weeks of data, 292 participants were randomized and treated at
70 sites across 10 countries.
The safety population included 292 participants with atopic dermatitis involving ≤20% BSA. 
73 participants were treated with vehicle and 219 participants were treated with PF-06700841
(brepocitinib).
Treatment-Emergent AEs by 5 Most Common System Organ Class Categories
The 5 most common AEs by SOC were Infections and Infestations, Skin and Subcutaneous 
tissue disorders, General disorders and Administration site conditions, Investigations, and 
Respiratory, Thoracic and Mediastinal disorders. The most common reported AE in the 
study was in the SOC Skin and Subcutaneous disorders and was worsening of atopic 
dermatitis. The majority of the AEs were mild. 
Summary of Safety Results in Adolescent Population
Six male adolescents were enrolled in the study. Two were in the vehicle QD group and 
1 each in the vehicle BID, 0.1% QD, 0.3% QD and 1% QD groups.  
Out of 6 adolescents that were enrolled in the study, 3 developed AE’s, which were all mild 
in severity. One adolescent participant developed neutropenia of 890/mL absolute neutrophil 
count at Day 64 in 0.3% QD active group. The neutrophil count, which was borderline low 
at baseline level consistent with presumed diagnosis of benign ethnic neutropenia, 
subsequently returned to the previous level. Two participants in vehicle QD group had AEs, 
one of worsening atopic dermatitis from D12 to D19 requiring use of concomitant 
medication, and one burning with application of IP from D1 to D27, which spontaneously 
resolved. 
There were no deaths in the study.
There were no cases of malignancies.
Hematological disorders and other clinical lab results
Except for 1 adolescent participant who experienced decrease in neutrophil count to less than 
1000/mm3, there were no other hematologic abnormalities reaching discontinuation criteria.


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Two participants in active groups reached >3 x ULN for alanine aminotransferase; one had 
131 U/L (in 0.3% QD group, and the other 106 U/L in 1% BID dosing group (ref range 
9-34 U/L). Eight participants (5 in active and 3 in vehicle treatment groups) had mild 
Creatine Kinase (CK) elevation >3 X ULN and <10 ULN, except for one participant in 
vehicle treatment group who had CK >10 X ULN. Abnormal CK results were sporadic, did 
not persist, and there was no temporal or dose dependent trend. There were no clinically 
significant trends in platelet, lymphocyte, neutrophil counts, or hemoglobin, bilirubin, 
aspartate, alanine transaminase and creatine kinase levels.
Skin tolerability
Overall, the drug was well tolerated. The skin tolerability is based on analysis of AEs and 
skin tolerability assessments. The study assessments were performed by principal 
investigator or qualified medical individual at each office visit, immediately before and after 
IP application. Reported AEs are presented in Results section above (SOC category: General 
disorders and application site reactions). The assessment of tolerability at site of IP 
applications before and after the treatment showed that majority of the participants had no 
evidence of local intolerability after IP application, with small number of participants having 
mild or moderate intolerability. The numbers of participants with mild and moderate 
intolerability are comparable through different dosing groups. 
There were 3 participants that have documented severe intolerability to IP application that 
led to early termination. One participant in vehicle QD group developed severe intolerability 
to IP application on Day 1, 1 in 3% QD group on Day 4 and 1 participant in 1% QD group.
The study met the primary efficacy endpoint. At Week 6 the percentage change from 
baseline based on the EASI score was statistically significant compared to vehicle with 
multiplicity adjustment in 1 of 4 active QD treatment groups (1% QD) and in 1 of 2 active 
BID treatment groups (1% BID). The highest percentage change from baseline (75.0%) was 
observed in the 1% BID treatment group. Key secondary endpoint results for the response 
rates based on IGA (clear [0] or almost clear [1] and a reduction from baseline of ≥2 points) 
were statistically significant in all 4 QD treatment groups (0.1% QD, 0.3% QD, 1% QD and 
3% QD) and in 1 of 2 BID treatment groups (0.3% BID).
1.5.3.1.13. 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 
PF-06700841 (brepocitinib) topical cream applied once or twice daily for 12 weeks in 
participants with mild to moderate chronic plaque psoriasis.
As of 20 August 2020, 8 cases reporting a total of 11 treatment emergent SAEs have been 
reported in the ongoing blinded Study B7931023. There are no SAEs assessed as related to 
blinded study treatment by the investigator. The SAEs are Pulmonary embolism, Urinary 
tract infection, Lethargy, Nervous system disorder, Skin laceration and Bursa injury, Cardiac 
failure and Respiratory failure, Sepsis and Thrombophlebitis, and Bacteremia.




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Table 4.
Summary of Steady State Plasma and Urine PF-06700841 (brepocitinib)
Pharmacokinetic Parameters Following Multiple Dose Administration 
(10 Days), Study B7931001
PF-06700841 (brepocitinib) 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)
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 
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 (brepocitinib) 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 (brepocitinib) 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.  Pharmacodynamic 
biomarkers response was best described by an indirect response PK/PD model indicating that 
AUC rather than Cmax is the important parameter to modulate disease response hence the 
recommendation is to administer the IP with no requirement regarding food in the current 
study.
Listed in Table 5 are the PK parameters following multiple-dose administration of 
PF-06700841 (brepocitinib) to psoriasis subjects. PF-06700841 (brepocitinib) 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 


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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. 
Table 5.
Summary of Plasma Steady State PF-06700841 (brepocitinib)
Pharmacokinetic Parameters Following Multiple Dose Administration 
(28 Days) in Psoriasis Subjects, Study B7931001
Parameter Summary Statisticsa by Treatment
Parameter, units
PF-06700841 (brepocitinib) 30 mg QD (P)
PF-06700841 (brepocitinib) 100 mg QD 
(P)
N, n
7, 7
5, 5
AUC, 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; P= patients with psoriasis.
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.
1.6. Rationale
1.6.1. Study Rationale
This multicenter, multiple-arm, placebo-controlled study will be the first determination of 
safety and efficacy of PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib) in subjects 
with moderate to severe CD.  The original objectives of this study were to evaluate the 
efficacy (based on clinically meaningful endoscopic improvement), safety, tolerability, PK, 
and PD of 200 mg for 8 weeks followed by 50 mg for 4 weeks of PF-06651600 (ritlecitinib) 
dosed once daily and 60 mg of PF-06700841 (brepocitinib) dosed once daily during an 
induction period of 12 weeks, followed by an open label extension period at doses of 50 mg 
and 30 mg of PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib), respectively, for 
52 weeks.  


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With the implementation of PA5, the aim of the study is revised.  The study modifications 
are based on: 
1. A strategic decision the part of the sponsor to prioritize future development of 
PF-06651600 (ritlecitinib), a JAK3/TEC inhibitor currently in development for a 
number of additional autoimmune diseases namely ulcerative colitis, alopecia areata 
and vitiligo; and 
2. A desire to enable efficient comparison with contemporary and emerging trials in 
Crohn’s disease. 
The decision to eliminate the PF-06700841 (brepocitinib) cohort from this study B7981007 is 
not due to any specific safety, efficacy or quality concerns that would negatively affect the 
overall benefit/risk for patients in this trial or in other trials.
The total induction period for both assets is 12 weeks.  The 12-week PF-06651600 
(ritlecitinib) hybrid induction dosing is a consequence of available nonclinical long-term 
toxicity data supporting higher 200 mg treatment for only 8 weeks (a lower 50 mg dose is 
being used for the remainder of the 12 week induction period). 
Dermatologic rashes have been observed in the Phase 1 PF-06651600 (ritlecitinib) 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.
Increases in serum creatinine have been observed in the Phase 1 PF-06700841 (brepocitinib)
studies.  However, nonclinical data suggest that this could be due to inhibition of a creatinine 
transporter in the proximal tubule rather than 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.
Histologic findings that could impact auditory function were observed in the chronic dog 
toxicology studies with PF-06651600 (ritlecitinib).  As the translation of this finding to 
humans is unknown at this time, a dose of PF-06651600 (ritlecitinib) is being used for 
treatment after 8 weeks that is 7.8 times lower than the dose level for which these histologic 
findings were NOT observed in dogs.  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 IL-6 inhibition have been observed with drugs that inhibit 
IL-6 signaling.  Therefore, lipid profiles will be assessed in the clinical programs.
Simvastatin is highly metabolized in the gut and modeling based on in vitro data suggests 
that PF-06651600 (ritlecitinib) time dependent inhibition of CYP3A may result in a clinically 
relevant increase in simvastatin plasma levels.  Thus, simvastatin use with PF-06651600 
(ritlecitinib) is currently prohibited.  Since PF-06651600 (ritlecitinib) is metabolized by 
CYP3A moderate to potent inhibitors and inducers of CYP3A are prohibited (Appendix 10).


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In vitro characterization of PF-06700841 (brepocitinib) ability to inhibit drug transporters 
indicates that it is likely to inhibit drug transporters OCT2, MATE and MDR1.  Based on 
these results, drugs with a low therapeutic index that are transported by (MDR1) (digoxin) or
OCT2/MATE (dofetilide) are prohibited.
Since PF-06700841 (brepocitinib) is metabolized by CYP3A moderate to potent inhibitors 
and inducers of CYP3A are prohibited (Appendix 10).
All endoscopies will be read by a central reader who will be blinded to study treatment.  
During the endoscopic evaluations, intestinal biopsies will be obtained and subsequently 
interrogated to provide evidence for pharmacological modulation of the JAK pathways and to 
define parameters that might be used to enable a precision medicine strategy in future clinical 
trials.  Furthermore, the peripheral blood and stool may be profiled to provide correlative 
peripheral biomarkers that could complement the precision medicine discovery in intestinal 
biopsies.
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 a smaller overall 
study size.  The inclusion of these two investigational drugs is appropriate as the target 
population and efficacy outcome measures are identical for both.
1.6.2. Dose Rationale
The dose selection strategy was designed to balance pharmacology and safety for this study 
with a 12 week induction period followed by a 52 week OLE in subjects with moderate to 
severe CD.  PK was assumed to be similar between healthy subjects and subjects with 
moderate to severe CD.  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.
1.6.2.1. PF-06651600 (ritlecitinib) Dose Rationale
A 2-compartment PK model with clearance and volume modeled as a function of dose 
described the concentration profiles at each dose level from the first-in-human study in 
healthy subjects (B7981001) and under fasted and fed conditions (B7981003).  The predicted 
PK parameters for PF-06651600 (ritlecitinib) based on simulations using the PK model are 
provided in Table 6.


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Table 6.
Summary of Predicted Geometric Mean Steady State Total Plasma 
PF-06651600 (ritlecitinib) Pharmacokinetic and Pharmacodynamic 
Parameters During the Induction and Chronic Periods of Multiple Dose 
Administration
Dose
mg QD
Total Cmax
ng/mL
Predicted
Marginsa
Cmaxa
Total AUCtau
ng.hr/mL
Predicted
Marginsa
AUCa
IP-10 % 
Reduction 
from Baseline
Induction
200
1254 (2.1)
12
3712 (14)
14
42 (19)
Induction/Chronic Dosing
50
259.5 (3.4)
5b
662.0 (20)
7b
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.
a.
Induction: NOAEL-highest dose in dogs, 45 mg/kg/day; Week 8 mean male and female Cmax (free) = 12,000 
ng/mL; Cmax (total) = 14,634 ng/mL; AUCtau (free) = 44,100 ng•h/mL; AUCtau (total) = 53,780 ng•h/mL.
b.
Chronic Dosing: 9 month oral dog NOAEL-5 mg/kg; mean male and female Cmax (free) = 1115 ng/mL; 
Cmax (total) = 1297 ng/mL; AUCtau (free) = 4018 ng•h/mL; AUCtau (total) = 4672 ng•h/mL, dog (fu) = 0.82.
The predicted exposure during the induction period at the top dose of 200 mg QD for 
8 weeks is projected to maintain 12- and 14-fold safety margins for Cmax and AUCtau, 
respectively.  During the remaining 4 weeks of the induction period at 50 mg QD and the 
OLE for 52 weeks the 50 mg dose is projected to maintain a safety margin for Cmax and 
AUCtau of 5- and 7-fold, respectively.
In human whole blood lymphocytes, PF-06651600 (ritlecitinib) inhibited JAK1/JAK3/TEC
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 (18-42%) of IP-10 is indicative of modulation of 
interferon gamma.  The predicted mean percent (%) inhibition of IL-15 was 44 and 81, 
respectively for the 50 mg and 200 mg. The corresponding values for IL-21 mean percent 
inhibition were 30 and 71, respectively for the 50 and 200 mg.
Pharmacological modulation of the target can be inferred from the predicted inhibition of 
IL-15 and IL-21.
1.6.2.2. PF-06700841 (Brepocitinib) Dose Rationale
This Section is no longer applicable to newly enrolled participants under PA5.
A 2-compartment PK model with clearance and volume modeled as a function of dose 
described the concentration profiles at each dose level from the first-in-human study in 
healthy subjects, subjects with psoriasis and under fasted and fed conditions (B7931001).  
The predicted PK parameters for PF-06700841 (brepocitinib) based on simulations using the 
PK model are provided in Table 7.


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Table 7.
Summary of Predicted Steady State Total Plasma PF-06700841
(brepocitinib) Pharmacokinetic and Pharmacodynamic Parameters
Dose
mg QD
Total Cmax
ng/mL
Predicted 
Cmax
Margins
Total 
AUCtau 
ng·hr/m
L
Predicted
AUC 
Marginsa
Percent Reduction from Baseline
hsCRP
IP-10
Neutrophils
Reticulocytes
Induction Treatment Period
60
433.3 (27)
7.2
3797 (43)
3.9
84 (6.4)
51 (21)
32 (70)
50 (34)
Maintenance Treatment Period
30
201 (29)
15
1575 (43)
9.3
82 (7.7)
47 (26)
30 (45)
36 (35)
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; 
a 9 month oral monkey NOAEL-20 mg/kg; mean male and female Cmax (free) = 2263 ng/mL; Cmax (total) = 3100 ng/mL; 
AUCtau (free) = 10741 ng•h/mL; AUCtau (total) = 14700 ng•h/mL, monkey (fu) = 0.73; human fu = 0.61
The predicted exposure during the induction period at the top dose of 60 mg QD for 
12 weeks is projected to maintain 7.2- and 3.9-fold safety margins for Cmax and AUCtau, 
respectively.  During the chronic dosing period the 30 mg dose administered QD for 
52 weeks is projected to maintain safety margins for Cmax and AUCtau of 15- and 9.8-fold, 
respectively.
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 mean 
percent reductions in the hsCRP levels ranged between 69% and 84% over the dose range 
10-60 mg.  Similarly, the mean 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.
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 CD.
1.6.3. Summary of Benefits and Risks
IBD is a serious disease with potentially life-threatening sequelae. 
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 (ritlecitinib) 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. 


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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 (ritlecitinib) compared to placebo after 8 week treatment in seropositive 
subjects with moderate to severe active RA and an inadequate response to methotrexate.  
PF-06651600 (ritlecitinib) 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 (ritlecitinib) 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 (ritlecitinib) and PF-06700841 (brepocitinib) in 
subjects with moderate to severe active AA.  PF-06651600 (ritlecitinib) appeared generally 
safe and well tolerated. There were no deaths in the study. There were no subjects with 
SAEs in the PF-06651600 (ritlecitinib) group. The number of AEs was higher in the placebo 
group relative to the PF-06651600 (ritlecitinib) 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.
The safety profile observed during the Phase 1 program for PF-06700841 (brepocitinib)
appears to be acceptable at dosages up to 175 mg administered orally as multiple doses over 
10 days in healthy volunteers.  A 28 day dosing duration was explored in psoriasis patients, 
who received the maximum PF-06700841 (brepocitinib) dose level of 100 mg daily.  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 (brepocitinib)
for 4 weeks.  As with other immunomodulators, the risk of infection is potential concern due 
to the immunosuppressive effects of PF-06700841 (brepocitinib).  To limit this risk, a 
maximum daily dose of 60 mg 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. 
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 


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for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study. 
Banked biospecimens retained in the BBS also can be used in research on IBD and other 
inflammatory diseases.
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision. 
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 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo at Week 12 in subjects with 
moderate to severe CD.

Proportion of subjects achieving SES-CD 50 
(≥50% reduction in SES-CD from baseline) at 
Week 12.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 (ritlecitinib) and PF-06700841 
(brepocitinib) compared to placebo in subjects 
with moderate to severe CD over 12 weeks. 

Incidence and severity of laboratory 
abnormalities, vital signs, 12-lead ECG, 
adverse events, serious adverse events and 
withdrawals due to adverse events.

Incidence of serious infections.

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo during induction of 
additional endoscopic endpoints in subjects with 
moderate to severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 
(reduction of ≥3 points from baseline in 
SES-CD score) at Week 12.

Mean change from baseline in SES-CD score 
at Week 12.

Proportion of subjects achieving SES-CD 25 
(≥25% reduction in SES-CD from baseline) at 
Week 12.

Proportion of subjects achieving endoscopic 
remission (SES-CD ≤2) at Week 12. 

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 12.


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Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):

To evaluate the effect of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on outcomes based on 
additional clinical criteria.

Proportion of subjects achieving clinical 
response and remission using SF, and AP
measures at Weeks 2, 4, 6, 8, 10 and 12.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD 
and clinical remission by SF and AP) at 
Week 12.

Proportion of subjects with a CDAI-100 
response (defined by a decrease in CDAI score 
of at least 100 points from baseline) and 
proportion of subjects who are remitters 
(defined as CDAI <150) at Weeks 2, 4, 8 
and 12.

The scores and change from baseline in IBDQ
total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and 
Social Function) at Weeks 4, 8, and 12.

The proportion of subjects with IBDQ total 
score ≥170 at Weeks 4, 8, and 12.

The proportion of subjects with ≥16 point 
increase in IBDQ total score from baseline at 
Weeks 4, 8, and 12.

Proportion of subjects achieving IBDQ 
symptom domain response at Weeks 4, 8, 
and 12. 

The scores and change from baseline in 
EQ-5D-3L + VAS at Weeks 4, 8, and 12.

The scores and change from baseline in SF-36
v2 acute: PCS & MCS, and 8 domain scores at 
Weeks 4, 8, and 12.

Mean change from baseline in PGIS score at 
Weeks 4, 8 and 12.

To evaluate the effect of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on histopathology score.

Change from baseline in Global Histologic 
Disease Activity (GHAS) score at Week 12.

Proportion of subjects achieving histologic 
remission at Week 12 (defined as GHAS
score ≤4).  

To assess the effect of PF-06651600 (ritlecitinib) 
and PF-06700841 (brepocitinib) compared to 
placebo on disease and mechanistic biomarkers 
over time.

Change from baseline in serum high sensitivity 
C-reactive protein (hsCRP) levels over time.

Change from baseline in fecal calprotectin 
over time.

Change from baseline in serum IP-10 levels 
over time.


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
Change from baseline in BCL-2 gene 
expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and TBNK cells.

To describe the PK of PF-06651600 (ritlecitinib) 
and PF-06700841 (brepocitinib) compared to 
placebo in subjects with moderate to severe CD.

PF-06651600 (ritlecitinib) concentrations at 
Weeks 2, 4, 8 and 12.

PF-06700841 (brepocitinib) concentrations at 
Weeks 2, 4, 8 and 12.

To collect non-banked samples (eg, intestinal 
biopsies, stool for microbiome analysis, serum and 
plasma for analysis of proteins and a whole blood 
tube for RNA analysis) for exploratory research, 
unless prohibited by local regulations or ethics 
committee decision. 

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples 
unless prohibited by local regulations or ethics 
committee decision. 

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section.
2.2. Objectives and Endpoints during the Open Label Extension Period
Primary Objective(s):
Primary Endpoint(s):

To assess the safety and tolerability of 
PF-06651600 (ritlecitinib) and PF-06700841 
(brepocitinib) therapy during open label 
extension period for subjects with moderate to 
severe CD.

Incidence and severity of laboratory 
abnormalities, vital signs, 12-lead ECG,
adverse events, serious adverse events and 
withdrawals due to adverse events.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib) as 
maintenance therapy in subjects with moderate to 
severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement (CMEI 
response) at Week 64 among subjects who 
achieved CMEI response at Week 12.

Proportion of subjects achieving SES-CD 25 
and SES-CD 50 at Week 64 among subjects 
who achieved SES-CD 25 and SES-CD 50 at 
Week 12 respectively.
Exploratory Objective(s):
Exploratory Endpoint(s):

To evaluate the efficacy of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
therapy during the open label extension period for 
subjects with moderate to severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 
(reduction of ≥3 points from baseline in 
SES-CD) at Week 64.

Proportion of subjects achieving SES-CD 25 
and SES-CD 50 (≥25% and ≥50% reduction in 
SES-CD from baseline) at Week 64.


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
Proportion of subjects achieving endoscopic 
remission (SES-CD ≤2) at Week 64.

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 64.

To evaluate the effect of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib) on 
outcomes based on additional clinical criteria.

Proportion of subjects achieving clinical 
response and remission as defined by SF and 
AP endpoints at Weeks 16, 20, 24, 32, 40, 48, 
56 and 64.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD 
and clinical remission by SF, AP) at Week 64.

Proportion of subjects with a CDAI-100 
response or CDAI remission (CDAI <150) at 
Weeks 16, 32 and 64. The scores and change 
from baseline in IBDQ Total score and 
domains (Bowel Symptoms, Systemic 
Symptoms, Emotional Function and Social 
Function) at Weeks 16, 32 and 64.

The proportion of subjects with IBDQ total 
score ≥170 at Weeks 16, 32 and 64.

The proportion of subjects with ≥16 point 
increase in IBDQ total score from baseline at 
Weeks 16, 32 and 64.

Proportion of subjects achieving IBDQ 
symptom domain response at Weeks 16, 32 
and 64. 

The scores and change from baseline in 
EQ-5D-3L + VAS at Weeks 16, 32 and 64.

The scores and change from baseline in SF-36
v2: PCS & MCS, and 8 domain scores at 
Weeks 16, 32 and 64.

Mean change from baseline in PGIS score at 
Weeks 16, 32 and 64.

To evaluate the effect of PF-06651600 
(ritlecitinib) and PF-06700841 (brepocitinib)
compared to placebo on histopathology score.

Change from baseline in GHAS score at 
Week 64.

Proportion of subjects achieving histologic 
remission (GHAS ≤4) at Week 64.  

To describe the PK of PF-06651600 (ritlecitinib) 
and PF-06700841 (brepocitinib) in subjects with 
moderate to severe CD.

PF-06651600 (ritlecitinib) concentrations at 
Weeks 16, 20, 32, 56 and 64.

PF-06700841 (brepocitinib) concentrations at 
Weeks 16, 20, 32, 56 and 64.

To explore the relationship between PK, PD, and 
clinical endpoints.

Change from baseline in serum hsCRP levels 
over time.


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
Change from baseline in fecal calprotectin.

Change from baseline in serum IP-10 levels 
over time.

Change in baseline in BCL-2 gene expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and TBNK cells.

To collect non-banked samples (eg, intestinal 
biopsies, stool for microbiome analysis, serum and 
plasma for analysis of proteins and a whole blood 
tube for RNA analysis) for exploratory research, 
unless prohibited by local regulations or ethics 
committee decision. 

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples
unless prohibited by local regulations or ethics 
committee decision. 

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, multicenter 
study in subjects with moderate to severe active 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 230-250 subjects
in total will be randomized into the study.
The 12-week induction period will be placebo-controlled and double-blind within each 
investigational product.  Subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive either active or placebo treatments.  In the induction period, 
200 mg QD for 8 weeks followed by 50 mg QD for 4 weeks of PF-06651600 (ritlecitinib)
and matching placebo in a 2:1 ratio and for subjects enrolled prior to implementation of PA5, 
60 mg QD for 12 weeks of PF-06700841 (brepocitinib) and matching placebo in a 2:1 ratio 
will be investigated.  The hybrid dosing regimen for PF-06651600 (ritlecitinib) during the 
12-week induction period is a consequence of available nonclinical long-term toxicity data 
supporting 200 mg treatment for only up to 8 weeks.  For analysis, placebo groups will be 
combined. 
After the completion of the induction period, subjects will enter the 52-week OLE period.  
There will be no re-randomization at the beginning of the OLE period.  Subjects will receive 
the same study drug that they were randomized to receive during the induction period, and 
there will be no placebo arms.  Placebo subjects from the induction period will also receive 
active drug in the OLE period. The matching placebo subjects from the double-blind 
PF-06651600 (ritlecitinib) treatment/placebo induction period will receive 50 mg of 
PF-06651600 (ritlecitinib), while the corresponding placebos from the double-blind 
PF-06700841 (brepocitinib)/placebo induction period will receive 30 mg of PF-06700841
(brepocitinib) for 52 weeks. 


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After completion of the OLE period, subjects will enter the 4-week follow up period.  Any 
subjects, who discontinues early from the double-blind period prior to the Week 12 visit,
should undergo the procedures for an Early Termination (Induction) visit on the last day the 
subject takes the investigational product or as soon as possible thereafter.  For subjects who 
discontinue early from OLE period (after the Week 12 visit, but prior to the Week 52 visit), 
the procedures scheduled for an Early Termination (OLE) visit will be performed on the last 
day the subject takes the investigational product or as soon as possible thereafter. These 
early withdrawal subjects, along with subjects who complete the induction period but are not 
willing to participate in the OLE period, will be asked to complete the Follow-up visit
approximately 4 weeks after the last dose of study drug.
The original objectives of this study were to evaluate the efficacy [based on clinically 
meaningful endoscopic improvement (reduction of ≥3 points from baseline in SES-CD score) 
at Week 12 as assessed by central reading], safety, tolerability, PK, and PD of 200 mg for 
8 weeks followed by 50 mg for 4 weeks of PF-06651600 (ritlecitinib) dosed once daily and 
60 mg of PF-06700841 (brepocitinib) dosed once daily during an induction period of 
12 weeks, followed by an open label extension period at doses of 50 mg and 30 mg of 
PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib), respectively, for 52 weeks.  
Amendment 5 of Protocol B7981007 revises the original design to eliminate the 
PF-06700841 (brepocitinib) and placebo arms and to change the primary endpoint during 
induction from CMEI to SES-CD 50 (to enable efficient comparison with contemporary and 
emerging trials in Crohn’s disease). Therefore, upon approval of Amendment 5 by regional 
Regulatory Authorities and Ethics Committees, Protocol B7981007 will be conducted as a 
Phase 2a, randomized, double-blind, placebo-controlled, parallel group study focused on the 
evaluation of the efficacy and safety profile of the PF-06651600 (ritlecitinib) in subjects with 
moderate to severe active CD. All eligible participants that have been randomized to 
PF-06700841 (brepocitinib)/PF-06700841 (brepocitinib) placebo or currently actively 
receiving PF-06700841 (brepocitinib)/PF-06700841 (brepocitinib) placebo under previous 
protocol amendments will continue to receive PF 06700841 (brepocitinib) through to 
completion. This study modification is solely a strategic decision on the part of the sponsor 
to prioritize future development of PF-06651600 (ritlecitinib), a JAK3/TEC inhibitor 
currently in development for a of number of additional autoimmune diseases namely 
ulcerative colitis, alopecia areata and vitiligo. The decision to eliminate the PF-06700841 
(brepocitinib) cohort from this study B7981007 is not due to any specific safety, efficacy or 
quality concerns that would negatively affect the overall benefit/risk for patients in this trial 
or in other trials.




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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 (including Women of Child Bearing Potential
(WOCBP)) ≥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. Documented diagnosis of ileal, ileocolonic, or colonic CD with a minimum disease 
duration of 3 months, as determined by endoscopic and histopathology assessment.
3. Endoscopic (central reading) confirmation of active disease with total SES-CD total 
score of at least 7 (≥7)).  For isolated ileal disease, SES-CD total score should be at 
least 4 (≥4).
4. An average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) 
score ≥2.0.
5. Must have inadequate response to, loss of response to, or intolerance to at least one 
conventional therapy for CD:

Steroids;

Immunosuppressants (azathioprine [AZA], 6-MP, or methotrexate [MTX]);

Anti-TNF inhibitors (infliximab, adalimumab, or certolizumab);

Anti-integrin inhibitors (eg, vedolizumab);

Anti-IL-12/23 inhibitor (ustekinumab).
However, this inclusion should be met only after the usual clinical practice in each 
center has been fulfilled, which may involve administration of more than one line of 
previous treatment.
Note: The information below is provided for guidance only.  Local standards of 
care, as well as investigator assessment should be considered in any assessment.


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Inadequate response to, loss of response to, or intolerance to corticosteroid treatment 
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 of ≥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 
anti-integrin inhibitors, or ustekinumab (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 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)), or one 8 week 
regimen of at least one IV weight-based loading dose infusion and one 90 mg 
maintenance dose of ustekinumab. 

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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6. Subjects currently receiving the following treatment for CD are eligible providing 
they have been on stable doses as described below:

Oral corticosteroids (prednisone or equivalent up to 25 mg/day; budesonide up to 
9 mg/day; See Appendix 11). 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.

Oral 5-ASA or sulfasalazine are allowed providing that the dose is stable for at 
least 4 weeks prior to baseline.

Crohn’s disease-related antibiotics are allowed providing that the dose is stable 
for at least 4 weeks prior to baseline. If antibiotics are stopped prior to baseline, 
they must be discontinued at least 4 days prior to baseline.
7. Female subjects of childbearing potential must test negative for pregnancy at 
screening visit and baseline visit.
8. 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. 
9. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, infectious 
colitis, radiation colitis, diverticular disease, ulcerative colitis (UC), or clinical 
findings suggestive of UC.


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2. Presence of active (draining) fistulae or intra-abdominal or perineal abscesses. 
3. Strictures with obstructive symptoms.
4. Short bowel syndrome.
5. History of bowel perforation requiring surgical intervention within the past 
12 months.
6. Previous bowel surgery resulting in an existing stoma.  Subjects who have a j-pouch 
are excluded, as a j-pouch can result in a stoma.
7. History of bowel surgery within 6 months prior to baseline.
8. Subjects considered in imminent need for surgery or with elective surgery scheduled 
to occur during the study. 
9. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
10. Subjects with primary sclerosing cholangitis.
11. Subjects with evidence of colonic adenomas, dysplasia or neoplasia.  However, 
subjects with prior history of adenomatous polyps or any adenomatous polyps 
identified on screening will be eligible if the polyps have been completely removed
and the subjects are free of polyps at baseline per the assessment of the investigator 
based on the screening colonoscopy.
12. Subjects receiving the following therapies within the time period described below or 
expected to receive any of these therapies during the study period:
a.
>9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral 
systemic corticosteroid dose within 2 weeks prior to baseline.
b. IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid 
enemas/suppositories within 2 weeks prior to baseline.
c.
Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline.
d. Anti-TNF inhibitors (or biosimilars thereof) as described below:

Infliximab within 8 weeks prior to baseline;

Adalimumab within 8 weeks prior to baseline;

Certolizumab within 8 weeks prior to baseline;
e.
Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.


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f.
Ustekinumab within 8 weeks prior to baseline.
g. Interferon therapy within 8 weeks prior to baseline.
h. 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).
i.
Subjects who have received rituximab or other selective B lymphocyte-depleting 
agents within 1 year prior to baseline.
j.
Subjects previously receiving leukocyte apheresis, including selective 
lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 
6 months prior to baseline.
k. Other marketed immunosuppressants or biologics with immunomodulatory 
properties within 3 months prior to baseline.
l.
Subjects who have received other JAK inhibitors within 3 months prior to 
baseline.
m. Subjects who have not responded to or have been intolerant of other JAK 
inhibitors.
n. 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.
13. 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.
14. Presence of active enteric infections (positive stool culture and sensitivity). 
Clostridium difficile infection (reference C. diff section) or pseudomembranous 
colitis, or 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.
15. Abnormal findings on the chest x-ray film such as presence of tuberculosis (TB), 
general infections, heart failure, or malignancy.  A chest X-ray or other appropriate 
diagnostic imaging modality (ie, CT with or without IV contrast or MRI) performed 
within 12 weeks prior to screening may substitute for the chest X-ray taken at 
Screening.  Documentation of the official negative reading must be located and 
available in the source documentation prior to Baseline (Day 1) randomization.


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16. Any history of either untreated or inadequately treated latent or active TB infection, 
current treatment for active or latent TB infection or evidence of currently active TB 
by chest x-ray, residing with or frequent close contact with individual(s) with active 
TB.  Subjects who have a positive Interferon Gamma Release Assay during screening 
or within 12 weeks prior to randomization, except as noted below.  The following are 
acceptable assays prior to screening: QuantiFERON® - TB Gold test (QFT-G), 
QuantiFERON® - TB Gold In-Tube test (QFT-GIT) and T-SPOT® - TB test.
Covance tests that replace the above specified tests are permitted.

Subjects with prior active tuberculosis (except for multi drug resistant TB) that 
has no current evidence of active disease and has completed an adequate course of 
therapy for active tuberculosis (a multi-drug regimen recognized by the World 
Health Organization to which the organism has demonstrated appropriate 
sensitivity), negative chest radiograph for active disease and negative Interferon 
Gamma Release Assay (IGRA) are eligible.

Subjects that have an indeterminate QFT-G may have QFT-G test repeated and, 
will be eligible if the repeat (QFT-G) test is negative at time of randomization.  
Subjects with repeat indeterminate IGRA results may be enrolled after 
consultation with pulmonary or infectious disease specialist that determines low 
risk of infection (ie, subject would be acceptable for immunosuppressant 
(eg, anti-TNF) 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 IGRA results provided the 
treatment is well documented in the subject’s medical records and/or source 
documentation prior to enrollment in the study.
17. 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). 
18. Subjects will be screened for hepatitis B virus infection and will be excluded if 
positive for hepatitis B surface antigen (HBsAg).  Subjects with HBsAg negative 
testing, but who test positive for hepatitis B core antibody (HBcAb) must have further 
testing for hepatitis B surface antibody (HBsAb).  If HBsAb is negative, the subject 
will be excluded from the study. 
19. Subjects will be screened for hepatitis C virus (HCV Ab). 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.


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20. Clinically significant infections within 6 months of baseline (eg, those requiring 
hospitalization or parenteral antimicrobial therapy, or opportunistic infections), 
history of any infection requiring antimicrobial therapy within 2 weeks of baseline, or 
a history of any infection otherwise judged by the investigator to have the potential 
for exacerbation by participation in the study.
21. 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 cancer of the skin or cervical carcinoma in situ).
22. Presence of transplanted organ; skin grafts are allowed. 
23. 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.
24. 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.
25. 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;

Heart failure NYHA (New York Heart Association) III, NYHA IV.
26. 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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27. 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 (at least 1 highly effective method) of contraception as 
outlined in this protocol for the duration of the study and for at least 28 days after the 
last dose of investigational product.
28. 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.
29. Subjects receiving prohibited concomitant medications, including moderate to potent 
CYP3A inducers or inhibitors (See Appendix 10) 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.
30. Subjects receiving strong P-gp inhibitors (eg, quinidine) within 5 half-lives prior to 
baseline.
31. Subjects receiving narrow therapeutic index substrates of MDR1 (eg, digoxin), OCT2 
or MATE (eg, dofetilide) within 5 half-lives prior to baseline.
32. Prior evidence of liver injury or toxicity due to methotrexate.
33. Abnormality in hematology and/or chemistry profiles during screening:

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).

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).

eGFR <60 mL/min/1.73m2 based on the age appropriate calculation.

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.


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
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 
≥1.5 times the upper limit of normal (ULN).

Proteinuria ≥3+.

Creatine kinase (CK) >3 times the ULN and positive urine myoglobin.

Glycosylated hemoglobin (HbA1C) >10%.

Subjects with HbA1C > ULN without a diagnosis of diabetes mellitus should 
be evaluated prior to randomization for evaluation.
Screening laboratory tests if considered by the investigator to be transient and 
inconsistent with the subject’s clinical condition may be repeated once during the 
screening period for confirmation.
34. Donation of blood in excess of 500 mL within 8 weeks prior to baseline.
35. History of alcohol or drug abuse with less than 6 months of abstinence prior to 
baseline.
36. 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.
37. History of thrombotic event(s), including deep venous thrombosis (DVT), and known 
inherited conditions that predispose to hypercoagulability.
4.3. Randomization Criteria 
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria.  This study will enroll a total of approximately 230-250 subjects (expected to 
provide approximately 196-210 completers).  Eligible subjects will be randomly assigned to 
a treatment group through the sponsor’s interactive response technology (IRT) system in the 
allocation ratio stratified by:
1. Anti-TNF experience (yes or no).
2. Steroid use at baseline (yes or no).
3. Baseline disease activity/extent (no isolated ileal disease and baseline SES-CD >15, 
no isolated ileal disease and baseline SES-CD ≤15, or isolated ileal disease).
Upon implementation of PA5, eligible subjects will be randomized to PF-06651600 
(ritlecitinib) or matching placebo in a 2:1 ratio.  For analyses purposes, the two placebo arms 
from the induction period will be combined.


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There will be no re-randomization at the beginning of the open label extension period.
4.4. Lifestyle Requirements
In order to participate in the study, subjects must be aware of the following lifestyle 
guideline: 

Agree to avoid strenuous exercise during the study, especially within one week prior 
to the scheduled study visits and maintain adequate hydration, if possible.
4.4.1. Contraception
In this study, fertile male subjects and female subjects who are of childbearing potential as 
applicable to the study may receive PF-06651600 (ritlecitinib) or PF-06700841
(brepocitinib), both of which have been associated with demonstrated 
teratogenicity/fetotoxicity in animals (more details in the IB). 
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 or tubal ligation.
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.
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.
The required contraception methods listed above meet the recommendations of study 
B7981018.
4.4.2. 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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4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the 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 (ritlecitinib) and PF-06700841
(brepocitinib) 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.
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 64.  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 and/or chronic therapy 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
For the induction phase, blinded PF-06651600 (ritlecitinib) and matching placebos will be 
provided as tablets in blister cards for oral administration.  For the induction phase of 
subjects enrolled prior to implementation of PA5, blinded PF-06700841(brepocitinib) and 
matching placebos will be supplied as tablets in bottles for oral administration. The 
designation “PF-06651600-15” and “PF-06700841-15” may appear on labeling and indicates 
a salt.  They are equivalent to “PF-06651600” (ritlecitinib) and “PF-06700841” (brepocitinib)
with regard to this protocol.  The PF-06651600 (ritlecitinib) 50 mg tablets and their matching 
placebos will be supplied in separate blister cards and labeled according to local regulatory 
requirements.  The PF-06700841 (brepocitinib) 5 mg and 25 mg tablets and their matching 


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placebos will be supplied in separate bottles and labeled according to local regulatory 
requirements. 
For the open label extension period, PF-06651600 (ritlecitinib) tablets will be supplied in 
blisters. For the open label extension period, PF-06700841 (brepocitinib) tablets will be 
supplied in bottles.
5.5. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each 
visit from baseline visit through Week 56.  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 12
for investigational product dispensing during public emergencies if applicable.
5.6. Administration
Subjects will receive IP as outpatients.  PF-06651600 (ritlecitinib) and PF-06700841
(brepocitinib) 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.
Subjects should take the IP orally for 12 weeks during the induction period and an additional 
52 weeks during the OLE period for a total of 64 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, 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. 
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 Term (Induction) visit.  During the OLE period, 
if dosing is missed for more than 7 consecutive days, the subject should be considered for 
discontinuation following consultation with the sponsor and should undergo the procedures
for an Early Term (OLE) visit. Also, the subject will be asked to complete the Follow-up 
visit approximately 4 weeks after the last dose of study drug.


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5.7. 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 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. 
5.8. 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 and at the end of the trial.
5.8.1. 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.
Returned test article can be destroyed only after the sponsor monitor has verified the 
accuracy of the dispensing and inventory record.  The monitor must verify that site staff 
follows instructions regarding the return of investigational product to the Supply Chain 
Organization or vendor for destruction.
5.9. 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).
5.9.1. Oral Corticosteroids
Any oral corticosteroids taken during the screening and treatment periods of the study will be 
captured on the appropriate CRF.
5.9.2. 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 68).  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 (prednisone equivalent up to 25 mg/day; 
budesonide up to 9 mg/day See Appendix 11) for at least 2 weeks prior to baseline 
and through end of induction period (Week 12, except for the case of subjects
undergoing optional steroid tapering in the OLE 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 OLE period, steroids may be slowly 
tapered per local guidelines.  Steroid tapering is allowed only in the OLE period. 
Subject may reduce the daily dose of prednisone or equivalent by 2.5 to 5 mg weekly 
(based on their symptom’s) 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 CD 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.  Subjects requiring a second step up in corticosteroid usage will be required to 
discontinue the study. See Appendix 11 for guidance on steroid equivalency.
5.9.3. 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 68).

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 68).

Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline and 
through Week 68.

Biologics including anti-TNF inhibitors (eg, infliximab, adalimumab, certolizumab), 
or biosimilars thereof, within 8 weeks prior to baseline and through end of study 
(Week 68).

Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline and 
through end of study (Week 68).

Ustekinumab within 8 weeks prior to baseline and through end of study (Week 68).

Interferon therapy within 8 weeks prior to baseline and through end of study 
(Week 68).


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
Lymphocyte-depleting agents/therapies within 1 year prior to baseline and through 
end of study (Week 68).

Leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte 
apheresis, or plasma exchange within 6 months prior to baseline and through end of 
study (Week 68). 

Rituximab or other selective B lymphocyte-depleting agents within 1 year prior to 
baseline and through end of study (Week 68).

Other marketed immunosuppressants or biologics with immunomodulatory properties 
within 3 months prior to baseline and through end of study (Week 68).

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 68).

Any live (attenuated) vaccines from 30 days prior to baseline and through the end of 
study (Week 68).

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 68).

Moderate to potent CYP3A inducers or inhibitors as listed in Appendix 10 through 
end of the study (Week 68).

Simvastatin or simvastatin-containing products from 5 days prior to baseline and 
through end of study (Week 68).

Strong P-gp inhibitors (eg, quinidine) within 5 half-lives prior to baseline and through 
end of study (Week 68).

Narrow therapeutic index substrates of MDR1 (eg, digoxin), OCT2 or MATE 
(eg, dofetilide).
5.9.4. 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 68).  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. 
5.10. Rescue Medication 
During the induction phase, if subjects require rescue medication, they will be discontinued 
from treatment and should undergo the procedures for an Early Term (Induction) visit.
During the OLE period, if subjects require rescue medication, they will be discontinued from 
treatment and should undergo the procedures for an Early Term (OLE) visit.
After any discontinuation, subjects will be asked to complete the Follow-up visit 
approximately 4 weeks after the last dose of study drug.
6. STUDY PROCEDURES 
Refer to Appendix 12 for Alternative Measures During Public Emergencies if applicable. 
Visits should occur when scheduled, within the time window indicated in the Schedule of 
Activities.  Written informed consent must be obtained prior to performing any 
protocol-specific procedures, including washout of prohibited medications.  To prepare for 
study participation, subjects will be instructed on the use of Lifestyle Requirements (see 4.4) 
and Concomitant Treatments (see Section 5.9).
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal 
results; the last value will be used to determine eligibility.  If results return to normal 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). 
Where possible the following order of activities should be followed during the clinic visits.
1. Assessments: IBDQ, SF-36, EQ-5D-3L+ VAS, eDiary data collection (stool 
frequency, abdominal pain, general wellbeing and PGIS).
2. ECGs.
3. Vital signs.
4. Blood and Urine Sample Collection.
5. Investigational Product Dosing.


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6.1. Screening
For screening procedures, see Schedule of Activities and ASSESSMENTS section.
Complete medical history should include: 

History of CD, including duration of disease, extent of disease, extra-intestinal 
manifestations, duration of current flares, number of flares in the preceding year, and 
CD related hospitalizations; 

History of chicken pox and shingles;

History if skin rash, skin infection and any abnormalities that may predispose the 
subject to infection; 

Reasons for previous CD medication intolerance (ie, discontinuation of medication 
due to an AE as determined by the investigator); 

History of previous vaccinations, specifically influenza, pneumococcal, varicella, and 
zoster.
Subjects will be instructed on the collection of eDiary data.  The number of liquid stools or 
very soft stools, the intensity of abdominal pain, general well-being and PGIS questionnaire
will be collected continuously for 12 weeks throughout the induction phase in the eDiary.  
During the OLE phase subjects will be requested to complete their eDiary until Visit 16, 
from Visit 24 to 32, and from Visit 56 to 64.
Colonoscopy should be performed within 10 days of baseline, preferably 5 to 7 days prior to 
the baseline to allow stool diary data collection. 
6.2. Induction Period
For treatment period procedures, see Schedule of Activities and ASSESSMENTS section.
Collect a genomic banked biospecimen (Prep D1) at baseline (Week 0/Day 1).  If missed, 
collect at the next available time point when biospecimens are being collected in conjunction 
with a subject visit (only for randomized subjects).
6.3. Open Label Extension Period
For open label extension period procedures, see Schedule of Activities and ASSESSMENTS
section.


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6.3.1. Follow-up Contact
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 the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (see the Contraception section).  Contact with the subject 
may be done via a phone call.
For follow-up and end of study procedures, see Schedule of Activities and ASSESSMENTS
section.
6.4. Subject Withdrawal
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 early term procedures.  The only exception to 
this is when a subject specifically withdraws consent for any further contact with him or her 
or persons previously authorized by the subject to provide this information.  Subjects should 
notify the investigator in writing of the decision to withdraw consent from future follow-up, 
whenever possible.  The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is only from further receipt of 
investigational product or also from study procedures and/or 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.
Any subjects, who discontinues early from the double-blind induction period prior to the 
Week 12 visit, should undergo the procedures for an Early Term (Induction) visit on the last 
day the subject takes the investigational product or as soon as possible thereafter.  For 
subjects who discontinue early from the OLE period (after the Week 12 visit, but prior to the 
Week 68 visit), the procedures scheduled for an Early Term (OLE) visit will be performed on 
the last day the subject takes the investigational product or as soon as possible thereafter.
After any discontinuation, subjects will be asked to complete the Follow-up visit 
approximately 4 weeks after the last dose of study drug.
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 


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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.
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.

Platelet counts <100 x 109/L (<100,000/mm3).

Lymphocytes <800/mm3; <0.8 x 109/L.

CK > 3x ULN (this also triggers urine myoglobin).

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).


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
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 meeting criteria that require the infection to be classified as serious 
adverse event (See Section 7.1.7).

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.

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.


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
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 CD for disease 
progression.

Subjects who are inadequately responding to investigational product in the opinion of 
the investigator.

Surgery for CD.

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.
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.


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For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
Refer to Appendix 12 for Alternative Measures During Public Emergencies if applicable.
7.1. Safety
7.1.1. Clinical Laboratory Tests
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, ECGs, 
and clinical laboratory results in all subjects who received at least 1 dose of study 
medication.  Investigators and Pfizer Clinicians will review individual subject data 
throughout the conduct of the trial to ensure subjects’ well-being.
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)
Basophils (Abs)
Lymphocytes (Abs)
Monocytes (Abs)
Reticulocyte count
WBEDT
Reticulocyte count %
PT/INR/PTT
BUN/Urea & Creatinine
Cystatin C
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (Bicarbonate)
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
TBNK cells
Viral Surveillance
Stool sampleg to detect 
enteric infections and C. 
difficile toxins A and B
Stool sample for 
microbiome
Stool sample for fecal 
calprotectin 
Exploratory samples 
(serum, plasma, blood 
RNA, DNA)
Colonic tissue biopsies
Skin biopsies/swabsi
Urine Myoglobinj
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.


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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.
j.
At screening and in case of CK >3x ULN during the study. Additional tests may be performed during 
the study at the investigator’s discretion, as indicated by signs and symptoms of ongoing AEs.
7.1.2. 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.2
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.3,4  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.5
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. 
7.1.3. 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.6
7.1.4. 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 


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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 
confirmed pregnancy, the subject will be withdrawn from administration of investigational 
product but will remain in the study in follow-up. 
7.1.5. Interferon Gamma Release Assay Tuberculin Test
Subjects may be screened for TB using an IGRA per local guidelines.  IGRA will be used 
locally (where feasible) during screening or within 12 weeks prior to screening to test for 
active/latent tuberculosis (TB).  The following are acceptable assays: QuantiFERON®-TB 
Gold test (QFT-G), QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT® TB 
test. Covance tests that replace the above specified tests are permitted.  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.  The specific IGRA method, or test, used should 
comply with local country-specific guidelines.  The type (name) and results of the IGRA TB 
test must be known and located in source documentation. 
Subjects with a documented positive IGRA TB test performed within 12 weeks prior to 
Screening are excluded.  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 consultation with pulmonary or infectious disease specialist that determines low risk of 
infection (ie, subject would be acceptable for immunosuppressant (eg, anti-TNF) treatment 
without additional action).
The sample(s) will be analyzed by the site’s local laboratory.  Refer to local lab for any 
additional processing information and shipping instructions.
7.1.6. Screening for Clostridium Difficile
C. difficile testing is performed at 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 


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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.
7.1.7. 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;
OR

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. 


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7.1.8. Viral Surveillance
Blood samples for the analysis of viral load for Cytomegalovirus (CMV), Epstein–Barr virus
(EBV), Herpes Simplex Virus (HSV1), HSV2 and Varicella Zoster Virus (VZV) will be 
collected according to the times outlined in the Schedule of Activities.  Additional sample 
collection instructions will be provided in the lab manual. 
Note: Due to long turnaround time, the reporting time of these labs could be quite delayed.
In addition to time points specified, a plasma sample for viral surveillance sample may also 
be taken at the time of an adverse event, as clinically appropriate.
7.1.9. Vital Signs (Blood Pressure, Pulse Rate, and Temperature)
Blood pressure will be measured in the subject’s dominant arm and recorded to the 
nearest mmHg.  It is preferred that the same arm be used throughout the study.  The same 
blood pressure cuff, which has been properly calibrated, should be used to measure blood 
pressure each time.  When the timing of these measurements coincides with a blood 
collection, blood pressure, temperature and pulse rate should be obtained first.
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. 
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. 
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.
Vital signs (including blood pressure, pulse rate and temperature) and ECG should be 
performed before laboratory blood collection and endoscopic procedure.
7.1.10. Medical History, Physical Examination, Height and Weight
Medical history, including CD 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 Examination:
A standard physical examination will be performed at the visits identified in Schedule of 
Activities.  The following parameters and body systems will minimally be examined and any 
abnormalities described: General appearance, skin (presence of rash), head, eyes, ears, nose 
and throat (HEENT), lungs (auscultation), heart (auscultation for presence of murmurs, 
gallops, rubs, peripheral edema), abdominal (palpation and auscultation), neurologic (mental 
status, station, gait, reflexes, motor and sensory function, coordination) and, lymph nodes.


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Targeted Physical Examination:
An abbreviated physical examination will be performed at the visits identified in Schedule of 
Activities.  The following parameters and body systems will minimally be examined and any 
abnormalities described: Skin, lungs, heart, abdomen and lymph nodes.  Additional organ 
systems may be examined at the investigator decision.  Any clinically significant changes 
from the baseline examination should be recorded as AEs.  Body temperature also will be 
collected at these visits.
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 want to have an 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).
Additional targeted PE may be performed during the study at the investigator’s discretion.
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).
Note: Elbow circumference will only be measured for male subjects with height ≤163 cm. 
This is to allow frame determination (for the weight item in Crohn’s Disease Activity Index 
[CDAI] for only randomized male subjects with height ≤163 cm (only 1 subject at the time of 
this amendment with a height less than 163). This does not impact the CDAI calculation for 
subjects with height greater than 163 cm.
7.1.10.1. 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
Appendix 9, for Dermatology/Skin Category) and managed as shown below.


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Table 8.
Management of Dermatological Events
Dermatologic Event (CTCAE v 4.0)*
Course of Management
Acne/Acneiform Rash/Maculopapular Rash
Grade 1/2
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 9 for clarification.
In any event of an unexplained rash, a blood sample for viral surveillance will be collected 
for the analysis of viral load including but not limited to CMV, EBV, HSV1, HSV2, and 
VZV.  For a suspected infectious rash, a swab (for microbiological assessment) of the 
affected area will also be taken for culture and sensitivity to assess for any bacterial or fungal 
pathogens.  For any occurrence of a suspected herpetiform rash (eg, herpes zoster and herpes 
simplex) an additional swab of the affected area will be collected for confirmation.  Details 
for these collections will be provided in the laboratory manual.
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.
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 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. 


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All treatment-related reports of rash will be followed up until resolution or clinically stable or 
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 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. 
7.1.11. 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. 
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.
7.1.12. Electrocardiogram
Single twelve (12) lead ECGs will be obtained on all subjects.  All scheduled ECGs should 
be performed before laboratory blood collection, endoscopic procedure and after 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. 


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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.
7.1.13. 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 and read by a 
qualified radiologist is required at screening or within the 12 weeks prior to screening.  A
chest X-ray or other appropriate diagnostic chest imaging modality [ie, Computerised 
Tomography (CT with or without IV contrast) or Magnetic Resonance Imaging (MRI)]
performed within 12 weeks prior to screening, may substitute for the Chest X-ray taken at 
Screening.  Documentation of the official reading must be located and available in the source 
documentation.
7.2. Diagnostic and Efficacy Assessments
7.2.1. Endoscopy
Screening colonoscopy should be performed within 10 days of baseline, preferably 5 to 
7 days prior to the baseline.  The endoscopic subscore by the Central Reader must be 
available at the baseline visit.  The SES-CD score (see Appendix 2) by the central reader will 
be used to determine eligibility for entry criteria.  The endoscopic and pathology reports and 
any photographs and /or video recordings taken during the screening colonoscopy must be 
available in the source documents prior to Baseline (Day 1) randomization. Colonoscopy 
and SES-CD scoring are also performed during the week prior to the Week 12 and Week 64
visits (or early withdrawal visit where applicable).  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.  Colonoscopy should be performed at the Early Termination 
(ET) visit unless the previous colonoscopy was less than 8 weeks prior to this.
7.2.2. Biopsy Collection from Ileocolonic Mucosa for Histology, RNA, Epigenetic, 
Tissue microbiome and Tissue Protein
Ileocolonic tissue biopsies will be collected at screening, Week 12, 64, and early withdrawal 
visits during the endoscopy.  Jumbo forceps should be used to obtain biopsies during each 
colonoscopy procedure.  Biopsies should be taken one at a time, and each should be 
immediately placed into a separate sample collection tube, as specified in the central vendor 
procedure manual.  During each endoscopy procedure, a total of 19 biopsies should be 
obtained from each subject, if possible, in the following manner:


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1. A total of 12 biopsies spanning six segments (rectum, sigmoid, left colon, transverse 
colon, right colon, and ileum) will be obtained for histology.  Two biopsies should be 
obtained from the most affected areas in each segment.  In the case of an unaffected 
segment, two biopsies should be obtained from a location based on the investigator’s 
discretion.
2. A total of 7 additional biopsies will be obtained for translational medicine 
assessments.  Six biopsies should be taken from inflamed ileocolonic mucosa in the 
most affected segment (1 biopsy for RNA analysis, 2 biopsies for protein analysis,
and 3 biopsies for epigenetic and/or cytometry/microbiome analyses).  An additional 
biopsy should be taken from adjacent uninflamed ileocolonic mucosa for RNA 
analysis.  All inflamed pre-treatment biopsies should be obtained in a targeted manner 
from the most affected area.  During post-treatment endoscopies, samples should be 
obtained from inflamed mucosa at approximately the same anatomic location as the 
baseline assessment. If no inflammation is observed, post-treatment biopsies should 
be obtained at approximately the same anatomic location as the baseline assessment
based on the investigator’s discretion.
Frankly ulcerated areas should be avoided.  For all biopsies collected, record the colonic 
segment and approximate distance from the anal verge for each sample in the source 
documents.  If 19 biopsies cannot be collected during the endoscopy, then samples from 
inflamed tissues should be prioritized in the order of histology, RNA analysis, protein 
analysis, and epigenetic and/or cytometry/microbiome analysis. 
Due to the rejection of the Import License for the Fetal Bovine Serum required for the 
processing of 1 tissue sample for cytometry, this sample will not be collected for subjects in 
South Africa. Therefore in South Africa, 18 tissue samples will be collected instead of the 
protocol defined 19 samples.
Histological, gene expression (RNA), protein analysis and epigenetic and/or 
cytometry/microbiome analysis may be conducted on the biopsy samples that are obtained.  
Pfizer and the central laboratory vendor will provide sites with instructions for collection, 
processing, and shipment of biopsy samples.  These samples may be used for the evaluation 
of exploratory biomarkers that may include markers related to CD, UC and/or other 
inflammatory conditions and/or the mechanism of action of PF-06651600 (ritlecitinib) and 
PF-06700841 (brepocitinib).  Detailed processing, storage and shipment instructions will be 
provided in the Lab Manual.
7.2.3. Subject eDiary
An eDiary will be provided to subjects at the screening visit (Visit 1) in order to record the 
following:

The number of liquid stools or very soft stools.

The intensity of abdominal pain.


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
General well-being.

PGIS questionnaire.
Subjects should enter eDiary data continuously for 12 weeks throughout the induction phase.  
During the OLE phase subjects will be requested to complete their eDiary until Visit 16, 
from Visit 24 to 32, and from Visit 56 to 64.
Subject Diary data will be assessed by the investigator or designate throughout the study.
The information extracted will be used for calculation of stool frequency (SF), abdominal 
pain (AP) and CDAI score taking into account the continuous 7 days data recorded prior to 
each study clinic visit.  The Subject Diary is a source document for SF, AP and CDAI data 
collection and is to be collected at the last subject visit and retained in the Site Master File. 
7.2.4. Stool Frequency (SF) and Abdominal Pain (AP)
SF and AP calculation will be dependent on the parameters recorded in the subjects’ diary 
(stool frequency and abdominal pain).  For any visit that has an endoscopy (screening, 
Week 12 and Week 64 and Early Term (if required), SF and AP scores should be calculated 
based on diary data obtained on 7 consecutive days prior to two (2) days of bowel 
preparation (if applicable), including any dietary modification as part of the bowel 
preparation.  For example, subjects should have their SF and AP scores calculated based on 
7-consecutive diary data prior to two (2) days of bowel preparation for colonoscopy. For all 
remaining visits that do not require an endoscopy, the CDAI calculations including SF/AP 
scores will need to be calculated based on the 7 days prior to the study visit. For more details 
please refer to Appendix 3.
7.2.5. Crohn’s Disease Activity Index (CDAI)
The Crohn’s Disease Activity Index (CDAI) is a validated instrument to measure the 
response to treatment in Crohn’s Disease studies (see Appendix 3).  Scores range from 0 to 
approximately 600.  The algorithm for calculating the CDAI score was first published by 
William Best and colleagues in a 1976 article in the journal Gastroenterology.
CDAI calculation will be dependent on the parameters recorded in the subjects’ diary 
(number of liquid stools, the intensity of abdominal pain, general well-being and the need for 
antidiarrheal drugs) AND the parameters assessed at clinic visit by investigator (the 
occurrence of extraintestinal symptoms or signs, the presence of abdominal mass, hematocrit 
and body weight). Investigators should complete CDAI parameters (need for antidiarrheal 
drug, abdominal mass and number of complications) at the clinic after the PRO assessments 
and prior to any clinical assessments at the study visit.
For any visit that has an endoscopy (screening, Week 12 and Week 64 and Early Term (if 
required)), CDAI scores should be calculated based on diary data obtained on 7 consecutive 
days without bowel preparation, including any dietary modification as part of the bowel 
preparation.  For example, subjects who have the colonoscopy performed prior to study drug 
should have their CDAI scores calculated based on 7-consecutive diary data prior to 2 days 
of bowel preparation.  For all remaining visits that do not require an endoscopy, the CDAI 


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calculations including SF/AP scores will need to be calculated based on the 7 days prior to 
the study visit.
Please refer to Appendix 3 for review of the CDAI and Appendix 4: Frame Determination as 
it relates to question 8 of the CDAI.  The wrist measurement will be measured at the 
screening visit to determine frame size and recorded on the appropriate CRF page.
Hematocrit (Hct) value needed for the calculation of the CDAI score:

An Hct value obtained via the central lab atthe baseline visit and other scheduled 
study visits during the induction period will be used to calculate the CDAI score.  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfClia/Results.cfm?Analyte_Name
=Hematocrit&Clia_Complexity=waived&SortColumn=DATE%5FEFFECTIVE%20
DESC&PAGENUM=10.
7.2.6. Patient Reported Outcomes (PRO) for Health Outcomes Assessment
Patient reported outcomes (PRO) assessments are self-administered during the study. Refer 
to Appendix 12 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).

European Quality of Life Questionnaire – 5 Dimensions-3 Levels (EQ-5D-3L) & 
Visual Analog Scale (EQ-5D VAS).

Patient Global Impression of Severity (PGIS).
7.2.6.1. 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 CD.  The IBDQ is comprised of 32-items, 
which are grouped into 4 dimensions: bowel function, emotional status, systemic symptoms 
and social function.7 The 4 domains are scored as follows:


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
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.7,8 See Appendix 5.
7.2.6.2. 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.
7.2.6.3. 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 
CD.9  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.
7.2.6.4. Patient Global Impression of Severity (PGIS)
The Patient Global Impression of Severity (PGIS) is a patient completed numeric rating scale 
question to assess the overall impression of disease severity experienced by the patient.  The 
PGIS score ranges from 0 (None) to 10 (Extremely Severe).  The PGIS will be assessed daily 
beginning approximately 2 weeks prior to screening endoscopy and throughout the induction 
phase and between Visit 12 to 16, Visit 24 to 32 and Visit 56 to 64 in OLE phase See 
Appendix 8.


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7.3. 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.
As part of understanding the pharmacodynamics of the study drug and the disease under 
study, samples may be used for evaluation of the bioanalytical method.  These data will be 
used for internal (ie, Pfizer) exploratory purposes and will not be included in the clinical 
report.
7.3.1. High-Sensitivity C-Reactive Protein (hsCRP)
Blood samples for determination of hsCRP will be obtained at the times specified in the 
Schedule of Activities.
7.3.2. Interferon Gamma-Induced Protein 10 (IP-10)
Blood samples for the analysis of IP-10 will be collected (prior to dosing) into appropriately 
labeled tubes containing no preservative, anticoagulant or serum separator according to the 
times outlined in the Schedule of Activities.
7.3.3. FACS Analysis (TBNK Cells)
Whole blood samples will be collected for standard T cell, B cell and NK cell (TBNK) 
analysis according to the times outlined in the Schedule of Activities.
7.3.4. Exploratory Serum Protein Biomarkers
Blood samples (10 mL) for analysis of exploratory serum biomarkers will be collected into 
appropriately labeled glass tubes containing no preservatives; anticoagulant or serum 
separator according to the times specified in the Schedule of Activities and may be analyzed.  
Serum should be aliquotted before storing.
7.3.5. Fecal Calprotectin
A stool sample for determination of fecal calprotectin will be obtained at the times specified 
in the Schedule of Activities.


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The study site personnel will provide appropriately labeled containers and instructions to the 
subject on how best to collect a sufficient fecal sample.  During screening period, collection 
of stool MUST be prior to administration of any bowel prep for endoscopy. For example, 
subject can collect their sample 1 week prior to bowel prep. One week is not a set time 
period; subject may collect the stool sample sooner than 1 week too. This only applies to 
stool sample collection during screening period. During treatment period, 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.
7.3.6. Stool Samples for Microbiome Analysis
A stool sample for microbiome analysis will be obtained at the times specified in the 
Schedule of Activities.  Sequencing of the DNA present in the stool will be performed.  DNA 
generally comes from microorganisms like bacteria, viruses, fungi and parasites that may be 
present in the stool.  During this process, some human DNA may be inadvertently sequenced, 
but will not be used for the final microbiome analysis.  The analysis vendors will analyze the 
DNA contained in the stool to better understand disease activity and response to therapy. 
The study site personnel will provide appropriately labeled containers and instructions to the 
subject on how best to collect a sufficient stool sample.  During screening period, collection 
of stool MUST be prior to administration of any bowel prep for endoscopy. For example, 
subject can collect their sample one week prior to bowel prep. One week is not a set time 
period; subject may collect the stool sample sooner than one week too. During treatment 
period 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.
7.4. Pharmacokinetics
7.4.1. Plasma for PK Analysis of Investigational Product
Blood samples for PK analysis will be collected into appropriately labeled tubes at times 
specified in the Schedule of Activities.
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  The 
exact date and time of the sample collection is noted on the source document and data 
collection tool (eg, CRF).
Details regarding the collection, processing, storage and shipping of the blood samples will 
be provided in the lab manual.  The samples must be processed and shipped as indicated to 
maintain sample integrity.  Any deviations from the processing steps (eg, sample collection 
and processing steps, interim storage or shipping conditions), including any actions taken, 
must be documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any deviation 
from the specified sample handling procedure resulting in compromised sample integrity will 
be considered a protocol deviation.
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
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As part of understanding the PK of the IP, samples may be used for further characterization 
and/or evaluation of the bioanalytical method.  These data will be used for internal 
exploratory purposes and will not be included in the clinical report.  Samples collected for 
this purpose will be retained in accordance with local regulations and, if not used within this 
timeframe, will be destroyed.
7.4.2. Shipment of Plasma Samples for PK Analysis
The shipment address and contact information for the lab will be provided to the investigator 
site prior to the initiation of the trial.
7.5. Pharmacogenomics
7.5.1. Gene Expression Analysis 
Blood samples for the assessment of gene expression (mRNA analysis) will be collected in 
appropriately labeled PAXgene Blood RNA Tubes.  Samples will be collected according to 
the times outlined in the Schedule of Activities.  These samples may be used for the 
evaluation of exploratory biomarkers that may include markers related to ulcerative colitis, 
Crohn’s disease and/or other inflammatory conditions and/or the mechanism of action of 
PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib).  These samples are for 
biomarker analysis and will not be used for genetic testing.  Detailed processing, storage and 
shipment instructions will be provided in the Lab Manual.
Colon tissue biopsies will also be taken and may be used for histology, gene expression and 
protein analysis and are described in Section 7.2.2.
7.6. Banked Biospecimens
Banked biospecimens will be collected from subjects for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.  They will be handled in a 
manner that protects each subject’s privacy and confidentiality.  Banked biospecimens will 
be assigned the subject’s study identification code (ID) at the site.  The data generated from 
these banked biospecimens will also be indexed by this ID.  Biospecimens will be kept until 
destruction in facilities with access limited to authorized personnel, and biospecimen-derived 
data will be stored on password-protected computer systems.  The key between the subject’s 
ID and the subject’s direct personally identifying information (eg, name, address) will be 
held at the study site.  Biospecimens will be used only for the purposes described in the 
protocol and informed consent document; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored for many years (no time limit) to allow for research in the future, 
including research conducted during the lengthy drug-development process and also 
postmarketing research.  Subjects may withdraw their consent for the use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any remaining 
biospecimens will be destroyed, but data already generated from the biospecimens will 
continue to be available to protect the integrity of existing analyses. 


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Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected at the 
time specified in the Schedule of Activities section of the protocol to be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response and 
disease/condition under study.  For example, putative safety biomarkers, drug-metabolizing 
enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 
of drug action may be examined.  The primary purpose is to examine DNA; however, the 
biospecimen may also be used to study other molecules (eg, RNA, proteins, and metabolites).
Additional banked biospecimens to be retained for such exploratory analyses in this study 
include the following:

Prep B1.5 (K2EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): A 4-mL blood biospecimen will be 
collected at times specified in the Schedule of Activities section of the protocol.

Prep B2.5 (serum collection optimized for biomarker/proteomic/metabonomic 
analysis): A 4-mL blood biospecimen will be collected at times specified in the 
Schedule of Activities section of the protocol.

Prep R1 (PAXGene whole-blood collection optimized for RNA analysis): A 2.5 mL 
blood biospecimen will be collected at times specified in the Schedule of Activities
section of the protocol.
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or IRB/EC decision. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document that they will not be compensated 
in this event.
7.6.1. Additional Research
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.


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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.  
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 


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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.
For subjects who are screen failures, the active collection period ends when screen failure 
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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 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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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 (brepocitinib) 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 1.5.3.1.1).
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. 
All subjects will have serum creatinine based and serum cystatin-C based eGFR calculated at 
times specified in the Schedule of Activities. 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 
medical event irrespective of availability of all the results of the investigations performed to 
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All relevant test results will be forwarded to Pfizer immediately by the PI. 
This requirement applies to all subjects in 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 
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 
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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.
8.4.5. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
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 
provided prior to the un-blinding of the trial and maintained by the sponsor.  The SAP may 
modify what is outlined in the protocol where appropriate; however, any major modifications 
of the primary endpoint definitions or their analyses will also be reflected in a protocol 
amendment.
9.1. Sample Size Determination
Using a 2-sample test of proportions and assuming that the true SES-CD 50 rate is 12% for 
the placebo group and 29% for PF-06651600 (ritlecitinib) at Week 12, a sample size of 
approximately 70 completed subjects in PF-06651600 (ritlecitinib) arm and 60 completed 
subjects in combined placebo arm will have about 80% probability to statistically detect a 
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end of study with a local type-I error 5% 1-sided. A sample size of 50 completed subjects in 
PF-06700841 (brepocitinib) arm and 60 completed subjects in combined placebo arm will 
have about 72% probability to statistically detect a greater SES-CD 50 response rate in 
PF-06700841 (brepocitinib) compared to placebo at the end of study with a local type-I error 
5% 1-sided.  This takes into account that the first interim analysis didn’t stop for early 
efficacy or futility. Since the probability for the trial stopping for early efficacy at first 
interim based on CMEI is 3% when there is no treatment effect, the type-I error for the 
comparison of each active arm to placebo is controlled at 8%. More details on the past
interim analyses are described in Section 9.6.
In order to evaluate the primary endpoint of SES-CD 50, we expect that 83 subjects in 
PF-06651600 (ritlecitinib) arm and 71 subjects in combined placebo arm to be randomized 
and dosed into the primary study population, assuming a 15% drop out rate. Including 
subjects already randomized to the PF-06700841 (brepocitinib) arm prior to amendment 5, a 
total of approximately 230 - 250 subjects would be enrolled for the study.
9.2. Efficacy Analysis During Induction 
All subjects who receive at least one dose of randomized study medication and have a 
baseline and at least one post-baseline measurement (after taking randomized study 
medication) will be included in the efficacy data analyses.  All the comparisons during the 
induction period will be to placebo.  There will be no comparisons between the two active 
treatments PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib).
9.2.1. Analysis of the Primary Endpoint During Induction
The primary efficacy endpoint is proportion of subjects achieving SES-CD 50 defined as 
≥50% reduction in SES-CD from baseline change from baseline in SES-CD at Week 12.  The 
SES-CD 50 data comparing active treatment group and placebo group will be analyzed using 
the Cochran Mantel Hanzel (CMH) test, adjusting the stratification factors, ie, status of 
previous treatment of anti TNF therapy.  Treatment differences in the SES-CD 50 response
and the corresponding 2-sided 90% confidence intervals adjusted for stratification factors 
will be computed using the methods proposed by Cochran12 with the minimum risk weights 
proposed by Mehrotra and Railkar.11 It is anticipated to have small numbers in each 
investigation site, so the investigation site effect will not be an adjustment factor. 
The observed risk rate and the associated confidence interval of the risk differences will be 
presented.  The unconditional exact method as described by Chan and Zhang (1999)13 will be 
used to compute the confidence intervals.  More details will be documented in the Statistical 
Analysis Plan.  The primary analysis population will be based on a modified intent-to-treat
(mITT) analysis set, which is defined as all randomized subjects who received at least one 
dose of randomized treatment.  Treatment failure approach will be used for missing value 
imputation from drop out subjects. Additional sensitivity analyses for the primary endpoint 
will be described in the SAP.


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9.2.2. Analysis of Secondary Endpoints During Induction
The binary secondary endpoints are proportion of subjects achieving SES-CD 25
(≥25% reduction from baseline), and CMEI (≥3 points reduction from baseline), endoscopic 
remission (SES-CD ≤2) and mucosal healing (complete absence of ulcers) at Week 12.  
These endpoints will be analyzed similar to the primary efficacy endpoint using the CMH
test comparing the treatment differences by adjusting the stratification factor, status of 
previous treatment of anti TNF therapy.  Point estimation of difference and 90% CI will be 
provided using the same methods proposed for the primary endpoints.  The continuous 
secondary endpoint for change from baseline in SES-CD at Week 12 will be analyzed using 
an analysis of covariance (ANCOVA) model which will include terms for treatment group, 
the stratification factors (if there are a sufficient number of subjects in each stratum, 
otherwise, the stratification factors will be dropped from the model), and the baseline 
SES-CD score.
The analysis population will be on the mITT analysis set.  The analyses on continuous 
secondary endpoints will not account for missing values, ie, it will be based on the Data As
Observed (DAO) approach without explicit imputation to handle the missing data.  
Treatment failure approach will be used for missing value imputation for binary endpoints.
9.3. Analysis of Other Endpoints During Induction
9.3.1. Pharmacokinetic Analysis
The PK concentration population is defined as all enrolled subjects who received at least one 
dose of PF-06651600 (ritlecitinib) or PF-06700841 (brepocitinib) and in whom at least one 
concentration value is reported.
PK concentrations will be summarized and presented with summary statistics.  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.
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 standard operating procedures (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 of the induction period.  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 to the induction period.  The details of the 
procedures will be described in the PK/PD Unblinding Plan for Modeling and
Simulation for study B7981007 which will be finalized prior to the start of the PK/PD 
unblinding.


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9.3.3. Analysis of Exploratory Biomarkers
Exploratory biomarkers may be summarized by treatment group and may be graphically 
displayed.  Appropriate analysis may be performed as needed.  The analysis population will 
be based on a mITT analysis set and will not account for missing values.
9.3.4. Unblinding for Biomarkers
In order to expedite the analyses of the biomarkers at the end of the induction period, 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.
9.3.5. Analysis of Health Outcomes Endpoints
IBDQ data will consist of 32 individual items, scores for the 4 dimensions (bowel function, 
emotional status, systemic symptoms and social function) and a total score.  All data will be 
listed and data for the 4 dimensions and total score summarized by time post-dose for each 
treatment.  Week 12 changes from baseline for the 4 dimensions and total score will be 
plotted and summarized by treatment group to visually assess compound-specific changes.  
All IBDQ data (baseline and Week 12) will be summarized across time.  For binary health 
outcomes variables, descriptive statistics will be summarized by treatment group and CMH 
methods proposed above will be used to compare each treatment group to placebo group.  
For continuous health outcomes variable (eg, IBQD total score and domain scores, 
EQ-5D/VAS), descriptive statistics will be summarized by treatment group and analysis of 
variance/ variance/Longitudinal Data Analysis model will be used to compare each treatment 
group and placebo group.  The primary analysis population for the health outcomes will be 
based on a mITT analysis set.  The analyses on continuous endpoints will not account for 
missing values, ie, it will be based on the Data as Observed (DAO) approach without explicit 
imputation to handle the missing data.  Treatment failure approach will be used for missing 
value imputation for binary endpoints from drop out subjects.
9.4. Safety Analysis During Induction
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. 


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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 and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Data Standards.  Categorical outcomes (eg, AEs, ECGs) 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 and vital signs will also be summarized.  Subject listings will be produced for 
these safety endpoints accordingly. 
9.5. Analysis During the Open Label Extension Period
9.5.1. Secondary Efficacy Analysis
The secondary efficacy endpoints are:

Proportion of subjects achieving clinically meaningful endoscopic improvement 
(CMEI response) at Week 64 among subjects who achieved CMEI response at 
Week 12. 

Proportion of subjects achieving SES CD 25 at Week 64 among subjects who 
achieved SES CD 25 at Week 12.

Proportion of subjects achieving SES CD 50 at Week 64 among subjects who 
achieved SES CD 50 at Week 12 respectively.
Descriptive statistics will be provided for the secondary efficacy endpoints. These endpoints 
will be analyzed using the same analysis technique as the primary endpoint. We will also 
produce graphs for the efficacy endpoint for both the induction and OLE period. Detailed 
methodologies of these analyses will be described in the SAP.
9.5.2. Exploratory Efficacy Analysis
Descriptive statistics will be provided for the exploratory efficacy analysis.  The binary 
endpoints such as endoscopic response, endoscopic remission, clinical response and 
remission will be summarized with frequency and percentage by time point.  The continuous 
variables will be summarized with n, mean, median, standard deviation etc.  These 
summaries may be provided by the strata of responding status at entry. 
All subjects who have received at least one dose of planned investigational product in the 
extension part will be included into the exploratory efficacy analysis.  Detailed 
methodologies of these analyses will be described in the SAP.
9.5.3. Pharmacokinetic Analysis
Blood samples will be collected at specified times for analysis of plasma concentrations of 
PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib). Plasma concentration data 
obtained from all subjects will be summarized and presented with summary statistics.


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9.5.4. Exploratory Pharmacodynamic Analysis
Exploratory biomarkers will be listed and summarized by visit, and change from baseline for 
these endpoints will also be summarized at specific time points as reported in the SOA.
Appropriate regression models may be used to look at association between these endpoints 
and any covariates of clinical interests.
9.5.5. Safety Analysis
Safety and tolerability are the primary endpoint during the open label extension period.  A set 
of safety summary tables will be produced to evaluate potential risks associated with the 
safety and tolerability of administering the study medication.  All clinical AEs, SAEs, 
on-treatment AEs, as well as discontinuations due to AEs will be summarized with frequency 
and percentage.  Continuous outcomes (eg, vitals, safety lab parameters, etc) will be 
summarized using n, mean, median, standard deviation etc.
Change from baseline on selected safety endpoints may be additionally summarized.  Subject 
listings may also be produced for these safety endpoints.  The safety endpoints will be listed 
and summarized in accordance with Pfizer Data Standards.  Detailed methodologies of these 
analyses will be described in the SAP.
9.6. Interim Analysis 
This protocol may include 2 interim analyses using CMEI for both active treatments.  Details 
regarding the analysis procedures to be used for the interim analysis will be provided in the 
interim analysis plan (IAP).  The first interim analysis will be performed when approximately 
60% of subjects have completed or had the chance to complete the Week 12 visit.  The 
objective of this interim analysis is to determine if there is evidence of lack of differentiation 
(“futility”) or significant efficacy for the active treatments compared to placebo.  The 
non-binding futility decision at this interim analysis isbased on conditional power evaluated 
on a total of approximately 150 subjects who complete or had the chance to complete 
Week 12.  
The study will be stopped for futility for that active treatment arm if conditional probability 
of claiming efficacy by the end of study is <10% for that active arm.  If the non-binding 
futility condition is met for both active arms, the study may be stopped at this interim point.  
Efficacy stopping rule will be derived from the Hwang-Shih-DeCani gamma family16 of
spending function, with parameter 0, at each interim. The study may be stopped for efficacy,
if efficacy condition is met by at least one active arm. 
Second interim analysis may be performed when approximately 80% of the subjects have 
completed or had the chance to complete the Week 12 visit.  The objective of this second
interim analysis is to determine if there is evidence of significant efficacy for the active arms 
compared to placebo.  Using the same Hwang-Shih-DeCani gamma family16 spending 
function, if one of the active arms enters efficacy region computed from this interim, the trial 
will stop for efficacy at the second interim look.


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The interim analyses results will be used to facilitate internal decision-making.  The results 
will only be distributed to a select list of individuals involved in the internal decision-making 
process in order to protect the integrity of the study.  This list of individuals will be provided 
in the interim analysis plan/charter.  The results of the interim analyses will not enable 
individuals directly involved in running the study (such as investigators) to identify treatment 
assignments for individual subjects still in the study. 
During these interim analyses, some members of the study team may be unblinded and 
replaced with blinded colleagues.  The subjects, investigators, and individuals from the 
sponsor (or designee) who interact with the investigators and monitor safety will continue to 
be blinded to individual study treatments throughout the follow up period of the study.
9.7. 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 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.
An internal review committee (IRC) will be formed to assess the interim analyses as 
described in Section 9.6. Details on the IRC will be included in the interim analysis charter.
9.8. Safety Adjudication Committees
Suspected opportunistic infections, neuroaudiometry and cardiovascular events (eg,
thrombotic and embolic events) will be subject to review by separate external blinded 
adjudication committees based on the known mechanism of action for JAK inhibitors. These 
events will be forwarded for adjudication either by the study team or by its designee. Event 
documents may be requested from sites and may include (but not be limited to): hospital 
discharge summaries, operative reports, clinic notes, diagnostic tests, pathology reports, 
autopsy reports and death certificate information, as applicable. Obtaining and submitting 
this documentation will be the responsibility of the study site. Additional events of interest 
may be adjudicated by an external blinded adjudication committee as needed.
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.


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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.
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 


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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 ommitting 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 nameswill 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.
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.


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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 patient last visit.
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 (ritlecitinib) and/or PF-06700841 (brepocitinib) 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 1 month.  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. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (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.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


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


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16. REFERENCES
1.
Sandborn WJ, et. al. Tofacitinib as induction and maintenance therapy forUlcerative 
Colitis. N Engl J Med. 2017 376:1723-1736.
2.
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.
3.
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. 
4.
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.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
Mehrotra DV, Railkar R. Minimum risk weights for comparing treatments in stratified
binomial trials. Statistics in Medicine 2001; 19:811-825.
12.
Cochran WG. Some methods for strengthening the common chi-square tests. Biometrics 
1954; 10:417-451).
13.
Chan ISF, Zhang Z. Test-based exact confidence intervals for the difference of two
binomial proportions. Biometrics 1999, 55, 1201–1209.


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14.
B.E. Sands1, C. Gasink2, D. Jacobstein2, L.L. Gao3, J. Johanns4, P. Szapary4, J. 
Colombel5, S. Targan6, S. Ghosh7, W. Sandborn8; 1Icahn School of Medicine at Mt 
Sinai, New York/US, 2Janssen Research and Development, LLC, 19477 - Spring 
House/US, 3Janssen Research & Development, LLC, Spring House/US, 4Janssen 
Research & Development, LLC, 19477 - Spring House/US, 5Icahn School of Medicine 
at Mount Sinai, New York/US, 6Cedars-Sinai Medical Center, Los 
Angeles/US, 7Division Of Gastroenterology, University of Calgary, 
Calgary/CA, 8UCSD, La Jolla/US. ECCO presentation 2016.
15.
P. Rutgeerts1, C. Gasink2, D. Chan2, Y. Lang2, P. Pollack2, S. Hanauer3, D. Wolf4, 
D. Jacobstein2, J. Johanns2, P. Szapary2, B.G. Feagan5, W. Sandborn6; 1University of 
Leuven, Leuven/BE, 2Janssen Research and Development, LLC, 19477 - Spring 
House/US, 3Feinberg School of Medicine, 60611 - Chicago/US, 4Atlanta 
Gastroenterology Associates, Atlanta/US, 5Robarts Clinical Trials Inc., Robarts Res 
Inst, U of Western Ont, N6A 5K8 - London, ON/CA, 6UCSD, La Jolla/US. ECCO 
presentation 2016.
16.
Jennison C and Turnbull BW (2000), Group Sequential Methods with Applications to 
Clinical Trials. Boca Raton: Chapman and Hall.
17.
Sostegni R, Daperna M, Scaglione N, et al. Crohn's disease: monitoring disease activity. 
BJP. 2003;17(2):11-7.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
AA
Alopecia Areata
Aetau
Cumulative amount of drug recovered unchanged in urine up to 
24 hours
ANC
Absolute neutrophil count
ANCOVA
analysis of covariance
AP
Abdominal pain
API
active pharmaceutical ingredient
AST
aspartate aminotransferase
AT3
Antithrombin III
ATP
adenosine triphosphate
AUC24
area under the concentration-time curve 
AUCinf
area under the concentration-time curve from time 0 to infinity
AUC0-72
area under the concentration-time curve from time 0 to 72
BA
bioavailability
BAEP
brainstem auditory evoked potential BAEP
BBS
Biospecimen Banking System
Bcl2
B-cell lymphoma 2
BCG
Bacillus Calmette-Guerin
BCRP
breast cancer resistant protein 
BID
twice a day
BMI
body mass index
BMX
bone marrow tyrosine kinase on chromosome X
BP
blood pressure
BSA
body surface area
BSEP
bile salt export pump
BTX
bone marrow tyrosine kinase
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CFB
Change from baseline
CHD
Coronary heart disease
CK
creatine kinase
CK-MB
creatine kinase myocardial band
CL
clearance
CL/F
Apparent clearance
Cmax
maximum concentration 
CMEI
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Abbreviation
Term
CMH
Cochran Mantel Hanzel
CMV
cytomegalovirus
CNS
Central nervous system
CO
cross over
COE
Cross over extension
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
coronavirus disease 2019
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
Computerized tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
CYP450
cytochrome P450 
CYP
cytochrome
DDI
Drug drug interaction
DAO
data as observed
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DVT
Deep vein thrombosis
DU
dispensable unit
ESAI
Eczema Area and Severity Index
eDiary
Electronic diary
EBV
epstein–barr virus
EC
ethics committee
ECG
electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EE
ethinyl estradiol
EFD
Embryo fetal development
eGFR
Estimated glomerular filtration rate
ET
Early termination
EU
European Union
EudraCT
European Clinical Trials Database
FIH
First in human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GDH
glutamate dehydrogenase
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal


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Abbreviation
Term
GLP
Good laboratory practice
GST
glutathione-S-transferase 
rGST
recombinant glutathione-S-transferase 
Hct
hematocrit
hCG
human chorionic gonadotropin
HBsAg 
hepatitis B surface antigen
HBcAb 
hepatitis B core antibody
HCV RNA PCR
hepatitis C virus ribonucleic acid polymerase chain reaction
HCV Ab
hepatitis C antibody
HDL
high-density lipoprotein
HEENT
head, eyes, ears, nose and throat
HIV
human immunodeficiency virus
HRQL
health-related quality of life
hsCRP
high sensitivity C-reactive protein
HSV
herpes simplex virus
IA
interim analyses
IAP
interim analysis plan
IB
Investigators brochure
IBD
Inflammatory bowel disease
IBDQ
Inflammatory bowel disease questionnaire 
IC50
half maximal inhibitory concentration 
ICH
International Conference on Harmonisation
ID
identification
IFN
interferon
Ig
immunoglobulin
IGRA
Interferon gamma release assay
IL
interleukin
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IP-10
interferon gamma induced protein 10
IR
immediate release
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ITT
Intent to treat
ITK
IL-2 inducible T-cell kinase
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IV
intravenous
IWR
interactive web response
JAK
Janus kinase
KDIGO
Kidney Disease: Improving Global Outcomes


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Abbreviation
Term
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LDL
Low density lipoprotein
LFT
liver function test
LLN
Lower Limit of Normal 
LLOQ
lower limit of quantitation
LN
levonorgestrel
LOAEL
Lowest Observed Adverse Effect Level 
LSLV
last subject last visit 
OC
oral contraceptive
OLE
open label extension
M1-1
mu 1-1 
mITT
modified intent-to-treat
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
MR
modified release
MRA
Magnetic Resonance Angiogram
MRI
magnetic resonance imaging
mRNA
messenger ribonucleotide acid
MTX
methotrexate
N/A
not applicable
NADPH
nicotinamide adenine dinucleotide phosphate 
NCA
National cancer institute
NK
Natural Killer
NOAEL
No observed adverse effect level
NYHA
New York Heart Association
OATP
organic anion transporting polypeptides 
OAT
organic anion transporting
OCT
Organic cation transporter
OLE
Open label extension
P1-1
pi 1-1 
PA5
Protocol Amendment 5
PASI
psoriasis area and severity index
PCD
primary completion date
PCOA
Patient-Centered Outcome Assessments
PCR
polymerase chain reaction
PCS
Physical component summary
PD
Pharmacodynamics(s)
PE
physical exam


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Abbreviation
Term
PFS
prefilled syringe
PGA
Physician’s global assessment
P-gp
P-glycoprotein
PGIS
patient global impression of severity
PGx
Pharmacogenomics(s)
PI
principal investigator
PK
pharmacokinetic
PO
oral
POC
proof of concept
PPD
Purified protein derivative
PRO
Patient reported outcome
PT
prothrombin time
rGST
recombinant glutathione-S-transferase 
RA
Rheumatoid Arthritis
Rac
Observed accumulation ratio
Rss
Steady state accumulation ratio
RNA
ribonucleic acid
QD
one daily
QFT-G
Quantiferon-gold
QFT-GIT
QuantiFERON® - TB gold in-tube
QTc
corrected QT interval
QTcF
Corrected QT interval by Fredericia
QW
once weekly
SAD
Single ascending dose
SAE
serious adverse event
SALT
Severity of Alopecia Tool
SAP
statistical analysis plan
SBE
Single blind extension
SC
subcutaneous
SCr
serum creatinine
SES-CD
simple endoscopic score for Crohn’s disease
SF
stool frequency
SF-36
Short form 36
SLE
Systemic lupus erythematosus
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
SSC
special safety concern
TBNK
T, B and NK cells
T1/2
Terminal half life
TB
tuberculosis


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Abbreviation
Term
TBili
total bilirubin
TEAE
Treatment emergent adverse event
TEC
tyrosine kinase expressed in hepatocellular carcinoma (TEC)
TE-SAE
treatment emergent-serious adverse event
Th
T helper
Tmax
time to reach maximum concentration
TNF
Tumor necrosis factor
TXK
tyrosine kinase expressed in T cells
TPMP
thiopurine methyltransferase
TYK
tyrosine-protein kinase
UC
Ulcerative colitis
UCEIS
Ulcerative Colitis Endoscopic Index of Severity
UDP
uridine 5'-diphospho
UGT
uridine 5'-glucuronosyltransferase 
ULN
upper limit of normal
URI
upper respiratory tract infection
US
United States
UV
Ultra violet
Vss
steady state volume of distribution 
VAS
visual analog scale
VHP
Voluntary Harmonization Procedure
VZV
varicella zoster virus
Vz/F
apparent oral volume of distribution
WBC
white blood cells
WOCBP
Women of child bearing potential


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Appendix 8. Patient Global Impression of Severity (PGIS)
Please rate the severity of your Crohn Disease over the past 24 hours.
0
1
2
3
4
5
6
7
8
9
10
(None)
(Extremely Severe)


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Appendix 9. 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 caused to permanently discontinue IP.


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Appendix 10. 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 or substrates, strong P-glycoprotein (P-gp) 
inhibitors, substrate of MDR1, or substrate of OCT2/MATE.
Moderate to Potent 
CYP3A Inhibitors*
Moderate to 
Potent CYP3A 
Inducers**
Substrates of CYP3A 
Strong 
P-gp 
inhibitors
Substrates 
of MDR1 
Substrates 
of 
OCT2/M
ATE
Amprenavir
Avasimibe#
Simvastatin or 
Simvastatin-containing 
products
Quinidine
Digoxin
Dofetilide
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


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Moderate to Potent 
CYP3A Inhibitors*
Moderate to 
Potent CYP3A 
Inducers**
Substrates of CYP3A 
Strong 
P-gp 
inhibitors
Substrates 
of MDR1 
Substrates 
of 
OCT2/M
ATE
Voriconazole#
* 
All prohibited drugs that are CYP3A inhibitors require at least a 7 day or 5 half-lives (whichever is 
longer) 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) prior to the first dose of study drug.
# 
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 11. 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
Note: these dose relationships apply to oral administration


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Appendix 12. 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 participant. 
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 12.1. Eligibility
Not Applicable.
Appendix 12.2. 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 study intervention(s), including compliance and missed doses.

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 (as 
available). Confirm that the participant is adhering to the contraception method(s) 
required in the protocol. Refer to Section 4.4.1 and Section 7.1.4. 


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
In situations where participants are unable to attend sites for protocol required 
pregnancy testing, the participant should, if possible, visit a local laboratory for 
pregnancy testing (where allowable by law or local guidance). If this is not 
possible, the study site should make every effort to develop a plan to provide a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL to be 
performed by the participant at home. The site should document the pregnancy 
test outcome in a source document and enter the result into the study database 
and/or CRF as required.
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 
Appendix 12.3. Alternative Facilities for Safety Assessments
Appendix 12.3.1. 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 12.4. 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. 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.


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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.
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 
treatment/intervention must be considered. 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 12.5. 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. 
Appendix 12.6. 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 12.7. 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:


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
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 third 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;

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.







SAP_001.pdf: 
Protocol B7981007 (PF-06651600, PF-06700841) Statistical Analysis Plan Amendment 2
DMB02-GSOP-RF02 5.0 Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 1
TMF Doc ID: 98.03
Protocol B7981007
A PHASE 2A, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PARALLEL GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
ORAL PF-06651600 AND PF-06700841 AS INDUCTION AND OPEN LABEL 
EXTENSION TREATMENT IN SUBJECTS WITH MODERATE TO SEVERE CROHN’S 
DISEASE
Statistical Analysis Plan 
(SAP)
Version:
Amendment 2
Date:
27-June-2022


Protocol B7981007 (PF-06651600, PF-06700841) Statistical Analysis Plan Amendment 2
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TMF Doc ID: 98.03
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives .......................................................................................................6
Induction Period..................................................................................6
Open Label Extension Period .............................................................8
2.2. Study Design ...........................................................................................................10
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ...........................................................................................................13
3.1. Induction Period ......................................................................................................13
Primary Endpoint(s)..........................................................................13
Secondary Endpoint(s)......................................................................13
Tertiary/Exploratory Endpoint(s) .....................................................13
3.2. Open Label Extension Period..................................................................................14
Primary Endpoint(s)..........................................................................14
Exploratory Endpoint(s) ...................................................................14
3.3. Baseline Variables...................................................................................................16
3.4. Safety Endpoints .....................................................................................................16
Adverse Events .................................................................................16
Laboratory Data................................................................................17
Vital Signs, including Height and Weight........................................17
Physical Examinations......................................................................17
4. ANALYSIS SETS ...............................................................................................................17
4.1. Full Analysis Set .....................................................................................................17
4.2. Pharmacokinetics Set ..............................................................................................17
4.3. Safety Analysis Set..................................................................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................18
5.1. Hypotheses and Decision Rules ..............................................................................18
Induction Period................................................................................18


Protocol B7981007 (PF-06651600, PF-06700841) Statistical Analysis Plan Amendment 2
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TMF Doc ID: 98.03
Open Label Extension Period ...........................................................18
5.2. General Methods .....................................................................................................18
Analyses for Binary Data..................................................................19
Analyses for Longitudinal Continuous Data ....................................19
Analyses for Non-longitudinal Continuous Data .............................19
Analyses for Categorical Data..........................................................20
Analyses for Time to Event Data......................................................20
5.3. Methods to Manage Missing Data ..........................................................................20
Binary Endpoint................................................................................20
Continuous Endpoints.......................................................................20
6. ANALYSES AND SUMMARIES ......................................................................................21
6.1. Induction Study Period............................................................................................21
Primary Endpoint(s)..........................................................................21
Secondary Endpoint(s)......................................................................22
Tertiary/Exploratory Endpoint(s) .....................................................22
Pharmacokinetic Endpoint(s)............................................................24
6.2. Open Label Extension Period..................................................................................24
6.3. Subgroup Analyses..................................................................................................24
6.4. Baseline and Other Summaries and Analyses.........................................................25
Baseline Summaries..........................................................................25
Study Conduct and Subject Disposition ...........................................25
Study Treatment Exposure ...............................................................25
Concomitant Medications and Non-Drug Treatments......................25
6.5. Safety Summaries and Analyses .............................................................................25
Adverse Events .................................................................................26
Laboratory Data................................................................................26
Vital Signs, including Height and Weight........................................27
Electrocardiogram.............................................................................27
Physical Examination .......................................................................27
7. INTERIM ANALYSES.......................................................................................................27
7.1. Introduction .............................................................................................................27


Protocol B7981007 (PF-06651600, PF-06700841) Statistical Analysis Plan Amendment 2
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PFIZER CONFIDENTIAL 
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TMF Doc ID: 98.03
7.2. Interim Analyses and Summaries............................................................................27
7.3. Data Monitoring Committee ...................................................................................28
8. REFERENCES ....................................................................................................................28
9. APPENDICES .....................................................................................................................28
Appendix 1. Summary of Efficacy Analyses.................................................................28
Appendix 2. Definition and Use of Visit Windows in Reporting ..................................30
LIST OF TABLES
Table 1
Summary of Major Changes in SAP Amendments ................................................5
Table 2.
Study Objectives and Endpoints during Induction Period......................................6
Table 3.
Study Objectives and Endpoints during the Open Label Extension Period ...........8
LIST OF FIGURES
Figure 1. Original Study Design Schematic.............................................................................12
Figure 2. Study Schematic Post Implementation of Protocol Amendment 5 ..........................12


Protocol B7981007 (PF-06651600, PF-06700841) Statistical Analysis Plan Amendment 2
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PFIZER CONFIDENTIAL 
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1. VERSION HISTORY
This SAP amendment for study B7981007 is based on the protocol dated 27JUL2021.
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1
Not Applicable
Not Applicable
Amendment 1
Statistical analyses were aligned with the 
change of primary endpoint, additional 
sensitivity analyses were added. 
Due to strategic reasons, the main hypothesis 
of interest is to compare PF-06651600 and 
placebo. There will be no multiplicity 
adjustment.
Protocol Amendment 5
Amendment 2
For binary response defined on endpoints 
including CDAI, SF/AP, IBDQ and GHAS, 
and open label summary of all efficacy 
endpoints, missing values after study 
treatment discontinuation will be handled by 
non-responder imputation (NRI) method, 
others will be removed from the analysis 
(i.e., the missing visits will not contribute to 
the denominator in the calculation of the 
proportion).
Considerable amount of 
missing data before
treatment discontinuation
ends up in the study for 
exploratory data, and they 
are caused by various 
reasons such as site logistics 
in and poor participants 
diary compliance that are 
most likely not related to 
efficacy. For OLE period
summary, imputation rule is 
relaxed as well. 
CDAI-100 and CDAI remission endpoint 
will be summarized only for subjects with 
baseline CDAI 220.
Endpoints are more 
clinically meaningful and 
traditionally defined for 
population with moderate 
and above disease 
population.
If an AE started in induction and resolved in 
OLE, it will be counted as TEAE only in 
induction.
It is more clinically desired 
to present it once only. 


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2. INTRODUCTION
This SAP amendment provides the detailed methodology for summary and statistical 
analyses of the data collected in Study B7981007.  This document may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoint definition 
or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives
Induction Period
Study objectives and corresponding endpoints during 12-week (Weeks 1-12) induction 
period are provided in the Table 2 below.
Table 2.
Study Objectives and Endpoints during Induction Period
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 compared to placebo at Week 12 
in subjects with moderate to severe Crohn’s 
disease (CD).

Proportion of subjects achieving SES--CD 50 
(50% reduction in SESCD from baseline) at 
Week 12 as assessed by central reading.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the safety and tolerability of 
PF-06651600 and PF-06700841 compared to 
placebo in subjects with moderate to severe CD 
over 12 weeks.

Incidence and severity of laboratory 
abnormalities, vital signs, 12-lead ECG, 
adverse events, serious adverse events and 
withdrawals due to adverse events.

Incidence of serious infections.

To evaluate the efficacy of PF-06651600 and 
PF-06700841 compared to placebo during 
induction of additional endoscopic endpoints in 
subjects with moderate to severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 
(reduction of ≥3 points from baseline in SES-
CD score) at Week 12.

Change from baseline in SES-CD score at 
Week 12.

Proportion of subjects achieving SES-CD 25 
and (25% reduction in SES-CD from 
baseline) at Week 12.

Proportion of subjects achieving endoscopic 
remission (SES-CD 2) at Week 12.

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 12.
Tertiary/Exploratory Objective(s):
Tertiary/Exploratory Endpoint(s):

To evaluate the effect of PF-06651600 and 
PF-06700841 compared to placebo on 
outcomes based on additional clinical criteria.

Proportion of subjects achieving clinical 
response and remission using stool frequency 


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(SF) and abdominal pain (AP) measures at 
Weeks 2, 4, 6, 8, 10, and 12.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD 
and clinical remission by SF and AP) at 
Week 12.

Proportion of subjects with a Crohn’s Disease 
Activity Index (CDAI)-100 response (defined 
by a decrease in CDAI score of at least 
100 points from baseline) and proportion of 
subjects who are remitters (defined as 
CDAI <150) at Weeks 2, 4, 8, and 12.

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, 8, 
and 12.

The proportion of subjects with IBDQ total 
score 170 at Weeks 4, 8, and 12.

The proportion of subjects with 16 point 
increase in IBDQ total score from baseline at 
Weeks 4, 8, and 12.

Proportion of subjects achieving IBDQ bowel 
symptom domain response at Weeks 4, 8, and 
12.

The scores and change from baseline in Euro 
Quality of Life Questionnaire 5 Dimensions 3 
Levels (EQ-5D-3L) + Visual Analog Scale 
(VAS) at Weeks 4, 8, and 12.

The scores and change from baseline in Short 
Form-36, Version 2 Acute (SF-36 v2): 
physical and mental component summary 
scores (PCS & MCS), and 8 domain scores at 
Weeks 4, 8, and 12.

Change from baseline in Patient Global 
Impression of Severity (PGIS) score at 
Weeks 4, 8, and 12.

To evaluate the effect of PF-06651600 and 
PF-06700841 compared to placebo on 
histopathology score.

Change from baseline in Global Histologic  
Activity Score (GHAS) at Week 12.

Proportion of subjects achieving histologic 
remission at Week 12 (defined as GHAS 4).

To assess the effect of PF-06651600 and 
PF-06700841 compared to placebo on disease 
and mechanistic biomarkers over time.

Change from baseline in serum high sensitivity 
C-reactive protein (hsCRP) levels over time.


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
Change from baseline in fecal calprotectin 
over time.

Change from baseline in serum interferon 
gamma-induced protein 10 (IP-10) levels over 
time.

Change from baseline in (B-cell lymphoma 2)
BCL-2 gene expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and T, B and NK 
(TBNK) cells.

To describe the pharmacokinetics (PK) of 
PF-06651600 and PF-06700841 compared to 
placebo in subjects with moderate to severe 
CD.

PF-06651600 concentrations at Weeks 2, 4, 8,
and 12.

PF-06700841 concentrations at Weeks 2, 4, 8,
and 12.

To collect non-banked samples (e.g., intestinal 
biopsies, stool for microbiome analysis, serum 
and plasma for analysis of proteins and a whole 
blood tube for RNA analysis) for exploratory 
research, unless prohibited by local regulations 
or ethics committee decision.

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples 
unless prohibited by local regulations or ethics 
committee decision.

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section of the 
protocol.
Open Label Extension Period
Study objectives and corresponding endpoints during the 52-week (Weeks 12-64) open label 
extension (OLE) period are provided in the Table 3 below.
Table 3.
Study Objectives and Endpoints during the OLE Period
Primary Objective(s):
Primary Endpoint(s):

To assess the safety and tolerability of 
PF-06651600 and PF-06700841 therapy during 
open label extension period for subjects with 
moderate to severe CD.

Incidence and severity of laboratory 
abnormalities, vital signs, 12-lead ECG, 
adverse events, serious adverse events and 
withdrawals due to adverse events.
Exploratory Objective(s):
Exploratory Endpoint(s):

To evaluate the efficacy of PF-06651600 and 
PF-06700841 therapy during open label 
extension period for subjects with moderate to 
severe CD.

Proportion of subjects achieving clinically 
meaningful endoscopic improvement 
(reduction of 3 points from baseline in 
SES-CD) at Week 64.

Proportion of subjects achieving SES-CD 25 
and SES-CD 50 at Week 64.


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
Proportion of subjects achieving endoscopic 
remission at Week 64.

Proportion of subjects achieving mucosal 
healing (complete absence of ulcers) at 
Week 64.

To evaluate the effect of PF-06651600 and 
PF-06700841 on outcomes based on additional 
clinical criteria.

Proportion of subjects achieving clinical 
response and remission as defined by SF and 
AP endpoints at Weeks 16, 20, 24, 32, 40, 48, 
56, and 64.

Proportion of subjects achieving deep 
remission (endoscopic remission by SES-CD 
and clinical remission by SF, AP) at Week 64.

Proportion of subjects with a CDAI-100 
response or CDAI remission at Weeks 16, 32,
and 64.

The scores and change from baseline in IBDQ 
Total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and 
Social Function) at Weeks 16, 32, and 64.

The proportion of subjects with IBDQ total 
score 170 at Weeks 16, 32, and 64.

The proportion of subjects with 16 point 
increase in IBDQ total score from baseline at 
Weeks 16, 32, and 64.

Proportion of subjects achieving IBDQ bowel 
symptom domain response at Weeks 16, 32,
and 64.

The scores and change from baseline in 
EQ-5D-3L + VAS at Weeks 16, 32, and 64.

The scores and change from baseline in SF-36 
v2: PCS & MCS, and 8 domain scores at
Weeks 16, 32, and 64.

Change from baseline in PGIS score at 
Weeks 16, 32, and 64.

To evaluate the effect of PF-06651600 and 
PF-06700841 compared to placebo on 
histopathology score.

Change from baseline in GHAS at Week 64.

Proportion of subjects achieving histologic 
remission at Week 64.

To describe the PK of PF-06651600 and 
PF-06700841 in subjects with moderate to 
severe CD.

PF-06651600 concentrations at Weeks 16, 20, 
32, 56, and 64.

PF-06700841 concentrations at Weeks 16, 20, 
32, 56, and 64.


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
To explore the relationship between PK, PD, 
and clinical endpoints.

Change from baseline in serum hsCRP levels 
over time.

Change from baseline in fecal calprotectin.

Change from baseline in serum IP-10 levels 
over time.

Change in baseline in BCL-2 gene expression.

Change from baseline in hematological values 
including reticulocytes, hemoglobin, 
neutrophils, platelets, and TBNK cells.

To collect non-banked samples (e.g., intestinal 
biopsies, stool for microbiome analysis, serum 
and plasma for analysis of proteins and a whole 
blood tube for RNA analysis) for exploratory 
research, unless prohibited by local regulations 
or ethics committee decision.

To collect banked biospecimens samples for 
exploratory research, unless prohibited by local 
regulations or ethics committee decision. 

Collection of non-banked exploratory samples 
unless prohibited by local regulations or ethics 
committee decision.

Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision.  Additional information 
on collection and potential use is provided in 
the Banked Biospecimens section of the 
protocol.
2.2. Study Design
This is a Phase 2a, randomized, double-blind, placebo-controlled, parallel group, multicenter 
study in subjects with moderate to severe active 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 period, and 4) a 4-week follow up period.  Approximately 230~250 subjects in 
total will be randomized into the study.
The 12-week induction period will be placebo-controlled and double-blind within each 
investigational product.  Subjects who meet the eligibility criteria at the baseline visit will be 
randomly assigned to receive either active or placebo treatments.  In the induction period, 
200 mg QD for 8 weeks followed by 50 mg QD for 4 weeks of PF-06651600 and matching 
placebo in a 2:1 ratio and 60 mg QD for 12 weeks of PF-06700841 and matching placebo in 
a 2:1 ratio will be investigated.  The hybrid dosing regimen for PF-06651600 during the 
12-week induction period is a consequence of available nonclinical long-term toxicity data 
supporting 200 mg treatment for only up to 8 weeks.  For analysis, placebo groups will be 
combined.
After the completion of the induction period, subjects will enter the 52 weeks OLE period.  
There will be no rerandomization at the beginning of the OLE period.  Subjects will receive 
the same study drug that they were randomized to receive during the induction period, and 
there will be no placebo arms.  Placebo subjects from the induction period will also receive 
active drug in the OLE period.  The matching placebo subjects from the double-blind 
PF06651600 treatment/placebo induction period will receive 50 mg of PF-06651600, while 


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the corresponding placebos from the double-blind PF-06700841/placebo induction period 
will receive 30 mg of PF-06700841 for 52 weeks.
After completion of the OLE period, subjects will enter the 4-week follow-up period.  Any 
subjects, who discontinues early from the double-blind period prior to the Week 12 visit, 
should undergo the procedures for an Early Termination (Induction) visit on the last day the 
subject takes the investigational product or as soon as possible thereafter.  For subjects who 
discontinue early from OLE period (after the Week 12 visit, but prior to the Week 52 visit), 
the procedures scheduled for an Early Termination (ET) visit will be performed on the last 
day the subject takes the investigational product or as soon as possible thereafter.  These 
early withdrawal subjects, along with subjects who complete the induction period but are not 
willing to participate in the OLE period, will be asked to complete the Follow-up visit 
approximately 4 weeks after the last dose of study drug.
The original objectives of this study were to evaluate the efficacy [based on clinically 
meaningful endoscopic improvement (reduction of 3 points from baseline in SES-CD score) 
at Week 12 as assessed by central reading], safety, tolerability, PK, and PD of 200 mg for 
8 weeks followed by 50 mg for 4 weeks of PF-06651600 (ritlecitinib) dosed once daily and 
60 mg of PF-06700841 (brepocitinib) dosed once daily during an induction period of 
12 weeks, followed by an open label extension period at doses of 50 mg and 30 mg of 
PF-06651600 (ritlecitinib) and PF-06700841 (brepocitinib), respectively, for 52 weeks.  
Amendment 5 of Protocol B7981007 revises the original design to eliminate the 
PF-06700841 (brepocitinib) and placebo arms.  Therefore, upon approval of Amendment 5 
by regional Regulatory Authorities and Ethics Committees, Protocol B7981007 will be 
conducted as a Phase 2a, randomized, double-blind, placebo-controlled, parallel group study 
focused on the evaluation of the efficacy and safety profile of the PF-06651600 (ritlecitinib) 
in subjects with moderate to severe active CD.  Participants that have been randomized under 
previous amendments will continue to receive PF-06700841 (brepocitinib) through 
completion.  This study modification is solely a strategic decision on the part of the sponsor 
to prioritize future development of PF-06651600 (ritlecitinib), a JAK3/TEC inhibitor 
currently in development for a variety of other inflammatory/autoimmune indications and to 
enable efficient comparison with contemporary and emerging trials in Crohn’s disease.  The 
decision to eliminate the PF-06700841 (brepocitinib) cohort of the study is not due to any 
specific safety or efficacy concerns that would negatively affect the overall benefit/risk for 
participants in this trial or in other trials.




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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Induction Period
Primary Endpoint(s)
The primary efficacy endpoint during the induction period is:

Proportion of subjects achieving SES-CD 50 (50% reduction in SES-CD from 
baseline) at Week 12.  
Secondary Endpoint(s)
Secondary endpoints during the induction period are:

Incidence and severity of laboratory abnormalities, vital signs, 12-lead ECG, adverse 
events, serious adverse events, and withdrawals due to adverse events.

Incidence of serious infections.

Change from baseline in SES-CD score at Week 12.

Proportion of subjects achieving SESCD 25 (25% reduction in SES-CD from 
baseline) and CMEI (Clinically Meaningful Endoscopic Improvement defined as a 
reduction of 3 points from baseline) at Week 12.

Proportion of subjects achieving endoscopic remission (SES-CD 2) at Week 12.

Proportion of subjects achieving mucosal healing (complete absence of ulcers) at 
Week 12.
Tertiary/Exploratory Endpoint(s)
      Below are tertiary/exploratory endpoints during the induction period. CDAI-100 and 
CDAI remission will only be summarized for subjects with baseline CDAI220.

Proportion of subjects achieving clinical response and remission using stool 
frequency (SF) and abdominal pain (AP) measures at Weeks 2, 4, 6, 8, 10, and 12.

Proportion of subjects achieving deep remission (endoscopic remission by SES-CD 
and clinical remission by SF and AP) at Week 12.

Proportion of subjects with a CDAI-100 response at Weeks 2, 4, 8, and 12.

Proportion of subjects with CDAI remission (CDAI <150) at Weeks 2, 4, 8, and 12.

The scores and change from baseline in IBDQ total score and domains (Bowel 
Symptoms, Systemic Symptoms, Emotional Function and Social Function) at 
Weeks 4, 8, and 12.


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
Proportion of subjects with IBDQ total score 170 at Weeks 4, 8, and 12.

Proportion of subjects with 16 point increase in IBDQ total score from baseline at 
Weeks 4, 8, and 12.

Proportion of subjects achieving IBDQ bowel symptom domain response at Weeks 4, 
8, and 12.

The scores and change from baseline in EQ-5D-3L + VAS at Weeks 4, 8, and 12.

The scores and change from baseline in Short Form-36, Version 2 Acute (SF-36 v2): 
physical and mental component summary scores (PCS & MCS), and 8 domain scores 
at Weeks 4, 8, and 12.

Change from baseline in PGIS score at Weeks 4, 8, and 12.

Change from baseline in GHAS at Week 12.

Proportion of subjects achieving histologic remission (GHAS 4) at Week 12.

Change from baseline in serum hsCRP levels over time.

Change from baseline in fecal calprotectin over time.

Change from baseline in serum IP-10 levels over time.

Change from baseline in BCL-2 gene expression.

Change from baseline in hematological values including reticulocytes, hemoglobin, 
neutrophils, platelets, and T, B and NK (TBNK) cells.

PF-06651600 concentrations at Weeks 2, 4, 8, and 12.

PF-06700841 concentrations at Weeks 2, 4, 8, and 12.
3.2. Open Label Extension Period
Primary Endpoint(s)
The primary endpoint during the OLE period is:

Incidence and severity of laboratory abnormalities, vital signs, 12-lead ECG, adverse 
events, serious adverse events, and withdrawals due to adverse events.
Exploratory Endpoint(s)
Exploratory endpoints during the OLE period are:

Proportion of subjects achieving clinically meaningful endoscopic improvement 
(reduction of 3 points from baseline in SES-CD) at Week 64.

Proportion of subjects achieving SES-CD 25 and SES-CD 50 at Week 64.


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
Proportion of subjects achieving endoscopic remission at Week 64.

Proportion of subjects achieving mucosal healing (complete absence of ulcers) at 
Week 64.

Proportion of subjects achieving clinical response and remission as defined by SF and 
AP endpoints at Weeks 16, 20, 24, 32, 40, 48, 56, and 64.

Proportion of subjects achieving deep remission (endoscopic remission by SES-CD 
and clinical remission by SF, AP) at Week 64.

Proportion of subjects with a CDAI-100 response or CDAI remission at Weeks 16, 
32, and 64.

The scores and change from baseline in IBDQ Total score and domains (Bowel 
Symptoms, Systemic Symptoms, Emotional Function and Social Function) at 
Weeks 16, 32, and 64.

The proportion of subjects with IBDQ total score 170 at Weeks 16, 32, and 64.

The proportion of subjects with 16 point increase in IBDQ total score from baseline 
at Weeks 16, 32, and 64.

Proportion of subjects achieving IBDQ bowel symptom domain response at 
Weeks 16, 32, and 64.

The scores and change from baseline in EQ5D3L + VAS at Weeks 16, 32, and 64.

The scores and change from baseline in SF36 v2: PCS & MCS, and 8 domain scores 
at Weeks 16, 32, and 64.

Change from baseline in PGIS score at Weeks 16, 32, and 64.

Change from baseline in GHAS at Week 64.

Proportion of subjects achieving histologic remission at Week 64.

PF-06651600 concentrations at Weeks 16, 20, 32, 56, and 64.

PF-06700841 concentrations at Weeks 16, 20, 32, 56, and 64.

Change from baseline in serum hsCRP levels over time.

Change from baseline in fecal calprotectin.

Change from baseline in serum IP-10 levels over time.


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
Change in baseline in BCL-2 gene expression.

Change from baseline in hematological values including reticulocytes, hemoglobin, 
neutrophils, platelets, and TBNK cells.
3.3. Baseline Variables
Baseline data collected/measured at Screening visit are:

Medical history, history of alcohol, smoking and drug abuse, and height

HBsAg, HBcAb, HCV Ab, HCV RNA PCR if HCV Ab positive

Fecal calprotectin and SES-CD
Baseline data collected/measured at Baseline (Day 1) are listed below:

Weight, complete physical examination, and vital signs & temperature

hsCRP, SF, AP, CDAI, PGIS, IBDQ, EQ-5D-3L + VAS, and SF-36

Hematology (including coagulation panel) and serum chemistry (including fasting 
lipid panel)
3.4. Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs, 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.
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 and SAEs

Incidence of withdrawals due to AEs 

Incidence of serious infections


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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), basophils (Abs), 
lymphocytes (Abs), monocytes (Abs), reticulocyte count, and coagulation panel

Serum chemistry: blood urea nitrogen, creatinine, cystatin C, glucose (fasting), 
calcium, sodium, potassium chloride, ttotal CO2 (bicarbonate), 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)
Vital Signs, including Height and Weight
Vital sign measurements are pulse rate, blood pressures, respiratory rate, oral or tympanic 
temperature, respiratory rate, pulse rate, and blood pressure.
Height, weight and Body Surface Area (BSA) are collected at pre- and post-treatment.
Physical Examinations
Complete physical examinations consist of assessments of general appearance; skin; head, 
eyes, ears, nose and throat; mouth, heart; lungs; breast (optional); abdomen; external 
genitalia (optional); extremities; neurologic function; and lymph nodes.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and release of the database and classifications 
will be documented per standard operating procedures. For OLE period summary, only 
subjects who received at least one OLE treatment will be included correspondingly for full 
analysis set, safety and PK analysis sets.
4.1. Full Analysis Set
The full analysis set analysis set will include all randomized subjects who received at least 
one dose of the randomized investigational drug (PF-06651600, PF-06700841, or placebo).
4.2. Pharmacokinetics Set
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.


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4.3. Safety Analysis Set
The safety (SAF) analysis set is defined as those subjects who received at least one dose of 
the investigational drug.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Subject Last Visit (LSLV).
An interim analysis may be performed when Week 12 data has been accumulated for
approximately 50% of the subjects initially randomized.
After the induction treatment period (Week 0-12) is finished for all the subjects, some 
members of the study team, who are otherwise not responsible for continued study conduct 
until the database is locked, will be unblinded so that a report for the induction period data 
can be generated. The subjects, investigators, and site personnel will continue to be blinded 
to randomized study treatments throughout the remaining period of the study (including the 
extension period). The database will be officially released after last subject last visit occurs. 
The final analysis will be then conducted, and the CSR will be issued. The decision rules for 
the final analyses are also described in the next section.
5.1. Hypotheses and Decision Rules
Induction Period
Null hypothesis is the proportion of subjects achieving Week 12 centrally
read SES-CD 50 is the same for the active (PF-06651600 or PF-06700841) and 
placebo arms.  Using a between-group comparison at Week 12, for PF-06651600 vs 
placebo and PF-06700841 vs placebo, the treatment will be considered superior to placebo if 
the lower bound of the 90% confidence interval is greater than 0. There will be no 
multiplicity adjustment across the compounds. Due to strategic reasons, the main hypothesis 
of interest is to compare PF-06651600 and placebo. 
Open Label Extension Period
There will be no hypothesis testing for the two active treatment (PF-06651600 and 
PF-06700841) arms in the OLE period.
5.2. General Methods
In general, number and percent will be presented for binary and categorical variables.  
Number, mean, standard deviation (or standard error of the mean), median, minimum, and 
maximum will be presented for continuous variables.  In addition, graphics may be used to 
present the data – specific details will be outlined in the study List of Table (LOT).


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For analyses purposes, the two placebo arms from the induction period will be combined.  
There will be no comparisons between the two active treatments PF-06651600 and 
PF-06700841.
Analyses for Binary Data
The binary data comparing active treatment group and placebo group will be analyzed using 
the Cochran Mantel Hanzel (CMH) test adjusting the baseline disease stratification factor
below:

Baseline disease activity/extent
o
no isolated ileal disease and baseline SES-CD >15
o
no isolated ileal disease and baseline SES-CD 15
o
isolated ileal disease
Rate (%) differences and the corresponding 2-sided 90% confidence intervals adjusted for 
stratification factors will be computed using the methods proposed by Cochran with the 
minimum risk weights proposed by Mehrotra and Railkar.  It is anticipated to have small 
numbers in each investigation site, so the investigation site effect will not be an adjustment 
factor.
For analyses without adjustment by stratification such as subset analyses, the estimated risk 
difference and the associated confidence interval of the risk differences will be presented.  
The unconditional exact method as described by Chan and Zhang (1999) will be used to 
compute the confidence intervals.
Analyses for Longitudinal Continuous Data
Mixed Model for Repeated Measurements (MMRM): longitudinal continuous data will be 
analyzed by MMRM including the fixed effects of treatment, visit, and treatment-by-visit 
interaction, along with baseline value as a covariate when available.  Unstructured covariance 
matrix will be assumed when possible.  If there are a sufficient number of subjects in each 
stratum, the stratification factors will be used as covariates in the model.
At each visit, estimates of mean values and the mean differences between the active treated 
group and the placebo group will be derived from the model, together with the corresponding 
p-values, standard errors and 90% confidence intervals.
Analyses for Non-longitudinal Continuous Data
Analysis of Covariance (ANCOVA): non-longitudinal continuous data will be analyzed by 
ANCOVA with treatment as the factor and baseline value as a covariate.  If there are a 


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sufficient number of subjects in each stratum, the stratification factors will be used as 
covariates in the model.
Estimates of mean values and the mean differences between the active treated group and the 
placebo group will be derived from the model, together with the corresponding p-values, 
standard errors and 90% confidence intervals.
Analyses for Categorical Data
None.
Analyses for Time to Event Data
None.
5.3. Methods to Manage Missing Data
Observed data will be used for descriptive statistics, i.e., missing data will not be imputed.  
For PK concentration, zero will be imputed for values below lower limits of detection
(LLOD) or quantification (LLOQ). For biomarkers and other lab parameters, ½*LLOD or 
½*LLOQ will be imputed. 
Binary Endpoint
For statistical analysis of binary response defined on SES-CD endpoints, subjects with 
missing values will be handled by non-responder imputation (NRI) method, i.e., setting any 
missing values to be non-responsive (0), except that the visits missing due to COVID-19 will 
be removed from the analysis (i.e., the missing visits will not contribute to the denominator 
in the calculation of the proportion).
For statistical analysis of binary response defined on all other endpoints including CDAI, 
SF/AP, IBDQ and GHAS, missing values after study treatment discontinuation will be 
handled by non-responder imputation (NRI) method, others will be removed from the 
analysis (i.e., the missing visits will not contribute to the denominator in the calculation of 
the proportion).
Continuous Endpoints
For non-patient reported outcome variables, the missing continuous data will be used as is 
(Observed Case – OC).
For PRO endpoints, rules suggested by the developers of these PROs will be followed in 
calculating the values of a given component at a scheduled assessment.  If these 
rules are not enough for imputing a value, then the missing values will be handled in the 
same way as non-patient reported outcome variables.


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6. ANALYSES AND SUMMARIES
6.1. Induction Study Period
Analysis will be done pairwise between an active (PF-06651600 or PF-06700841) treated 
group and placebo.  All efficacy analyses will be based on full analysis set.
Primary Endpoint(s)

Endpoint: Proportion of subjects achieving SES-CD 50 at Week 12

Statistical Method: Risk Difference using Mehrotra and Railkar method in Section 
5.2.1

Missing Data: Missing data, except that the visits missing due to COVID-19, will be 
handled by NRI.
Primary Analysis (NRI) - Setting any missing values to be non-responsive (0) for those 
treatment failure subjects withdraw from the study prior to Week 12
The reason of change of primary endpoint was to enable efficient comparison with 
contemporary and emerging trials for Crohn’s disease, and same measurement SES-CD is 
still used for the primary endpoint, thus concern for inflation of type 1-error is minimized.
For final analysis in the end of study, all study data will be used cumulatively, and hypothesis 
testing will be performed at alpha=0.05 for each compound. Considering the alpha spent at 
the past interim for CMEI is 0.03, the overall type 1 error for each compound is controlled at 
0.08.
Sensitivity Analysis
In order to address the concern for potential inflation of type 1-error due to the change of 
primary endpoint, we consider a hypothetic adaptive design where both unblinded analyses 
of CMEI and SES-CD 50 were performed at the past interim when approximately 60% of 
subjects completed week 12 visit, and SES-CD 50 was then decided to be the primary 
endpoint going forward, the following analysis that still preserves type 1-error will be 
performed. 
Inverse normal method is a way to preserve type-1 error for an adaptive design combining 
result from different stages. 
 = Φ	(	) + √1 −Φ	(),  = √0.6 , since interim was at 60% subjects
p1 and p2 are p-value for stage 1 (before interim) and stage 2 (after interim).
Close testing procedure is a way to control type-1 error for multiple hypothesis tests.
Define below two hypothesis tests:


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	: 	 =  where 	 and  are the SES-CD 50 rate for PF-06700841 and combined 
placebo respectively. 
: 	 = , where 	 and  are the CMEI rate for PF-06700841 and combined 
placebo respectively. 
To control the family wise error rate in strong sense under this hypothetical adaptive design, 
close testing procedure requires that the adaptively chosen hypothesis (H10 ) will only be 
rejected at a type 1 error alpha level if combined p-value (by inverse normal method) for the 
intersection test (H10∩ H20)<alpha and combined p-value for H10<alpha
For intersection test H10∩ H20:

P-value for stage 1 is defined as min {2(	), ()}, where (	) ≤() are the smaller 
and bigger p-value of the two hypothesis tests with only stage 1 data from subjects 
who completed week 12 or discontinued early from induction phase before interim.

P-value for stage 2 is the p-value for SES-CD 50 with stage 2 data from subjects who 
completed week 12 or discontinued early from induction phase after interim.
For H10, the p-values at each stage are based on independent SES-CD 50 data from each 
stage.
Secondary Endpoint(s)
The endpoint below will be analyzed using ANCOVA method (see Section 5.2.3) with no 
imputations for any missing data (OC).

Change from baseline in SES-CD score at Week 12
The secondary binary efficacy endpoints below will be analyzed using CMH method with 
NRI for any missing data.

Proportion of subjects achieving SES-CD 25 and CMEI at Week 12.

Proportion of subjects achieving endoscopic remission (SES-CD 2) at Week 12.

Proportion of subjects achieving mucosal healing (complete absence of ulcers) at 
Week 12.
Tertiary/Exploratory Endpoint(s)
The tertiary/exploratory non-longitudinal endpoint below will be analyzed using ANCOVA 
method with no imputations for any missing data (OC).

Change from baseline in GHAS at Week 12.


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The tertiary/exploratory longitudinal efficacy endpoints below will be analyzed using 
MMRM method (see Section 5.2.2) with no imputations for any missing data (OC), i.e.
subjects with partial data will be included in MMRM analysis.

The change from baseline in IBDQ total score and domains (Bowel Symptoms, 
Systemic Symptoms, Emotional Function and Social Function) at Weeks 4, 8, and 12.

The change from baseline in EQ-5D-3L + VAS at Weeks 4, 8, and 12.

The change from baseline in Short Form-36, Version 2 Acute (SF-36 v2): physical 
and mental component summary scores (PCS & MCS), and 8 domain scores at 
Weeks 4, 8, and 12.

Change from baseline in PGIS score at Weeks 4, 8, and 12.

Change from baseline in serum hsCRP levels over time.

Change from baseline in fecal calprotectin over time.

Change from baseline in serum IP10 levels over time.

Change from baseline in BCL-2 gene expression.

Change from baseline in hematological values including reticulocytes, hemoglobin, 
neutrophils, platelets, and T, B and NK (TBNK) cells.
The tertiary/exploratory binary efficacy endpoints below will be analyzed using CMH 
method. Exact methods will be used for the all the timepoints. CDAI-100 and CDAI 
remission will only be summarized for subjects with baseline CDAI 220. Missing values 
after study treatment discontinuation will be handled by non-responder imputation (NRI) 
method, others will be removed from the analysis (i.e., the missing visits will not contribute 
to the denominator in the calculation of the proportion).

Proportion of subjects achieving clinical response (≥30% reduction from baseline in 
AP or SF with neither worse than baseline) and remission (defined as SF ≤1.5 and AP 
≤1, and both not worse than baseline) using stool frequency (SF) and abdominal pain 
(AP) measures at Weeks 2, 4, 6, 8, 10, and 12.

Proportion of subjects achieving deep remission (endoscopic remission by SES-CD 
and clinical remission by SF and AP) at Week 12.

Proportion of subjects with a CDAI-100 response at Weeks 2, 4, 8, and 12.

Proportion of subjects with CDAI remission (CDAI <150) at Weeks 2, 4, 8, and 12.

Proportion of subjects with IBDQ total score 170 at Weeks 4, 8, and 12.


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
Proportion of subjects with 16 point increase in IBDQ total score from baseline at 
Weeks 4, 8, and 12.

Proportion of subjects achieving IBDQ bowel symptom domain response at Weeks 4, 
8, and 12. 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).

Proportion of subjects achieving histologic remission (GHAS 4) at Week 12.
Pharmacokinetic Endpoint(s)
The PK endpoints are:

PF-06651600 concentrations at Weeks 2, 4, 8, and 12.

PF-06700841 concentrations at Weeks 2, 4, 8, and 12.
The concentrations will be summarized and presented with summary statistics.  A population 
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.
6.2. Open Label Extension Period
Summary statistics for any endpoints collected/measured during the OLE period (see Section 
3.2) will be provided.  There will be no direct comparisons (i.e. testing or p-values generated) 
between the two active treatment arms in the OLE period. All open label efficacy data, 
missing values after study treatment discontinuation will be handled by non-responder 
imputation (NRI) method, others will be removed from the analysis (i.e., the missing visits 
will not contribute to the denominator in the calculation of the proportion). For SES-CD 50 
and CDAI remission at week 12 and week 64, within subject comparison will be made by 
McNemar’s test for active treatment sequences. 
6.3. Subgroup Analyses
Proportion of subjects achieving SES-CD 50 at Week 12 may be summarized for the subsets 
below (tables will be generated if we have sufficient number of subjects in each stratum):

Anti-TNF experience (yes or no).

Steroid use at baseline (yes or no).

Baseline disease activity/extent
o
no isolated ileal disease and baseline SES-CD >15


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o
no isolated ileal disease and baseline SES-CD 15
o
isolated ileal disease
6.4. Baseline and Other Summaries and Analyses
Baseline Summaries
Demographics and medical history including variables defined in Section 3.3 will be 
summarized by treatment group according to Pfizer standards.
Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized, separately for induction 
and OLE periods, according to Pfizer standards.
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 total number of applications, the total 
number of days of dosing, and number and percentage of subjects who are compliant with the 
dosing regimen.
Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
6.5. Safety Summaries and Analyses
Safety analysis will be based on the SAF analysis set.
All clinical AEs, SAEs, treatment-emergent signs and symptoms (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 (e.g., AEs) will be summarized by 
subject counts and percentage.  Continuous outcome (e.g., 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.


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Adverse Events
The safety data will be summarized in accordance with Pfizer Data Standards.  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. TEAE will be summarized 
separately for the induction period and open label extension period. If an AE started in 
induction and resolved in OLE, it will be counted as TEAE only in induction. However if 
such cross-period AE caused subject discontinuation during OLE period, that cross-period 
AE will be reported under OLE treatment period for summary of subject discontinuation 
from study drug or study.
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 due to AEs;

Serious infections, defined as any infection (for e.g., viral, bacterial, and fungal) 
requiring hospitalization or parenteral antimicrobials. This definition 
programmatically should be consistent with 7.1.7 in the protocol.
As such, safety analysis is generally considered as an exploratory analysis and its purpose is 
to generate hypotheses for further investigation. There will be no adjustment for multiple 
comparisons or stratification factors in the analyses unless specified.
Laboratory Data
Laboratory data will be listed and summarized in accordance with the Pfizer reporting 
standards. The incidence of clinical laboratory abnormalities and changes in lipid profile and 
creatinine will be summarized for each treatment group.
In addition, the absolute value, change from baseline, and percent change from baseline will 
be computed by visit and treatment group for hemoglobin, hematocrit, platelets, neutrophils, 
lymphocytes, serum creatinine, serum cystatin, creatinine based eGFR (estimated glomerular 
filtration rate), and cystatin based eGFR, liver function tests (ALT, AST, bilirubin, creatinine 
kinase), total cholesterol, triglycerides, HDL, LDL, and HDL to LDL ratio. Correspondingly, 
plots over time of these laboratory data will generated.
Laboratory test values meeting retest criteria and discontinuation criteria in protocol will be 
summarized, respectively.


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Vital Signs, including Height and Weight
Vital signs including weight will be summarized at:

Baseline, Weeks 2, 4, 8, 12, and Early Termination of induction period

Weeks 16, 20, 24, 32, 40, 48, 56, 64, and 68/Early Termination of OLE period
Electrocardiogram
ECG parameters, if applicable, will be summarized at:

Baseline, Week 12, and Early Termination of induction period

Weeks 32, 48, and 64/Early Termination of OLE period
Physical Examination
Physical examinations will be summarized at:

Baseline, Week 12, and Early Termination of induction period

Week 64 and Early Termination of OLE period
7. INTERIM ANALYSES
7.1. Introduction
There will be one interim analysis plan (IAP) for this study.
Details regarding the analysis procedures used for the past interim analysis based on CMEI 
endpoint when approximately 60% of subjects completed Week 12 visit was provided in the 
interim analysis plan.  
7.2. Interim Analyses and Summaries
The interim analysis results will be used to facilitate internal decision-making.  The results 
will only be distributed to a select list of individuals involved in the internal decision-making 
process in order to protect the integrity of the study.  This list of individuals will be provided 
in the interim analysis plan.  The results of the interim analysis will not enable individuals 
directly involved in running the study (such as investigators) to identify treatment 
assignments for individual subjects still in the study.  There are no prospective plans to stop 
the study early for success as a result of the interim analyses. During the interim analysis, 
some members of the study team may be unblinded and replaced with blinded colleagues.  
The subjects, investigators, and individuals from the sponsor (or designee) who interact with 
the investigators and monitor safety will continue to be blinded to individual study treatments 
throughout the follow up period of the study.  Additional interim analyses may be performed 
based on emerging data.


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7.3. Data Monitoring Committee
This study uses 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.
8. REFERENCES
1.
Siddiqui O, MMRM vs. LOCF: A Comprehensive comparison based on simulation 
study and 25 NDA Datasets, Journal of Biopharmaceutical Statistics 19: 227-246, 2009.
2.
Lanchin JM, A review of methods for futility stopping based on conditional power, 
Statistics in Medicine, 2005; 24: 2747-2764. 
3.
Mehrotra, D., Raikar, R. “Minimum Risk Weights for Comparing Treatments in 
Stratified Binomial Trials”. Statistics in Medicine, 2000, 19, pp. 811-825.
9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Efficacy analyses comparing active and placebo arms in the induction period will be based 
on the full analysis set.
Efficacy Endpoints
Analysis 
Method
Missing
Data
Proportion of subjects achieving SES-CD 50 at Week 12
CMH
NRI
Proportion of subjects achieving SES-CD 50 at Week 12
CMH
OC
Change from baseline in SES-CD score at Week 12
ANCOVA
OC
Proportion of subjects achieving SES-CD 25 and CEMI at Week 12
CMH
NRI
Proportion of subjects achieving endoscopic remission (SES-CD 2) at 
Week 12
CMH
NRI
Proportion of subjects achieving mucosal healing (complete absence of ulcers) 
at Week 12
CMH
NRI
Change from baseline in GHAS  at Week 12
ANCOVA
OC
The scores and change from baseline in IBDQ total score and domains (Bowel 
Symptoms, Systemic Symptoms, Emotional Function and Social Function) at 
Weeks 4, 8, and 12
MMRM
OC


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Efficacy Endpoints
Analysis 
Method
Missing
Data
The scores and change from baseline in EQ-5D-3L + VAS at Weeks 4, 8, and 
12
MMRM
OC
The scores and change from baseline in Short Form-36, Version 2 Acute 
(SF-36 v2): physical and mental component summary scores (PCS & MCS), 
and 8 domain scores at Weeks 4, 8, and 12
MMRM
OC
Change from baseline in PGIS score at Weeks 4, 8, and 12
MMRM
OC
Change from baseline in serum hsCRP levels over time
MMRM
OC
Change from baseline in fecal calprotectin over time
MMRM
OC
Change from baseline in serum IP-10 levels over time
MMRM
OC
Change from baseline in BCL-2 gene expression
MMRM
OC
Change from baseline in hematological values including reticulocytes, 
hemoglobin, neutrophils, platelets, and T, B and NK (TBNK) cells
MMRM
OC
Proportion of subjects achieving clinical response and remission using stool 
frequency (SF) and abdominal pain (AP) measures at Weeks 2, 4, 6, 8, 10, and 
12
CMH
NRI
Proportion of subjects achieving deep remission (endoscopic remission by 
SES-CD and clinical remission by SF and AP) at Week 12
CMH
NRI
Proportion of subjects with a CDAI-100 response at Weeks 2, 4, 8, and 12
CMH
NRI
Proportion of subjects with CDAI remission (CDAI <150) at Weeks 2, 4, 8, 
and 12
CMH
NRI
Proportion of subjects with IBDQ total score 170 at Weeks 4, 8, and 12
CMH
NRI
Proportion of subjects with 16 point increase in IBDQ total score from 
baseline at Weeks 4, 8, and 12
CMH
NRI
Proportion of subjects achieving IBDQ bowel symptom domain response at 
Weeks 4, 8, and 12
CMH
NRI
Proportion of subjects achieving histologic remission (GHAS 4) at Week 12
CMH
NRI


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Appendix 2. 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 (e.g., ECG, vital signs), visit windows 
will be applied for summary statistics by study visits if required. For induction phase 
completers, any SES-CD results collected within the first 10 days and other efficacy 
variables within the first 5 days in OLE will be analyzed under induction treatment.
Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to Day 0
Induction Period Weeks 0-12
Week 0
Day 1, Baseline
Day 1
Week 2
15
Day 2 to 22
Week 4
29
Day 23 to 43
Week 8
57
Day 44 to 71
Week 12
85
Day 72 to 99
OLE Period Weeks 12-64
Week 16
113
Days 100 to 127
Week 20
141
Days 128 to 155
Week 24
169
Days 156 to 197
Week 32
225
Days 198 to 253
Week 40
281
Days 254 to 309
Week 48
337
Days 310 to 365
Week 56
393
Days 366 to 421
Week 64
449
Days 422 to 463
Follow Up/End of Study
Week 68
-
Days 464 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.


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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.
Safety analysis will follow Pfizer standards.
Appendix 3. Calculation of IBDQ Scores 
The IBDQ is a questionnaire consisting of 32 items.  Each item is scored from 1 to 7 with 
1 being the worst possible response and 7 being the best possible response.
Bowel Function Domain Score is calculated as the sum of the scores for questions 1, 5, 9, 13, 
17, 20, 22, 24, 26 and 29.
Emotional Status Doman Score is calculated as the sum of the score for questions 3, 7, 11, 
15, 19, 21, 23, 25, 27, 28, 30 and 31.
Systematic Symptoms Domain Score is calculated as the sum of the scores for questions 2, 6, 
10, 14 and 18.
Social Function Domain score is calculated as the sum of the scores for questions 4, 8, 12, 16 
and 32.
The Total IBDQ Score is calculated as the sum of the four domain scores above.
For the four domains, the score will be calculated as long as at least 50% of items within the 
domain are non-missing.  Missing scores will be replaced using the mean of the non-missing 
scores within the domain.  This leads to each domain score being calculated as:
Domain score = Sum of non-missing scores x Number of items in the domain  
Number of non-missing items in domain
If any of the four domain scores cannot be calculated due to more than 50% of the items 
having missing scores, then the total score will not be calculated.